Skin protection behaviour and sex differences in melanoma location in patients with multiple primary melanomas.

PubMed

Warren, Matthew; McMeniman, Erin; Adams, Agnieszka; De'Ambrosis, Brian

2017-02-01

Previous studies have shown that sunscreen usage, sun-protection measures and self-examination rates in patients with single primary melanomas (SPM) are similar to that in the general population. This study hypothesises that these rates would be different in a population with multiple primary melanomas (MPM). We further hypothesise that there would be a sex difference in melanoma location in patients with MPM. The objectives of this study were to determine skin protection measures, self-examinations and melanoma location in a cohort of patients with MPM. A survey was conducted on 137 patients with MPM examining their sun-protection measures, skin self-examination rates and medical and phenotypic characteristics. These data were combined with a review of their medical records to examine the patients' skin cancer history. Patients with MPM had higher rates of skin self-evaluation (74% vs 22%), sunscreen usage (70% vs 45%) and other sun-protection measures (95% vs 46%) than has been published for patients with a history of a SPM. We have also shown that women have a higher risk of developing melanomas on their arms (p < 0.01) and lower legs (p < 0.05) than men. This report showed the rates of skin self-examination, sunscreen usage and other sun-protection methods in patients with MPM is higher than in studies of patients with SPM. It also highlighted sex differences in terms of melanoma location for patients with MPM. Further studies to examine the cause of the differences in these forms of protective behaviour could help improve the utilisation of these important preventative measures in all patients. © 2015 The Australasian College of Dermatologists.

Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma.

PubMed

Colombino, Maria; Lissia, Amelia; Capone, Mariaelena; De Giorgi, Vincenzo; Massi, Daniela; Stanganelli, Ignazio; Fonsatti, Ester; Maio, Michele; Botti, Gerardo; Caracò, Corrado; Mozzillo, Nicola; Ascierto, Paolo A; Cossu, Antonio; Palmieri, Giuseppe

2013-08-29

Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening. Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients' geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases. Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease.

Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma

PubMed Central

2013-01-01

Background Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. Methods Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening. Results Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients’ geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases. Conclusions Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease. PMID:23987572

Similar survival of patients with multiple versus single primary melanomas based on Utah Surveillance, Epidemiology, and End Results data (1973-2011).

PubMed

Grossman, Douglas; Farnham, James M; Hyngstrom, John; Klapperich, Marki E; Secrest, Aaron M; Empey, Sarah; Bowen, Glen M; Wada, David; Andtbacka, Robert H I; Grossmann, Kenneth; Bowles, Tawnya L; Cannon-Albright, Lisa A

2018-03-01

Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. Survival curves (n = 887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi-squared 39.29, P < .001). However, a multivariate Cox proportional hazards model showed no significant survival difference (hazard ratio 1.07, P = .55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P = .96). Breslow depth, ulceration status, and specific cause of death were not available for all patients. Patients with MPM had similar survival times as patients with SPM. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Vitamin D receptor polymorphisms in patients with cutaneous melanoma.

PubMed

Orlow, Irene; Roy, Pampa; Reiner, Anne S; Yoo, Sarah; Patel, Himali; Paine, Susan; Armstrong, Bruce K; Kricker, Anne; Marrett, Loraine D; Millikan, Robert C; Thomas, Nancy E; Gruber, Stephen B; Anton-Culver, Hoda; Rosso, Stefano; Gallagher, Richard P; Dwyer, Terence; Kanetsky, Peter A; Busam, Klaus; From, Lynn; Begg, Colin B; Berwick, Marianne

2012-01-15

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis. Copyright © 2011 UICC.

Vitamin D receptor polymorphisms in patients with cutaneous melanoma

PubMed Central

Orlow, Irene; Roy, Pampa; Reiner, Anne S.; Yoo, Sarah; Patel, Himali; Paine, Susan; Armstrong, Bruce K.; Kricker, Anne; Marrett, Loraine D.; Millikan, Robert C.; Thomas, Nancy E.; Gruber, Stephen B.; Anton-Culver, Hoda; Rosso, Stefano; Gallagher, Richard P.; Dwyer, Terence; Kanetsky, Peter A.; Busam, Klaus; From, Lynn; Begg, Colin B.; Berwick, Marianne

2011-01-01

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene SNPs in a large international multi-center population-based case-control study of melanoma. Buccal DNAs were obtained from 1207 people with incident multiple primary melanoma and 2469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, htSNPs with ≥10% MAF in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3’ gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25% to 33% for 6 polymorphisms: rs10875712 (OR 1.28; 95%CI, 1.01–1.62), rs4760674 (OR 1.33; 95% CI, 1.06–1.67), rs7139166 (OR 1.26; 95%CI, 1.02–1.56), rs4516035 (OR 1.25; 95%CI, 1.01–1.55), rs11168287 (OR 1.27; 95%CI, 1.03–1.57), rs1544410 (OR 1.30; 95%CI, 1.04–1.63); for 2 polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65–1.02), rs7965281 (OR, 0.78; 95%CI, 0.62–0.99). We recognize the potential false positive findings due to multiple comparisons; however the 8 significant SNPs in this study outnumbered the 2 significant tests expected to occur by chance. The vitamin D receptor may play a role in melanomagenesis. PMID:21365644

Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy.

PubMed

Casula, Milena; Muggiano, Antonio; Cossu, Antonio; Budroni, Mario; Caracò, Corrado; Ascierto, Paolo A; Pagani, Elena; Stanganelli, Ignazio; Canzanella, Sergio; Sini, Mariacristina; Palomba, Grazia; Palmieri, Giuseppe

2009-10-03

Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease. A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16(CDKN2A), BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16(CDKN2A) genes. For melanoma susceptibility, investigations at germline level indicated that p16(CDKN2A) was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16(CDKN2A) gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16(CDKN2A) silencing). Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.

Elevated Blood Neutrophil-to-Lymphocyte Ratio: A Readily Available Biomarker Associated with Death due to Disease in High Risk Nonmetastatic Melanoma.

PubMed

Davis, Jeremy L; Langan, Russell C; Panageas, Katherine S; Zheng, Junting; Postow, Michael A; Brady, Mary S; Ariyan, Charlotte; Coit, Daniel G

2017-07-01

Elevated peripheral blood neutrophil-to-lymphocyte ratio (NLR) is associated with poor oncologic outcomes in patients with stage IV melanoma and other solid tumors, but its impact has not been characterized for patients with high-risk, nonmetastatic melanoma. Retrospective review of a melanoma database identified patients with high-risk melanoma who underwent operation with curative intent at a single institution. NLR was calculated from blood samples obtained within 2 weeks before operation. Multiple primary melanomas and concurrent hematologic or other metastatic malignancies were excluded. Cumulative incidence of death due to disease was estimated, and Gray's test was used to examine the effect of NLR on melanoma disease-specific death (DOD). Multivariable competing risks regression models assessed associated factors. Data on 1431 patients with high-risk, nonmetastatic melanoma were analyzed. Median follow-up for survivors was 4 years. High NLR (≥3 or as continuous variable) was associated with older age, male sex, thicker primaries, higher mitotic index, and more advanced nodal status. On multivariate analysis, high NLR (≥3 or as a continuous variable), older age, male sex, ulcerated primary, lymphovascular invasion, and positive nodal status were all independently associated with worse DOD. NLR is a readily available blood test that was independently associated with DOD in patients with high-risk, nonmetastatic melanoma. It is unclear whether high NLR is a passive indicator of poor prognosis or a potential therapeutic target. Further studies to evaluate the prognostic role of NLR to potentially identify those more likely to benefit from adjuvant immunotherapy may prove informative.

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

PubMed

Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A; Cornelissen-Steijger, Paulien D M; Geukes Foppen, Marnix H; Kemper, Kristel; Goding, Colin R; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G; Ribas, Antoni; Lo, Roger S; Peeper, Daniel S

2014-12-15

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China.

PubMed

Hao, Mengze; Zhao, Gang; Du, Xiaoling; Yang, Yun; Yang, Jilong

2016-08-01

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

THE MOLECULAR PATHOLOGY OF MELANOMA: AN INTEGRATED TAXONOMY OF MELANOCYTIC NEOPLASIA

PubMed Central

Bastian, Boris C.

2016-01-01

Melanomas are comprised of multiple biologically distinct categories, which differ in cell of origin, age of onset, clinical and histologic presentation, pattern of metastasis, ethnic distribution, causative role of UV radiation, predisposing germ line alterations, mutational processes, and patterns of somatic mutations. Neoplasms are initiated by gain of function mutations in one of several primary oncogenes, typically leading to benign melanocytic nevi with characteristic histologic features. The progression of nevi is restrained by multiple tumor suppressive mechanisms. Secondary genetic alterations override these barriers and promote intermediate or overtly malignant tumors along distinct progression trajectories. The current knowledge about pathogenesis, clinical, histological and genetic features of primary melanocytic neoplasms is reviewed and integrated into a taxonomic framework. PMID:24460190

[A case of pulmonary malignant melanoma mimicking lung abscess].

PubMed

Mochizuki, Hideaki; Chikui, Emiko; Tokumaru, Aya; Kato, Takayuki; Arai, Tomio; Takahashi, Hideki

2011-06-01

An 84-year-old man was admitted with paresis of the right lower limb. Hemorrhagic lesions were demonstrated in the left frontoparietal lobe and cerebellum by cranial computed tomography (CT) and magnetic resonance imaging (MRI). Chest CT revealed an ill-defined mass measuring 4 x 6 cm in the left lower lobe of the lung, although bronchoscopic examination failed to obtain pathological diagnosis. Clinical diagnosis of primary lung cancer with multiple brain metastases was made, and he underwent whole brain radiotherapy. The pulmonary and cerebral lesions mimicked abscesses during his clinical course, and he died of respiratory failure due to bilateral pneumonia three months after admission. Autopsy revealed that both the pulmonary and brain lesions were malignant melanomas, but no other melanoma lesions could be identified despite meticulous investigation. Although malignant melanoma with an unknown primary site is rare in Japan, careful evaluation of the CT and MRI findings might be the key to correct diagnosis in this case.

Malignant Melanoma Presenting as a Mediastinal Malignant Melanoma Presenting as a Mediastinal Unknown Primary Origin?

PubMed

Pujani, Mukta; Hassan, Mohd Jaseem; Jetley, Sujata; Raina, Prabhat Kumar; Kumar, Mukesh

2017-01-01

The most common site of primary malignant melanoma is the skin, however, virtually any organ system may be involved. Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The mediastinum as the site for malignant melanoma is extremely rare, both as a primary or metastatic lesion. Primary malignant melanoma of mediastinum is very rare with only a handful of reports in the literature. We hereby report a rare case of malignant melanoma of mediastinum in a 31 year old male who was initially misdiagnosed on fine needle aspiration cytology as adenocarcinoma for which he received chemotherapy with clinical deterioration. Even on extensive meticulous search, no primary was discovered.

Associations of non-melanoma skin cancer and melanoma, extra-cutaneous cancers and smoking in adults: a US population-based study.

PubMed

Silverberg, J I; Ratner, D

2015-07-01

Non-melanoma skin cancer (NMSC) and melanoma are common malignancies in the US and may be associated with other types of cancer. We sought to determine whether NMSC and melanoma are associated with extra-cutaneous cancers and identify modifiable risk factors for such an association. We analysed data from 447,801 adult participants in the 1997-2011 National Health Interview Surveys. Survey logistic regression models were constructed that accounted for the complex sample weights. History of NMSC, melanoma and 27 primary extra-cutaneous cancers was assessed. NMSC was associated with increased odds of one (multinomial survey logistic regression, unadjusted odds ratio [95% CI]: 2.43 [2.20-2.68]) or multiple (2.94 [2.21-3.92]) extra-cutaneous malignancies. Melanoma was also associated with increased odds of one (3.25 [2.70-3.90]) or multiple (6.11 [4.34-8.61]) extra-cutaneous malignancies. Extra-cutaneous cancers were more common in younger patients (ages 18-39 and 40-49 years) and Caucasians with NMSC or melanoma (P < 0.0001). Smokers with a history of NMSC or melanoma had even higher odds of extra-cutaneous malignancy at ages 18-39 and 40-49 years compared to smokers without NMSC or melanoma (P < 0.0001). History of NMSC was associated with higher odds of malignancies of the bladder, brain, breast, colon, oesophagus, kidney, lung, lymphoma, melanoma, prostate, soft tissue, throat/pharynx, thyroid and uterus. Melanoma was associated with malignancies of the bladder, breast, colon, kidney, lung, pancreas, prostate, soft tissue, throat/pharynx, thyroid and uterus. The prevalence of extra-cutaneous cancers increased between 1997 and 2011 in all subjects (4.51% and 5.73%, P < 0.0001), with even higher rates of increase in those with history of NMSC or melanoma. Patients with history of NMSC and melanoma have increased odds of developing extra-cutaneous cancers, especially those with younger age and smoking history. © 2014 European Academy of Dermatology and Venereology.

Cryotherapy for conjunctival primary acquired melanosis and malignant melanoma. Experience with 62 cases.

PubMed

Jakobiec, F A; Rini, F J; Fraunfelder, F T; Brownstein, S

1988-08-01

Sixty-two patients were treated by some combination of cryotherapy and surgery with an average follow-up of 3.3 years for one of the following diseases: focal or diffuse flat conjunctival primary acquired melanosis (PAM) with atypia but without a nodule of melanoma (10 cases); unifocal malignant melanoma with or without focal or diffuse PAM (30 cases); and multinodular/multicentric melanoma with and without PAM (22 cases). Of the ten patients who had PAM with atypia, invasive nodules of malignant melanoma did not develop. A second treatment was required to control the disease in four of the ten patients with extensive or diffuse lesions, and one has mild persistent disease. Of the 30 patients with unifocal nodules of malignant melanoma, 27 remained free of recurrence after one treatment, and 2 are asymptomatic after two treatments. One patient with a thick nodule at presentation required a parotidectomy and radical neck dissection for cervical metastases after recurrence in the conjunctival sac. In the group of 22 patients with multinodular malignant melanoma, only two did not have recurrent disease after one treatment. Of those who received multiple therapies, seven remained free of recurrence for at least 2 years after the last treatment; regional or distant metastases developed in nine; four required exenteration; and eight died. Conjunctival adjunctive cryotherapy avoids exenteration in extensive lesions of pure PAM and in unifocal melanoma, but even after multiple therapies, multinodular malignant melanoma had a 45% rate of metastasis. Metastasis was related to the presence of PAM sine pigmento in four patients (microscopically but not clinically detectable PAM); to the location of the nodules (9 of 10 patients who experienced metastases had forniceal, palpebral, and/or caruncular nodules); to the thickness or depth of invasion of the nodules (greater than 2 mm); and to the development of intralymphatic spread ("in-transit" local metastasis) within the conjunctival sac in six patients. No metastases were encountered among patients with strictly limbal nodules and among five patients with invasive nodules composed of spindle cells in part or in toto. Therapeutic success in this spectrum of melanocytic proliferations is closely correlated with the clinical extent of the disease when initiating definitive therapy.

Rare Presentations of Primary Melanoma and Special Populations: A Systematic Review

PubMed Central

Kottschade, Lisa A.; Grotz, Travis E.; Dronca, Roxana S.; Salomao, Diva R.; Pulido, Jose S.; Wasif, Nabil; Jakub, James W.; Bagaria, Sanjay P.; Kumar, Riten; Kaur, Judith S.; Morita, Shane Y.; Moran, Steven L.; Nguyen, Jesse T.; Nguyen, Emily C.; Hand, Jennifer L.; Erickson, Lori A.; Brewer, Jerry D.; Baum, Christian L.; Miller, Robert C.; Swanson, David L.; Lowe, Val; Markovic, Svetomir N.

2013-01-01

A subset of patients with melanoma present in rare and unique clinical circumstances requiring specific considerations with respect to diagnostic and therapeutic interventions. Herein we present our review of patients with: (1) primary mucosal melanoma of the head and neck, gastrointestinal and genitourinary tracts; (2) primary melanoma of the eye; (3) desmoplastic melanoma; (4) subungual melanoma; (5) melanoma in special populations: children, non-Caucasians, as well as a discussion of familial melanoma. PMID:23563206

Direct evidence on the immune-mediated spontaneous regression of human cancer: an incentive for pharmaceutical companies to develop a novel anti-cancer vaccine.

PubMed

Saleh, F; Renno, W; Klepacek, I; Ibrahim, G; Dashti, H; Asfar, S; Behbehani, A; Al-Sayer, H; Dashti, A; Kerry, Crotty

2005-01-01

To develop an effective pharmaceutical treatment for a disease, we need to fully understand the biological behavior of that disease, especially when dealing with cancer. The current available treatment for cancer may help in lessening the burden of the disease or, on certain occasions, in increasing the survival of the patient. However, a total eradication of cancer remains the researchers' hope. Some of the discoveries in the field of medicine relied on observations of natural events. Among these events is the spontaneous regression of cancer. It has been argued that such regression could be immunologically-mediated, but no direct evidence has been shown to support such an argument. We, hereby, provide compelling evidence that spontaneous cancer regression in humans is immunologically-mediated, hoping that the results from this study would stimulate the pharmaceutical industry to focus more on cancer vaccine immunotherapy. Our results showed that patients with >3 primary melanomas (very rare group among cancer patients) develop significant histopathological spontaneous regression of further melanomas that they could acquire during their life (P=0.0080) as compared to patients with single primary melanoma where the phenomenon of spontaneous regression is absent or minimal. It seems that such regression resulted from the repeated exposure to the tumor which mimics a self-immunization process. Analysis of the regressing tumors revealed heavy infiltration by T lymphocytes as compared to non-regressing tumors (P<0.0001), the predominant of which were T cytotoxic rather than T helper. Mature dendritic cells were also found in significant number (P<0.0001) in the regressing tumors as compared to the non regressing ones, which demonstrate an active involvement of the different arms of the immune system in the multiple primary melanoma patients in the process of tumor regression. Also, MHC expression was significantly higher in the regressing versus the non-regressing tumors (P <0.0001), which reflects a proper tumor antigen expression. Associated with tumor regression was also loss of the melanoma common tumor antigen Melan A/ MART-1 in the multiple primary melanoma patients as compared to the single primary ones (P=0.0041). Furthermore, loss of Melan A/ MART-1 in the regressing tumors significantly correlated with the presence of Melan A/ MART-1-specific CTLs in the peripheral blood of these patients (P=0.03), which adds to the evidence that the phenomenon of regression seen in these patients was immunologically-mediated and tumor-specific. Such correlation was also seen in another rare group of melanoma patients, namely those with occult primary melanoma. The lesson that we could learn from nature in this study is that inducing cancer regression using the different arms of the immune system is possible. Also, developing a novel cancer vaccine is not out of reach.

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

PubMed

Orlow, Irene; Reiner, Anne S; Thomas, Nancy E; Roy, Pampa; Kanetsky, Peter A; Luo, Li; Paine, Susan; Armstrong, Bruce K; Kricker, Anne; Marrett, Loraine D; Rosso, Stefano; Zanetti, Roberto; Gruber, Stephen B; Anton-Culver, Hoda; Gallagher, Richard P; Dwyer, Terence; Busam, Klaus; Begg, Colin B; Berwick, Marianne

2016-01-01

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study

PubMed Central

Orlow, Irene; Reiner, Anne S.; Thomas, Nancy E.; Roy, Pampa; Kanetsky, Peter A.; Luo, Li; Paine, Susan; Armstrong, Bruce K.; Kricker, Anne; Marrett, Loraine D.; Rosso, Stefano; Zanetti, Roberto; Gruber, Stephen B.; Anton-Culver, Hoda; Gallagher, Richard P.; Dwyer, Terence; Busam, Klaus; Begg, Colin B.; Berwick, Marianne

2016-01-01

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics. PMID:26521212

[A Case of Delayed Dia-gnosis of Acral Lentiginous Melanoma].

PubMed

Gottvaldová, M; Jedličková, H; Poprach, A; Vašků, V

2015-01-01

Melanoma is a malignant skin disease. The tumor development is caused by an uncontrollable proliferation of melanocytes. The most common occurrence is on the skin, but melanoma may also develop on the mucous membrane, meninges, and eyes. Some melanomas develop from melanocytic nevus. Acral lentiginous melanoma occurs on palms, feet, fingers and under nails, and is the most common type of melanoma for phototype VI. The most important factor for successful treatment of malignant melanoma is an early detection, excision of the primary tumor and histological staging. Surgical treatment of an early-stage melanoma is a key to successful therapy; however, many patients (mostly men) do not seek medical attention before it istoo late. This case study presents a 59-year-old patient, who suffers from white coat syndrome and whose finger was amputated for alleged gangrene. Subsequently, brownish black nodules appeared across his arm. Histological examination proved metastases of malignant melanoma. It was only at this phase, when the patient admitted a nevus at the tip of his amputated finger, from which ulceration and gangrene gradually emerged. This case demonstrates a combination of multiple unfavorable factors, which led to delayed diagnosis and therapy.

Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis.

PubMed

Kuk, Deborah; Shoushtari, Alexander N; Barker, Christopher A; Panageas, Katherine S; Munhoz, Rodrigo R; Momtaz, Parisa; Ariyan, Charlotte E; Brady, Mary Sue; Coit, Daniel G; Bogatch, Kita; Callahan, Margaret K; Wolchok, Jedd D; Carvajal, Richard D; Postow, Michael A

2016-07-01

Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006-2010 and 2011-2013 had better overall survival than patients diagnosed in 2000-2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes. Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma. Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy. ©AlphaMed Press.

Prognosis of Mucosal, Uveal, Acral, Nonacral Cutaneous, and Unknown Primary Melanoma From the Time of First Metastasis

PubMed Central

Kuk, Deborah; Shoushtari, Alexander N.; Barker, Christopher A.; Panageas, Katherine S.; Munhoz, Rodrigo R.; Momtaz, Parisa; Ariyan, Charlotte E.; Brady, Mary Sue; Coit, Daniel G.; Bogatch, Kita; Callahan, Margaret K.; Wolchok, Jedd D.; Carvajal, Richard D.

2016-01-01

Background. Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. Materials and Methods. We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. Results. Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006–2010 and 2011–2013 had better overall survival than patients diagnosed in 2000–2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes. Conclusion. Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma. Implications for Practice: Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy. PMID:27286787

Unusual presentations of melanoma: melanoma of unknown primary site, melanoma arising in childhood, and melanoma arising in the eye and on mucosal surfaces.

PubMed

Sondak, Vernon K; Messina, Jane L

2014-10-01

Most melanomas present as primary tumors on the skin surface in adults; however, melanomas also arise in the eye and on the mucosal surfaces or present as apparently metastatic disease without any known history of a cutaneous primary. Melanoma is also being diagnosed during childhood more frequently than ever. Surgeons need to be aware of and understand these unusual presentations of melanoma to optimally manage their patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Lymphoscintigraphy mapping of truncal malignant melanoma: A study of 212 patients at the Christie NHS Foundation Trust.

PubMed

El Muntasar, Ahmed; Oudit, Deems

2017-01-01

Malignant melanoma (MM) on the trunk, because of its anatomical location, has multiple potential lymphatic basins to which to drain. The aim of this study is to map the location of the sentinel lymph node (SLN) on the basis of the anatomical location of the primary malignant melanoma on the trunk. Patients diagnosed with MM on the trunk who had undergone a SLN biopsy from January 2006 to March 2015 were identified in the Christie NHS Foundation Trust through a computer database search. The anterior and posterior surfaces of the trunk were divided into four sections each. A total of 212 patients were evaluated. MM was more common on the posterior trunk, accounting for 73% of cases, and 57% of melanomas were on the right side of the trunk. The axillary basins were involved in drainage in 91.5% of all truncal melanomas. Drainage was to a single lymphatic basin in 68.3% of cases. The incidence of drainage to multiple lymphatic basins was not uniform for the anterior and posterior surfaces of the trunks. One-third of MM on the posterior surface of the trunk will drain to multiple basins. Around 50% of the melanomas of the upper back drain to a contralateral basin. Independent of the location of the MM, the axillary basins were the most common location of drainage, with a total of 91% of the cohort. Therefore, the location of the SLN could be predicted, depending on the location of the MM on the trunk. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Multiple Primary and Histology Coding Rules - SEER

Cancer.gov

Download the coding manual and training resources for cases diagnosed from 2007 to 2017. Sites included are lung, breast, colon, melanoma of the skin, head and neck, kidney, renal pelvis/ureter/bladder, benign brain, and malignant brain.

The significance of BRAF V600E mutation status discordance between primary cutaneous melanoma and brain metastases: The implications for BRAF inhibitor therapy.

PubMed

Hannan, Enda J; O'Leary, Donal P; MacNally, Stephen P; Kay, Elaine W; Farrell, Michael A; Morris, Patrick G; Power, Colm P; Hill, Arnold D K

2017-12-01

To compare BRAF V600E status of primary melanoma and brain metastases to assess for discordance by cross-sectional study, and to evaluate clinical implications on BRAF inhibitor therapy.Brain metastases are common in patients with advanced melanoma. Between 40% and 60% of melanomas demonstrate BRAF mutations, BRAF V600E being most common. Selective BRAF inhibitor therapy has shown improvement in outcome in patients with melanoma. It has been demonstrated that not all metastatic lesions carry the same BRAF mutation status as the primary, but the frequency in which discordance occurs remains unclear. Establishing this may have implications in the use of BRAF inhibitors in patients with melanoma brain metastases.Patients who underwent metastectomy for melanoma brain metastases were identified using our local histopathology database. A review of histology of the primary lesion and the metastasis was performed for each patient, assessing for BRAF mutation status discordance.Fourty-two patients who underwent a brain metastectomy following excision of a melanoma primary were identified over a 7-year period. Median survival was 9 months. The median Breslow thickness for the primary lesion was 3.4 mm. Six patients (14%) had discrepancy between the BRAF status of a melanoma primary and metastatic lesion. Of these 6 patients, 3 had a BRAF mutation positive primary with a BRAF mutation negative metastatic lesion, while the other 3 had a BRAF mutation negative primary with BRAF mutation positive metastasis.There is an important discordance rate in the BRAF mutation status of melanoma primaries versus brain metastases.

Clinical correlates and prognostic value of different metastatic sites in patients with malignant melanoma of the skin: a SEER database analysis.

PubMed

Abdel-Rahman, Omar

2018-03-01

Population-based data on the clinical correlates and prognostic value of the pattern of metastases among patients with cutaneous melanoma are needed. Surveillance, Epidemiology and End Results (SEER) database (2010-2013) has been explored through SEER*Stat program. For each of six distant metastatic sites (bone, brain, liver, lung, distant lymph nodes, and skin/subcutaneous), relevant correlation with baseline characteristics were reported. Survival analysis has been conducted through Kaplan-Meier analysis, and multivariate analysis has been conducted through a Cox proportional hazard model. A total of 2691 patients with metastatic cutaneous melanoma were identified in the period from 2010 to 2013. Patients with isolated skin/subcutaneous metastases have the best overall and melanoma-specific survival (MSS) followed by patients with isolated distant lymph node metastases followed by patients with isolated lung metastases. Patients with isolated liver, bone, or brain metastases have the worst overall and MSS (p < .0001 for both end points). Multivariate analysis revealed that age more than 70 at diagnosis (p = .012); multiple sites of metastases (p <.0001), no surgery to the primary tumor (p <.0001), and no surgery to the metastatic disease (p < .0001) were associated with worse overall survival (OS). For MSS, nodal positivity (p = .038), multiple sites of metastases (p < .0001), no surgery to the primary tumor (p < .0001), and no surgery to the metastatic disease (p < .0001) were associated with worse survival. The prognosis of metastatic cutaneous melanoma patients differs considerably according to the site of distant metastases. Further prospective studies are required to evaluate the role of local treatment in the management of metastatic disease.

Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms.

PubMed

Yan, Hongxia; Zhang, Ping; Kong, Xue; Hou, Xianglian; Zhao, Li; Li, Tianhang; Yuan, Xiaozhou; Fu, Hongjun

2017-04-01

In malignant melanoma, tumor-associated macrophages play multiple roles in promoting tumor growth, such as inducing the transformation of melanocytes under ultraviolet irradiation, increasing angiogenesis in melanomas, and suppressing antitumor immunity. Because granzyme B- and perforin-expressing Tr1 cells could specifically eliminate antigen-presenting cells of myeloid origin, we examined whether Tr1 cells in melanoma could eliminate tumor-promoting macrophages and how the interaction between Tr1 cells and macrophages could affect the growth of melanoma cells. Tr1 cells were characterized by high interleukin 10 secretion and low Foxp3 expression and were enriched in the CD4 + CD49b + LAG-3 + T-cell fraction. Macrophages derived from peripheral blood monocytes in the presence of modified melanoma-conditioned media demonstrated tumor-promoting capacity, exemplified by improving the proliferation of cocultured A375 malignant melanoma cells. But when primary Tr1 cells were present in the macrophage-A375 coculture, the growth of A375 cells was abrogated. The conventional CD25 + Treg cells, however, were unable to inhibit macrophage-mediated increase in tumor cell growth. Further analyses showed that Tr1 cells did not directly eliminate A375 cells, but mediated the killing of tumor-promoting macrophages through the secretion of granzyme B and perforin. The tumor-infiltrating interleukin 10 + Foxp3 - CD4 + T cells expressed very low levels of granzyme B and perforin, possibly suggested the downregulation of Tr1 cytotoxic capacity in melanoma tumors. Together, these data demonstrated an antitumor function of Tr1 cells through the elimination of tumor-promoting macrophages, which was not shared by conventional Tregs.

Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma

PubMed Central

Thomas, Nancy E.; Edmiston, Sharon N.; Alexander, Audrey; Groben, Pamela A.; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; From, Lynn; Busam, Klaus J.; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A.; Luo, Li; Reiner, Anne S.; Paine, Susan; Frank, Jill S.; Bramson, Jennifer I.; Marrett, Lorraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E.; Ollila, David W.; Begg, Colin B.; Berwick, Marianne; Conway, Kathleen

2015-01-01

Importance NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. Objective To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. Design, Setting, and Participants A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Main Outcomes and Measures Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. Results The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8–3.4) or BRAF (HR, 1.5, 95% CI, 0.8–2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1–7.7) or BRAF (HR 3.1; 95% CI 1.2–8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. Conclusions and Relevance Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may impact its response to immunotherapies. Further, the approximately three-fold increased death rate for higher risk tumors harboring NRAS or BRAF mutations compared to wildtype melanomas after adjusting for other prognostic factors indicates that the prognostic implication of NRAS and BRAF mutations deserves further investigation, particularly in higher AJCC stage primary melanomas. PMID:26146664

Primary Tumor Thickness is a Prognostic Factor in Stage IV Melanoma: A Retrospective Study of Primary Tumor Characteristics.

PubMed

Luen, Stephen; Wong, Siew Wei; Mar, Victoria; Kelly, John W; McLean, Catriona; McArthur, Grant A; Haydon, Andrew

2018-01-01

Stage IV melanoma exhibits a diverse range of tumor biology from indolent to aggressive disease. Many important prognostic factors have already been identified. Despite this, the behavior of metastatic melanoma remains difficult to predict. We sought to determine if any primary tumor characteristics affect survival following the diagnosis of stage IV melanoma. All patients diagnosed with stage IV melanoma between January 2003 and December 2012 were identified from the Victorian Melanoma Service database. Retrospective chart review was performed to collect data on primary tumor characteristics (thickness, ulceration, mitotic rate, melanoma subtype, or occult primary). Known and suspected prognostic factors were additionally collected (time to diagnosis of stage IV disease, age, sex, stage, receipt of chemotherapy, and era of recurrence). The effect of primary tumor characteristics on overall survival from the date of diagnosis of stage IV disease was assessed. A total of 227 patients with a median follow-up of 5 years from diagnosis of stage IV disease were identified. Median overall survival of the cohort was 250 days.Of the primary tumor characteristics assessed, only tumor thickness affected survival from diagnosis of stage IV disease, hazard ratio=1.09 (1.02 to 1.16), P=0.008. This remained significant in multivariate analysis, P=0.007. Other primary tumor characteristics did not significantly influence survival. Primary tumor thickness is a significant prognostic factor in stage IV melanoma. Our data suggest that the biology of the primary melanoma may persist to influence the behavior of metastatic disease.

Other primary systemic cancers in patients with melanoma: Analysis of balanced acral and nonacral melanomas.

PubMed

Bae, Soo Hyeon; Seon, Hyun Ju; Choi, Yoo Duk; Shim, Hyun-Jeong; Lee, Jee-Bum; Yun, Sook Jung

2016-02-01

Although other primary systemic cancers in patients with melanoma have been studied, there have been few focusing on acral melanomas. We assessed other primary systemic cancers in patients with acral and nonacral melanomas. We analyzed other primary cancers in 452 patients with melanoma from 1994 to 2013. Metachronous cancers were defined as those given a diagnosis more than 2 months after diagnosis of melanoma. The others were considered prechronous or synchronous cancers. Among 51 cases of other primary cancers, gastrointestinal cancer (35.3%, n = 18/51) was the most common, followed by thyroid (17.6%), lung (11.8%), and breast (5.9%). Those were more prevalent in the acral melanoma group (12.8%, n = 31/243) compared with the nonacral melanoma group (9.6%, n = 20/209). Of 23 cases of metachronous cancer, the risk was the highest in bone marrow, followed by oral cavity, bladder, colon, lung, and thyroid. Among 28 cases of prechronous or synchronous cancers, gastrointestinal tract (35.7%, n = 10/28) was the most common site, followed by thyroid (17.9%), breast (10.7%), and lung (7.1%). The study is limited by a small number of patients. Careful follow-up and imaging studies are necessary for early detection of other primary cancers and metastatic lesions in patients with melanoma. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Profiles of Brain Metastases: Prioritization of Therapeutic Targets.

PubMed

Ferguson, Sherise D; Zheng, Siyuan; Xiu, Joanne; Zhou, Shouhao; Khasraw, Mustafa; Brastianos, Priscilla K; Kesari, Santosh; Hu, Jethro; Rudnick, Jeremy; Salacz, Michael E; Piccioni, David; Huang, Suyun; Davies, Michael A; Glitza, Isabella C; Heymach, John V; Zhang, Jianjun; Ibrahim, Nuhad K; DeGroot, John F; McCarty, Joseph; O'Brien, Barbara J; Sawaya, Raymond; Verhaak, Roeland G W; Reddy, Sandeep K; Priebe, Waldemar; Gatalica, Zoran; Spetzler, David; Heimberger, Amy B

2018-06-19

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of non-small cell lung cancer, breast cancer, and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry), and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification, and mutations among brain metastases, extracranial metastases, and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8178 non-small cell lung cancers (5098 primaries; 2787 systemic metastases; 293 brain metastases), 7064 breast cancers (3496 primaries; 3469 systemic metastases; 99 brain metastases), and 1757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1, and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication, and/or repair. This article is protected by copyright. All rights reserved. © 2018 UICC.

Updated evidence-based clinical practice guidelines for the diagnosis and management of melanoma: definitive excision margins for primary cutaneous melanoma.

PubMed

Sladden, Michael J; Nieweg, Omgo E; Howle, Julie; Coventry, Brendon J; Thompson, John F

2018-02-19

Definitive management of primary cutaneous melanoma consists of surgical excision of the melanoma with the aim of curing the patient. The melanoma is widely excised together with a safety margin of surrounding skin and subcutaneous tissue, after the diagnosis and Breslow thickness have been established by histological assessment of the initial excision biopsy specimen. Sentinel lymph node biopsy should be discussed for melanomas ≥ 1 mm thickness (≥ 0.8 mm if other high risk features) in which case lymphoscintigraphy must be performed before wider excision of the primary melanoma site. The 2008 evidence-based clinical practice guidelines for the management of melanoma (http://www.cancer.org.au/content/pdf/HealthProfessionals/ClinicalGuidelines/ClinicalPracticeGuidelines-ManagementofMelanoma.pdf) are currently being revised and updated in a staged process by a multidisciplinary working party established by Cancer Council Australia. The guidelines for definitive excision margins for primary melanomas have been revised as part of this process. Main recommendations: The recommendations for definitive wide local excision of primary cutaneous melanoma are: melanoma in situ: 5-10 mm margins invasive melanoma (pT1) ≤ 1.0 mm thick: 1 cm margins invasive melanoma (pT2) 1.01-2.00 mm thick: 1-2 cm margins invasive melanoma (pT3) 2.01-4.00 mm thick: 1-2 cm margins invasive melanoma (pT4) > 4.0 mm thick: 2 cm margins Changes in management as a result of the guideline: Based on currently available evidence, excision margins for invasive melanoma have been left unchanged compared with the 2008 guidelines. However, melanoma in situ should be excised with 5-10 mm margins, with the aim of achieving complete histological clearance. Minimum clearances from all margins should be assessed and stated. Consideration should be given to further excision if necessary; positive or close histological margins are unacceptable.

Association of Patient Risk Factors and Frequency of Nevus-Associated Cutaneous Melanomas.

PubMed

Haenssle, Holger A; Mograby, Nerjes; Ngassa, Anni; Buhl, Timo; Emmert, Steffen; Schön, Michael P; Rosenberger, Albert; Bertsch, Hans Peter

2016-03-01

The reported frequencies of associations between primary cutaneous melanomas and melanocytic nevi vary widely between 4% and 72%. However, earlier histopathologic studies were limited by their retrospective design and did not assess the influence of important patient-related risk factors. To identify the frequency of nevus-associated melanomas and correlate patient- and melanoma-related factors. A prospective, single-center, observational study with systematic documentation of melanoma risk factors, clinical and dermoscopic criteria of excised lesions, and results of histopathologic examination was conducted at a university-based dermatology clinic. Participants included 832 patients at high risk for developing melanoma. Evaluation was performed at regular intervals between April 1, 1997, and May 31, 2012, and data analysis was conducted between September 1, 2012, and December 31, 2013. Assessment of the frequency of nevus-associated melanoma and the influence of patient- and melanoma-related factors on their manifestation. During the study, 190 melanomas (81 [42.6%] in situ and 109 [57.4%] invasive) were diagnosed in 113 of the 832 patients (13.6%); there were 42 women (37.2%) and 71 men (62.8%). The median (SD) Breslow thickness of invasive melanomas was 0.42 (0.43) mm. Histopathologic examination revealed remnants of melanocytic nevi in 103 melanomas (54.2%). Most nevus-associated melanomas were found on the trunk (67 [65.1%]); however, statistical significance for the localization was not present (P = .06). In univariate analyses, reported as odds ratios (95% CIs), nevus-associated melanomas were found significantly more frequently in patients of lower melanoma risk (risk group 1 [>50 common and/or ≤ 3 atypical nevi], 2.75 [1.14-6.64]; P = .02), with more than 100 nevi (1.63 [1.02-3.60]; P = .04), or with the diagnosis of in situ melanoma (14.01 [6.14-31.96]; P < .001). In contrast, nevus-associated melanomas were found significantly less frequently in patients with 1 or more previous melanomas (0.28 [0.21-0.83]; P = .005). All other factors (eg, age, skin type, hair color, and melanoma thickness) showed no significant influence on the manifestation of nevus-associated melanomas. These observations were confirmed in a separate analysis including all 109 invasive melanomas. Multivariate regression analysis identified 3 independent patient-related factors (high nevus count, low risk for melanoma, and female sex) and 1 melanoma-related factor (in situ melanoma) to be indicative of a significantly increased probability of nevus-associated melanomas. In this prospective study of a high-risk patient cohort, 54.2% of primary melanomas were associated with melanocytic nevi. Patients with many nevi and without previous melanomas or traits of familial atypical mole and multiple melanoma syndrome had a higher frequency of nevus-associated melanomas. These patients could thus benefit from sequential digital dermoscopy in addition to total-body photography.

Concurrent BRAF and PTEN mutations in melanoma of unknown origin presenting as a breast mass

PubMed Central

Agosto-Arroyo, Emmanuel; Rosa, Marilin; Chau, Alec; Khazai, Laila

2017-01-01

Background: Metastases represent a small percentage of the malignancies affecting the breast, and only 5% of melanomas originate from non-cutaneous sites. Multiple genetic aberrations have been associated with the development of melanocytic lesions, including BRAF V600E mutation. Mutations in PTEN gene have also been related to the pathogenesis of multiple malignancies. Purpose/Method: This is the case of a 28-year-old female who presented with a tender, palpable mass in the upper outer quadrant of the right breast. Ultrasound showed a 1-cm solid mass, initially diagnosed as invasive ductal carcinoma on biopsy. During pre-operative workup, a second mass was identified and biopsied. Immunohistochemical stains performed on the second mass biopsy demonstrated that the neoplastic cells were positive for cytokeratin AE1/3, pan-melanoma, tyrosinase, and SOX-10 and negative for CK7, CAM5.2, and GATA-3. Subsequent workup showed widespread metastatic disease involving the liver, lungs, bones, and brain. The brain metastasis tested positive for BRAF p.V600E and PTEN p.R130Efs*4 mutations. Thorough skin and eye examination did not reveal a primary melanoma. Conclusion: Only few reports have been published of melanoma presenting as a breast mass. This is an interesting case due to the clinical presentation, diagnostic challenges, and genetic mutations profile. PMID:28607685

BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma.

PubMed

Colombino, Maria; Capone, Mariaelena; Lissia, Amelia; Cossu, Antonio; Rubino, Corrado; De Giorgi, Vincenzo; Massi, Daniela; Fonsatti, Ester; Staibano, Stefania; Nappi, Oscar; Pagani, Elena; Casula, Milena; Manca, Antonella; Sini, Mariacristina; Franco, Renato; Botti, Gerardo; Caracò, Corrado; Mozzillo, Nicola; Ascierto, Paolo A; Palmieri, Giuseppe

2012-07-10

The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.

ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ungerer, Christopher; Doberstein, Kai; Buerger, Claudia

2010-10-22

Research highlights: {yields} Strong ADAM15 expression is found in normal melanocytes. {yields} ADAM15 expression is significantly downregulated in patients with melanoma metastasis. {yields} TGF-{beta} can downregulate ADAM15 expression in melanoma cells. {yields} Overexpression of ADAM15 in melanoma cells inhibits migration, proliferation and invasion of melanoma cells. {yields} Conclusion: ADAM15 represents an tumor suppressor protein in melanoma. -- Abstract: In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far.more » In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-{gamma} and TGF-{beta} downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma.« less

Primary melanoma of the gallbladder: Does it exist? Report of a case and review of the literature

PubMed Central

Safioleas, Michail; Agapitos, Emmanouil; Kontzoglou, Konstantinos; Stamatakos, Michail; Safioleas, Panagiotis; Mouzopoulos, George; Kostakis, Alkiviadis

2006-01-01

With the occasion of a case of malignant melanoma of the gallbladder, which appeared to be primary, we have reviewed the literature and the result of this research was that primary melanoma of the gallbladder remains a questionable medical entity. Only few cases of both primary and metastatic gallbladder melanoma have been reported so far, and the only agreement is that surgery is the mainstay treatment. The role of adjuvant chemotherapy, hormonotherapy or immunotherapy for both primary and metastatic disease remains undefined. PMID:16830389

Melanoma Biomolecules: Independently Identified but Functionally Intertwined

PubMed Central

Dye, Danielle E.; Medic, Sandra; Ziman, Mel; Coombe, Deirdre R.

2013-01-01

The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (<1 mm thick) will have recurrence and die within 10 years, despite no evidence of local or metastatic spread at the time of diagnosis. Thus, there is a need for additional prognostic markers to help identify those patients that may be at risk of recurrent disease. Many studies and several meta-analyses have compared gene and protein expression in melanocytes, naevi, primary, and metastatic melanoma in an attempt to find informative prognostic markers for these patients. However, although a large number of putative biomarkers have been described, few of these molecules are informative when used in isolation. The best approach is likely to involve a combination of molecules. We believe one approach could be to analyze the expression of a group of interacting proteins that regulate different aspects of the metastatic pathway. This is because a primary lesion expressing proteins involved in multiple stages of metastasis may be more likely to lead to secondary disease than one that does not. This review focuses on five putative biomarkers – melanoma cell adhesion molecule (MCAM), galectin-3 (gal-3), matrix metalloproteinase 2 (MMP-2), chondroitin sulfate proteoglycan 4 (CSPG4), and paired box 3 (PAX3). The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology. PMID:24069584

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma.

PubMed

Feller, Liviu; Khammissa, Razia A G; Lemmer, Johan

2017-01-01

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown.

A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma

PubMed Central

Lemmer, Johan

2017-01-01

Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown. PMID:28638859

Is initial excision of cutaneous melanoma by General Practitioners (GPs) dangerous? Comparing patient outcomes following excision of melanoma by GPs or in hospital using national datasets and meta-analysis.

PubMed

Murchie, Peter; Amalraj Raja, Edwin; Brewster, David H; Iversen, Lisa; Lee, Amanda J

2017-11-01

Melanomas are initially excised in primary care, and rates vary internationally. Until now, there has been no strong evidence one way or the other that excising melanomas in primary care is safe or unsafe. European guidelines make no recommendations, and the United Kingdom (UK) melanoma guidelines require all suspicious skin lesions to be initially treated in secondary care based on an expert consensus, which lacks supporting evidence, that primary care excision represents substandard care. Despite this, studies have found that up to 20% of melanomas in the UK are excised by general practitioners (GPs). Patients receiving primary care melanoma excision may fear that their care is substandard and their long-term survival threatened, neither of which may be justified. Scottish cancer registry data from 9367 people diagnosed with melanoma in Scotland between 2005 and 2013 were linked to pathology records, hospital data and death records. A Cox proportional hazards regression analysis, adjusting for key confounders, explored the association between morbidity and mortality and setting of primary melanoma excision (primary versus secondary care). A pooled estimate of the relative hazard of death of having a melanoma excised in primary versus secondary care including 7116 patients from a similar Irish study was also performed. The adjusted hazard ratio (95% CI) of death from melanoma for those having primary care excision was 0.82 (0.61-1.10). Those receiving primary care excision had a median (IQR) of 8 (3-14) out-patient attendances compared to 10 (4-17) for the secondary care group with an adjusted relative risk (RR) (95% CI) of 0.98 (0.96-1.01). Both groups had a median of 1 (0-2) hospital admissions with an adjusted rate ratio of 1.05 (0.98-1.13). In the meta-analysis, with primary care as the reference, the pooled adjusted hazard ratio (HR, 95% CI) was 1.26 (1.07-1.50) indicating a significantly higher all-cause mortality among those with excision in secondary care. The results of the Scottish and pooled analyses suggest that those receiving an initial excision for melanoma in primary care do not have poorer survival or increased morbidity compared to those being initially treated in secondary care. A randomised controlled trial to inform a greater role for GPs in the initial excision of melanoma is justified in the light of these results. Copyright © 2017 Elsevier Ltd. All rights reserved.

Intracranial Tumor Cell Migration and the Development of Multiple Brain Metastases in Malignant Melanoma.

PubMed

Simonsen, Trude G; Gaustad, Jon-Vidar; Rofstad, Einar K

2016-06-01

A majority of patients with melanoma brain metastases develop multiple lesions, and these patients show particularly poor prognosis. To develop improved treatment strategies, detailed insights into the biology of melanoma brain metastases, and particularly the development of multiple lesions, are needed. The purpose of this preclinical investigation was to study melanoma cell migration within the brain after cell injection into a well-defined intracerebral site. A-07, D-12, R-18, and U-25 human melanoma cells transfected with green fluorescent protein were injected stereotactically into the right cerebral hemisphere of nude mice. Moribund mice were killed and autopsied, and the brain was evaluated by fluorescence imaging or histological examination. Intracerebral inoculation of melanoma cells produced multiple lesions involving all regions of the brain, suggesting that the cells were able to migrate over substantial distances within the brain. Multiple modes of transport were identified, and all transport modes were observed in all four melanoma lines. Thus, the melanoma cells were passively transported via the flow of cerebrospinal fluid in the meninges and ventricles, they migrated actively along leptomeningeal and brain parenchymal blood vessels, and they migrated actively along the surfaces separating different brain compartments. Migration of melanoma cells after initial arrest, extravasation, and growth at a single location within the brain may contribute significantly to the development of multiple melanoma brain metastases. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Integrated genomic classification of melanocytic tumors of the central nervous system using mutation analysis, copy number alterations and DNA methylation profiling.

PubMed

Griewank, Klaus; Koelsche, Christian; van de Nes, Johannes A P; Schrimpf, Daniel; Gessi, Marco; Möller, Inga; Sucker, Antje; Scolyer, Richard A; Buckland, Michael E; Murali, Rajmohan; Pietsch, Torsten; von Deimling, Andreas; Schadendorf, Dirk

2018-06-11

In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria can be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. Targeted next-generation-sequencing, array-based genome-wide methylation analysis and BAP1 immunohistochemistry was performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, incl. 47 primary tumors of the central nervous system, 16 uveal melanomas. 13 cutaneous melanoma metastasis and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation and copy-number profiles were correlated with clinicopathological features. Combining mutation, copy-number and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group. Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma and blue nevus-like melanoma share molecular similarity with chromosome 3 and BAP1 alterations markers of poor prognosis. Copyright ©2018, American Association for Cancer Research.

Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers.

PubMed

Pritchard, Antonia L; Johansson, Peter A; Nathan, Vaishnavi; Howlie, Madeleine; Symmons, Judith; Palmer, Jane M; Hayward, Nicholas K

2018-01-01

While a number of autosomal dominant and autosomal recessive cancer syndromes have an associated spectrum of cancers, the prevalence and variety of cancer predisposition mutations in patients with multiple primary cancers have not been extensively investigated. An understanding of the variants predisposing to more than one cancer type could improve patient care, including screening and genetic counselling, as well as advancing the understanding of tumour development. A cohort of 57 patients ascertained due to their cutaneous melanoma (CM) diagnosis and with a history of two or more additional non-cutaneous independent primary cancer types were recruited for this study. Patient blood samples were assessed by whole exome or whole genome sequencing. We focussed on variants in 525 pre-selected genes, including 65 autosomal dominant and 31 autosomal recessive cancer predisposition genes, 116 genes involved in the DNA repair pathway, and 313 commonly somatically mutated in cancer. The same genes were analysed in exome sequence data from 1358 control individuals collected as part of non-cancer studies (UK10K). The identified variants were classified for pathogenicity using online databases, literature and in silico prediction tools. No known pathogenic autosomal dominant or previously described compound heterozygous mutations in autosomal recessive genes were observed in the multiple cancer cohort. Variants typically found somatically in haematological malignancies (in JAK1, JAK2, SF3B1, SRSF2, TET2 and TYK2) were present in lymphocyte DNA of patients with multiple primary cancers, all of whom had a history of haematological malignancy and cutaneous melanoma, as well as colorectal cancer and/or prostate cancer. Other potentially pathogenic variants were discovered in BUB1B, POLE2, ROS1 and DNMT3A. Compared to controls, multiple cancer cases had significantly more likely damaging mutations (nonsense, frameshift ins/del) in tumour suppressor and tyrosine kinase genes and higher overall burden of mutations in all cancer genes. We identified several pathogenic variants that likely predispose to at least one of the tumours in patients with multiple cancers. We additionally present evidence that there may be a higher burden of variants of unknown significance in 'cancer genes' in patients with multiple cancer types. Further screens of this nature need to be carried out to build evidence to show if the cancers observed in these patients form part of a cancer spectrum associated with single germline variants in these genes, whether multiple layers of susceptibility exist (oligogenic or polygenic), or if the occurrence of multiple different cancers is due to random chance.

The interaction between vitamin D receptor polymorphisms and sun exposure around time of diagnosis influences melanoma survival.

PubMed

Orlow, Irene; Shi, Yang; Kanetsky, Peter A; Thomas, Nancy E; Luo, Li; Corrales-Guerrero, Sergio; Cust, Anne E; Sacchetto, Lidia; Zanetti, Roberto; Rosso, Stefano; Armstrong, Bruce K; Dwyer, Terence; Venn, Alison; Gallagher, Richard P; Gruber, Stephen B; Marrett, Loraine D; Anton-Culver, Hoda; Busam, Klaus; Begg, Colin B; Berwick, Marianne

2018-03-01

Evidence on the relationship between the vitamin D pathway and outcomes in melanoma is growing, although it is not always clear. We investigated the impact of measured levels of sun exposure at diagnosis on associations of vitamin D receptor gene (VDR) polymorphisms and melanoma death in 3336 incident primary melanoma cases. Interactions between six SNPs and a common 3'-end haplotype were significant (p < .05). These SNPs, and a haplotype, had a statistically significant association with survival among subjects exposed to high UVB in multivariable regression models and exerted their effect in the opposite direction among those with low UVB. SNPs rs1544410/BsmI and rs731236/TaqI remained significant after adjustment for multiple testing. These results suggest that the association between VDR and melanoma-specific survival is modified by sun exposure around diagnosis, and require validation in an independent study. Whether the observed effects are dependent or independent of vitamin D activation remains to be determined. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Severe sunburn and subsequent risk of primary cutaneous malignant melanoma in scotland.

PubMed Central

MacKie, R. M.; Aitchison, T.

1982-01-01

A case-control study of occupational and recreational sun exposure, Mediterranean and other sun-exposed holidays, tanning history and history of isolated episodes of severe sunburn has been carried out on 113 patients with cutaneous malignant melanoma and 113 age- and sex-matched controls. Social class and skin type were also considered in the analysis of the data which involved the use of conditional multiple logistic regression. A highly significant increase in the history of severe sunburn was recorded in melanoma patients of both sexes in the 5-year period preceding presentation with their tumour. Higher social class and negative history of recreational sun exposure were also significantly increased in patients by comparison with controls. In the male group severe sunburn, lack of occupational sun exposure and higher social class were significant factors while in the female group only severe sunburn was significantly increased in the melanoma patients. This study thus provides evidence to suggest that short intense episodes of UV exposure resulting in burning may be one of the aetiological factors involved in subsequent development of melanoma. PMID:7150488

Fatty acid receptor GPR120: a novel marker for human melanoma.

PubMed

Kleemann, Johannes; Hrgovic, Igor; Ter-Nedden, Jan; Kleimann, Pia; Steinhorst, Katja; Härle, Katja; Müller, Jutta; Kaufmann, Roland; Meissner, Markus; Kippenberger, Stefan

2018-03-21

The correlation between ultraviolet radiation of the skin and melanoma incidence in humans is well established. Interestingly, epidemiologic data suggest also a correlation to an increased BMI pointing to metabolic trigger factors in melanoma pathogenesis. To substantiate this connection, we studied the expression of G-protein-coupled receptor 120 (GPR120), a receptor sensitive to unsaturated long-chain free fatty acids in melanoma tissues. One-hundred fourteen tissue sections histologically confirmed as nevi (n=32), primary melanoma (n=39), and melanoma metastasis (n=43) were immunohistochemically stained against GPR120. The staining was evaluated by three trained dermatopathologists and independently scored. Compared with nevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR120 staining. Only three out of 32 nevi showed strong GPR120 expression [median immunoreactivity-scoring system (IRS) score: 1, range: 0-10], whereas in primary melanomas 14 out of 39 were highly GPR120-positive (median IRS score: 7, range: 0-12) and in melanoma metastasis 27 out of 43 were highly GPR120-positive (median IRS score: 9, range: 0-12). GPR120 expression and tumor thickness (mm) show a statistically significant correlation in primary melanoma (P=0.011). Moreover, GPR120-positive staining was found throughout the epidermis and in sebaceous and sweat glands, which is yet not described. This study identified GPR120 as a novel marker for melanoma, indicating that melanoma cells are sensitive to free fatty acids. It is tempting to speculate that pharmacologically interfering with GPR120 signaling might improve melanoma therapy.

High expression of FOXP3 in primary melanoma is associated with tumour progression.

PubMed

Gerber, A L; Münst, A; Schlapbach, C; Shafighi, M; Kiermeir, D; Hüsler, R; Hunger, R E

2014-01-01

The antitumour immune response plays an important role in the prognosis of melanoma. High numbers of circulating regulatory T cells have been associated with rapid disease progression. To assess the influence of forkhead box protein (FOXP)3, CD1a and langerin expression on the prognosis of primary melanoma. We analysed 185 primary melanomas by immunohistochemical staining for expression of the regulatory T-cell marker FOXP3 and the dendritic cell markers langerin and CD1a, and correlated marker expression with clinical outcome. Disease-free survival and overall survival were significantly longer in patients expressing low levels of FOXP3 in the primary melanoma, whereas they were associated with high expression of CD1a. The negative prognostic value of FOXP3 expression was independent of the Breslow tumour thickness. Langerin expression did not correlate with the clinical outcome. High expression of FOXP3 in the primary melanoma may be used as an additional independent prognostic marker for early tumour progression in patients with melanoma. © 2013 British Association of Dermatologists.

Genetic profiling of a rare condition: co-occurrence of albinism and multiple primary melanoma in a caucasian family

PubMed Central

Tommasi, Stefania; Strippoli, Sabino; Pellegrini, Cristina; Concetta Fargnoli, Maria; Pilato, Brunella; Natalicchio, Iole; Guida, Gabriella; Pinto, Rosamaria

2017-01-01

Multiple primary melanoma (MPM) is a rare condition, whose genetic basis has not yet been clarified. Only 8-12% of MPM are due to germline mutations of CDKN2A. However, other genes (POT1, BRCA1/2, MC1R, MGMT) have been demonstrated to be involved in predisposition to this pathology. To our knowledge, this is the first family study based on two siblings with the rare coexistence of MPM and oculocutaneous albinism (OCA), an autosomal recessive disease characterized by the absence or decrease in pigmentation in the skin, hair, and eyes. In this study, we evaluated genes involved in melanoma predisposition (CDKN2A, CDK4, MC1R, MITF, POT1, RB1, MGMT, BRCA1, BRCA2), pathogenesis (BRAF, NRAS, PIK3CA, KIT, PTEN), skin/hair pigmentation (MC1R, MITF) and in immune pathways (CTLA4) to individuate alterations able to explain the rare onset of MPM and OCA in indexes and the transmission in their pedigree. From the analysis of the pedigree, we were able to identify a “protective” haplotype with respect to MPM, including MGMT p.I174V alteration. The second generation offspring is under strict follow up as some of them have a higher risk of developing MPM according to our model. PMID:27776349

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

PubMed Central

Gerlini, Gianni; Tun-Kyi, Adrian; Dudli, Christa; Burg, Günter; Pimpinelli, Nicola; Nestle, Frank O.

2004-01-01

CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n = 10) but not in primary melanoma lesions (n = 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor. PMID:15579430

Raman spectra of pigmented skin conditions

NASA Astrophysics Data System (ADS)

Bitar, Renata; Moreno, Marcelo; Oliveira, Andréa; Cartaxo, Sidney; Martinho, Herculano; Espírito Santo, Ana Maria do; Santos, Ivan Dunshee; Ferreira, Lydia Massako; Martin, Airton

2007-02-01

Melanoma is the most aggressive skin cancer and is invariably fatal if left untreated. Melanoma removal at early stages is almost always curative and therefore early detection is essential. Removal of every pigmented lesion is unacceptable for the patient, especially in the case of multiple skin lesions or lesions localized in cosmetically important parts of the body such as the face because of risk of scarring. The development of a technique to detect these changes in a noninvasive way is therefore crucial for melanoma detection. In this study, we have used FT-Raman Spectroscopy to investigate through PCA analysis the alterations in the molecular structure of 90 skin spectra, being 30 Pigmented Nevi, 30 Primary Melanoma, and 30 Metastasis, for 6 patients. For projection of data, the scores (Principal Components) PC1 to PC3 were calculated. PC1 versus PC3 for the 800 to 1800 cm -1 spectral region. PC1 versus PC2 for the 1200 to 1400 cm -1 spectral region. In both analysis, we could differentiate the three different types of tissues.

Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma.

PubMed

Thomas, Nancy E; Edmiston, Sharon N; Alexander, Audrey; Groben, Pamela A; Parrish, Eloise; Kricker, Anne; Armstrong, Bruce K; Anton-Culver, Hoda; Gruber, Stephen B; From, Lynn; Busam, Klaus J; Hao, Honglin; Orlow, Irene; Kanetsky, Peter A; Luo, Li; Reiner, Anne S; Paine, Susan; Frank, Jill S; Bramson, Jennifer I; Marrett, Lorraine D; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Cust, Anne E; Ollila, David W; Begg, Colin B; Berwick, Marianne; Conway, Kathleen

2015-06-01

NRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. A population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations. Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs <50 years]), superficial spreading subtype (nodular, 0.5 [0.2-1.0]; lentigo maligna, 0.4 [0.2-0.7]; and unclassified/other, 0.2 [0.1-0.5] [vs superficial spreading]), and presence of mitoses (1.7 [1.1-2.6]) (P < .05 for all). There was no significant difference in melanoma-specific survival (reported as hazard ratios [95% CIs]) for melanoma harboring mutations in NRAS (1.7 [0.8-3.4]) or BRAF (1.5 [0.8-2.9]) compared with WT melanoma, as adjusted for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher-risk (T2b or higher stage) tumors with NRAS (2.9 [1.1-7.7]) or BRAF (3.1 [1.2-8.5]) mutations (P = .04) but not for lower-risk (T2a or lower) tumors with NRAS (0.9 [0.3-3.0]) or BRAF (0.6 [0.2-1.7]) (P = .65), as adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies. The approximate 3-fold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with WT melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher–AJCC stage primary melanomas.

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

PubMed Central

Yokoyama, Satoru; Woods, Susan L.; Boyle, Glen M.; Aoude, Lauren G.; MacGregor, Stuart; Zismann, Victoria; Gartside, Michael; Cust, Anne E.; Haq, Rizwan; Harland, Mark; Taylor, John C.; Duffy, David L.; Holohan, Kelly; Dutton-Regester, Ken; Palmer, Jane M.; Bonazzi, Vanessa; Stark, Mitchell S.; Symmons, Judith; Law, Matthew H.; Schmidt, Christopher; Lanagan, Cathy; O’Connor, Linda; Holland, Elizabeth A.; Schmid, Helen; Maskiell, Judith A.; Jetann, Jodie; Ferguson, Megan; Jenkins, Mark A.; Kefford, Richard F.; Giles, Graham G.; Armstrong, Bruce K.; Aitken, Joanne F.; Hopper, John L.; Whiteman, David C.; Pharoah, Paul D.; Easton, Douglas F.; Dunning, Alison M.; Newton-Bishop, Julia A.; Montgomery, Grant W.; Martin, Nicholas G.; Mann, Graham J.; Bishop, D. Timothy; Tsao, Hensin; Trent, Jeffrey M.; Fisher, David E.; Hayward, Nicholas K.; Brown, Kevin M.

2012-01-01

So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log odds ratio (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility. PMID:22080950

Integrative Genome Comparison of Primary and Metastatic Melanomas

PubMed Central

Feng, Bin; Nazarian, Rosalynn M.; Bosenberg, Marcus; Wu, Min; Scott, Kenneth L.; Kwong, Lawrence N.; Xiao, Yonghong; Cordon-Cardo, Carlos; Granter, Scott R.; Ramaswamy, Sridhar; Golub, Todd; Duncan, Lyn M.; Wagner, Stephan N.; Brennan, Cameron; Chin, Lynda

2010-01-01

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes. PMID:20520718

Associations of Statins and Diabetes with Diagnosis of Ulcerated Cutaneous Melanoma.

PubMed

von Schuckmann, Lena A; Smith, David; Hughes, Maria Celia B; Malt, Maryrose; van der Pols, Jolieke C; Khosrotehrani, Kiarash; Smithers, Bernard M; Green, Adele C

2017-12-01

Ulcerated primary melanomas are associated with an inflammatory tumor microenvironment. We hypothesized that systemic proinflammatory states and anti-inflammatory medications are also associated with a diagnosis of ulcerated melanoma. In a cross-sectional study of 787 patients with newly diagnosed clinical stage IB or II melanoma, we estimated odds ratios for the association of proinflammatory factors (high body mass index, diabetes, cardiovascular disease, hypertension, and smoking) or the use of anti-inflammatory medications (statins, aspirin, corticosteroids, and nonsteroidal anti-inflammatory drugs), with ulcerated primary melanoma using regression models and subgroup analyses to control for melanoma thickness and mitotic rate. On the basis of information from 194 patients with ulcerated and 593 patients with nonulcerated primary melanomas, regular statin users had lower likelihood of a diagnosis of ulcerated primary melanoma (odds ratio 0.67, 95% confidence interval 0.45-0.99), and this association remained after adjusting for age, sex, thickness, and mitosis. When analysis was limited to melanomas that were ≤2 mm thick and had ≤2 mitoses/mm 2 (40 ulcerated; 289 without ulceration), patients with diabetes had significantly raised odds of diagnosis of ulcerated melanoma (odds ratio 2.90, 95% confidence interval 1.07-7.90), adjusted for age, sex, body mass index, and statin use. These findings support our hypotheses that statin use is inversely associated, and diabetes is positively associated, with ulcerated melanoma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Recent Successes and Future Directions in Immunotherapy of Cutaneous Melanoma

PubMed Central

Sadozai, Hassan; Gruber, Thomas; Hunger, Robert Emil; Schenk, Mirjam

2017-01-01

The global health burden associated with melanoma continues to increase while treatment options for metastatic melanoma are limited. Nevertheless, in the past decade, the field of cancer immunotherapy has witnessed remarkable advances for the treatment of a number of malignancies including metastatic melanoma. Although the earliest observations of an immunological antitumor response were made nearly a century ago, it was only in the past 30 years, that immunotherapy emerged as a viable therapeutic option, in particular for cutaneous melanoma. As such, melanoma remains the focus of various preclinical and clinical studies to understand the immunobiology of cancer and to test various tumor immunotherapies. Here, we review key recent developments in the field of immune-mediated therapy of melanoma. Our primary focus is on therapies that have received regulatory approval. Thus, a brief overview of the pathophysiology of melanoma is provided. The purported functions of various tumor-infiltrating immune cell subsets are described, in particular the recently described roles of intratumoral dendritic cells. The section on immunotherapies focuses on strategies that have proved to be the most clinically successful such as immune checkpoint blockade. Prospects for novel therapeutics and the potential for combinatorial approaches are delineated. Finally, we briefly discuss nanotechnology-based platforms which can in theory, activate multiple arms of immune system to fight cancer. The promising advances in the field of immunotherapy signal the dawn of a new era in cancer treatment and warrant further investigation to understand the opportunities and barriers for future progress. PMID:29276510

Primary mucosal melanomas: a comprehensive review

PubMed Central

Mihajlovic, Marija; Vlajkovic, Slobodan; Jovanovic, Predrag; Stefanovic, Vladisav

2012-01-01

Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas. PMID:23071856

Primary mucosal melanomas: a comprehensive review.

PubMed

Mihajlovic, Marija; Vlajkovic, Slobodan; Jovanovic, Predrag; Stefanovic, Vladisav

2012-01-01

Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas.

Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases.

PubMed

Jager, Martine J; Dogrusöz, Mehmet; Woodman, Scott E

2017-01-01

Uveal melanoma is an intraocular malignancy that, depending on its size and genetic make-up, may lead to metastases in up to 50% of cases. Currently, no therapy has been proven to improve survival. However, new therapies exploiting immune responses against metastases are being developed. The primary tumor is well characterized: tumors at high risk of developing metastases often contain macrophages and lymphocytes. However, these lymphocytes are often regulatory T cells that may suppress immune response. Currently, immune checkpoint inhibitors have shown marked efficacy in multiple cancers (eg, cutaneous melanoma) but do not yet improve survival in uveal melanoma patients. More knowledge needs to be acquired regarding the function of T cells in uveal melanoma. Other therapeutic options are related to the biochemical pathways. Targeting the RAF-MEK-ERK pathway with small molecule MEK inhibitors abrogates the growth of UM cells harboring GNAQ/GNA11 Q209 mutations, suggesting that these aberrant G-protein oncogenes mediate, at least in part, their effect through this hallmark proliferation pathway. Other pathways are also implicated, such as those involving c-Jun and YAP. Further studies may show how interference in the different pathways may affect survival. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Development of a primary melanoma in situ within a full-thickness skin graft overlying a free muscle flap: a case report.

PubMed

Dabek, Robert J; Baletic, Nemanja; McUmber, Harrison; Nahed, Brian; Haynes, Alex; Eberlin, Kyle R; Bojovic, Branko

2018-01-01

The development of a primary melanoma within the confines of free tissue transfer is a rare occurrence. In this report, we describe the development of a primary melanoma in situ within a full-thickness skin graft overlying a free latissimus dorsi muscle flap used to cover a scalp defect.

Convection-enhanced delivery of sorafenib and suppression of tumor progression in a murine model of brain melanoma through the inhibition of signal transducer and activator of transcription 3.

PubMed

Zou, Zhaoxia; Yin, Yufang; Lin, Jenny; Hsu, Li-Chen J; Brandon, Vanessa L; Yang, Fan; Jove, Richard; Jandial, Rahul; Li, Gang; Chen, Mike Y

2016-05-01

OBJECT Despite recent advances, metastatic melanoma remains a terminal disease, in which life-threatening brain metastasis occurs in approximately half of patients. Sorafenib is a multikinase inhibitor that induces apoptosis of melanoma cells in vitro. However, systemic administration has been ineffective because adequate tissue concentrations cannot be achieved. This study investigated if convection-enhanced delivery (CED) of sorafenib would enhance tumor control and survival via inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway in a murine model of metastatic brain melanoma. METHODS Melanoma cells treated with sorafenib in vitro were examined for signaling and survival changes. The effect of sorafenib given by CED was assessed by bioluminescent imaging and animal survival. RESULTS The results showed that sorafenib induced cell death in the 4 established melanoma cell lines and in 1 primary cultured melanoma cell line. Sorafenib inhibited Stat3 phosphorylation in HTB65, WYC1, and B16 cells. Accordingly, sorafenib treatment also decreased expression of Mcl-1 mRNA in melanoma cell lines. Because sorafenib targets multiple pathways, the present study demonstrated the contribution of the Stat3 pathway by showing that mouse embryonic fibroblast (MEF) Stat3 +/+ cells were significantly more sensitive to sorafenib than MEF Stat3 -/- cells. In the murine model of melanoma brain metastasis used in this study, CED of sorafenib increased survival by 150% in the treatment group compared with animals receiving the vehicle control (p < 0.01). CED of sorafenib also significantly abrogated tumor growth. CONCLUSIONS The data from this study indicate that local delivery of sorafenib effectively controls brain melanoma. These findings validate further investigation of the use of CED to distribute molecularly targeted agents.

Guidelines of the Brazilian Dermatology Society for diagnosis, treatment and follow up of primary cutaneous melanoma - Part I*

PubMed Central

Castro, Luiz Guilherme Martins; Messina, Maria Cristina; Loureiro, Walter; Macarenco, Ricardo Silvestre; Duprat Neto, João Pedreira; Giacomo, Thais Helena Bello Di; Bittencourt, Flávia Vasques; Bakos, Renato Marchiori; Serpa, Sérgio Schrader; Stolf, Hamilton Ometto; Gontijo, Gabriel

2015-01-01

The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In the first part, the following clinical questions were answered: 1) The use of dermoscopy for diagnosis of primary cutaneous melanoma brings benefits for patients when compared with clinical examination? 2) Does dermoscopy favor diagnosis of nail apparatus melanoma? 3) Is there a prognostic difference when incisional or excisional biopsies are used? 4) Does revision by a pathologist trained in melanoma contribute to diagnosis and treatment of primary cutaneous melanoma? What margins should be used to treat lentigo maligna melanoma and melanoma in situ? PMID:26734867

Prognostic factors for melanoma patients with lesions 0.76 - 1.69 mm in thickness. An appraisal of "thin" level IV lesions.

PubMed Central

Day, C L; Mihm, M C; Sober, A J; Harris, M N; Kopf, A W; Fitzpatrick, T B; Lew, R A; Harrist, T J; Golomb, F M; Postel, A; Hennessey, P; Gumport, S L; Raker, J W; Malt, R A; Cosimi, A B; Wood, W C; Roses, D F; Gorstein, F; Rigel, D; Friedman, R J; Mintzis, M M

1982-01-01

Fourteen variables were tested for their prognostic usefulness in 203 patients with clinical Stage I melanoma and primary tumor 0.76-169 mm thick. Only two variables, primary tumor location and level of invasion, were useful in predicting death from melanoma for these patients. Of the 12 deaths from melanoma, 11 occurred in patients with primary tumors located on the upper back, posterior arm, posterior neck, and posterior scalp (=BANS). There has been only one death from melanoma in 136 patients with melanoma located at other sites (11/67 vs 1/136, p less than 0.0001 Fisher's Exact Test). Of the 67 BANS patients, 51 had level II or level III lesions and five (10%0 died of melanoma. This compared with six deaths from melanoma in 16 patients (37.5%) with level IV BANS lesions (5/51 vs 6/16, p = 0.01 Fisher's Exact Test). The relatively high incidence of both melanoma deaths and regional node metastases for the BANS group merits consideration for testing the efficacy of elective regional node dissection for these patients. PMID:7055381

Gallium-67-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide for primary and metastatic melanoma imaging.

PubMed

Guo, Haixun; Yang, Jianquan; Shenoy, Nalini; Miao, Yubin

2009-12-01

The purpose of this study was to examine the melanoma imaging properties of a novel 67Ga-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A lactam bridge-cyclized alpha-MSH peptide, DOTA-GlyGlu-CycMSH {DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]}, was synthesized and radiolabeled with 67Ga. The melanoma targeting and pharmacokinetic properties of 67Ga-DOTA-GlyGlu-CycMSH were determined in B16/F1 flank primary melanoma-bearing and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. Flank primary melanoma and pulmonary metastatic melanoma imaging were performed by small animal single photon emission computed tomography (SPECT)/CT using 67Ga-DOTA-GlyGlu-CycMSH as an imaging probe. 67Ga-DOTA-GlyGlu-CycMSH was readily prepared with greater than 95% radiolabeling yield. 67Ga-DOTA-GlyGlu-CycMSH exhibited substantial tumor uptake (12.93 +/- 1.63%ID/g at 2 h postinjection) and prolonged tumor retention (5.02 +/- 1.35%ID/g at 24 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<0.30%ID/g) except for the kidneys at 2, 4, and 24 h postinjection. 67Ga-DOTA-GlyGlu-CycMSH exhibited significantly (p < 0.05) higher uptakes (1.44 +/- 0.75%ID/g at 2 h postinjection and 1.49 +/- 0.69%ID/g at 4 h postinjection) in metastatic melanoma-bearing lung than those in normal lung (0.15 +/- 0.10%ID/g and 0.17 +/- 0.11%ID/g at 2 and 4 h postinjection, respectively). Both flank primary B16/F1 melanoma and B16/F10 pulmonary melanoma metastases were clearly visualized by SPECT/CT using 67Ga-DOTA-GlyGlu-CycMSH as an imaging probe 2 h postinjection. 67Ga-DOTA-GlyGlu-CycMSH exhibited favorable melanoma targeting and imaging properties, highlighting its potential as an effective imaging probe for early detection of primary and metastatic melanoma.

A case of primary choroidal malignant melanoma in a cat.

PubMed

Bourguet, Aurélie; Piccicuto, Virginie; Donzel, Elise; Carlus, Marine; Chahory, Sabine

2015-07-01

This report describes the clinical presentation, diagnosis, histological lesions, and prognosis of a primary choroidal malignant melanoma in a 15-year-old cat. The animal was presented for unilateral blindness. On ocular examination, a raised pigmented mass protruding from the posterior pole into the vitreous body was observed by diffuse transillumination and indirect ophthalmoscopy. Ocular ultrasound and computer tomography (CT) scan confirmed localization of the tumor to the posterior segment. The diagnosis of primary choroidal melanoma was confirmed by histopathology after enucleation. To our knowledge, this is the first reported case of a feline malignant melanoma with a primary choroidal localization without iris involvement. © 2014 American College of Veterinary Ophthalmologists.

Update on primary mucosal melanoma.

PubMed

Tacastacas, Joselin D; Bray, Julie; Cohen, Yoon K; Arbesman, Joshua; Kim, Julian; Koon, Henry B; Honda, Kord; Cooper, Kevin D; Gerstenblith, Meg R

2014-08-01

Mucosal melanomas are aggressive cancers of mucosal surfaces with clinical and pathologic characteristics distinct from cutaneous melanomas, warranting different staging systems and treatment approaches. Surgical resection is performed frequently for the primary tumor, although the utility of lymph node surgery and radiation therapy is not established. Therapies targeted against C-KIT activating mutations, identified in many mucosal melanomas, are emerging as promising treatments. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Nucleoli cytomorphology in cutaneous melanoma cells - a new prognostic approach to an old concept.

PubMed

Donizy, Piotr; Biecek, Przemyslaw; Halon, Agnieszka; Maciejczyk, Adam; Matkowski, Rafal

2017-12-29

The nucleolus is an organelle that is an ultrastructural element of the cell nucleus observed in H&E staining as a roundish body stained with eosin due to its high protein content. Changes in the nucleoli cytomorphology were one of the first histopathological characteristics of malignant tumors. The aim of this study was to assess the relationship between the cytomorphological characteristics of nucleoli and detailed clinicopathological parameters of melanoma patients. Moreover, we analyzed the correlation between cytomorphological parameters of nucleoli and immunoreactivity of selected proteins responsible for, among others, regulation of epithelial-mesenchymal transition (SPARC, N-cadherin), cell adhesion and motility (ALCAM, ADAM-10), mitotic divisions (PLK1), cellular survival (FOXP1) and the functioning of Golgi apparatus (GOLPH3, GP73). Three characteristics of nucleoli - presence, size and number - of cancer cells were assessed in H&E-stained slides of 96 formalin-fixed paraffin-embedded primary cutaneous melanoma tissue specimens. The results were correlated with classical clinicopathological features and patient survival. Immunohistochemical analysis of the above mentioned proteins was described in details in previous studies. Higher prevalence and size of nucleoli were associated with thicker and mitogenic tumors. All three nucleolar characteristics were related to the presence of ulceration. Moreover, microsatellitosis was strongly correlated with the presence of macronucleoli and polynucleolization (presence of two or more nucleoli). Lack of immunologic response manifested as no TILs in primary tumor was associated with high prevalence of melanoma cells with distinct nucleoli. Interestingly, in nodular melanoma a higher percentage of melanoma cells with prominent nucleoli was observed. In Kaplan-Meier analysis, increased prevalence and amount, but not size of nucleoli, were connected with shorter cancer-specific and disease-free survival. (1) High representation of cancer cells with distinct nucleoli, greater size and number of nucleoli per cell are characteristics of aggressive phenotype of melanoma; (2) higher prevalence and size of nucleoli are potential measures of cell kinetics that are strictly correlated with high mitotic rate; and (3) high prevalence of cancer cells with distinct nucleoli and presence of melanocytes with multiple nucleoli are features associated with unfavorable prognosis in patients with cutaneous melanoma.

Aspiration cytology of extramammary tumors metastatic to the breast.

PubMed

Deshpande, A H; Munshi, M M; Lele, V R; Bobhate, S K

1999-11-01

This study was carried out to examine the cytomorphologic features of metastatic breast tumors and to assess the utility of fine-needle aspiration cytology (FNAC) in diagnosing these tumors. The study group comprised five females and one male, all presenting with a breast mass. Their ages ranged between 35 and 65 years. FNAC of the breast mass was done in all cases. Three of the cases were previously diagnosed as squamous cell carcinoma (SCC) of the cervix, mucinous cystadenocarcinoma (MCA) of the ovary, and melanoma. Three cases presented initially with a breast mass. These included melanoma, non-Hodgkin's lymphoma (NHL), and plasmacytoma. The diagnosis of NHL was confirmed on histology. The patient with plasmacytoma presented primarily with a breast lump but subsequently developed multiple myeloma, and in one case of melanoma the primary tumor was detected after breast metastases. Preoperative FNAC of extramammary tumors metastatic to the breast is invaluable because the management of the patient differs entirely from that of a primary neoplasm. An accurate diagnosis can be made with the help of clinical and radiological correlation. If available, a perusal of previous history and biopsy material may prove useful. Copyright 1999 Wiley-Liss, Inc.

The role of nitric oxide in melanoma.

PubMed

Yarlagadda, Keerthi; Hassani, John; Foote, Isaac P; Markowitz, Joseph

2017-12-01

Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself. Copyright © 2017 Elsevier B.V. All rights reserved.

In situ photoimmunotherapy: a tumour-directed treatment for melanoma.

PubMed

Naylor, M F; Chen, W R; Teague, T K; Perry, L A; Nordquist, R E

2006-12-01

We report a new immunological treatment for advanced cutaneous melanoma which combines laser stimulation with topical application of a toll-like receptor agonist. This treatment, in situ photoimmunotherapy (ISPI), provides an alternative to traditional therapies for melanoma patients with cutaneous metastases. A 6-week cycle of ISPI is carried out on cutaneous metastases located in a designated 20 x 20 cm treatment area: 2 weeks of pretreatment with twice-daily topical applications of imiquimod (5% cream under plastic occlusion), with a laser treatment session at week 2 and again at week 4. Topical imiquimod is continued for the entire 6-week cycle. Two patients with late-stage melanoma were treated with ISPI. Patient 1 had the primary tumour and local metastases on the left arm, as well as metastatic tumours in the lungs [American Joint Committee on Cancer (AJCC) stage IV]. Patient 2 had a head and neck melanoma with multiple local metastases (AJCC stage IIIC), which had failed repeated attempts at surgical resection and high-dose radiation therapy. Patient 1 is now free of all clinically detectable tumours (including the lung metastases) >20 months after the first treatment cycle. Patient 2 has been free of any clinical evidence of the tumour for over 6 months. These two cases demonstrate that ISPI can clear local tumour and trigger beneficial systemic responses, with a side-effect profile that compares favourably with other treatments for advanced melanoma.

Effect of time to sentinel-node biopsy on the prognosis of cutaneous melanoma.

PubMed

Tejera-Vaquerizo, Antonio; Nagore, Eduardo; Puig, Susana; Robert, Caroline; Saiag, Philippe; Martín-Cuevas, Paula; Gallego, Elena; Herrera-Acosta, Enrique; Aguilera, José; Malvehy, Josep; Carrera, Cristina; Cavalcanti, Andrea; Rull, Ramón; Vilalta-Solsona, Antonio; Lannoy, Emilie; Boutros, Celine; Benannoune, Naima; Tomasic, Gorana; Aegerte, Philippe; Vidal-Sicart, Sergi; Palou, Josep; Alos, L Lúcia; Requena, Celia; Traves, Víctor; Pla, Ángel; Bolumar, Isidro; Soriano, Virtudes; Guillén, Carlos; Herrera-Ceballos, Enrique

2015-09-01

In patients with primary cutaneous melanoma, there is generally a delay between excisional biopsy of the primary tumour and sentinel-node biopsy. The objective of this study is to analyse the prognostic implications of this delay. This was an observational, retrospective, cohort study in four tertiary referral hospitals. A total of 1963 patients were included. The factor of interest was the interval between the date of the excisional biopsy of the primary melanoma and the date of the sentinel-node biopsy (delay time) in the prognosis. The primary outcome was melanoma-specific survival and disease-free survival. A delay time of 40 days or less (hazard ratio (HR), 1.7; confidence interval (CI), 1.2-2.5) increased Breslow thickness (Breslow ⩾ 2 mm, HR, > 3.7; CI, 1.4-10.7), ulceration (HR, 1.6; CI, 1.1-2.3), sentinel-node metastasis (HR, 2.9; CI, 1.9-4.2), and primary melanoma localised in the head or neck were independently associated with worse melanoma-specific survival (all P < 0.03). The stratified analysis showed that the effect of delay time was at the expense of the patients with a negative sentinel-node biopsy and without regression. Early sentinel-node biopsy is associated with worse survival in patients with cutaneous melanoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry.

PubMed

Gassenmaier, Maximilian; Eigentler, Thomas Kurt; Keim, Ulrike; Goebeler, Matthias; Fiedler, Eckhard; Schuler, Gerold; Leiter, Ulrike; Weide, Benjamin; Grischke, Eva-Maria; Martus, Peter; Garbe, Claus

2017-12-01

For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91-1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96-1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Radiotherapy of oral malignant melanomas in dogs.

PubMed

Blackwood, L; Dobson, J M

1996-07-01

To evaluate response to radiotherapy in dogs with oral malignant melanomas. Clinical trial. 36 dogs with histologically confirmed oral malignant melanomas. The prescribed radiation dose was 36 Gy given in 4 fractions of 9 Gy at 7-day intervals. The primary radiation source was a linear accelerator. In 25 of 36 dogs, complete remission was achieved, and in 9 dogs, partial remission was achieved. Recurrence of the primary tumor was the cause of euthanasia of 4 dogs. Twenty-one dogs were euthanatized because of metastasis. Radiotherapy was an effective palliative treatment for the primary tumor in dogs with oral malignant melanomas. However, rapid development of metastatic disease remained a major challenge.

Clinics, prognosis and new therapeutic options in patients with mucosal melanoma: A retrospective analysis of 75 patients.

PubMed

Schaefer, Tim; Satzger, Imke; Gutzmer, Ralf

2017-01-01

Mucosal melanomas represent a rare entity with different risk factors and molecular features compared to cutaneous melanomas. They arise most commonly from mucosal surfaces in the head/neck region, the female genital tract (FGT) and the anorectal region. The aim of this study was to evaluate clinics, prognosis, and treatment options of patients with mucosal melanoma, in particular with regard to different primary sites.We retrospectively analyzed 75 patients with mucosal melanomas diagnosed in the years 1993 to 2015 in our department. The primary melanomas were located in the head/neck region (n = 32), the FGT (n = 24), and the anorectal region (n = 19).The median age of the patients was 66 years. At initial diagnosis the primary melanoma was not completely resectable in 11 (15%) patients, 18 (24%) patients had regional lymph node metastases, and 7 (9%) patients distant metastases. During follow-up, 22 (29%) patients suffered from a local recurrence, in particular patients with primary melanoma in the head/neck region without postoperative radiotherapy. By multivariate analysis location of the primary melanoma in the head/neck area or anorectal region and presence of metastases at time of diagnosis represented poor prognostic factors for recurrence-free survival. In 62 tested individuals 7 KIT mutations were found, 2 BRAF mutations in 57 tested patients. Four patients received targeted therapies, 14 checkpoint inhibitors, 4 (1/1 on vemurafenib, 1/7 on ipilimumab, and 2/7 on PD-1 inhibitors) patients showed responses of more than 100 days duration.Mucosal melanomas are often locally advanced or metastatic at initial diagnosis, thus they require extensive staging procedures. The high rate of local recurrences in the head/neck region can be significantly reduced by postoperative radiotherapy. For the potential use of medical treatment a mutation analysis for KIT and BRAF genes should be performed. The use of new immunologic and targeted therapies has to be further evaluated.

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations

PubMed Central

Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

2016-01-01

Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression. PMID:27095580

Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.

PubMed

Montagnani, Valentina; Benelli, Matteo; Apollo, Alessandro; Pescucci, Chiara; Licastro, Danilo; Urso, Carmelo; Gerlini, Gianni; Borgognoni, Lorenzo; Luzzatto, Lucio; Stecca, Barbara

2016-05-24

Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.

Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis

PubMed Central

Chatterjee, Aniruddha; Stockwell, Peter A; Ahn, Antonio; Rodger, Euan J; Leichter, Anna L; Eccles, Michael R

2017-01-01

Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, few studies have identified metastasis-related epigenetic drivers, in part because a framework for identifying driver epigenetic changes in metastasis has not been established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns in three cutaneous primary and metastatic melanoma cell line pairs to identify metastasis-related epigenetic drivers. Globally, metastatic melanoma cell lines were hypomethylated compared to the matched primary melanoma cell lines. Using whole genome RRBS we identified 75 shared (10 hyper- and 65 hypomethylated) differentially methylated fragments (DMFs), which were associated with 68 genes showing significant methylation differences. One gene, Early B Cell Factor 3 (EBF3), exhibited promoter hypermethylation in metastatic cell lines, and was validated with bisulfite sequencing and in two publicly available independent melanoma cohorts (n = 40 and 458 melanomas, respectively). We found that hypermethylation of the EBF3 promoter was associated with increased EBF3 mRNA levels in metastatic melanomas and subsequent inhibition of DNA methylation reduced EBF3 expression. RNAi-mediated knockdown of EBF3 mRNA levels decreased proliferation, migration and invasion in primary and metastatic melanoma cell lines. Overall, we have identified numerous epigenetic changes characterising metastatic melanoma cell lines, including EBF3-induced aggressive phenotypic behaviour with elevated EBF3 expression in metastatic melanoma, suggesting that EBF3 promoter hypermethylation may be a candidate epigenetic driver of metastasis. PMID:28030832

The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients.

PubMed

Lian, B; Cui, C L; Zhou, L; Song, X; Zhang, X S; Wu, D; Si, L; Chi, Z H; Sheng, X N; Mao, L L; Wang, X; Tang, B X; Yan, X Q; Kong, Y; Dai, J; Li, S M; Bai, X; Zheng, N; Balch, C M; Guo, J

2017-04-01

We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites. Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites. The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%, P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%, P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively. The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

[Fundus fluorescein angiography in metastatic choroidal carcinomas and differentiating metastatic choroidal carcinomas from primary choroidal melanomas].

PubMed

Li, Lei; Wang, Wen-Ji; Chen, Rong-Jia; Qian, Jiang; Luo, Chuan-Qi; Zhang, Yong-Jin; Shen, Ying; Ye, Xiao-Feng; Gao, Qiao-Yun

2011-01-01

To investigate the characteristics of fundus fluorescein angiography (FFA) in metastatic choroidal carcinomas and determine the value of FFA in differentiating metastatic choroidal carcinomas from primary choroidal melanomas. It was a retrospective case series. The retrospective analysis of clinical data and FFA findings was performed in 23 eyes of 22 patients with metastatic choroidal carcinomas and 31 eyes of 31 patients with primary choroidal melanomas as the control. Ocular fundus findings of metastatic choroidal carcinomas were divided into three types: solitary flat (tumor thickness less than 3 mm), solitary elevated (tumor thickness more than 3 mm) or diffuse type. FFA of the three types showed hypofluorescence during the arterial phase and progressive hyperfluorescence during the subsequent phases. The border of the lesions revealed retinal capillary dilation during the arteriovenous phase and persistent pinpoint leakage throughout the angiogram. Retinal capillary dilation and pinpoint leakage were more frequently presented in the solitary flat type. Simultaneous visualization of retinal and tumor circulation (the so called double circulation) was more frequently presented in the solitary elevated type. Pinpoint leakage could be detected in 17 (73.91%) eyes of metastatic choroidal carcinomas and in 5 (16.13%) eyes of primary choroidal melanomas. The difference between the visibility of pinpoint leakage in metastatic choroidal carcinomas and primary choroidal melanomas was statistically significant (P = 0.0000). When pinpoint leakage of FFA was used to differentiate metastatic choroidal carcinomas from primary choroidal melanomas, the sensitivity, specificity, accuracy, positive and negative predictive values were 73.91%, 83.87%, 79.63%, 77.27%, 81.25% respectively. FFA is helpful for the diagnosis of metastatic choroidal carcinomas. Pinpoint leakage on the border of lesions has some value in differentiating metastatic choroidal carcinomas from primary choroidal melanomas.

Pump-probe imaging of pigmented cutaneous melanoma primary lesions gives insight into metastatic potential

PubMed Central

Robles, Francisco E.; Deb, Sanghamitra; Wilson, Jesse W.; Gainey, Christina S.; Selim, M. Angelica; Mosca, Paul J.; Tyler, Douglas S.; Fischer, Martin C.; Warren, Warren S.

2015-01-01

Metastatic melanoma is associated with a poor prognosis, but no method reliably predicts which melanomas of a given stage will ultimately metastasize and which will not. While sentinel lymph node biopsy (SLNB) has emerged as the most powerful predictor of metastatic disease, the majority of people dying from metastatic melanoma still have a negative SLNB. Here we analyze pump-probe microscopy images of thin biopsy slides of primary melanomas to assess their metastatic potential. Pump-probe microscopy reveals detailed chemical information of melanin with subcellular spatial resolution. Quantification of the molecular signatures without reference standards is achieved using a geometrical representation of principal component analysis. Melanin structure is analyzed in unison with the chemical information by applying principles of mathematical morphology. Results show that melanin in metastatic primary lesions has lower chemical diversity than non-metastatic primary lesions, and contains two distinct phenotypes that are indicative of aggressive disease. Further, the mathematical morphology analysis reveals melanin in metastatic primary lesions has a distinct “dusty” quality. Finally, a statistical analysis shows that the combination of the chemical information with spatial structures predicts metastatic potential with much better sensitivity than SLNB and high specificity, suggesting pump-probe microscopy can be an important tool to help predict the metastatic potential of melanomas. PMID:26417529

Adrenal malignant melanoma masquerading as a pheochromocytoma in a patient with a history of a multifocal papillary and medullary thyroid carcinoma.

PubMed

Barmpari, Maria E; Savvidis, Christos; Dede, Anastasia D; Markogiannakis, Haridimos; Dikoglou, Christina; Xekouki, Paraskevi; Stratakis, Constantine A; Manouras, Andreas; Malaktari-Skarantavou, Sofia

2016-04-01

Adrenal masses usually represent benign and nonfunctional adrenal adenomas; however, primary or metastatic malignancy should also be considered. Discovery of an adrenal mass needs further evaluation in order to exclude malignancy and hormonal secretion. We present a rare case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. A 61-year-old male farmer was referred for evaluation of a mass in the right supraclavicular region and a left adrenal lesion. The patient had a history of a multifocal papillary and medullary thyroid carcinoma. Laboratory tests revealed increased 24hour urinary dopamine and also increased serum calcitonin and neuron specific enolase. A pathology report of the resected right supraclavicular mass and left adrenal showed a malignant melanoma. This is a case of a possibly primary adrenal malignant melanoma with imaging and biochemical features of a pheochromocytoma. Although this case is very rare and there are rigid diagnostic criteria for the diagnosis of primary adrenal melanoma, it underlines the fact that the differential diagnosis of a dopamine secreting adrenal mass should include primary or metastatic malignant melanoma in order to determine the best diagnostic approach for the patient and select the most appropriate surgical management.

[Primary Malignant Melanoma of the Gallbladder].

PubMed

Ujiie, Daisuke; Miyamoto, Kotaro; Onozawa, Hisashi; Hoshi, Nobuhiro; Nakayama, Koichi; Urazumi, Kojiro; Takenoshita, Seiichi; Kusakabe, Takashi

2016-11-01

Primary malignant melanoma of the gallbladder is a rare disease, and 37 cases have been reported in the literature.The current patient was a 78-year-old man who was admitted with a pelvic tumor and left leg edema due to compression of the external iliac vein by the pelvic tumor.The edema improved following resection of the tumor, which was diagnosed at pathology as a malignant melanoma.After surgery, the patient became anorexic and complained of discomfort in the upper right abdomen.A whole body FDG-PET scan demonstrated significant uptake in the gallbladder and in the lymph nodes of the lower abdomen.The patient underwent open cholecystectomy, and the pathological diagnosis was malignant melanoma. Junctional activity was seen in the gallbladder, suggesting that this was the primary site.No melanocytic lesions of the skin or eyes were detected, further supporting the diagnosis of primary malignant melanoma of the gallbladder.Chemotherapy was initiated, but the patient died on February 28, 2016.

Canine choroidal melanoma with metastases.

PubMed

Hyman, Jennifer A; Koch, Seth A; Wilcock, Brian P

2002-06-01

A 3-year-old-female, spayed Golden Retriever was examined for a unilateral retinal detachment with exophthalmos. Ultrasonographically, a mass was detected with intra- and extraocular extension. The orbit was exenterated and the dog recovered uneventfully. Histopathologic diagnosis was a primary choroidal melanoma with orbital extension, however, the behavioral and cytologic features were benign. Routine examinations postsurgically were nonremarkable. Twenty-one months after surgery the dog was euthanized for respiratory collapse with radiographic signs of metastasis. Necropsy revealed black lesions in the lung and liver. Histopathologic diagnosis was metastatic melanoma with morphology and behavior identical to the primary choroidal melanoma. This is the first definitive case of a canine choroidal melanoma with metastasis.

Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors

PubMed Central

Mudan, Satwinder; Kumar, Jayant; Mafalda, Neves C.; Kusano, Tomokazu; Reccia, Isabella; Zanallato, Artur; Dalgleish, Angus; Habib, Nagy

2017-01-01

Abstract Rationale: An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic-preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. Patient concerns: We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. Diagnosis: Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. Interventions: A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. Outcomes: The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins. At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. Lessons: Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the physiological T cell milieu, but the immunomodulation properties of RF can produce potentially additional therapeutic benefit. PMID:29245341

Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors.

PubMed

Mudan, Satvinder; Kumar, Jayant; Mafalda, Neves C; Kusano, Tomokazu; Reccia, Isabella; Zanallato, Artur; Dalgleish, Angus; Habib, Nagy

2017-12-01

An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic-preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins.At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the physiological T cell milieu, but the immunomodulation properties of RF can produce potentially additional therapeutic benefit.

Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma

PubMed Central

Puig, Susana; Potrony, Miriam; Cuellar, Francisco; Puig-Butille, Joan Anton; Carrera, Cristina; Aguilera, Paula; Nagore, Eduardo; Garcia-Casado, Zaida; Requena, Celia; Kumar, Rajiv; Landman, Gilles; Costa Soares de Sá, Bianca; Gargantini Rezze, Gisele; Facure, Luciana; de Avila, Alexandre Leon Ribeiro; Achatz, Maria Isabel; Carraro, Dirce Maria; Duprat Neto, João Pedreira; Grazziotin, Thais C.; Bonamigo, Renan R.; Rey, Maria Carolina W.; Balestrini, Claudia; Morales, Enrique; Molgo, Montserrat; Bakos, Renato Marchiori; Ashton-Prolla, Patricia; Giugliani, Roberto; Larre Borges, Alejandra; Barquet, Virginia; Pérez, Javiera; Martínez, Miguel; Cabo, Horacio; Cohen Sabban, Emilia; Latorre, Clara; Carlos-Ortega, Blanca; Salas-Alanis, Julio C; Gonzalez, Roger; Olazaran, Zulema; Malvehy, Josep; Badenas, Celia

2016-01-01

Purpose: CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America. Genet Med 18 7, 727–736. Methods: CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained. Genet Med 18 7, 727–736. Results: Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients. Genet Med 18 7, 727–736. Conclusion: The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first- or second-degree relatives. Genet Med 18 7, 727–736. PMID:26681309

Primary Vaginal Melanoma, A Rare and Aggressive Entity. A Case Report and Review of the Literature

PubMed Central

KALAMPOKAS, EMMANOUIL; KALAMPOKAS, THEODOROS; DAMASKOS, CHRISTOS

2017-01-01

Malignant melanoma of the vagina is a rare, aggressive malignancy of poor prognosis. It principally affects post-menopausal women, with a mean age of 57 years, and the factors that contribute to its appearance are not well known. The first case of primary malignant vaginal melanoma was reported in 1887 and modern literature has noted about 500 cases, globally. Vaginal melanomas constitute 0.3% of all malignant melanomas and fewer than 3% of all vaginal carcinomas. To date there is no clear consensus regarding treatment. An early, accurate diagnosis and prompt investigation is essential in reaching appropriate treatment decisions. We present a clinical case of primary vaginal melanoma and review the literature briefly, presenting the current treatment plans and updates of this rare gynecological malignancy. Considerations, epidemiology, associated risk factors, response to therapy and expected outcome are also discussed. Conclusion: Primary malignant vaginal melanoma is a rare but aggressive melanoma that affects women in their 6th and 7th decade of life. The tumor appears as a dark node or spindle but can also be amelanotic. The size of the tumor is indicative of the prognostic factors. Surgery seems to be the only efficient treatment. Postoperative adjuvant therapy might help in preventing recurrence of the tumor. The survival rate is largely dependent on nodal and distant metastasis of the disease after initial tumor resection. There is a dire need to form a proper therapeutic regime to control this disease. PMID:28064232

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence.

PubMed

O'Regan, Kevin; Breen, Micheál; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J; Hodi, F Stephen; Van den Abbeele, Annick D

2013-12-30

Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38-76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin.

MicroRNA-9 up-regulates E-cadherin through inhibition of NF-κB1-Snail1 pathway in melanoma.

PubMed

Liu, Shujing; Kumar, Suresh M; Lu, Hezhe; Liu, Aihua; Yang, Ruifeng; Pushparajan, Anitha; Guo, Wei; Xu, Xiaowei

2012-01-01

MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate gene expression. Hsa-miR-9 has been shown to have opposite functions in different tumour types; however, the underlying mechanism is unclear. Here we show that hsa-miR-9 is down-regulated in metastatic melanomas compared to primary melanomas. Overexpression of miR-9 in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity with decreased F-actin polymerization and down-regulation of multiple GTPases involved in cytoskeleton remodelling. miR-9 overexpression induced significant down-regulation of Snail1 with a concomitant increase in E-cadherin expression. In contrast, knockdown of miR-9 increased Snail1 expression as well as melanoma cell proliferation and migration capacity. Mechanistically, miR-9 expression down-regulated NF-κB1 in melanoma and the effect was abolished by mutations in the putative miR-9 binding sites within the 3'-untranslated region (UTR) of NF-κB1. Anti-miR-9 miRNA inhibitor also increased the expression of NF-κB1. The effects of miR-9 on Snail1 expression and melanoma cell proliferation and migration were rescued by overexpression of NF-κB1 in these cells. Furthermore, miR-9 overexpression resulted in significantly decreased melanoma growth and metastasis in vivo. In summary, miR-9 inhibits melanoma proliferation and metastasis through down-regulation of the NF-κB1-Snail1 pathway. This study finds a new mechanism that miR-9 utilizes to decrease E-cadherin expression and inhibit melanoma progression. The results suggest that function of microRNAs is context and tumour type-specific. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Treatment of uveal melanoma: where are we now?

PubMed Central

Yang, Jessica; Manson, Daniel K.; Marr, Brian P.; Carvajal, Richard D.

2018-01-01

Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease. PMID:29497459

Validation of the VE1 Immunostain for the BRAF V600E Mutation in Melanoma

PubMed Central

Pearlstein, Michelle V.; Zedek, Daniel C.; Ollila, David W.; Treece, Amanda; Gulley, Margaret L.; Groben, Pamela A.; Thomas, Nancy E.

2014-01-01

BACKGROUND BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. We assessed the validity of VE1, a monoclonal antibody against the BRAF V600E mutant protein, in the detection of mutant BRAF V600E melanomas as classified by DNA pyrosequencing. METHODS The cases were 76 metastatic melanoma patients with only one known primary melanoma who had had BRAF codon 600 pyrosequencing of either their primary (n=19), metastatic (n=57) melanoma, or both (n=17). All melanomas (n=93) were immunostained with the BRAF VE1 antibody using a red detection system. The staining intensity of these specimens was scored from 0 – 3+ by a dermatopathologist. Scores of 0 and 1+ were considered as negative staining while scores of 2+ and 3+ were considered positive. RESULTS The VE1 antibody demonstrated a sensitivity of 85% and a specificity of 100% as compared to DNA pyrosequencing results. There was 100% concordance between VE1 immunostaining of primary and metastatic melanomas from the same patient. V600K, V600Q, and V600R BRAF melanomas did not positively stain with VE1. CONCLUSIONS This hospital-based study finds high sensitivity and specificity for the BRAF VE1 immunostain in comparison to pyrosequencing in detection of BRAF V600E in melanomas. PMID:24917033

Ex-Vivo Expanded Allogeneic NK Cells For The Treatment Of Pediatric Solid Tumors

ClinicalTrials.gov

2018-05-11

Malignant Neoplasms of Bone and Articular Cartilage; Malignant Neoplasms of Female Genital Organs; Malignant Neoplasms of Independent (Primary) Multiple Sites; Malignant Neoplasms of Lip Oral Cavity and Pharynx; Malignant Neoplasms of Male Genital Organs; Malignant Neoplasms of Mesothelial and Soft Tissue; Malignant Neoplasms of Thyroid and Other Endocrine Glands; Malignant Neoplasms of Urinary Tract; Melanoma and Other Malignant Neoplasms of Skin

Transcriptional mechanisms of resistance to anti-PD-1 therapy

PubMed Central

Ascierto, Maria L.; Makohon-Moore, Alvin; Lipson, Evan J.; Taube, Janis M.; McMiller, Tracee L.; Berger, Alan E.; Fan, Jinshui; Kaunitz, Genevieve J.; Cottrell, Tricia R.; Kohutek, Zachary A.; Favorov, Alexander; Makarov, Vladimir; Riaz, Nadeem; Chan, Timothy A.; Cope, Leslie; Hruban, Ralph H.; Pardoll, Drew M.; Taylor, Barry S.; Solit, David B.; Iacobuzio-Donahue, Christine A; Topalian, Suzanne L.

2017-01-01

Purpose To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response. Materials and Methods Twenty-six melanoma specimens (four pre-mortem, 22 post-mortem) were subjected to whole-exome sequencing. Candidate immunologic markers and gene expression were assessed in ten cutaneous metastases showing response or progression during therapy. Results The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with over-expression of genes associated with extracellular matrix and neutrophil function. Conclusions Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes. PMID:28193624

Impact of sentinel lymphadenectomy on survival in a murine model of melanoma.

PubMed

Rebhun, Robert B; Lazar, Alexander J F; Fidler, Isaiah J; Gershenwald, Jeffrey E

2008-01-01

Lymphatic mapping and sentinel lymph node biopsy-also termed sentinel lymphadenectomy (SL)-has become a standard of care for patients with primary invasive cutaneous melanoma. This technique has been shown to provide accurate information about the disease status of the regional lymph node basins at risk for metastasis, provide prognostic information, and provide durable regional lymph node control. The potential survival benefit afforded to patients undergoing SL is controversial. Central to this controversy is whether metastasis to regional lymph nodes occurs independent of or prior to widespread hematogenous dissemination. A related area of uncertainty is whether tumor cells residing within regional lymph nodes have increased metastatic potential. We have used a murine model of primary invasive cutaneous melanoma based on injection of B16-BL6 melanoma cells into the pinna to address two questions: (1) does SL plus wide excision of the primary tumor result in a survival advantage over wide excision alone; and (2) do melanoma cells growing within lymph nodes produce a higher incidence of hematogenous metastases than do cells growing at the primary tumor site? We found that SL significantly improved the survival of mice with small primary tumors. We found no difference in the incidence of lung metastases produced by B16-BL6 melanoma cells growing exclusively within regional lymph nodes and cells growing within the pinna.

Clinicopathological findings of primary esophageal malignant melanoma: report of six cases and review of literature.

PubMed

Zheng, Jinfeng; Mo, Haiying; Ma, Shufang; Wang, Zhenzheng

2014-01-01

We studied images and histopathological features of primary esophageal malignant melanoma to explore the clinical pathological features, diagnosis, differential diagnoses, and treatment. Immunolabelling was conducted on six cases of esophageal malignant melanoma using histological and immunohistochemical techniques. Combined with the related literature, the clinical manifestations, imaging, histopathological and immunohistochemical features, treatment, and prognosis of primary esophageal malignant melanoma were observed and analyzed. The six patients with primary esophageal malignant melanoma were all male with an average age of 63.4 years. Poor food intake was observed in all patients, and the symptoms showed progressive aggravation. Endoscopic feed tube revealed dark brown and black nodular and polypoid lesions, 1/4-1/2 loop cavity. Tumor histopathology revealed the following characteristics: tumor cells arranged in nests, sheets and cords, round or polygonal, abundant and red-stained cytoplasm, melanin granules in the cytoplasm, heterogeneous nucleus sizes, centered or deviated nuclei, clearly identifiable nucleoli, and apparent pathological mitosis. The immune phenotype was as follows: tumor cells had diffuse expression of HMB45, Melan A, and S100. The cells were CK negative, and the Ki67-positive cell number was 40%-45%. Primary esophageal malignant melanoma is rare with high malignancy and poor prognosis. Immunohistochemical staining is helpful for diagnosing this tumor. The differential diagnosis includes low differentiated carcinoma, primitive neuroectodermal tumor, esophageal sarcomatoid carcinoma, esophageal lymphoma, and other tumors.

Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor

PubMed Central

Pandurengan, R. K.; Dumont, A. G.; Araujo, D. M.; Ludwig, J. A.; Ravi, V.; Patel, S.; Garber, J.; Benjamin, R. S.; Strom, S. S.; Trent, J. C.

2010-01-01

Background: We sought to investigate the characteristics and survival rate of patients with gastrointestinal stromal tumor (GIST) associated with other primary malignancies. Patients and methods: A total of 783 patients with GIST were identified from 1995 to 2007. Additional primaries included tumors not considered metastasis, invasion, or recurrence of GIST, nor non-melanoma skin cancer. Data on gender, age at diagnosis, follow-up time after diagnosis, and death were collected. Results: Of the 783 patients with GIST, 153(20%) were identified with at least one additional primary. Patients with additional primaries were more often men (M : F 1.5 versus 1.3) and older (66 versus 53 years). More patients had another cancer diagnosed before (134) than after (52) GIST. Primaries observed before GIST were cancers of the prostate (25), breast (12), esophagus (9), and kidney (7) and melanoma (6). Lung (5) and kidney (5) primaries were the most frequent after GIST. The 5-year survival was 68% for patients with primaries before GIST, 61% for patients with primaries after GIST, 58% for patients with GIST only, and 49% for patients with two or more primaries in addition to GIST (P = 0.002). Conclusions: Approximately 20% of patients with GIST develop other cancers. Inferior median 5-year survival was observed in patients with GIST with two or more other cancers. The etiology and clinical implications of other malignancies in patients with GIST should be investigated. PMID:20348145

Primary Vaginal Melanoma, A Rare and Aggressive Entity. A Case Report and Review of the Literature.

PubMed

Kalampokas, Emmanouil; Kalampokas, Theodoros; Damaskos, Christos

2017-01-02

Malignant melanoma of the vagina is a rare, aggressive malignancy of poor prognosis. It principally affects post-menopausal women, with a mean age of 57 years, and the factors that contribute to its appearance are not well known. The first case of primary malignant vaginal melanoma was reported in 1887 and modern literature has noted about 500 cases, globally. Vaginal melanomas constitute 0.3% of all malignant melanomas and fewer than 3% of all vaginal carcinomas. To date there is no clear consensus regarding treatment. An early, accurate diagnosis and prompt investigation is essential in reaching appropriate treatment decisions. We present a clinical case of primary vaginal melanoma and review the literature briefly, presenting the current treatment plans and updates of this rare gynecological malignancy. Considerations, epidemiology, associated risk factors, response to therapy and expected outcome are also discussed. Primary malignant vaginal melanoma is a rare but aggressive melanoma that affects women in their 6th and 7th decade of life. The tumor appears as a dark node or spindle but can also be amelanotic. The size of the tumor is indicative of the prognostic factors. Surgery seems to be the only efficient treatment. Postoperative adjuvant therapy might help in preventing recurrence of the tumor. The survival rate is largely dependent on nodal and distant metastasis of the disease after initial tumor resection. There is a dire need to form a proper therapeutic regime to control this disease. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Prognostic and predictive values of oncogenic BRAF, NRAS, c-KIT and MITF in cutaneous and mucous melanoma.

PubMed

Pracht, M; Mogha, A; Lespagnol, A; Fautrel, A; Mouchet, N; Le Gall, F; Paumier, V; Lefeuvre-Plesse, C; Rioux-Leclerc, N; Mosser, J; Oger, E; Adamski, H; Galibert, M-D; Lesimple, T

2015-08-01

Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAF- or NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy. © 2015 European Academy of Dermatology and Venereology.

Immunohistochemical detection of XIAP in melanoma.

PubMed

Emanuel, Patrick O M; Phelps, Robert G; Mudgil, Adarsh; Shafir, Michail; Burstein, David E

2008-03-01

The X-linked inhibitor of apoptosis protein (XIAP) is the most potent of the inhibitor of apoptosis family of eight proteins. High levels of XIAP have been found in melanoma cell lines and are believed to play a role in therapeutic resistance in a number of malignancies. XIAP expression has not been investigated in clinically obtained melanoma tissue samples, nor have studies attempted to correlate XIAP expression with prognostic variables or clinical aggressiveness of melanomas. Sixty-seven patients with primary cutaneous malignant melanoma for whom clinical follow up was available were identified from the records of the Mount Sinai Hospital, comprising 37 thin melanomas (Breslow thickness < 1.0 mm) and 30 thick melanomas (Breslow thickness > 1.0 mm). Archival paraffin sections from primary lesions and corresponding metastases were stained with monoclonal anti-XIAP antibody using routine immunohistochemical methods. Six benign intradermal nevi and four in situ melanomas were XIAP negative. 9 of 37 thin melanomas (24%) were XIAP positive. In contrast, 21 of 30 (73%) thick melanomas were XIAP positive, including 3 of 4 ulcerated melanomas that were strongly positive. Over a follow-up period ranging from 6 months to 6 years, 23 melanomas metastasized (22 thick, 1 thin). In total, XIAP was immunohistochemically detected in 17 of 23 metastases (74%). Metastasis occurred in 1 of 9 XIAP-positive thin melanomas; 0 of 28 XIAP-negative thin melanomas; 17 of 22 XIAP-positive thick melanomas, and 5 of 8 XIAP-negative thick melanomas (63%). XIAP is immunohistochemically detectable nearly three times more frequently in thick compared with thin melanomas. These results suggest that XIAP elevation may be correlated with increasing melanoma thickness and tumor progression.

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence

PubMed Central

O’Regan, Kevin; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J.; Stephen Hodi, F.; Van den Abbeele, Annick D.

2013-01-01

Abstract Purpose: Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. Materials and methods: This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38–76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. Results: At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Conclusion: Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin. PMID:24434078

Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dracopoli, N.C.; Harnett, P.; Bale, S.J.

The gene for familial malignant melanoma and its precursor lesion, the dysplastic nevus, has been assigned to a region of the distal short arm of chromosome 1, which is frequently involved in karyotypic abnormalities in melanoma cells. The authors have examined loci on chromosome 1p for loss-of-constitutional heterozygosity in 35 melanomas and 21 melanoma cell lines to analyze the role of these abnormalities in melanocyte transformation. Loss-of-heterozygosity at loci on chromosome 1p was identified in 15/35 (43%) melanomas and 11/21 (52%) melanoma cell lines. Analysis of multiple metastases derived from the same patient and of melanoma and lymphoblastoid samples frommore » a family with hereditary melanoma showed that the loss-of-heterozygosity at loci on distal 1p is a late event in tumor progression, rather than the second mutation that would occur if melanoma were due to a cellular recessive mechanism. Comparisons with neuroblastoma and multiple endocrine neoplasia (MEN2) suggest that the frequent 1p loss-of-heterozygosity in these malignancies is a common late event of neuroectodermal tumor progression.« less

In vivo immunologic selection of class I major histocompatibility complex gene deletion variants from the B16-BL6 melanoma.

PubMed

Talmadge, J E; Talmadge, C B; Zbar, B; McEwen, R; Meeker, A K; Tribble, H

1987-06-01

The mechanism by which tumor allografts escape host immunologic attack was investigated. B16-BL6 cells (the bladder 6 subline of the B16 melanoma) (H-2b) were transfected with a gene (Dd) encoding an allogeneic class I major histocompatibility complex antigen. Clones that expressed Dd antigen were injected into the footpads of nonimmune syngeneic mice, syngeneic immune mice, and nude mice. Under conditions of immunologic selection a clone that contained multiple copies of the transfected gene formed variants that lacked the transfected gene. Primary tumors and pulmonary metastases of immunized mice and pulmonary metastases of nonimmunized mice had lost the Dd gene and, in most cases, all of the associated plasmid. In contrast, in immunodeficient nude mice, primary tumors and pulmonary metastases retained the Dd gene and the associated plasmid. Deletion of genes encoding cell surface antigens may be one of the mechanisms by which allogeneic tumors escape immunologic attack.

Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients.

PubMed

Sturm, Richard A; Fox, Carly; McClenahan, Phil; Jagirdar, Kasturee; Ibarrola-Villava, Maider; Banan, Parastoo; Abbott, Nicola C; Ribas, Gloria; Gabrielli, Brian; Duffy, David L; Peter Soyer, H

2014-01-01

A germline polymorphism of the microphthalmia transcription factor (MITF) gene encoding a SUMOylation-deficient E318K-mutated protein has recently been described as a medium-penetrance melanoma gene. In a clinical assessment of nevi from 301 volunteers taken from Queensland, we identified six individuals as MITF E318K mutation carriers. The phenotype for 5 of these individuals showed a commonality of fair skin, body freckling that varied over a wide range, and total nevus count between 46 and 430; in addition, all were multiple primary melanoma patients. The predominant dermoscopic signature pattern of nevi was reticular, and the frequency of globular nevi in carriers varied, which does not suggest that the MITF E318K mutation acts to force the continuous growth of nevi. Excised melanocytic lesions were available for four MITF E318K carrier patients and were compared with a matched range of wild-type (WT) melanocytic lesions. The MITF staining pattern showed a predominant nuclear signal in all sections, with no significant difference in the nuclear/cytoplasmic ratio between mutation-positive or -negative samples. A high incidence of amelanotic melanomas was found within the group, with three of the five melanomas from one patient suggesting a genetic interaction between the MITF E318K allele and an MC1R homozygous red hair color (RHC) variant genotype.

[Primary malignant melanoma of the central nervous system: A diagnostic challenge].

PubMed

Quillo-Olvera, Javier; Uribe-Olalde, Juan Salvador; Alcántara-Gómez, Leopoldo Alberto; Rejón-Pérez, Jorge Dax; Palomera-Gómez, Héctor Guillermo

2015-01-01

The rare incidence of primary malignant melanoma of the central nervous system and its ability to mimic other melanocytic tumors on images makes it a diagnostic challenge for the neurosurgeon. A 51-year-old patient, with a tumor located in the right forniceal callosum area. Total surgical excision was performed. Histopathological result was consistent with the diagnosis of primary malignant melanoma of the central nervous system, after ruling out extra cranial and extra spinal melanocytic lesions. The primary malignant melanoma of the central nervous system is extremely rare. There are features in magnetic resonance imaging that increase the diagnostic suspicion; nevertheless there are other tumors with more prevalence that share some of these features through image. Since there is not an established therapeutic standard its prognosis is discouraging. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Comparing initial diagnostic excision biopsy of cutaneous malignant melanoma in primary versus secondary care: A study of Irish National data.

PubMed

Doherty, Sarah M; Jackman, Louise M; Kirwan, John F; Dunne, Deirdre; O'Connor, Kieran G; Rouse, John M

2016-12-01

The incidence of melanoma is rising worldwide. Current Irish guidelines from the National Cancer Control Programme state suspicious pigmented lesions should not be removed in primary care. There are conflicting guidelines and research advising who should remove possible melanomas. To determine whether initial diagnostic excision biopsy of cutaneous malignant melanoma in primary versus secondary care leads to poorer survival. Analysis of data comprising 7116 cases of cutaneous malignant melanoma from the National Cancer Registry Ireland between January 2002 and December 2011. Single predictor variables were examined by the chi-square or Mann-Whitney U test. The effects of single predictor variables on survival were examined by Cox proportionate hazards modelling and a multivariate Cox model of survival based on excision in a non-hospital setting versus hospital setting was derived with adjusted and unadjusted hazard ratios. Over a 10-year period 8.5% of melanomas in Ireland were removed in a non-hospital setting. When comparing melanoma death between the hospital and non-hospital groups, the adjusted hazard ratio was 1.56 (95%CI: 1.08-2.26); (P = .02), indicating a non-inferior outcome for the melanoma cases initially treated in the non-hospital group, after adjustment for significant covariates. This study suggests that initial excision biopsy carried out in general practice does not lead to a poorer outcome. [Box: see text].

Intercellular crosstalk in human malignant melanoma.

PubMed

Dvořánková, Barbora; Szabo, Pavol; Kodet, Ondřej; Strnad, Hynek; Kolář, Michal; Lacina, Lukáš; Krejčí, Eliška; Naňka, Ondřej; Šedo, Aleksi; Smetana, Karel

2017-05-01

Incidence of malignant melanoma is increasing globally. While the initial stages of tumors can be easily treated by a simple surgery, the therapy of advanced stages is rather limited. Melanoma cells spread rapidly through the body of a patient to form multiple metastases. Consequently, the survival rate is poor. Therefore, emphasis in melanoma research is given on early diagnosis and development of novel and more potent therapeutic options. The malignant melanoma is arising from melanocytes, cells protecting mitotically active keratinocytes against damage caused by UV light irradiation. The melanocytes originate in the neural crest and consequently migrate to the epidermis. The relationship between the melanoma cells, the melanocytes, and neural crest stem cells manifests when the melanoma cells are implanted to an early embryo: they use similar migratory routes as the normal neural crest cells. Moreover, malignant potential of these melanoma cells is overdriven in this experimental model, probably due to microenvironmental reprogramming. This observation demonstrates the crucial role of the microenvironment in melanoma biology. Indeed, malignant tumors in general represent complex ecosystems, where multiple cell types influence the growth of genetically mutated cancer cells. This concept is directly applicable to the malignant melanoma. Our review article focuses on possible strategies to modify the intercellular crosstalk in melanoma that can be employed for therapeutic purposes.

Genetics of metastasis: melanoma and other cancers.

PubMed

Turner, Noel; Ware, Olivia; Bosenberg, Marcus

2018-05-02

Melanoma is a malignant neoplasm of melanocytes that accounts for the majority of skin cancer deaths despite comprising less than 5% of all cutaneous malignancies. Its incidence has increased faster than that of any other cancer over the past half-century and the annual costs of treatment in the United States alone have risen rapidly. Although the majority of primary melanomas are cured with local excision, metastatic melanoma historically carries a grim prognosis, with a median survival of 9 months and a long-term survival rate of 10%. Given the urgent need to develop treatment strategies for metastatic melanoma and the explosion of genetic technologies over the past 20 years, there has been extensive research into the genetic alterations that cause melanocytes to become malignant. More recently, efforts have focused on the genetic changes that drive melanoma metastasis. This review aims to summarize the current knowledge of the genetics of primary cutaneous and ocular melanoma, the genetic changes associated with metastasis in melanoma and other cancer types, and non-genetic factors that may contribute to metastasis.

Malignancy without immortality? Cellular immortalization as a possible late event in melanoma progression

PubMed Central

Soo, Julia K; MacKenzie Ross, Alastair D; Kallenberg, David M; Milagre, Carla; Heung Chong, W; Chow, Jade; Hill, Lucy; Hoare, Stacey; Collinson, Rebecca S; Hossain, Mehnaz; Keith, W Nicol; Marais, Richard; Bennett, Dorothy C

2011-01-01

Cell senescence is a permanent growth arrest following extended proliferation. Cultured cancer cells including metastatic melanoma cells often appear immortal (proliferate indefinitely), while uncultured benign nevi (moles) show senescence markers. Here, with new explantation methods, we investigated which classes of primary pigmented lesions are typically immortal. Nevi yielded a few proliferating cells, consistent with most nevus cells being senescent. No nevus culture (0/28) appeared immortal. Some thin and thick melanoma cultures proved immortal under these conditions, but surprisingly few (4/37). All arrested cultures displayed three senescence markers in some cells: β-galactosidase, nuclear p16, and heterochromatic foci/aggregates. However, melanoma cultures also showed features of telomeric crisis (arrest because of ultrashort telomeres). Moreover, crisis markers including anaphase bridges were frequent in uncultured vertical growth-phase (VGP) melanomas. Conversely, all immortal melanoma cultures expressed telomerase reverse transcriptase and telomerase, showing aneuploidy. The findings suggest that primary melanomas are typically precrisis, with immortalization/telomere maintenance as a late event. PMID:21418545

The Evolving Role of Radiation Therapy in the Management of Malignant Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khan, Niloufer; Khan, Mohammad K., E-mail: drkhurram2000@gmail.com; Almasan, Alex

2011-07-01

The incidence of melanoma is rising in the United States, leading to an estimated 68,720 new diagnoses and 8,650 deaths annually. The natural history involves metastases to lymph nodes, lung, liver, brain, and often to other sites. Primary treatment for melanoma is surgical excision of the primary tumor and affected lymph nodes. The role of adjuvant or definitive radiation therapy in the treatment of melanoma remains controversial, because melanoma has traditionally been viewed as a prototypical radioresistant cancer. However, recent studies suggest that under certain clinical circumstances, there may be a significant role for radiation therapy in melanoma treatment. Stereotacticmore » radiosurgery for brain metastases has shown effective local control. High dose per fraction radiation therapy has been associated with a lower rate of locoregional recurrence of sinonasal melanoma. Plaque brachytherapy has evolved into a promising alternative to enucleation at the expense of moderate reduction in visual acuity. Adjuvant radiation therapy following lymphadenectomy in node-positive melanoma prevents local and regional recurrence. The newer clinical data along with emerging radiobiological data indicate that radiotherapy is likely to play a greater role in melanoma management and should be considered as a treatment option.« less

The unpredictability of lymphatic drainage from the ear in melanoma patients, and its implications for management.

PubMed

Peach, Howard S; van der Ploeg, Augustinus P T; Haydu, Lauren E; Stretch, Jonathan R; Shannon, Kerwin F; Uren, Roger F; Thompson, John F

2013-05-01

The ear is known to have variable lymphatic drainage. The purpose of this study was to define better the lymphatic drainage patterns of the ear by correlating the location of primary tumors, classified according to the embryologically derived anatomical subunits of the ear, with their mapped sentinel nodes (SNs) identified by lymphoscintigraphy (LS). Lymphatic drainage data for patients with a primary melanoma of the ear were reviewed and correlated with the precise primary melanoma site. Between 1993 and 2010, LS was performed in 111 patients with a primary melanoma on the ear, identifying 281 SNs in 195 lymph node (LN) fields. The mean numbers of SNs and LN fields identified by LS per patient were 2.65 and 1.76. SN biopsy was performed in 71 patients (64 %). The mean number of SNs removed was 2.36. The 111 ear melanomas were mostly located on the helical rim (55 %), followed by the lobule (24.3 %). The five different primary ear sites drained mainly to SNs in level CII, level CV and the preauricular region. Drainage was most often to level CII (36.4 %). Drainage to the contralateral neck was not observed. Lymphatic drainage of the ear has no predictable pattern and can be to SNs anywhere in the ipsilateral neck. Most commonly drainage is to cervical level II and the preauricular and postauricular LN fields. LS defines the lymphatic drainage pattern in individual melanoma patients and is essential for accurate SN identification and reliable SN biopsy.

Progression of cutaneous melanoma: implications for treatment

PubMed Central

Leong, Stanley P. L.; Mihm, Martin C.; Murphy, George F.; Hoon, Dave S. B.; Kashani-Sabet, Mohammed; Agarwala, Sanjiv S.; Zager, Jonathan S.; Hauschild, Axel; Sondak, Vernon K.; Guild, Valerie; Kirkwood, John M.

2015-01-01

The survival rates of melanoma, like any type of cancer, become worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in-transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment before its spread is the most effective treatment. Recently, new approaches have revolutionized the diagnosis and treatment of melanoma. Genomic profiling and sequencing will form the basis for molecular taxonomy for more accurate subgrouping of melanoma patients in the future. New insights of molecular mechanisms of metastasis are summarized in this review article. Sentinel lymph node biopsy has become a standard of care for staging primary melanoma without the need for a more morbid complete regional lymph node dissection. With recent developments in molecular biology and genomics, novel molecular targeted therapy is being developed through clinical trials. PMID:22892755

miR-137 inhibits the invasion of melanoma cells through downregulation of multiple oncogenic target genes.

PubMed

Luo, Chonglin; Tetteh, Paul W; Merz, Patrick R; Dickes, Elke; Abukiwan, Alia; Hotz-Wagenblatt, Agnes; Holland-Cunz, Stefan; Sinnberg, Tobias; Schittek, Birgit; Schadendorf, Dirk; Diederichs, Sven; Eichmüller, Stefan B

2013-03-01

MicroRNAs are small noncoding RNAs that regulate gene expression and have important roles in various types of cancer. Previously, miR-137 was reported to act as a tumor suppressor in different cancers, including malignant melanoma. In this study, we show that low miR-137 expression is correlated with poor survival in stage IV melanoma patients. We identified and validated two genes (c-Met and YB1) as direct targets of miR-137 and confirmed two previously known targets, namely enhancer of zeste homolog 2 (EZH2) and microphthalmia-associated transcription factor (MITF). Functional studies showed that miR-137 suppressed melanoma cell invasion through the downregulation of multiple target genes. The decreased invasion caused by miR-137 overexpression could be phenocopied by small interfering RNA knockdown of EZH2, c-Met, or Y box-binding protein 1 (YB1). Furthermore, miR-137 inhibited melanoma cell migration and proliferation. Finally, miR-137 induced apoptosis in melanoma cell lines and decreased BCL2 levels. In summary, our study confirms that miR-137 acts as a tumor suppressor in malignant melanoma and reveals that miR-137 regulates multiple targets including c-Met, YB1, EZH2, and MITF.

Clinicopathologic features and surgical management of primary umbilical melanoma: a case series.

PubMed

Di Monta, Gianluca; Caracò, Corrado; Marone, Ugo; Grimaldi, Antonio Maria; Anniciello, Anna Maria; Di Marzo, Massimiliano; Simeone, Ester; Mori, Stefano

2015-04-15

Primary umbilical melanoma is an uncommon tumor that is poorly described in the medical literature. The umbilical region is a particular anatomic site owing to the presence of embryonal remnants, which can be a potential metastatic pathway, as well as the braided lymphatic network drainage. Hence, primary malignant neoplasms affecting the umbilicus require a different and more radical surgical approach compared with other melanomas. In this report, we describe a series of three patients of Caucasian ethnicity who presented with primary umbilical melanoma at the National Cancer Institute of Naples, Italy. All patients underwent wide excision of the tumor including the underlying peritoneum. No surgical complications, either immediate or delayed, were observed in any of the patients. Sentinel lymph node biopsy was negative in two cases. Two of the patients developed metastatic disease and died after systemic medical therapy. The other patient is currently in follow-up, and remains disease-free after 21 months. The umbilicus has vascular and embryological connections with the underlying peritoneum, so that early visceral involvement is more likely to occur with primary umbilical melanomas. As such, tumor resection including the underlying peritoneum is required to avoid local relapse, whilst sentinel lymph node biopsy appears to be of poor diagnostic value.

Second cancers discovered by (18)FDG PET/CT imaging for choroidal melanoma.

PubMed

Chin, Kimberly; Finger, Paul T; Kurli, Madhavi; Tena, Lawrence B; Reddy, Shantan

2007-08-01

Positron-emission tomography/computed tomography (PET/CT) is a unique imaging tool that aids in the detection of cancerous lesions. It is currently and widely used for cancer staging (both initial and follow-up). Here we report our findings of second primary cancers incidentally discovered during PET/CT staging of patients with choroidal melanomas. We performed a retrospective case review of 139 patients with uveal melanoma who were subsequently evaluated by whole-body [18-fluorine-labeled] 2-deoxy-2-fluoro-D-glucose ((18)FDG) PET/CT imaging. In this series, 93 were scanned before treatment and 46 during the course of their follow-up systemic examinations. Their mean follow-up was 50.9 months. Six patients (4.3%) had second primary cancers revealed by PET/CT imaging. Three patients (50%) were synchronous (found at initial staging), and the remaining 3 patients (50%) were metachronous (found at follow-up staging). Second primary cancers were found in the lung, breast, uterus, colon, and thyroid. Although whole-body PET/CT scans were ordered as part of the staging process of patients with diagnosed choroidal melanoma, both synchronous and metachronous second primary cancers were found. PET/CT has become an indispensable tool for staging, diagnosis, and treatment planning for choroidal melanoma. The possibility of detecting second primary cancers should also be considered valuable.

Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades

PubMed Central

KIRCHOFF, DANIEL D.; DEUTSCH, GARY B.; FOSHAG, LELAND J.; LEE, JI HEY; SIM, MYUNG-SHIN; FARIES, MARK B.

2016-01-01

Mucosal melanoma represents a distinct minority of disease sites and portends a worse outcome. The ideal treatment and role of adjuvant therapy remains unknown at this time. We hypothesized that a combination of neoadjuvant and adjuvant therapies would improve survival in these aggressive melanomas. Our large, prospectively maintained melanoma database was queried for all patients diagnosed with mucosal melanoma. Over the past five decades, 227 patients were treated for mucosal melanoma. There were 82 patients with anorectal, 75 with sinonasal, and 70 with urogenital melanoma. Five-year overall survival and melanoma-specific survival for the entire cohort were 32.8 and 37.5 per cent, respectively, with median overall survival of 38.7 months. One hundred forty-two patients (63.8%) underwent adjuvant therapy and 15 were treated neoadjuvantly (6.6%). There was no survival difference by therapy type or timing, disease site, or decade of diagnosis. There was improved survival in patients undergoing multiple surgeries (Hazard Ratio [HR] 0.55, P = 0.0005). Patients receiving neoadjuvant therapy had significantly worse survival outcomes (HR 2.49, P = 0.013). Over the past five decades, improvements have not been seen in outcomes for mucosal melanoma. Although multiple surgical interventions portend a better outcome in patients with mucosal melanoma, adjuvant treatment decisions must be individualized. PMID:26802836

Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades.

PubMed

Kirchoff, Daniel D; Deutsch, Gary B; Foshag, Leland J; Lee, Ji Hey; Sim, Myung-Shin; Faries, Mark B

2016-01-01

Mucosal melanoma represents a distinct minority of disease sites and portends a worse outcome. The ideal treatment and role of adjuvant therapy remains unknown at this time. We hypothesized that a combination of neoadjuvant and adjuvant therapies would improve survival in these aggressive melanomas. Our large, prospectively maintained melanoma database was queried for all patients diagnosed with mucosal melanoma. Over the past five decades, 227 patients were treated for mucosal melanoma. There were 82 patients with anorectal, 75 with sinonasal, and 70 with urogenital melanoma. Five-year overall survival and melanoma-specific survival for the entire cohort were 32.8 and 37.5 per cent, respectively, with median overall survival of 38.7 months. One hundred forty-two patients (63.8%) underwent adjuvant therapy and 15 were treated neoadjuvantly (6.6%). There was no survival difference by therapy type or timing, disease site, or decade of diagnosis. There was improved survival in patients undergoing multiple surgeries (Hazard Ratio [HR] 0.55, P = 0.0005). Patients receiving neoadjuvant therapy had significantly worse survival outcomes (HR 2.49, P = 0.013). Over the past five decades, improvements have not been seen in outcomes for mucosal melanoma. Although multiple surgical interventions portend a better outcome in patients with mucosal melanoma, adjuvant treatment decisions must be individualized.

The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions

PubMed Central

Pilloni, L.; Bianco, P.; Difelice, E.; Cabras, S.; Castellanos, M.E.; Atzori, L.; Ferreli, C.; Mulas, P.; Nemolato, S.; Faa, G.

2011-01-01

C-Kit (CD117), the receptor for the stem cell factor, a growth factor for melanocyte migration and proliferation, has shown differential immunostaining in various benign and malignant melanocytic lesions. The purpose of this study is to compare c-Kit immunostaining in benign nevi and in primary and metastatic malignant melanomas, to determine whether c-Kit can aid in the differential diagnosis of these lesions. c-Kit immunostaining was performed in 60 cases of pigmented lesions, including 39 benign nevi (5 blue nevi, 5 intra-dermal nevi, 3 junctional nevi, 15 cases of primary compound nevus, 11 cases of Spitz nevus), 18 cases of primary malignant melanoma and 3 cases of metastatic melanoma. The vast majority of nevi and melanomas examined in this study were positive for c-Kit, with minimal differences between benign and malignant lesions. C-Kit cytoplasmatic immunoreactivity in the intraepidermal proliferating nevus cells, was detected in benign pigmented lesions as well as in malignant melanoma, increasing with the age of patients (P=0.007) in both groups. The patient’s age at presentation appeared to be the variable able to cluster benign and malignant pigmented lesions. The percentage of c-Kit positive intraepidermal nevus cells was better associated with age despite other variables (P=0.014). The intensity and percentage of c-Kit positivity in the proliferating nevus cells in the dermis was significantly increased in malignant melanocytic lesions (P=0.015 and P=0.008) compared to benign lesions (compound melanocytic nevi, Spitz nevi, intradermal nevi, blue nevi). Immunostaning for c-Kit in metastatic melanomas was negative. Interestingly in two cases of melanoma occurring on a pre-existent nevus, the melanoma tumor cells showed strong cytoplasmatic and membranous positivity for c-kit, in contrast with the absence of any immunoreactivity in pre-existent intradermal nevus cells. C-Kit does not appear to be a strong immunohistochemical marker for distinguishing melanoma from melanocytic nevi, if we consider c-Kit expression in intraepidermal proliferating cells. The c-Kit expression in proliferating melanocytes in the dermis could help in the differential diagnosis between a superficial spreading melanoma (with dermis invasion) and a compound nevus or an intradermal nevus. Finally, c-Kit could be a good diagnostic tool for distinguishing benign compound nevi from malignant melanocytic lesions with dermis invasion and to differentiate metastatic melanoma from primary melanoma. PMID:22193299

Ocular melanoma: an overview of the current status

PubMed Central

Jovanovic, Predrag; Mihajlovic, Marija; Djordjevic-Jocic, Jasmina; Vlajkovic, Slobodan; Cekic, Sonja; Stefanovic, Vladisav

2013-01-01

Ocular melanoma is the second most common type of melanoma after cutaneous and the most common primary intraocular malignant tumor in adults. Large majority of ocular melanomas originate from uvea, while conjunctival melanomas are far less frequent. Incidence of uveal melanoma has remained stable over last three decades. Diagnosis is in most cases established by clinical examination with great accuracy. Local treatment of uveal melanoma has improved, with increased use of conservative methods and preservation of the eye, but survival rates have remained unchanged. Recent advances in cytogenetics and genetics enhanced prognostication and enabled to determine tumors with high metastatic potential. However, due to lack of effective systemic therapy, prognosis of patients with metastasis remains poor and metastatic disease remains the leading cause of death among patients with uveal melanoma. Conjunctival melanoma is rare, but its incidence is increasing. It mostly occurs among white adults. In majority of cases it originates from preceding primary acquired melanosis. Current standard treatment for conjunctival melanoma is wide local excision with adjuvant therapy, including brachytherapy, cryotherapy and topical application of chemotherapeutic agent. Rarity of this tumor limits conduction of controlled trials to define the best treatment modality. As well as for uveal melanoma, prognosis of patients with metastasis is poor because there is no effective systemic therapy. Better understanding of underlying genetic and molecular abnormalities implicated in development and progression of ocular melanomas provides a great opportunity for development of targeted therapy, which will hopefully improve prognosis of patients with metastatic disease. PMID:23826405

A Retrospective Study, an Initial Lesion of Primary Malignant Melanoma of the Esophagus Revealed by Endoscopy.

PubMed

Fukuda, Sho; Ito, Hirotaka; Ohba, Reina; Sato, Yuichirou; Ohyauchi, Motoki; Igarashi, Takehiko; Obana, Nobuya; Iijima, Katsunori

2017-08-15

A 66-year-old man presented to his previous physician with epigastric discomfort in 2014. He was then referred to our hospital due to suspected primary malignant melanoma of the esophagus (PMME). A biopsy showed atypical cells containing melanin granules. A diagnosis of PMME was thus made. We investigated the endoscopic findings of the previous physician, which revealed a black point-like pigmentation at the same site since 2009. In 2010, black pigmentation was also observed at the same site. Although esophageal melanosis was suspected, no biopsy was performed. This case demonstrates the process by which esophageal melanomas develop into malignant melanomas.

Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy.

PubMed

Casula, Milena; Colombino, Maria; Satta, Maria P; Cossu, Antonio; Lissia, Amelia; Budroni, Mario; Simeone, Ester; Calemma, Rosa; Loddo, Cinzia; Caracò, Corrado; Mozzillo, Nicola; Daponte, Antonio; Comella, Giuseppe; Canzanella, Sergio; Guida, Michele; Castello, Giuseppe; Ascierto, Paolo A; Palmieri, Giuseppe

2007-01-01

Clinical predictors for germline mutations of candidate genes in large clinic based population of patients with cutaneous malignant melanoma (CMM) are widely awaited. Using denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing, 557 consecutively-collected CMM patients originating from South Italy were screened for CDKN2A germline mutations; subsets of them were screened for mutations in the BRAF and BRCA2 genes. Seven CDKN2A mutations were detected in 14 (2.5%) CMM patients. Relative risk of carrying a CDKN2A mutation for CMM patients was demonstrated to significantly increase with the presence of familial recurrence of melanoma (risk ratio (RR)=6.31; p=0.0009), multiple primary melanomas (RR=3.43; p=0.0014), and early onset age (RR=4.56; p=0.0026). All CDKN2A mutations were observed in non-Sardinian patients (14/441; 3.2%), whereas BRAF and BRCA2 genes were found mutated in Sardinian patients (3/116; 2.6%). Such indicators of the presence of CDKN2A mutations will be useful in counselling patients about undergoing genetic testing. Our findings strongly suggest that mutation rates of candidate cancer genes may deeply vary among CMM patients from different geographical areas.

Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics.

PubMed

Bailey, Fiona P; Clarke, Kim; Kalirai, Helen; Kenyani, Jenna; Shahidipour, Haleh; Falciani, Francesco; Coulson, Judy M; Sacco, Joseph J; Coupland, Sarah E; Eyers, Patrick A

2018-03-01

Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models. The poor overall response of UM cells to FDA-approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1-dependent kinase subnetwork in JQ1-exposed cells that contained multiple cell cycle-regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome-wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients. © 2017 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons.

Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis).

PubMed

Jager, Martine J; Magner, J Antonio Bermudez; Ksander, Bruce R; Dubovy, Sander R

2016-08-01

To determine whether some of the most often used uveal melanoma cell lines resemble their original tumor. Analysis of the literature, patient charts, histopathology, mutations, chromosome status, HLA type, and expression of melanocyte markers on cell lines and their primary tumors. We examined five cell lines and the primary tumors from which they were derived. Four of the five examined primary tumors were unusual: one occupied the orbit, two were recurrences after prior irradiation, and one developed in an eye with a nevus of Ota. One cell line did not contain the GNA11 mutation, but it was present in the primary tumor. Three of the primary tumors had monosomy 3 (two of these lacked BAP1 expression); however, all five cell lines showed disomy 3 and BAP1 expression. All of the cell lines had gain of 8q. Two cell lines lacked expression of melanocyte markers, although these were present in the corresponding primary tumor. All cell lines could be traced back to their original uveal melanoma. Four of the five primary tumors were unusual. Cell lines often differed from their primary tumor in chromosome status and melanocyte markers. However, their specific chromosome aberrations and capacity to continue proliferation characterize them as uveal melanoma cell lines.

Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis)

PubMed Central

Jager, Martine J.; Magner, J. Antonio Bermudez; Ksander, Bruce R.; Dubovy, Sander R.

2016-01-01

Purpose To determine whether some of the most often used uveal melanoma cell lines resemble their original tumor. Methods Analysis of the literature, patient charts, histopathology, mutations, chromosome status, HLA type, and expression of melanocyte markers on cell lines and their primary tumors. We examined five cell lines and the primary tumors from which they were derived. Results Four of the five examined primary tumors were unusual: one occupied the orbit, two were recurrences after prior irradiation, and one developed in an eye with a nevus of Ota. One cell line did not contain the GNA11 mutation, but it was present in the primary tumor. Three of the primary tumors had monosomy 3 (two of these lacked BAP1 expression); however, all five cell lines showed disomy 3 and BAP1 expression. All of the cell lines had gain of 8q. Two cell lines lacked expression of melanocyte markers, although these were present in the corresponding primary tumor. Conclusions All cell lines could be traced back to their original uveal melanoma. Four of the five primary tumors were unusual. Cell lines often differed from their primary tumor in chromosome status and melanocyte markers. However, their specific chromosome aberrations and capacity to continue proliferation characterize them as uveal melanoma cell lines. PMID:28018010

Cytology of primary vaginal melanoma: An unusual report on fine needle aspiration.

PubMed

Agarwal, Poojan; Kaushal, Manju

2017-03-01

Primary malignant melanoma of the vagina is an extremely uncommon malignancy comprising of less than 10% malignancies of the female genital tract and 0.3% of all melanomas. Melanoblasts are neural crest derivatives and are notorious for causing primary cutaneous neoplasms. However, they involve virtually every organ of the body including eye, intestines and ocular mucosa, probably due to aberrancies in cell migration. Vagina is a rare site and primary melanoma of the vagina occurs in postmenopausal women with vaginal discharge, bleeding, or mass as common presenting complaints. Only a handful of case reports are available describing this entity on biopsy and PAP smear samples; however, fine needle aspiration has seldom been discussed. In the present report we discuss a case of an elderly female who complained of mass protruding through the vaginal opening, FNAC was done from the mass as well as from the right inguinal lymph node. An extensive clinicoradiological workup, and immunohistochemical confirmation is essential to rule out metastatic lesions and confirm primary. Diagn. Cytopathol. 2017;45:252-256. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Histology-specific microRNA alterations in melanoma.

PubMed

Poliseno, Laura; Haimovic, Adele; Segura, Miguel F; Hanniford, Douglas; Christos, Paul J; Darvishian, Farbod; Wang, Jinhua; Shapiro, Richard L; Pavlick, Anna C; Berman, Russell S; Hernando, Eva; Zavadil, Jiri; Osman, Iman

2012-07-01

We examined the microRNA signature that distinguishes the most common melanoma histological subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM). We also investigated the mechanisms underlying the differential expression of histology-specific microRNAs. MicroRNA array performed on a training cohort of 82 primary melanoma tumors (26 SSM, 56 NM), and nine congenital nevi (CN) revealed 134 microRNAs differentially expressed between SSM and NM (P<0.05). Out of 134 microRNAs, 126 remained significant after controlling for thickness and 31 were expressed at a lower level in SSM compared with both NM and CN. For seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191, and miR-933), the downregulation was associated with selective genomic loss in SSM cell lines and primary tumors, but not in NM cell lines and primary tumors. The lower expression level of six out of seven microRNAs in SSM compared with NM was confirmed by real-time PCR on a subset of cases in the training cohort and validated in an independent cohort of 97 melanoma cases (38 SSM, 59 NM). Our data support a molecular classification in which SSM and NM are two molecularly distinct phenotypes. Therapeutic strategies that take into account subtype-specific alterations might improve the outcome of melanoma patients.

Histology-Specific MicroRNA Alterations in Melanoma

PubMed Central

Poliseno, Laura; Haimovic, Adele; Segura, Miguel F.; Hanniford, Douglas; Christos, Paul J.; Darvishian, Farbod; Wang, Jinhua; Shapiro, Richard L.; Pavlick, Anna C.; Berman, Russell S.; Hernando, Eva; Zavadil, Jiri; Osman, Iman

2013-01-01

We examined the microRNA signature that distinguishes the most common melanoma histological subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM). We also investigated the mechanisms underlying the differential expression of histology-specific microRNAs. MicroRNA array performed on a training cohort of 82 primary melanoma tumors (26 SSM, 56 NM), and nine congenital nevi (CN) revealed 134 microRNAs differentially expressed between SSM and NM (P<0.05). Out of 134 microRNAs, 126 remained significant after controlling for thickness and 31 were expressed at a lower level in SSM compared with both NM and CN. For seven microRNAs (let-7g, miR-15a, miR-16, miR-138, miR-181a, miR-191, and miR-933), the downregulation was associated with selective genomic loss in SSM cell lines and primary tumors, but not in NM cell lines and primary tumors. The lower expression level of six out of seven microRNAs in SSM compared with NM was confirmed by real-time PCR on a subset of cases in the training cohort and validated in an independent cohort of 97 melanoma cases (38 SSM, 59 NM). Our data support a molecular classification in which SSM and NM are two molecularly distinct phenotypes. Therapeutic strategies that take into account subtype-specific alterations might improve the outcome of melanoma patients. PMID:22551973

Analysis of sentinel node positivity in primary cutaneous melanoma: an 8-year single institution experience.

PubMed

Joyce, K M; McInerney, N M; Piggott, R P; Martin, F; Jones, D M; Hussey, A J; Kerin, M J; Kelly, J L; Regan, P J

2017-11-01

Sentinel lymph node biopsy (SLNB) is a standard method for determining the pathologic status of the regional lymph nodes. The aim of our study was to determine the incidence and clinicopathologic factors predictive of SLN positivity, and to evaluate the prognostic importance of SLNB in patients with cutaneous melanoma. We performed a retrospective analysis of a prospectively maintained database of all patients who underwent SLNB for primary melanoma at our institution from 2005 to 2012. Statistical analysis was performed using χ 2 and Fischer exact test. In total, 318 patients underwent SLNB, of which 65 were for thin melanoma (≤1 mm). There were 36 positive SLNB, 278 negative SLNB and in four cases the SLN was not located. The incidence rate for SLNB was 11.3% overall and 1.5% in thin melanomas alone. Statistical analysis identified Breslow thickness >1 mm (P = 0.006), Clark level ≥ IV (P = 0.004) and age <75 years (P = 0.035) as the strongest predictors of SLN positivity. Our overall false negativity rate was 20% (9/45) with one case of false-negative SLNB in thin melanomas. Breslow thickness of the primary tumour remains the strongest predictor of SLN positivity. Our findings point to a possible limited role for SLNB in thin melanoma due to its low positivity rate, associated false-negative rate and related morbidity.

Uveal Melanoma: From Diagnosis to Treatment and the Science in Between

PubMed Central

Chattopahdyay, Chandrani; Kim, Dae Won; Gombos, Dan; Oba, Junna; Qin, Yong; Williams, Michelle; Esmaeli, Bita; Grimm, Elizabeth; Wargo, Jennifer; Woodman, Scott; Patel, Sapna

2017-01-01

Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the U.S., an age-adjusted risk of 5 per million. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomical spread, molecular changes, and responses to systemic therapy. Once metastatic, therapy options are limited, and often extrapolated from cutaneous melanoma therapies despite routine exclusion of uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress and data from these well-designed investigations will help guide future directions in this orphan disease. PMID:26991400

Primary cutaneous melanoma of the scalp: Patterns of recurrence.

PubMed

Sparks, David S; Read, Tavis; Lonne, Michael; Barbour, Andrew P; Wagels, Michael; Bayley, Gerard J; Smithers, B Mark

2017-03-01

Patients with primary melanoma of the scalp have been reported to have worse disease-related outcomes compared with other anatomical regions. There are few studies in the literature specifically addressing recurrence patterns and treatment outcomes for primary scalp melanoma as a discrete anatomical sub-region. We sought to identify key features adversely influencing disease control and survival and to clarify the role of resection plane, margin, and method of reconstruction in the management of this disease process. A retrospective clinical study of medical records was performed evaluating all patients with primary melanoma of the scalp treated at two hospitals in southeast Queensland between 2004 and 2014. A total of 107 patients were eligible for analysis. There were 46 recurrences in 38 patients in the cohort accounting for a recurrence rate of 35.5%. The local recurrence rate was 15.9% with 12 in-transit metastases after diagnosis. Regional and distant recurrence rates were 12.1% and 15%, respectively. At a median follow up of 30.5 months, disease-free survival was 47% and overall survival was also 47%. On multi-variate analysis, the deeper resection plane (sub-galeal) had a lower disease-free survival rate compared with the supra-galeal resection plane (P = 0.032). Our results support the hypothesis that primary scalp melanoma represents a unique aggressive subcategory with high rates of in-transit disease and poor disease-related and survival outcomes. There is a need for robust prospective comparative studies to address the significance of resection plane in the management of patients with scalp melanoma. © 2016 Wiley Periodicals, Inc.

Overexpression of adenylate cyclase-associated protein 2 is a novel prognostic marker in malignant melanoma.

PubMed

Masugi, Yohei; Tanese, Keiji; Emoto, Katsura; Yamazaki, Ken; Effendi, Kathryn; Funakoshi, Takeru; Mori, Mariko; Sakamoto, Michiie

2015-12-01

Malignant melanoma is one of the lethal malignant tumors worldwide. Previously we reported that adenylate cyclase-associated protein 2 (CAP2), which is a well-conserved actin regulator, was overexpressed in hepatocellular carcinoma; however, CAP2 expression in other clinical cancers remains unclear. The aim of the current study was to clarify the clinicopathological significance of CAP2 overexpression in malignant melanoma. Immunohistochemical analyses revealed that many melanoma cells exhibited diffuse cytoplasmic expression of CAP2, whereas no normal melanocytes showed detectable immunostaining for CAP2. A high level of CAP2 expression was seen in 14 of 50 melanomas and was significantly correlated with greater tumor thickness and nodular melanoma subtypes. In addition, a high level of CAP2 expression was associated with poor overall survival in univariate and multivariate analyses. For 13 patients, samples of primary and metastatic melanoma tissue were available: four patients exhibited higher levels of CAP2 expression in metastatic tumor compared to the primary site, whereas no patient showed lower levels of CAP2 expression in metastatic melanomas. Our findings show that CAP2 overexpression is a novel prognostic marker in malignant melanoma and that CAP2 expression seems to increase stepwise during tumor progression, suggesting the involvement of CAP2 in the aggressive behavior of malignant melanoma. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

MicroRNA signatures differentiate melanoma subtypes

PubMed Central

Chan, Elcie; Patel, Rajeshvari; Nallur, Sunitha; Ratner, Elena; Bacchiocchi, Antonella; Hoyt, Kathleen; Szpakowski, Sebastian; Godshalk, Sirie; Ariyan, Stephan; Sznol, Mario; Halaban, Ruth; Krauthammer, Michael; Tuck, David; Slack, Frank J

2011-01-01

Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma. PMID:21543894

PRIMARY ACQUIRED MELANOSIS OF THE CONJUNCTIVA: EXPERIENCE WITH 311 EYES

PubMed Central

Shields, Jerry A.; Shields, Carol L.; Mashayekhi, Arman; Marr, Brian P.; Benavides, Raquel; Thangappan, Archana; Phan, Laura; Eagle, Ralph C.

2007-01-01

Purpose To evaluate clinical features and risks for transformation of conjunctival primary acquired melanosis (PAM) into melanoma. Methods Retrospective chart review and Kaplan-Meier estimates of times to PAM enlargement, recurrence, and transformation into melanoma. Main outcome measures: PAM enlargement, recurrence, and transformation into melanoma. Results The mean patient age at diagnosis of PAM was 56 years; 62% were female and 96% Caucasian. The conjunctival quadrant(s) affected by PAM and its extent in clock hours were recorded. Initial management included observation in 62%, biopsy combined with cryotherapy in 34%, and other methods in 4%. Of PAM that was observed, Kaplan-Meier estimates at 10 years revealed PAM enlargement in 35% and transformation into melanoma in 12%. Of those that underwent incisional or excisional biopsy, 10-year estimates of PAM recurrence and transformation into melanoma were 58% and 11%, respectively. Progression to melanoma occurred in 0% of PAM without atypia, 0% of PAM with mild atypia, and 13% of PAM with severe atypia. Multivariable analysis revealed that the most significant factor for both PAM recurrence and progression to melanoma was extent of PAM in clock hours. Conclusion PAM without atypia or with mild atypia shows 0% progression into melanoma, whereas PAM with severe atypia shows progression into melanoma in 13%. The greater the extent of PAM in clock hours, the greater the risk for transformation into melanoma. PMID:18427595

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells.

PubMed

Botti, Gerardo; Fratangelo, Federica; Cerrone, Margherita; Liguori, Giuseppina; Cantile, Monica; Anniciello, Anna Maria; Scala, Stefania; D'Alterio, Crescenzo; Trimarco, Chiara; Ianaro, Angela; Cirino, Giuseppe; Caracò, Corrado; Colombino, Maria; Palmieri, Giuseppe; Pepe, Stefano; Ascierto, Paolo Antonio; Sabbatino, Francesco; Scognamiglio, Giosuè

2017-02-23

The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma. Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF V600E A375 and NRAS Q61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro. BRAF V600E/V600K and NRAS Q61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions (P = 0.002). COX-2 expression significantly correlated with PD-L1 expression in both primary (P = 0.001) and not matched metastatic (P = 0.048) lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF V600E A375 and NRAS Q61R SK-MEL-2 melanoma cell lines. COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

PubMed Central

Peinado, Héctor; Alečković, Maša; Lavotshkin, Simon; Matei, Irina; Costa-Silva, Bruno; Moreno-Bueno, Gema; Hergueta-Redondo, Marta; Williams, Caitlin; García-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Hoffman, Caitlin; Badal, Karen; Garcia, Benjamin A.; Callahan, Margaret K.; Yuan, Jianda; Martins, Vilma R.; Skog, Johan; Kaplan, Rosandra N.; Brady, Mary S.; Wolchok, Jedd D.; Chapman, Paul B.; Kang, Yibin; Bromberg, Jacqueline; Lyden, David

2013-01-01

Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. PMID:22635005

Unusual presentation of a metastatic uveal melanoma in a cat.

PubMed

Planellas, Marta; Pastor, Josep; Torres, Ma Dolores; Peña, Teresa; Leiva, Marta

2010-11-01

A 10 year-old, spayed female Domestic Short-Haired (DSH) cat was diagnosed with a large primary uveal melanoma and exenteration was recommended. Thoracic radiographs, abdominal ultrasonography, and complete blood count and serum biochemistry panel did not reveal any abnormality compatible with metastatic disease and surgery was performed. Histopathologic study of the eye confirmed a diffuse iris melanoma. Five months later, the cat presented with a lameness of the right anterior extremity. On physical exam the right elbow was swollen and painful. Radiographs showed a severe osteolysis of the radial head and proximal diaphysis. Fine needle aspiration of the radius head identified a round cell neoplasm with scattered cells containing intracytoplasmatic pigmented granules, compatible with metastatic melanoma. The owners decided not to treat the patient with chemotherapy and declined a biopsy. Two months later, the cat died and necropsy was performed confirming bone metastasis of the uveal melanoma. A diagnosis of generalized metastasis from primary diffuse iris melanoma was made. This report describes, for the first time, long bone metastasis from an uveal melanoma in a cat. © 2010 American College of Veterinary Ophthalmologists.

Cross-Priming of Naive Cd8 T Cells against Melanoma Antigens Using Dendritic Cells Loaded with Killed Allogeneic Melanoma Cells

PubMed Central

Berard, Frederic; Blanco, Patrick; Davoust, Jean; Neidhart-Berard, Eve-Marie; Nouri-Shirazi, Mahyar; Taquet, Nicolas; Rimoldi, Donata; Cerottini, Jean Charles; Banchereau, Jacques; Palucka, A. Karolina

2000-01-01

The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA+CD27+CD8+ T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201+ naive T cells primed by DCs loaded with HLA-A201− melanoma cells are able to kill several HLA-A201+ melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols. PMID:11104796

The utility of ultrasound in patients with melanoma.

PubMed

Uren, Roger F; Sanki, Amira; Thompson, John F

2007-11-01

The highest quality gray-scale ultrasound images are obtained with high-frequency transducers; however, such high frequencies do not penetrate more than a few centimeters into body tissue. Fortunately, in patients with melanoma, the structures of interest are close to the skin surface, making them ideal targets for examination with high-resolution ultrasound. These include primary cutaneous melanomas, uveal melanomas and the regional lymph nodes draining the skin that lie in the axilla, groin, neck and other locations. Although ultrasound study of primary melanomas arising in the skin and eye has provided some insights, a major role for ultrasound has evolved recently, to provide early detection of metastatic melanoma in regional lymph nodes. Ultrasound is clearly superior to clinical palpation of the nodes during follow-up and, when combined with guided fine-needle biopsy, allows the earliest possible surgical intervention for regional nodal metastases. In the future the use of ultrasound contrast agents may improve the sensitivity of ultrasound in the detection of very small metastatic deposits.

Genetics of Primary Intraocular Tumors

PubMed Central

Nagarkatti-Gude, Nisha; Wang, Yujuan; Ali, Mohammad Javed; Honavar, Santosh G.; Jager, Martine J.; Chan, Chi-Chao

2012-01-01

Primary intraocular neoplasms are tumors that originate within the eye. The most common malignant primary intraocular tumor in adults is uveal melanoma and the second is primary intraocular lymphoma or vitreoretinal (intraocular) lymphoma. The most common malignant intraocular tumor in children is retinoblastoma. Genetics plays a vital role in the diagnosis and detection of ocular tumors. In uveal melanoma, monosomy 3 is the most common genetic alteration and somatic mutations of BAP1, a tumor suppressor gene, have been reported in nearly 50% of primary uveal melanomas. The retinoblastoma gene RB1 is the prototype tumor suppressor gene—mutations in RB1 alleles lead to inactivated RB protein and the development of retinoblastoma. Immunoglobulin heavy chain (IgH) or T-cell receptor (TCR) gene rearrangement is observed in B-cell or T-cell primary vitreoretinal lymphoma, respectively. Other factors related to the genetics of these three common malignancies in the eye are discussed and reviewed. PMID:22834783

Malignant melanoma of the nose.

PubMed

Souza, S D; Sujata, G

2001-04-01

Invasive tumors containing abnormal melanocvtes are termed ax malignant melanomas. Primary malignant melanomas of the nasal and paranasal cavities are extremely rare. A 65 years old female presented with bleeding from the nose and a gradually increasing mass in the left nostril. Histopathological examination of the specimen showed "poorly differentiated carcinoma" like features. But S-100 staining proved it to be a malignant melanoma. This case is reported here for its rarity. The literature on malignant melanoma is reviewed and the aetiology pathology, diagnostic and therapeutic problems are also discussed.

Synthesis and preclinical characterization of [18F]FPBZA: a novel PET probe for melanoma.

PubMed

Wu, Shih-Yen; Huang, Shih-Pin; Lo, Yen-Chen; Liu, Ren-Shyan; Wang, Shyh-Jen; Lin, Wuu-Jyh; Shen, Chih-Chieh; Wang, Hsin-Ell

2014-01-01

Benzamide can specifically bind to melanoma cells. A 18F-labeled benzamide derivative, [18F]N-(2-diethylaminoethyl)-4-[2-(2-(2-fluoroethoxy) ethoxy)ethoxy]benzamide ([18F]FPBZA), was developed as a promising PET probe for primary and metastatic melanoma. [18F]FPBZA was synthesized via a one-step radiofluorination in this study. The specific uptake of [18F]FPBZA was studied in B16F0 melanoma cells, A375 amelanotic melanoma cells, and NB-DNJ-pretreated B16F0 melanoma cells. The biological characterization of [18F]FPBZA was performed on mice bearing B16F0 melanoma, A375 amelanotic melanoma, or inflammation lesion. [18F]FPBZA can be prepared efficiently with a yield of 40-50%. The uptake of [18F]FPBZA by B16F0 melanoma cells was significantly higher than those by A375 tumor cells and NB-DNJ-pretreated B16F0 melanoma cells. B16F0 melanoma displayed prominent uptake of [18F]FPBZA at 2 h (7.81±0.82%ID/g), compared with A375 tumor and inflammation lesion (3.00±0.71 and 1.67±0.56%ID/g, resp.). [18F]FPBZA microPET scan clearly delineated B16F0 melanoma but not A375 tumor and inflammation lesion. In mice bearing pulmonary metastases, the lung radioactivity reached 4.77±0.36%ID/g at 2 h (versus 1.16±0.23%ID/g in normal mice). Our results suggested that [18F]FPBZA PET would provide a promising and specific approach for the detection of primary and metastatic melanoma lesions.

Synthesis and Preclinical Characterization of [18F]FPBZA: A Novel PET Probe for Melanoma

PubMed Central

Huang, Shih-Pin; Lo, Yen-Chen; Liu, Ren-Shyan; Shen, Chih-Chieh

2014-01-01

Introduction. Benzamide can specifically bind to melanoma cells. A 18F-labeled benzamide derivative, [18F]N-(2-diethylaminoethyl)-4-[2-(2-(2-fluoroethoxy) ethoxy)ethoxy]benzamide ([18F]FPBZA), was developed as a promising PET probe for primary and metastatic melanoma. Methods. [18F]FPBZA was synthesized via a one-step radiofluorination in this study. The specific uptake of [18F]FPBZA was studied in B16F0 melanoma cells, A375 amelanotic melanoma cells, and NB-DNJ-pretreated B16F0 melanoma cells. The biological characterization of [18F]FPBZA was performed on mice bearing B16F0 melanoma, A375 amelanotic melanoma, or inflammation lesion. Results. [18F]FPBZA can be prepared efficiently with a yield of 40–50%. The uptake of [18F]FPBZA by B16F0 melanoma cells was significantly higher than those by A375 tumor cells and NB-DNJ-pretreated B16F0 melanoma cells. B16F0 melanoma displayed prominent uptake of [18F]FPBZA at 2 h (7.81 ± 0.82 %ID/g), compared with A375 tumor and inflammation lesion (3.00 ± 0.71 and 1.67 ± 0.56 %ID/g, resp.). [18F]FPBZA microPET scan clearly delineated B16F0 melanoma but not A375 tumor and inflammation lesion. In mice bearing pulmonary metastases, the lung radioactivity reached 4.77 ± 0.36 %ID/g at 2 h (versus 1.16 ± 0.23 %ID/g in normal mice). Conclusions. Our results suggested that [18F]FPBZA PET would provide a promising and specific approach for the detection of primary and metastatic melanoma lesions. PMID:25254219

Sentinel node biopsy status is strongly predictive of survival in cutaneous melanoma: Extended follow-up of Oxford patients from 1998 to 2014.

PubMed

Thomson, David R; Rughani, Milap G; Kuo, Rachel; Cassell, Oliver C S

2017-10-01

Sentinel lymph node biopsy (SLNB) is widely used as a key investigatory tool for cutaneous melanoma, with results incorporated into the latest AJCC staging guidelines. We present the results of our extended follow-up of sentinel lymph node biopsy for melanoma over a sixteen-year period. Data were collected prospectively from June 1998 to December 2014 from a single tertiary skin cancer referral centre. Chi-squared analysis was used to analyse patient demographics and primary tumour pathology. Survival analysis was conducted using Cox regression models and Kaplan-Meier survival curves. Over a sixteen-year period 1527 patients underwent SLNB in 1609 basins, with 2876 nodes harvested. 347 patients (23%) had a positive biopsy. The most common primary tumour sites for males was the back (32%); women had a significantly higher number of melanomas occurring on the lower and upper limbs (45% and 26% respectively) [all p < 0.0001, Chi-squared]. Mean follow-up time was 4.9 years. Patients with a positive SLNB at diagnosis were significantly more likely to die from melanoma (subhazard ratio 5.59, p = 0.000, 95% CI 3.59-8.69). Breslow thickness and ulceration were also significant predictors of melanoma-specific mortality. For patients with a primary Breslow >4.0 mm ten-year disease free survival was 52% for SLNB negative and 26% for SLNB positive patients. For Breslow thicknesses of 2.01-4 mm these values were 66% and 32% respectively. Sentinel lymph node biopsy status is strongly predictive of survival across all thicknesses of primary cutaneous melanoma. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Mitotic rate in primary melanoma: interobserver and intraobserver reliability, analyzed using H&E sections and immunohistochemistry.

PubMed

Garbe, Claus; Eigentler, Thomas K; Bauer, Jürgen; Blödorn-Schlicht, Norbert; Cerroni, Lorenzo; Fend, Falko; Hantschke, Markus; Kurschat, Peter; Kutzner, Heinz; Metze, Dieter; Mielke, Volker; Preßler, Harald; Reusch, Michael; Reusch, Ursula; Stadler, Rudolf; Tronnier, Michael; Yazdi, Amir; Metzler, Gisela

2016-09-01

In 2009, the AJCC issued a revised melanoma staging system. In addition to tumor thickness and ulceration, the mitotic rate was introduced as the third major prognostic parameter for the classification of primary cutaneous melanoma. Given that, according to the 2009 AJCC classification, the detection of one or more dermal tumor mitoses leads to an upstaging - from stage Ia to Ib - of melanomas with a tumor thickness of ≤ 1.0 mm, we set out to investigate the reproducibility of this new parameter. In order to assess interobserver reliability, 17 dermatopathologists und pathologists - all well versed in the diagnosis of cutaneous melanoma - analyzed the mitotic rate in 15 thin primary cutaneous melanomas (mean tumor thickness 0.91 mm) using identical slides. Mitotic rates were determined on H&E and phosphohistone H3 (Ser10)-stained samples. Without knowledge of their previous assessment, five of the aforementioned examiners reevaluated the samples after more than one year in order to ascertain intraobserver reliability. Interobserver reliability of the mitotic rate in thin primary melanomas is disappointing and independent of whether H&E or immunohistochemically stained samples are used (kappa value: 0.088 [H&E], 0.154 [IH], respectively). Kappa values improved to 0.345 (H&E) and 0.403 (IH) when using a cutoff of 0/1 vs. 2+ mitoses. Similarly unsatisfactory, kappa values for intraobserver reliability ranged from 0.18 and 0.348, depending on the individual examiner. Given the unsatisfactory reproducibility and large variations in assessing the mitotic rate, it remains a matter of debate whether this diagnostic parameter should play a role in therapeutic decisions. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Protocol for the melatools skin self-monitoring trial: a phase II randomised controlled trial of an intervention for primary care patients at higher risk of melanoma.

PubMed

Mills, Katie; Emery, Jon; Lantaff, Rebecca; Radford, Michael; Pannebakker, Merel; Hall, Per; Burrows, Nigel; Williams, Kate; Saunders, Catherine L; Murchie, Peter; Walter, Fiona M

2017-11-28

Melanoma is the fifth most common cancer in the UK. Incidence rates have quadrupled over the last 30 years and continue to rise, especially among younger people. As routine screening of the general population is not currently recommended in the UK, a focus on secondary prevention through early detection and prompt treatment in individuals at increased risk of melanoma could make an important contribution to improve melanoma outcomes. This paper describes the protocol for a phase II, multisite, randomised controlled trial, in the primary care setting, for patients at increased risk of melanoma. A skin self-monitoring (SSM) smartphone 'App' was used to improve symptom appraisal and encourage help seeking in primary care, thereby promoting early presentation with skin changes suspicious of melanoma. We aim to recruit 200 participants from general practice waiting rooms in the East of England. Eligible patients are those identified at higher melanoma risk (using a real-time risk assessment tool), without a personal history of melanoma, aged 18 to 75 years. Participants will be invited to a primary care nurse consultation, and randomised to the intervention group (standard written advice on skin cancer detection and sun protection, loading of an SSM 'App' onto the participant's smartphone and instructions on use including self-monitoring reminders) or control group (standard written advice alone). The primary outcomes are consultation rates for changes to a pigmented skin lesion, and the patient interval (time from first noticing a skin change to consultation). Secondary outcomes include patient sun protection behaviours, psychosocial outcomes, and measures of trial feasibility and acceptability. NHS ethical approval has been obtained from Cambridgeshire and Hertfordshire research ethics committee (REC reference 16/EE/0248). The findings from the MelaTools SSM Trial will be disseminated widely through peer-reviewed publications and scientific conferences. ISCTRN16061621. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Primary malignant melanoma of the vagina and treatment options: a case report].

PubMed

Tsvetkov, Ch; Gorchev, G; Tomov, S; Hinkova, N; Nikolova, M; Veselinova, T

2014-01-01

To present and analyze the clinical characteristics, treatment, and treatment options for a patient with primary malignant melanoma of the vagina and review of literature. A 71-year-old patient with a history of vaginal bleeding caused by four tumor growths located in the vagina is presented. The size of each formation was about 2 cm. Three of them were located in the proximal two-thirds of the anterior wall of the vagina and one in the distal third. Excisional biopsy was performed of the lesion located near the entrance of the vagina. Histopathological examination revealed that it was a malignant melanoma of the vagina, which was confirmed immunohistochemically. After ruling out a tumor of an unknown primary site, the patient underwent radical hysterectomy type IV total vaginectomy and pelvic lymph node dissection. Hystological examination proved a clinically asymptomatic melanoma lesion of the uterine cervix. After surgery, the patient was given chemotherapy with Dacarbasine and monthly immunotherapy with BCG vaccine. The patient survived 21 months after surgery without developing a local relapse and died of distant metastases in the spine. Radical surgery for primary melanoma of the vagina is a secure way of achieving locoregional control of multifocal disease. The wide local excision can be used in unifocal lesions with security in achieving clean surgical margins.

Vitamin D supplementation in cutaneous malignant melanoma outcome (ViDMe): a randomized controlled trial.

PubMed

De Smedt, J; Van Kelst, S; Boecxstaens, V; Stas, M; Bogaerts, K; Vanderschueren, D; Aura, C; Vandenberghe, K; Lambrechts, D; Wolter, P; Bechter, O; Nikkels, A; Strobbe, T; Emri, G; Marasigan, V; Garmyn, M

2017-08-23

Previous studies have investigated the protective effect of vitamin D serum levels, at diagnosis and during the follow-up period after treatment, on melanoma outcome. In the present study we assess whether vitamin D supplementation, in the follow-up period after diagnosis and surgical resection of the primary tumor, has a protective effect on relapse of cutaneous malignant melanoma and whether this protective effect correlates with vitamin D levels in serum and Vitamin D Receptor immunoreactivity in the primary tumor. This study is a multicenter randomized double blind placebo- controlled phase III trial. Patients between the age of 18 and 80 years diagnosed and treated surgically for a melanoma stage IB-III are eligible for randomization in a 1:1 ratio to active treatment or placebo. The study drug is taken each month and consists of either 100,000 International Unit cholecalciferol or arachidis oleum raffinatum used as a placebo. The primary endpoint is relapse free survival. The secondary endpoints are 25 hydroxyvitamin D3 serum levels at diagnosis and at 6 month intervals, melanoma subtype, melanoma site and stage of melanoma at diagnosis according to the 2009 American Joint Committee on Cancer melanoma staging and classification. At randomization a bloodsample is taken for DNA analysis. The study is approved by the local Ethics Committees. If we can confirm our hypothesis that vitamin D supplementation after removal of the tumor has a protective effect on relapse of cutaneous malignant melanoma we may reduce the burden of CMM at several levels. Patients, diagnosed with melanoma may have a better clinical outcome and improved quality of life. There will be a decrease in health care costs related to treatment of metastatic disease and there will be a decrease in loss of professional years, which will markedly reduce the economic burden of the disease. Clinical Trial.gov, NCT01748448 , 05/12/2012.

PROTEIN KINASE C δ IS A THERAPEUTIC TARGET IN MALIGNANT MELANOMA WITH NRAS MUTATION

PubMed Central

Takashima, Asami; English, Brandon; Chen, Zhihong; Cao, Juxiang; Cui, Rutao; Williams, Robert M.; Faller, Douglas V.

2014-01-01

NRAS is the second most frequently mutated gene in melanoma. Previous reports have demonstrated the sensitivity of cancer cell lines carrying KRAS mutations to apoptosis initiated by inhibition of protein kinase C delta (PKCδ). Here, we report that PKCδ inhibition is cytotoxic in melanomas with primary NRAS mutations. Novel small-molecule inhibitors of PKCδ were designed as chimeric hybrids of two naturally-occurring PKCδ inhibitors, staurosporine and rottlerin. The specific hypothesis interrogated and validated is that combining two domains of two naturally-occurring PKCδ inhibitors into a chimeric or hybrid structure retains biochemical and biological activity, and improves PKCδ isozyme selectivity. We have devised a potentially general synthetic protocol to make these chimeric species using Molander trifluorborate coupling chemistry. Inhibition of PKCδ, by siRNA or small molecule inhibitors, suppressed the growth of multiple melanoma cell lines carrying NRAS mutations, mediated via caspase-dependent apoptosis. Following PKCδ inhibition, the stress-responsive JNK pathway was activated, leading to the activation of H2AX. Consistent with recent reports on the apoptotic role of phospho-H2AX, knockdown of H2AX prior to PKCδ inhibition mitigated the induction of caspase-dependent apoptosis. Furthermore, PKCδ inhibition effectively induced cytotoxicity in BRAF-mutant melanoma cell lines that had evolved resistance to a BRAF inhibitor, suggesting the potential clinical application of targeting PKCδ in patients who have relapsed following treatment with BRAF inhibitors. Taken together, the present work demonstrates that inhibition of PKCδ by novel small molecule inhibitors causes caspase-dependent apoptosis mediated via the JNK-H2AX pathway in melanomas with NRAS mutations or BRAF inhibitor-resistance. PMID:24506253

Metastatic breast disease from cutaneous malignant melanoma.

PubMed

Moschetta, Marco; Telegrafo, Michele; Lucarelli, Nicola Maria; Martino, Gianluigi; Rella, Leonarda; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

2014-01-01

Malignant melanoma is one of the most rapidly increasing cancer in the world. Breast metastases from melanoma are uncommon but could reflect a widespread disease. We report a case of malignant widespread melanoma presenting with bilateral breast nodules in a 39 year-old pre-menopausal Caucasian woman with an history of cutaneous melanoma of the trunk. Breast clinical examination revealed the presence of a hard and mobile lump located on the left breast. Ultrasound detected two bilateral nodules corresponding to oval opacities with well-defined edges and without calcifications or architectural distortion on mammography. Fine needle aspiration cytology performed on both breast nodules confirmed that the breast lesions were metastases from primary cutaneous malignant melanoma. A total-body CT examination detected brain, lung and abdominal lymph nodes metastases. The breast represents an uncommon site of metastatic disease from extra-mammary tumors. Imaging features of breast metastases from melanoma usually do not allow a differential diagnosis with breast primary tumors. Breast metastases may be asymptomatic or palpable as dense and well-circumscribed nodules. Breast metastases indicate a widespread disease and should lead to avoid aggressive surgical procedures because of the poor prognosis of patients affected by metastatic melanoma. The detection of bilateral breast metastases from melanoma is highly suggestive of metastatic multi-organ disease and could be useful to address the therapeutic approach. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Melanoma of the vulva and vagina: principles of staging and their relevance to management based on a clinicopathologic analysis of 85 cases.

PubMed

Seifried, Susan; Haydu, Lauren E; Quinn, Michael J; Scolyer, Richard A; Stretch, Jonathan R; Thompson, John F

2015-01-01

Primary melanomas of the vulva and vagina are rare. As a result, it has been difficult to develop evidence-based guidelines for their management. By analyzing a large series of patients with vulval and vaginal melanomas, this study sought to document the most common presenting features, identify clinical and pathologic predictors of outcome, and provide management guidelines. A clinicopathologic analysis of 85 patients with primary melanomas of the vulva or vagina diagnosed and treated at Melanoma Institute Australia and associated units in Sydney, Australia, between 1960 and 2011 was performed. Predictors of disease-free and melanoma-specific survival (MSS) were determined. Patients with American Joint Committee on Cancer (AJCC) stage 0-II had a significantly better MSS (5Y MSS = 63.6 %, n = 59) compared with those with stage III disease (5Y MSS = 0 %, n = 12, p < 0.001). Tumor thickness, ulceration status, and pathologic clearance margin were significant predictors of MSS. Disease-free survival was predicted by these factors and additionally by tumor mitotic rate. The results of this study provide evidence to support the appropriateness of utilizing the AJCC (7th edition) cutaneous melanoma staging system for vulval and vaginal melanomas. Detection and removal of these melanomas at an early stage with pathologically confirmed clear margins confers the best chance of cure.

Role of epithelial-mesenchymal transition involved molecules in the progression of cutaneous melanoma.

PubMed

Murtas, Daniela; Maxia, Cristina; Diana, Andrea; Pilloni, Luca; Corda, Claudia; Minerba, Luigi; Tomei, Sara; Piras, Franca; Ferreli, Caterina; Perra, Maria Teresa

2017-12-01

Epithelial-mesenchymal transition (EMT) has been suggested to have a driving role in the acquisition of a metastatic potential by melanoma cells. Important hallmarks of EMT include both E-cadherin downregulation and increased expression of N-cadherin. This switch in distinct classes of adhesion molecules leads melanoma cells to lose contact with adjacent keratinocytes and interact instead with stromal fibroblasts and endothelial cells, thus promoting dermal and vascular melanoma invasion. Consequently, tumor cells migrate to distant host tissues and establish metastases. A key regulator in the induction of EMT in melanoma is the Notch1 signaling pathway that, when activated, is prompt to upregulate N-cadherin expression. By means of this strategy, melanoma cells gain enhanced survival, proliferation and invasion properties, driving the tumor toward a more aggressive phenotype. On the basis of these statements, the present study aimed to investigate the possible association between N-cadherin and Notch1 presence in primary cutaneous melanomas and lymph node metastases. Our results from immunohistochemical analysis confirmed a positive correlation between N-cadherin and Notch1 presence in the same tumor samples. Moreover, this study highlighted that a concomitant high expression of N-cadherin and Notch1, both in primary lesions and in lymph node metastases, predicts an adverse clinical outcome in melanoma patients. Therefore, N-cadherin and Notch1 co-presence can be monitored as a predictive factor in early- and advanced-stage melanomas and open additional therapeutic targets for the restraint of melanoma metastasis.

Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo.

PubMed

Faraone, Debora; Aguzzi, Maria Simona; Toietta, Gabriele; Facchiano, Angelo M; Facchiano, Francesco; Magenta, Alessandra; Martelli, Fabio; Truffa, Silvia; Cesareo, Eleonora; Ribatti, Domenico; Capogrossi, Maurizio C; Facchiano, Antonio

2009-08-01

Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. The expression of platelet-derived growth factor receptors (PDGF-Rs) is reported to be reduced in metastatic melanoma compared with benign nevi or normal skin; we then hypothesized that PDGF-Ralpha may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-Ralpha respond to serum with a significantly lower proliferation compared with that of controls. Apoptosis, cell cycle arrest, pRb dephosphorylation, and DNA synthesis inhibition were also observed in cells overexpressing PDGF-Ralpha. Proliferation was rescued by PDGF-Ralpha inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-Ralpha mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-Ralpha was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-Ralpha show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/Balpha and a marked increase of p38gamma, mitogen-activated protein kinase kinase 3, and signal regulatory protein alpha1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-Ralpha reached a significant 70% inhibition of primary melanoma growth (P < .001) and a similar inhibition of tumor angiogenesis. All together, these data demonstrate that PDGF-Ralpha strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.

IRF-8 Controls Melanoma Progression by Regulating the Cross Talk between Cancer and Immune Cells within the Tumor Microenvironment12

PubMed Central

Mattei, Fabrizio; Schiavoni, Giovanna; Sestili, Paola; Spadaro, Francesca; Fragale, Alessandra; Sistigu, Antonella; Lucarini, Valeria; Spada, Massimo; Sanchez, Massimo; Scala, Stefania; Battistini, Angela; Belardelli, Filippo; Gabriele, Lucia

2012-01-01

The transcription factor interferon regulatory factor-8 (IRF-8) is crucial for myeloid cell development and immune response and also acts as a tumor suppressor gene. Here, we analyzed the role of IRF-8 in the cross talk between melanoma cells and tumor-infiltrating leukocytes. B16-F10 melanoma cells transplanted into IRF-8-deficient (IRF-8-/-) mice grow more rapidly, leading to higher numbers of lung metastasis, with respect to control animals. These events correlated with reduced dendritic cell and T cell infiltration, accumulation of myeloid-derived suppressor cells and a chemokine/chemokine receptor expression profile within the tumor microenvironment supporting tumor growth, angiogenesis, and metastasis. Noticeably, primary tumors developing in IRF-8-/- mice displayed a clear-cut inhibition of IRF-8 expression in melanoma cells. Injection of the demethylating agent 5-aza-2′-deoxycytidine into melanoma-bearing IRF-8-/- animals induced intratumoral IRF-8 expression and resulted in the re-establishment of a chemokine/ chemokine receptor pattern favoring leukocyte infiltration and melanoma growth arrest. Importantly, intrinsic IRF-8 expression was progressively down-modulated during melanoma growth in mice and in human metastatic melanoma cells with respect to primary tumors. Lastly, IRF-8 expression in melanoma cells was directly modulated by soluble factors, among which interleukin-27 (IL-27), released by immune cells from tumor-bearing mice. Collectively, these results underscore a key role of IRF-8 in the cross talk between melanoma and immune cells, thus revealing its critical function within the tumor microenvironment in regulating melanoma progression and invasiveness. PMID:23308054

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

PubMed Central

Ferretti, Roberta; Bhutkar, Arjun; McNamara, Molly C.; Lees, Jacqueline A.

2016-01-01

Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma. PMID:26679841

Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

PubMed Central

Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M.; Hao, Hongying

2016-01-01

The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma. PMID:27063098

Lymphoscintigraphy defines new lymphatic pathways from cutaneous melanoma site: clinical implications and surgical management.

PubMed

Marone, Ugo; Aloj, Luigi; Di Monta, Gianluca; Caracò, Corrado

2011-01-01

Sentinel lymph node biopsy is commonly applied as staging procedure of regional lymph nodes in patients with cutaneous melanoma. Dynamic lymphoscintigraphy defines the lymphatic pathways from a primary melanoma site and allows to identify the node receiving lymphatic drainage from the primary tumor, which is the sentinel lymph node. In rare cases, lymphoscintigraphy shows sites of lymphatic drainage in nonclassical basins never described in the past when lymphatic drainage was considered only according to the anatomical proximity of the tumor primary site. These peculiar sentinel nodes, so-called "uncommon/interval" nodes, must be surgically removed because they may contain micrometastatic disease and may be the only site of nodal involvement.

Lymphoscintigraphy Defines New Lymphatic Pathways from Cutaneous Melanoma Site: Clinical Implications and Surgical Management

PubMed Central

Marone, Ugo; Aloj, Luigi; Di Monta, Gianluca; Caracò, Corrado

2011-01-01

Sentinel lymph node biopsy is commonly applied as staging procedure of regional lymph nodes in patients with cutaneous melanoma. Dynamic lymphoscintigraphy defines the lymphatic pathways from a primary melanoma site and allows to identify the node receiving lymphatic drainage from the primary tumor, which is the sentinel lymph node. In rare cases, lymphoscintigraphy shows sites of lymphatic drainage in nonclassical basins never described in the past when lymphatic drainage was considered only according to the anatomical proximity of the tumor primary site. These peculiar sentinel nodes, so-called “uncommon/interval” nodes, must be surgically removed because they may contain micrometastatic disease and may be the only site of nodal involvement. PMID:22242203

Marginal and joint distributions of S100, HMB-45, and Melan-A across a large series of cutaneous melanomas.

PubMed

Viray, Hollis; Bradley, William R; Schalper, Kurt A; Rimm, David L; Gould Rothberg, Bonnie E

2013-08-01

The distribution of the standard melanoma antibodies S100, HMB-45, and Melan-A has been extensively studied. Yet, the overlap in their expression is less well characterized. To determine the joint distributions of the classic melanoma markers and to determine if classification according to joint antigen expression has prognostic relevance. S100, HMB-45, and Melan-A were assayed by immunofluorescence-based immunohistochemistry on a large tissue microarray of 212 cutaneous melanoma primary tumors and 341 metastases. Positive expression for each antigen required display of immunoreactivity for at least 25% of melanoma cells. Marginal and joint distributions were determined across all markers. Bivariate associations with established clinicopathologic covariates and melanoma-specific survival analyses were conducted. Of 322 assayable melanomas, 295 (91.6%), 203 (63.0%), and 236 (73.3%) stained with S100, HMB-45, and Melan-A, respectively. Twenty-seven melanomas, representing a diverse set of histopathologic profiles, were S100 negative. Coexpression of all 3 antibodies was observed in 160 melanomas (49.7%). Intensity of endogenous melanin pigment did not confound immunolabeling. Among primary tumors, associations with clinicopathologic parameters revealed a significant relationship only between HMB-45 and microsatellitosis (P = .02). No significant differences among clinicopathologic criteria were observed across the HMB-45/Melan-A joint distribution categories. Neither marginal HMB-45 (P = .56) nor Melan-A (P = .81), or their joint distributions (P = .88), was associated with melanoma-specific survival. Comprehensive characterization of the marginal and joint distributions for S100, HMB-45, and Melan-A across a large series of cutaneous melanomas revealed diversity of expression across this group of antigens. However, these immunohistochemically defined subclasses of melanomas do not significantly differ according to clinicopathologic correlates or outcome.

Quantitative Proteomics Identifies Activation of Hallmark Pathways of Cancer in Patient Melanoma.

PubMed

Byrum, Stephanie D; Larson, Signe K; Avaritt, Nathan L; Moreland, Linley E; Mackintosh, Samuel G; Cheung, Wang L; Tackett, Alan J

2013-03-01

Molecular pathways regulating melanoma initiation and progression are potential targets of therapeutic development for this aggressive cancer. Identification and molecular analysis of these pathways in patients has been primarily restricted to targeted studies on individual proteins. Here, we report the most comprehensive analysis of formalin-fixed paraffin-embedded human melanoma tissues using quantitative proteomics. From 61 patient samples, we identified 171 proteins varying in abundance among benign nevi, primary melanoma, and metastatic melanoma. Seventy-three percent of these proteins were validated by immunohistochemistry staining of malignant melanoma tissues from the Human Protein Atlas database. Our results reveal that molecular pathways involved with tumor cell proliferation, motility, and apoptosis are mis-regulated in melanoma. These data provide the most comprehensive proteome resource on patient melanoma and reveal insight into the molecular mechanisms driving melanoma progression.

[Multiple conjunctival malignant melanomas (author's transl)].

PubMed

Haddad, R

1979-04-01

5 1/2 years after excision of pigmented malignant melanoma which apparently arose in a nevus of the paralimbal bulbar conjunctiva, this 42-year-old male presented himself with a nonpigmented mass of the lid margin which also proved to be a malignant melanoma. "Acquired melanosis sine pigmento" was considered as a site of origin, but histopathologically there is more evidence that this melanoma arose in a non-pigmented compound nevus.

Multidisciplinary management of very advanced stage III and IV melanoma: Proof-of-principle.

PubMed

Gutman, Haim; Ben-Ami, Eytan; Shapira-Frommer, Roni; Schachter, Jacob

2012-08-01

Patients with potentially resectable advanced stage III and IV melanoma are a selected subgroup that gain maximal advantage if treated in a melanoma center. Surgery combined with chemo/chemobiotherapy may yield durable remission and long-term palliation. Thirty-seven non-randomly selected patients underwent systemic therapy with the aim of consolidating treatment by surgery. Data were collected prospectively, and analyzed retrospectively. The median follow-up from diagnosis was 50 (3-307) months and 15 (1-156) months when calculated from the last intervention. Twenty-two males and 15 females, with a median age at diagnosis of 44 (20-71) years, with 13 trunk, 13 extremity, 3 head and neck and 8 unknown primary melanomas were included. There were 17 stage III and 20 stage IV patients with a median Breslow thickness of 3.7 (0.45-26) mm. Chemo/chemobiotherapy achieved 7 clinical complete responses (cCRs), 28 partial responses (PRs) and 2 instances of stable disease. Six of the 7 cCRs were operated on, securing pathological complete response in 5 and PR in one. Four of these five and the PR patient still have no evidence of disease (NED). Twenty-one of 30 PR patients were rendered NED by surgery; 14 of these 21 patients succumbed to melanoma, and one is alive with stable disease. Overall, 11 of 37 patients have not succumbed to melanoma, with a median of 72 (14-156) months survival following the last intervention. Of the eight patients with unknown primary melanomas, five have not succumbed to melanoma, with a median of 89 (30-156) months survival following the last intervention. Patients with marginally resectable stage III and IV melanoma have a significant 30% chance, according to this series, for durable remission if treated by a multidisciplinary team in a melanoma center using induction chemobiotherapy and surgery. Results are more favorable for patients with an unknown primary lesion. In view of the currently approved new effective treatments for melanoma, this study may be considered a proof-of-principle investigation, enabling long-term remissions by combining induction therapy and surgery.

Lack of relevant information for tumor staging in pathology reports of primary cutaneous melanoma.

PubMed

Busam, K J

2001-05-01

For the T classification of primary cutaneous melanoma, the current American Joint Committee on Cancer staging (AJCC) system relies on tumor thickness and level of invasion. A new T classification has been proposed based on thickness and ulceration. The slides and reports of 135 departmental pathology consultations of patients referred to a major cancer center with a diagnosis of primary cutaneous invasive malignant melanoma were examined. Whether the outside pathology reports contained information on tumor thickness, level of invasion, and ulceration was recorded. Dermatopathologists had issued 76.3% of the reports and general surgical pathologists, 24.3%. Information provided was as follows: tumor thickness, 97.8%; Clark level, 71.9%; and presence or absence of ulceration, 28.1%. Of the 97 melanomas with no comment on ulceration, 17 were indeed ulcerated. Thus, the lack of a comment on ulceration cannot be equated with the absence of ulceration. The present study documents that many pathology reports on melanomas lack sufficient information for AJCC staging. Therefore, review of outside pathology material is necessary not only to confirm or revise the tumor diagnosis but also to provide clinicians with histologic parameters required for AJCC staging.

Dysplastic Nevi and Melanoma

PubMed Central

Goldstein, Alisa M.; Tucker, Margaret A.

2013-01-01

Dysplastic nevi (DN) are described as being on a continuum between common acquired nevi and melanoma because they are morphologically and biologically intermediate between these two entities. Since initially being reported as histologic lesions observed in melanoma-prone families, there has been considerable debate about the definition of dysplastic nevi, the histologic and clinical criteria used to define them, and their biological importance. Their role as precursor lesions for melanoma is not their primary role in their relationship to melanoma because of the rarity of transformation of any individual nevus to a melanoma. Although there is still no single universally agreed upon histologic or clinical definition or even name for these nevi, dysplastic nevi should be considered important because of their association with an increased risk for melanoma. PMID:23549396

Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation

PubMed Central

Badal, Brateil; Solovyov, Alexander; Di Cecilia, Serena; Chan, Joseph Minhow; Chang, Li-Wei; Iqbal, Ramiz; Aydin, Iraz T.; Rajan, Geena S.; Chen, Chen; Abbate, Franco; Arora, Kshitij S.; Tanne, Antoine; Gruber, Stephen B.; Johnson, Timothy M.; Fullen, Douglas R.; Phelps, Robert; Bhardwaj, Nina; Bernstein, Emily; Ting, David T.; Brunner, Georg; Schadt, Eric E.; Greenbaum, Benjamin D.; Celebi, Julide Tok

2017-01-01

BACKGROUND. Melanoma is a heterogeneous malignancy. We set out to identify the molecular underpinnings of high-risk melanomas, those that are likely to progress rapidly, metastasize, and result in poor outcomes. METHODS. We examined transcriptome changes from benign states to early-, intermediate-, and late-stage tumors using a set of 78 treatment-naive melanocytic tumors consisting of primary melanomas of the skin and benign melanocytic lesions. We utilized a next-generation sequencing platform that enabled a comprehensive analysis of protein-coding and -noncoding RNA transcripts. RESULTS. Gene expression changes unequivocally discriminated between benign and malignant states, and a dual epigenetic and immune signature emerged defining this transition. To our knowledge, we discovered previously unrecognized melanoma subtypes. A high-risk primary melanoma subset was distinguished by a 122-epigenetic gene signature (“epigenetic” cluster) and TP53 family gene deregulation (TP53, TP63, and TP73). This subtype associated with poor overall survival and showed enrichment of cell cycle genes. Noncoding repetitive element transcripts (LINEs, SINEs, and ERVs) that can result in immunostimulatory signals recapitulating a state of “viral mimicry” were significantly repressed. The high-risk subtype and its poor predictive characteristics were validated in several independent cohorts. Additionally, primary melanomas distinguished by specific immune signatures (“immune” clusters) were identified. CONCLUSION. The TP53 family of genes and genes regulating the epigenetic machinery demonstrate strong prognostic and biological relevance during progression of early disease. Gene expression profiling of protein-coding and -noncoding RNA transcripts may be a better predictor for disease course in melanoma. This study outlines the transcriptional interplay of the cancer cell’s epigenome with the immune milieu with potential for future therapeutic targeting. FUNDING. National Institutes of Health (CA154683, CA158557, CA177940, CA087497-13), Tisch Cancer Institute, Melanoma Research Foundation, the Dow Family Charitable Foundation, and the Icahn School of Medicine at Mount Sinai. PMID:28469092

The gallium complex KP46 exerts strong activity against primary explanted melanoma cells and induces apoptosis in melanoma cell lines

PubMed Central

Valiahdi, Seied Mojtaba; Heffeter, Petra; Jakupec, Michael A.; Marculescu, Rodrig; Berger, Walter; Rappersberger, Klemens; Keppler, Bernhard K.

2012-01-01

The antineoplastic properties of gallium are well documented. Owing to their robust accumulation of gallium, melanoma cells should be amenable to gallium-based anticancer drugs. With the aim of improving the disappointingly low activity of inorganic gallium salts, we have developed the orally bioavailable gallium complex KP46 [tris(8-quinolinolato)gallium(III)] that was already successfully studied in a phase I clinical trial. To assess its therapeutic potential in malignant melanoma, its antiproliferative effects were investigated in series of human cell lines and primary explanted melanoma samples by means of the MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay and the Human Tumor Cloning Assay, respectively. When compared with other cell lines, the majority of melanoma cells rank among the KP46-sensitive cell lines (50% inhibitory concentration values: 0.8–3.7 μmol/l). Clinically achievable concentrations of KP46 proved to be highly effective in melanoma cells from primary explants of cutaneous and lymph node metastases. Colony growth was inhibited in 10 of 10 specimens by 5 lmol/l KP46 (corresponding to the steady-state plasma concentration measured earlier in a study patient) and in four of 10 specimens by 0.5 μmol/l KP46. In-vitro potency of KP46 is higher than that of dacarbazine or fotemustine and comparable with that of cisplatin. The effects induced by KP46 in melanoma cell lines involve cell cycle perturbations (S-phase arrest) and apoptosis (activation of caspase-9, PARP [poly(ADP-ribose) polymerase] cleavage, formation of apoptotic bodies). No effects on DNA secondary structure could be observed in an electrophoretic mobility shift assay using double-stranded plasmid DNA. Thus, further studies on the therapeutic applicability of KP46 in malignant melanoma are warranted. PMID:19584767

Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing.

PubMed

Sarkar, Debina; Oghabian, Ali; Bodiyabadu, Pasani K; Joseph, Wayne R; Leung, Euphemia Y; Finlay, Graeme J; Baguley, Bruce C; Askarian-Amiri, Marjan E

2017-06-27

The long non-coding RNA ANRIL , antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms. Despite the identification of multiple isoforms of ANRIL , expression of certain transcripts has been found to be tissue-specific and the characterisation of ANRIL transcripts remains incomplete. Several functions have been associated with ANRIL . In our judgement, studies on ANRIL functionality are premature pending a more complete appreciation of the profusion of isoforms. We found differential expression of ANRIL exons, which indicates that multiple isoforms exist in melanoma cells. In addition to linear isoforms, we identified circular forms of ANRIL ( circANRIL ). Further characterisation of circANR IL in two patient-derived metastatic melanoma cell lines (NZM7 and NZM37) revealed the existence of a rich assortment of circular isoforms. Moreover, in the two melanoma cell lines investigated, the complements of circANRIL isoforms were almost completely different. Novel exons were also discovered. We also found the family of linear ANRIL was enriched in the nucleus, whilst the circular isoforms were enriched in the cytoplasm and they differed markedly in stability. With respect to the variable processing of circANRIL species, bioinformatic analysis indicated that intronic Arthrobacter luteus (Alu) restriction endonuclease inverted repeats and exon skipping were not involved in selection of back-spliced exon junctions. Based on our findings, we hypothesise that " ANRIL " has wholly distinct dual sets of functions in melanoma. This reveals the dynamic nature of the locus and constitutes a basis for investigating the functions of ANRIL in melanoma.

Targeting PRMT5 as a Novel Radiosensitization Approach for Primary and Recurrent Prostate Cancer Treatment

DTIC Science & Technology

2015-08-01

6], breast cancer [7], melanoma [8], leukemia and lymphoma [9,10], and glioblastoma [11]. The overexpression of PRMT5 correlatesse 5;NF-Y, Nuclear...multiple human cancers [3 11], though it is unknown how PRMT5 expression is regulated by cancer signaling. In leukemia and lymphoma cells, down...family of tumor suppressors in leukemia and lymphoma cells, Mol. Cell. Biol. 28 (2008) 6262–6277. [10] S. Pal, R.A. Baiocchi, J.C. Byrd, M.R. Grever, S.T

Patterns of regional head and neck lymph node metastasis in primary conjunctival malignant melanoma

PubMed Central

Lim, M; Tatla, T; Hersh, D; Hungerford, J

2006-01-01

Objective To correlate patterns of regional lymph node metastasis with the site of origin in primary conjunctival malignant melanoma. Design Retrospective analysis (1990–2003) of clinical data. Setting Two London tertiary referral centres. Participants 12 patients presenting with regional metastases after failed local treatment for conjunctival malignant melanoma. Results 6 cases predominantly involving the temporal conjunctiva metastasised to the pre‐auricular lymph nodes. Two cases predominantly involving the nasal conjunctiva metastasised to the submandibular nodes. Of the two cases with purely multifocal disease, one metastasised to the pre‐auricular nodes and another to both submandibular and parotid nodes. One primary conjunctival malignant melanoma had its origin in temporal conjunctiva but metastasised to submandibular nodes, and another case originating from nasal conjunctiva metastasised to pre‐auricular nodes. Conclusions Temporal conjunctival melanotic lesions tend to metastasise clinically to pre‐auricular lymph nodes and nasal conjunctival melanotic lesions metastasise to the submandibular lymph nodes. Patterns appear consistent with laboratory‐based anatomically mapped lymphatic drainage basins of the conjunctiva. PMID:16928703

Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II*

PubMed Central

Castro, Luiz Guilherme Martins; Bakos, Renato Marchiori; Duprat Neto, João Pedreira; Bittencourt, Flávia Vasques; Giacomo, Thais Helena Bello Di; Serpa, Sérgio Schrader; Messina, Maria Cristina de Lorenzo; Loureiro, Walter Refkalefsky; Macarenco, Ricardo Silvestre e Silva; Stolf, Hamilton Ometto; Gontijo, Gabriel

2016-01-01

The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed? PMID:26982779

Primary orbital melanoma without ocular involvement in a Balinese cat

PubMed Central

2006-01-01

Abstract A 6.5-year-old spayed female Balinese cat was diagnosed with a large and locally invasive primary orbital melanoma, without ocular involvement or detectable metastatic disease. Advanced imaging and immunohistochemical studies helped in obtaining the diagnosis. Because of advanced unresectable disease and ensuing poor quality of life, the cat was euthanized. PMID:16604977

Primary intranasal melanoma with brain invasion in a dog.

PubMed

Lemetayer, Julie; Al-Dissi, Ahmad; Tryon, Kim; MacDonald-Dickinson, Valerie

2017-04-01

A 6-year-old castrated male boxer dog with right-sided dark purulent nasal discharge and acute bilateral blindness was diagnosed on magnetic resonance imaging (MRI) and then on necropsy with primary nasal malignant melanoma that extended into the brain, as well as concurrent ocular melanosis. There was no evidence of metastasis in other organs.

Primary intranasal melanoma with brain invasion in a dog

PubMed Central

Lemetayer, Julie; Al-Dissi, Ahmad; Tryon, Kim; MacDonald-Dickinson, Valerie

2017-01-01

A 6-year-old castrated male boxer dog with right-sided dark purulent nasal discharge and acute bilateral blindness was diagnosed on magnetic resonance imaging (MRI) and then on necropsy with primary nasal malignant melanoma that extended into the brain, as well as concurrent ocular melanosis. There was no evidence of metastasis in other organs. PMID:28373733

Novel somatic KIT exon 8 mutation with dramatic response to imatinib in a patient with mucosal melanoma: a case report.

PubMed

Rapisuwon, Suthee; Parks, Kellie; Al-Refaie, Waddah; Atkins, Michael B

2014-10-01

Primary mucosal melanomas represent ∼1.3% of all cases of melanoma diagnosed in the USA. The sinonasal location is the most common primary site. Mutations in the KIT gene occur in 10-22% of mucosal melanomas. Tumor response to imatinib mesylate has been reported in about half of the patients with tumors harboring KIT mutations. Responses are almost exclusively restricted to tumors with mutations in KIT exon 9 or 11. We report a case of a patient with a sinonasal mucosal melanoma with a novel exon 8 mutation (C443S) who had marked initial response to imatinib. Somatic exon 8 KIT mutations have not been previously reported in mucosal melanoma or in other human solid tumors; however, such mutations have been reported in canine and feline mast cell tumors. Protein transcripts from exon 8 play an important role in the structural and functional integrity of the extracellular domain of KIT. In preclinical studies, a mutation in exon 8 led to autophosphorylation, independent of KIT ligand, and constitutive activation of the tyrosine kinase. This biology may explain the successful application of imatinib in animals with tumors harboring exon 8 KIT mutations and in our patient with mucosal melanoma. This report expands the population of patients with melanoma who might benefit from imatinib to those with somatic exon 8 KIT mutations. Such mutations should be looked for in patients with mucosal melanoma.

Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma.

PubMed

Pritchard-Jones, R O; Dunn, D B A; Qiu, Y; Varey, A H R; Orlando, A; Rigby, H; Harper, S J; Bates, D O

2007-07-16

Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis - the growth of new vessels from preexisting vasculature - is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF(xxx)b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF(xxx)b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF(xxx)b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) P<0.001 metastatic vs nonmetastatic), irrespective of tumour thickness, while the surrounding epidermis showed no difference in expression. Staining for total VEGF expression showed staining in metastatic and nonmetastatic melanomas, and normal epidermis. An absence of VEGF(xxx)b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

Expression of Antimicrobial Peptides by Uveal and Cutaneous Melanoma Cells and Investigation of Their Role in Tumor Cell Migration and Vasculogenic Mimicry.

PubMed

Manarang, Joseph C; Otteson, Deborah C; McDermott, Alison M

2017-11-01

Antimicrobial peptides (AMPs) have been implicated in the pathogenesis of several cancers, although there is also evidence suggesting potential for novel, AMP-based antitumor therapies. Discerning potential roles of AMPs in tumor pathogenesis may provide valuable insight into the mechanisms of novel AMP-based antitumor therapy. mRNA expression of the AMPs α defensin (HNP-1); cathelicidin (LL-37); and β defensins (hBD-1, hBD-2, hBD-3, hBD-4) in human uveal and cutaneous melanoma cell lines, primary human uveal melanocytes, and primary human uveal melanoma cells was determined by reverse transcriptase polymerase chain reaction. An in vitro scratch assay and custom Matlab analysis were used to determine the AMP effects on melanoma cell migration. Last, the effect of specific AMPs on vasculogenic mimicry was determined by three-dimensional (3D) culture and light and fluorescence microscopy. Low-to-moderate AMP transcript levels were detected, and these varied across the cells tested. Overall, LL-37 expression was increased while hBD-4 was decreased in most melanoma cell lines, compared to primary cultured uveal melanocytes. There was no observable influence of HNP-1 and LL-37 on tumor cell migration. Additionally, aggressive cutaneous melanoma cells grown in 3D cultures exhibited vasculogenic mimicry, although AMP exposure did not alter this process. Collectively, our data show that although AMP mRNA expression is variable between uveal and cutaneous melanoma cells, these peptides have little influence on major characteristics that contribute to tumor aggressiveness and progression.

Locoregional spread of cutaneous melanoma: sonography findings.

PubMed

Catalano, Orlando; Caracò, Corrado; Mozzillo, Nicola; Siani, Alfredo

2010-03-01

This article reviews various aspects of locoregional spread of malignant cutaneous melanoma, as imaged with gray-scale sonography and Doppler techniques. The scenarios illustrated include disease staging (primary melanoma, satellite metastasis, in-transit metastasis, and lymphadenopathies), sentinel lymph node biopsy procedure, patient follow-up, recurrence detection, cutaneous metastasis, and sonographically guided intervention. High-resolution sonography allows recognition of small, clinically-occult melanomatous foci. It plays a major role in locoregional staging and follow-up of patients with cutaneous melanoma.

Prognostic Factors for Survival in Patients Treated With Stereotactic Radiosurgery for Recurrent Brain Metastases After Prior Whole Brain Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caballero, Jorge A.; Sneed, Penny K., E-mail: psneed@radonc.ucsf.edu; Lamborn, Kathleen R.

2012-05-01

Purpose: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT). Methods and Materials: Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS. Results: A total of 310 patients were analyzed, includingmore » 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients. Conclusions: Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS.« less

Intraocular (Eye) Melanoma—Health Professional Version

Cancer.gov

Intraocular (uveal) melanoma of the uveal tract (iris, ciliary body, and choroid), though rare, is the most common primary intraocular malignancy in adults. Find evidence-based information on intraocular melanoma treatment.

Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis

PubMed Central

De Semir, David; Nosrati, Mehdi; Bezrookove, Vladimir; Dar, Altaf A.; Federman, Scot; Bienvenu, Geraldine; Venna, Suraj; Rangel, Javier; Climent, Joan; Meyer Tamgüney, Tanja M.; Thummala, Suresh; Tong, Schuyler; Leong, Stanley P. L.; Haqq, Chris; Billings, Paul; Miller, James R.; Sagebiel, Richard W.; Debs, Robert; Kashani-Sabet, Mohammed

2012-01-01

Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma. PMID:22511720

Genomic analysis and clinical management of adolescent cutaneous melanoma.

PubMed

Rabbie, Roy; Rashid, Mamunur; Arance, Ana M; Sánchez, Marcelo; Tell-Marti, Gemma; Potrony, Miriam; Conill, Carles; van Doorn, Remco; Dentro, Stefan; Gruis, Nelleke A; Corrie, Pippa; Iyer, Vivek; Robles-Espinoza, Carla Daniela; Puig-Butille, Joan A; Puig, Susana; Adams, David J

2017-05-01

Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAF V 600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma-predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable. © 2017 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.

Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition.

PubMed

Blake, Zoë; Marks, Douglas K; Gartrell, Robyn D; Hart, Thomas; Horton, Patti; Cheng, Simon K; Taback, Bret; Horst, Basil A; Saenger, Yvonne M

2018-04-06

Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy. We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab. Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.

Downregulation of miR-125b in metastatic cutaneous malignant melanoma.

PubMed

Glud, Martin; Rossing, Maria; Hother, Christoffer; Holst, Line; Hastrup, Nina; Nielsen, Finn C; Gniadecki, Robert; Drzewiecki, Krzysztof T

2010-12-01

This study aimed to identify microRNA species involved in the earliest metastatic event in cutaneous malignant melanoma (MM). Samples from 28 patients with MM [stage T2 (tumor), M0 (distant metastasis)] were grouped by the presence of micrometastasis in the sentinel lymph nodes (N0/N1). Melanoma cells were harvested from primary, cutaneous MM tumors by laser-capture microdissection, and microRNA expression profiles were obtained by the microarray technique. Results were validated by quantitative reverse transcription PCR. We found that miR-125b was downregulated in the primary cutaneous melanomas that produced early metastases (T2, N1, M0) compared with the sentinel lymph node-negative (T2, N0, M0) melanomas. MiR-125b has earlier been found to be downregulated in other tumor types and in atypic naevi compared with the common acquired naevi. In conclusion, miR-125b may be involved in an early progression of cutaneous MM.

Primary malignant melanoma of the female urethra: Report of a rare neoplasm of the urinary tract.

PubMed

Bhutani, Namita; Kajal, Pradeep; Pawar, Devendra

2017-01-01

Melanoma is a malignant tumor that can affect any area of the anatomical economy. Its occurance in the female urethra is extremely rare. We report a case of primary malignant urethral melanoma developed in an elderly female patient. A 70 years old female presented with dysuria, poor stream, gross haematuria, intermittent blood spots, and a painful mass. On physical examination, there were no suspicious lesions on the skin. On external genital examination, a lesion at the level of the urethral meatus was observed. The mass was removed by wide local excision under spinal anaesthesia. The pathological diagnosis was malignant melanoma of the urethra. The common presentations include bleeding and/or discharge per urethra, voiding dysfunction and the presence of tumor mass. Survival depends on the stage, location and size of the neoplasm at the time of diagnosis. Despite major surgery, radiotherapy or immunotherapy; malignant melanoma usually has a poor prognosis. Melanoma of the female urethra is an extremely uncommon pathology leading to paucity of literature and any definite recommendations regarding management. The histological and immunohistochemical findings can be helpful in making an early and accurate diagnosis of malignant melanoma in the urogenital region. Copyright © 2017. Published by Elsevier Ltd.

Conjunctival amelanotic malignant melanoma arising in primary acquired melanosis sine pigmento.

PubMed

Jay, V; Font, R L

1998-01-01

The authors describe an amelanotic malignant melanoma of the conjunctiva in association with primary acquired melanosis (PAM) sine pigmento, and highlight the clinical and pathologic features of this rare entity. Histopathologic and immunohistochemical studies were performed on a conjunctival tumor in a 54-year-old white woman. Case report. Histopathologic examination revealed an invasive amelanotic melanoma of the conjunctiva, with anterior orbital extension arising from intraepithelial dysplastic melanocytes that lacked melanin pigment (PAM sine pigmento). Both the malignant melanoma cells and the intraepithelial dysplastic melanocytes in the areas of PAM exhibited S-100 and HMB-45 positivity. The patient underwent an orbital exenteration that disclosed tumor within the anterior orbit inferiorly. Amelanotic invasive malignant melanoma can arise in association with PAM sine pigmento, as seen in our patient who had orbital invasion necessitating exenteration. This aggressive form of conjunctival melanoma is often associated with a poor prognosis and risk of metastatic disease. Absence of conjunctival pigmentation in PAM sine pigmento prevents early clinical detection of this variant of PAM. This lack of pigmentation also makes clinical diagnosis virtually impossible, and diagnosis can only be established histopathologically. Awareness of this nonpigmented variety of PAM is crucial for early recognition and appropriate management of the associated melanoma.

Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey.

PubMed

Mikkelsen, Lauge H; Larsen, Ann-Cathrine; von Buchwald, Christian; Drzewiecki, Krzysztof T; Prause, Jan U; Heegaard, Steffen

2016-06-01

Mucosal melanomas constitute 1.3% of all melanomas and they may develop in any mucosal membrane. Conjunctival melanomas (0.5/million/year) and melanomas in the sinonasal cavity (0.5/million/year) are the most common, followed by anorectal melanomas (0.4/million/year) and melanomas in the oral cavity (0.2/million/year). Anorectal melanoma occurs slightly more often in females, whereas oral melanoma has a male predilection. Mucosal melanoma most commonly develops in a patient's sixth or seventh decade of life, and no differences between races have been found except for sinonasal melanoma and conjunctival melanoma, which are very rare in Black people. The symptoms are not tumour-specific and are related to the organ system affected, and the disease is most often diagnosed at an advanced clinical stage. The diagnosis of a primary tumour is difficult, and metastatic cutaneous melanoma and choroidal melanoma must be excluded. Mutations in KIT are frequently found, while BRAF and NRAS mutations are rarely found - except in conjunctival melanomas that carry BRAF mutations. Mutations in the TERT promotor region are also found in mucosal melanomas. Complete surgical resection with free margins is the treatment of choice. The prognosis is poor, with the 5-year survival rate ranging from 0% (gastric melanoma) to 80% (conjunctival melanoma). © 2016 APMIS. Published by John Wiley & Sons Ltd.

Nevus-associated melanomas: clinicopathologic features.

PubMed

Shitara, Danielle; Nascimento, Mauricio M; Puig, Susana; Yamada, Sérgio; Enokihara, Milvia M S S; Michalany, Nilceo; Bagatin, Ediléia

2014-10-01

The clinical significance of nevus-associated melanoma compared with de novo melanomas remains controversial. It has been suggested that nevus-associated melanomas have a higher Breslow thickness and therefore worse prognosis. Over a 10-year period, this study evaluated the incidence of nevus-associated melanoma and its prognostic significance related to clinicopathologic features. Cross-sectional study from 1995 through 2004 in a dermatopathology referral center. With available data, we evaluated sex, primary location, histologic subtype, Breslow thickness, Clark level, presence of ulceration, associated lesion, and histologic subtype of the associated lesion. Of 135,653 pathologic records from skin biopsy specimens over a 10-year period, 1,190 melanoma records were selected. Nevus-associated melanomas corresponded to 390 (32.8%) melanomas, with thin melanomas having a nevus 1.52 times the association observed with thick melanomas (>1.01 mm; 95% confidence interval, 1.16-1.99; P < .001). Superficial spreading melanoma was the most frequent, while no lentigo maligna melanoma was associated with nevi. The median Breslow thickness of nevus-associated melanomas was lower than that of de novo melanomas. Nevus-associated melanomas, which represent one-third of the melanomas in southeast Brazil, are associated with intermittent sun exposure, superficial spreading melanomas, and lower Breslow thickness. This is one of the largest series describing nevus-associated melanomas in Latin America. Copyright© by the American Society for Clinical Pathology.

Growth of melanoma brain tumors monitored by photoacoustic microscopy

NASA Astrophysics Data System (ADS)

Staley, Jacob; Grogan, Patrick; Samadi, Abbas K.; Cui, Huizhong; Cohen, Mark S.; Yang, Xinmai

2010-07-01

Melanoma is a primary malignancy that is known to metastasize to the brain and often causes death. The ability to image the growth of brain melanoma in vivo can provide new insights into its evolution and response to therapies. In our study, we use a reflection mode photoacoustic microscopy (PAM) system to detect the growth of melanoma brain tumor in a small animal model. The melanoma tumor cells are implanted in the brain of a mouse at the beginning of the test. Then, PAM is used to scan the region of implantation in the mouse brain, and the growth of the melanoma is monitored until the death of the animal. It is demonstrated that PAM is capable of detecting and monitoring the brain melanoma growth noninvasively in vivo.

Application of principal component analysis to multispectral imaging data for evaluation of pigmented skin lesions

NASA Astrophysics Data System (ADS)

Jakovels, Dainis; Lihacova, Ilze; Kuzmina, Ilona; Spigulis, Janis

2013-11-01

Non-invasive and fast primary diagnostics of pigmented skin lesions is required due to frequent incidence of skin cancer - melanoma. Diagnostic potential of principal component analysis (PCA) for distant skin melanoma recognition is discussed. Processing of the measured clinical multi-spectral images (31 melanomas and 94 nonmalignant pigmented lesions) in the wavelength range of 450-950 nm by means of PCA resulted in 87 % sensitivity and 78 % specificity for separation between malignant melanomas and pigmented nevi.

Dermoscopy of Melanomas on the Trunk and Extremities in Asians

PubMed Central

Mun, Je-Ho; Ohn, Jungyoon; Kim, Woo-Il; Park, Sung-Min; Kim, Moon-Bum

2016-01-01

The incidence of melanoma among the Asian population is lower compared to that among the Western European population. These populations differed in their most common histopathologic subtypes, acral lentiginous melanoma being the most common in the Asian population. Although the dermoscopic features of the melanomas on the acral skin have been thoroughly investigated in the Asian population, studies concerning the dermoscopic patterns of melanomas on the non-acral skin have been scarce. The aim of this study was to investigate the dermoscopic patterns of melanomas on the trunk and extremities in the Asian population. To achieve this, we evaluated the dermoscopic patterns of 22 primary melanomas diagnosed at two university hospitals in Korea. In addition, 100 benign melanocytic lesions were included as the control group for comparative analysis. A P value less than 0.05 was regarded as statistically significant. Melanoma-associated dermoscopic features such as asymmetry (odds ratio [OR], 30.00), multicolor pattern (OR, 30.12), blotches (OR, 13.50), blue white veils (OR, 15.75), atypical pigment networks (OR, 9.71), irregular peripheral streaks (OR, 6.30), atypical vascular patterns (OR, 11.50), ulcers (OR, 15.83), atypical dots/globules (OR, 3.15), shiny white lines (OR, 5.88), and regression structures (OR, 7.06) were more commonly observed in patients with melanomas than in patients of the control group. The mean dermoscopic scores obtained on the 7-point checklist, revised 7-point checklist, 3-point checklist, ABCD rule, and CASH algorithm were 5.36, 3.41, 2.05, 6.89, and 9.68, respectively, in the primary melanomas, and 1.33, 0.93, 0.46, 2.45, and 3.60, respectively, in the control group (all, P < 0.001). The present study showed that melanoma-related dermoscopic patterns were common in Asian patients. Dermoscopy is a reliable diagnostic tool for the melanomas of the trunk and extremities in the Asian populations. PMID:27391775

Protein B61 as a new growth factor: expression of B61 and up-regulation of its receptor epithelial cell kinase during melanoma progression.

PubMed

Easty, D J; Guthrie, B A; Maung, K; Farr, C J; Lindberg, R A; Toso, R J; Herlyn, M; Bennett, D C

1995-06-15

Epithelial cell kinase (ECK) is a receptor protein tyrosine kinase, the role of which in melanoma biology is unclear. Here we studied the role of ECK during melanoma progression. ECK mRNA was overexpressed in virtually all melanoma lines tested, and levels were significantly higher in cell lines from distant metastases than primary melanomas; melanocytes were negative. Gene amplification was not detected in melanomas. Levels of ECK protein corresponded well with mRNA levels. B61 or LERK-1, recently identified as an ECK ligand, stimulated the growth of ECK-expressing melanoma cell lines, its first identified biological activity. Melanoma chemotaxis and chemoinvasion were not affected by B61. Growth of normal melanocytes was not affected. mRNA for B61 was detected in both melanoma cell lines and normal melanocytes. B61 was also identified by Western blotting and ECK binding activity with the use of a BIAcore binding assay in melanoma cell-conditioned media. These results suggest that B61 is an autocrine growth factor for melanomas but not normal melanocytes.

Proteomic Analysis of Laser Microdissected Melanoma Cells from Skin Organ Cultures

PubMed Central

Hood, Brian L.; Grahovac, Jelena; Flint, Melanie S.; Sun, Mai; Charro, Nuno; Becker, Dorothea; Wells, Alan; Conrads, Thomas P

2010-01-01

Gaining insights into the molecular events that govern the progression from melanoma in situ to advanced melanoma, and understanding how the local microenvironment at the melanoma site influences this progression, are two clinically pivotal aspects that to date are largely unexplored. In an effort to identify key regulators of the crosstalk between melanoma cells and the melanoma-skin microenvironment, primary and metastatic human melanoma cells were seeded into skin organ cultures (SOCs), and grown for two weeks. Melanoma cells were recovered from SOCs by laser microdissection and whole-cell tryptic digests analyzed by nanoflow liquid chromatography-tandem mass spectrometry with an LTQ-Orbitrap. The differential protein abundances were calculated by spectral counting, the results of which provides evidence that cell-matrix and cell-adhesion molecules that are upregulated in the presence of these melanoma cells recapitulate proteomic data obtained from comparative analysis of human biopsies of invasive melanoma and a tissue sample of adjacent, non-involved skin. This concordance demonstrates the value of SOCs for conducting proteomic investigations of the melanoma microenvironment. PMID:20459140

Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck.

PubMed

Thierauf, Julia; Veit, Johannes A; Affolter, Annette; Bergmann, Christoph; Grünow, Jennifer; Laban, Simon; Lennerz, Jochen K; Grünmüller, Lisa; Mauch, Cornelia; Plinkert, Peter K; Hess, Jochen; Hoffmann, Thomas K

2015-12-01

Mucosal melanoma of the head and neck is a rare and aggressive tumor entity with a poor prognosis. The standard treatment is radical tumor resection, with or without adjuvant radiation, where conventional chemotherapies in advanced stage or recurrent diseases have shown little benefit. Overexpression of the programmed cell death ligand 1 (PD-L1) is a common feature in human cancer. Although PD-L1 is an acknowledged prognostic biomarker for dismal prognosis in other tumors of the head and neck, expression and clinical relevance of PD-L1 in mucosal melanoma have not been addressed so far. We assessed PD-L1 expression using immunohistochemical staining in 23 tumor samples from patients with primary mucosal melanoma and correlated expression status with clinicopathological and outcome data. Tumors were derived from the nasal cavity (43.5%), nasal sinuses (43.5%), and the conjunctiva (13%). All patients had undergone surgery; 39% of all patients received adjuvant radiation and 13% were administered systemic interferon therapy. The probability of 1- and 5-year overall survival was 87 and 34.8%, respectively. The mean overall survival was 51 months and the mean recurrence-free survival was 23 months. Immunohistochemical staining showed PD-L1 expression in 13% (3/23) of mucosal melanoma. In contrast, prominent PD-L1 staining was detected in 100% of tissue sections from a control group of cutaneous melanoma (n=9). PD-L1 expression in mucosal melanoma was not correlated with age, sex, nor anatomical localization of the tumor. Interestingly, patients with PD-L1-positive mucosal melanoma had a significantly longer recurrence-free survival (P=0.026). In contrast to cutaneous melanoma and some other malignancies, a relevant PD-L1 overexpression in mucosal melanoma could not be confirmed.

Expression of monoacylglycerol lipase as a marker of tumour invasion and progression in malignant melanoma.

PubMed

Baba, Yuko; Funakoshi, T; Mori, M; Emoto, K; Masugi, Y; Ekmekcioglu, S; Amagai, M; Tanese, K

2017-12-01

Accumulating evidence suggests that the lipid lytic enzyme monoacylglycerol lipase (MAGL) promotes tumour invasion and metastasis through up-regulation of pro-tumorigenic signalling lipids in several tumour cell lines. However, the expression status of MAGL in clinical melanoma tissues and its clinicopathological significance remain unclear. To correlate the tumour expression status of MAGL with the clinicopathological information of patients with malignant melanoma. Polymerase chain reaction (PCR) array screening was performed, and the results were validated using immunocytochemical analysis of tumour and non-tumour melanocytic cell lines. Immunohistochemical staining for MAGL was performed for 74 melanoma samples, including 48 primary and 26 metastatic tumours, in which the expression of MAGL was determined by evaluating the percentage of MAGL-positive tumour cells and the MAGL staining intensity. Finally, we analysed the association of MAGL expression status with tumour progression, tumour thickness and vascular invasion of the primary lesion. Immunocytochemical analysis revealed that MAGL was expressed in all 12 melanoma cell lines, but not in normal human epidermal melanocytes. In the immunohistochemical analysis, positive staining for MAGL was noted in 32 of 48 (64.5%) primary lesions, 14 of 17 (82.4%) lymph node metastatic lesions and 7 of 9 (77.8%) skin metastatic lesions. Metastatic tumours had a significantly higher staining intensity (P = 0.033 for lymph node, P = 0.010 for skin). In the analysis of primary lesions, higher MAGL expression correlated with greater tumour thickness (P = 0.015) and the presence of vascular invasion (P = 0.017). On further evaluation of MAGL-positive primary lesions, staining intensity of MAGL tended to be higher in deeper areas of the tumour mass. The expression of MAGL in tumour cells reflects the aggressiveness of melanoma cells and may serve as a marker of tumour progression. © 2017 European Academy of Dermatology and Venereology.

Genetic progression of malignant melanoma.

PubMed

Tímár, J; Vizkeleti, L; Doma, V; Barbai, T; Rásó, E

2016-03-01

Malignant melanoma of the skin is the most aggressive human cancer given that a primary tumor a few millimeters in diameter frequently has full metastatic competence. In view of that, revealing the genetic background of this potential may also help to better understand tumor dissemination in general. Genomic analyses have established the molecular classification of melanoma based on the most frequent driver oncogenic mutations (BRAF, NRAS, KIT) and have also revealed a long list of rare events, including mutations and amplifications as well as genetic microheterogeneity. At the moment, it is unclear whether any of these rare events have role in the metastasis initiation process since the major drivers do not have such a role. During lymphatic and hematogenous dissemination, the clonal selection process is evidently reflected by differences in oncogenic drivers in the metastases versus the primary tumor. Clonal selection is also evident during lymphatic progression, though the genetic background of this immunoselection is less clear. Genomic analyses of metastases identified further genetic alterations, some of which may correspond to metastasis maintenance genes. The natural genetic progression of melanoma can be modified by targeted (BRAF or MEK inhibitor) or immunotherapies. Some of the rare events in primary tumors may result in primary resistance, while further new genetic lesions develop during the acquired resistance to both targeted and immunotherapies. Only a few genetic lesions of the primary tumor are constant during natural or therapy-modulated progression. EGFR4 and NMDAR2 mutations, MITF and MET amplifications and PTEN loss can be considered as metastasis drivers. Furthermore, BRAF and MITF amplifications as well as PTEN loss are also responsible for resistance to targeted therapies, whereas NRAS mutation is the only founder genetic lesion showing any association with sensitivity to immunotherapies. Unfortunately, there are hardly any data on the possible organ-specific metastatic drivers in melanoma. These observations suggest that clinical management of melanoma patients must rely on the genetic analysis of the metastatic lesions to be able to monitor progression-associated changes and to personalize therapies.

Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma

PubMed Central

Taylor, Nicholas J.; Thomas, Nancy E.; Anton-Culver, Hoda; Armstrong, Bruce K.; Begg, Colin B.; Busam, Klaus J.; Cust, Anne E.; Dwyer, Terence; From, Lynn; Gallagher, Richard P.; Gruber, Stephen B.; Nishri, Diane E.; Orlow, Irene; Rosso, Stefano; Venn, Alison J.; Zanetti, Roberto; Berwick, Marianne; Kanetsky, Peter A.

2016-01-01

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment, and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics, and we assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis and inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features. PMID:27101944

The effect of multiple primary rules on population-based cancer survival

PubMed Central

Weir, Hannah K.; Johnson, Christopher J.; Thompson, Trevor D.

2015-01-01

Purpose Different rules for registering multiple primary (MP) cancers are used by cancer registries throughout the world, making international data comparisons difficult. This study evaluates the effect of Surveillance, Epidemiology, and End Results (SEER) and International Association of Cancer Registries (IACR) MP rules on population-based cancer survival estimates. Methods Data from five US states and six metropolitan area cancer registries participating in the SEER Program were used to estimate age-standardized relative survival (RS%) for first cancers-only and all first cancers matching the selection criteria according to SEER and IACR MP rules for all cancer sites combined and for the top 25 cancer site groups among men and women. Results During 1995–2008, the percentage of MP cancers (all sites, both sexes) increased 25.4 % by using SEER rules (from 14.6 to 18.4 %) and 20.1 % by using IACR rules (from 13.2 to 15.8 %). More MP cancers were registered among females than among males, and SEER rules registered more MP cancers than IACR rules (15.8 vs. 14.4 % among males; 17.2 vs. 14.5 % among females). The top 3 cancer sites with the largest differences were melanoma (5.8 %), urinary bladder (3.5 %), and kidney and renal pelvis (2.9 %) among males, and breast (5.9 %), melanoma (3.9 %), and urinary bladder (3.4 %) among females. Five-year survival estimates (all sites combined) restricted to first primary cancers-only were higher than estimates by using first site-specific primaries (SEER or IACR rules), and for 11 of 21 sites among males and 11 of 23 sites among females. SEER estimates are comparable to IACR estimates for all site-specific cancers and marginally higher for all sites combined among females (RS 62.28 vs. 61.96 %). Conclusion Survival after diagnosis has improved for many leading cancers. However, cancer patients remain at risk of subsequent cancers. Survival estimates based on first cancers-only exclude a large and increasing number of MP cancers. To produce clinically and epidemiologically relevant and less biased cancer survival estimates, data on all cancers should be included in the analysis. The multiple primary rules (SEER or IACR) used to identify primary cancers do not affect survival estimates if all first cancers matching the selection criteria are used to produce site-specific survival estimates. PMID:23558444

Development and External Validation of a Melanoma Risk Prediction Model Based on Self-assessed Risk Factors.

PubMed

Vuong, Kylie; Armstrong, Bruce K; Weiderpass, Elisabete; Lund, Eiliv; Adami, Hans-Olov; Veierod, Marit B; Barrett, Jennifer H; Davies, John R; Bishop, D Timothy; Whiteman, David C; Olsen, Catherine M; Hopper, John L; Mann, Graham J; Cust, Anne E; McGeechan, Kevin

2016-08-01

Identifying individuals at high risk of melanoma can optimize primary and secondary prevention strategies. To develop and externally validate a risk prediction model for incident first-primary cutaneous melanoma using self-assessed risk factors. We used unconditional logistic regression to develop a multivariable risk prediction model. Relative risk estimates from the model were combined with Australian melanoma incidence and competing mortality rates to obtain absolute risk estimates. A risk prediction model was developed using the Australian Melanoma Family Study (629 cases and 535 controls) and externally validated using 4 independent population-based studies: the Western Australia Melanoma Study (511 case-control pairs), Leeds Melanoma Case-Control Study (960 cases and 513 controls), Epigene-QSkin Study (44 544, of which 766 with melanoma), and Swedish Women's Lifestyle and Health Cohort Study (49 259 women, of which 273 had melanoma). We validated model performance internally and externally by assessing discrimination using the area under the receiver operating curve (AUC). Additionally, using the Swedish Women's Lifestyle and Health Cohort Study, we assessed model calibration and clinical usefulness. The risk prediction model included hair color, nevus density, first-degree family history of melanoma, previous nonmelanoma skin cancer, and lifetime sunbed use. On internal validation, the AUC was 0.70 (95% CI, 0.67-0.73). On external validation, the AUC was 0.66 (95% CI, 0.63-0.69) in the Western Australia Melanoma Study, 0.67 (95% CI, 0.65-0.70) in the Leeds Melanoma Case-Control Study, 0.64 (95% CI, 0.62-0.66) in the Epigene-QSkin Study, and 0.63 (95% CI, 0.60-0.67) in the Swedish Women's Lifestyle and Health Cohort Study. Model calibration showed close agreement between predicted and observed numbers of incident melanomas across all deciles of predicted risk. In the external validation setting, there was higher net benefit when using the risk prediction model to classify individuals as high risk compared with classifying all individuals as high risk. The melanoma risk prediction model performs well and may be useful in prevention interventions reliant on a risk assessment using self-assessed risk factors.

Exophytic Tumor Growth After Incomplete Removal of Polypoid Malignant Melanoma of the Maxillary Gingiva: A Case Report and Review of the Literature.

PubMed

Taga, Tomoharu; Nonaka, Taichiro; Manabe, Toshiaki; Bessho, Kazuhisa

2016-11-01

Polypoid malignant melanoma of the oral cavity is extremely rare. This report describes the case of the 3-time occurrence of a polypoid malignant melanoma of the maxillary gingiva in an 84-year-old woman who had removed the primary tumor by herself. The second polypoid malignant melanoma was a black 7-cm pedunculated mass surrounded by pigmented mucosa. Histologically, the tumor exhibited an ulcerated surface lined by squamous cells and contained polygonal cells with brown-and-black pigmentation. The third polypoid malignant melanoma was observed at the same location 7 months after surgery; it was a black hemorrhagic mass approximately 1.5 cm. Histologic analysis showed morphologic findings that were similar to those observed in the second polypoid melanoma. The patient died of lung metastasis 28 months after the second surgery. This report also reviews the 5 previously reported cases of polypoid malignant melanoma of the oral cavity, all of which occurred in the upper jaw. In 2 cases, initial exophytic growth of the tumor before invasion of the submucosa and relatively early detection resulted in a good prognosis. However, in 1 case, amelanotic melanoma located in the periodontal tissues was clinically misdiagnosed as epulis. Therefore, immunostaining for S-100 and HMB-45 should be considered for nonpigmented epulis-like lesions, and wide surgical resection of primary polypoid malignant melanomas at an early stage should result in a favorable prognosis. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Serum microRNAs as biomarkers for recurrence in melanoma

PubMed Central

2012-01-01

Background Identification of melanoma patients at high risk for recurrence and monitoring for recurrence are critical for informed management decisions. We hypothesized that serum microRNAs (miRNAs) could provide prognostic information at the time of diagnosis unaccounted for by the current staging system and could be useful in detecting recurrence after resection. Methods We screened 355 miRNAs in sera from 80 melanoma patients at primary diagnosis (discovery cohort) using a unique quantitative reverse transcription-PCR (qRT-PCR) panel. Cox proportional hazard models and Kaplan-Meier recurrence-free survival (RFS) curves were used to identify a miRNA signature with prognostic potential adjusting for stage. We then tested the miRNA signature in an independent cohort of 50 primary melanoma patients (validation cohort). Logistic regression analysis was performed to determine if the miRNA signature can determine risk of recurrence in both cohorts. Selected miRNAs were measured longitudinally in subsets of patients pre-/post-operatively and pre-/post-recurrence. Results A signature of 5 miRNAs successfully classified melanoma patients into high and low recurrence risk groups with significant separation of RFS in both discovery and validation cohorts (p = 0.0036, p = 0.0093, respectively). Significant separation of RFS was maintained when a logistic model containing the same signature set was used to predict recurrence risk in both discovery and validation cohorts (p < 0.0001, p = 0.033, respectively). Longitudinal expression of 4 miRNAs in a subset of patients was dynamic, suggesting miRNAs can be associated with tumor burden. Conclusion Our data demonstrate that serum miRNAs can improve accuracy in identifying primary melanoma patients with high recurrence risk and in monitoring melanoma tumor burden over time. PMID:22857597

MGDB: a comprehensive database of genes involved in melanoma.

PubMed

Zhang, Di; Zhu, Rongrong; Zhang, Hanqian; Zheng, Chun-Hou; Xia, Junfeng

2015-01-01

The Melanoma Gene Database (MGDB) is a manually curated catalog of molecular genetic data relating to genes involved in melanoma. The main purpose of this database is to establish a network of melanoma related genes and to facilitate the mechanistic study of melanoma tumorigenesis. The entries describing the relationships between melanoma and genes in the current release were manually extracted from PubMed abstracts, which contains cumulative to date 527 human melanoma genes (422 protein-coding and 105 non-coding genes). Each melanoma gene was annotated in seven different aspects (General Information, Expression, Methylation, Mutation, Interaction, Pathway and Drug). In addition, manually curated literature references have also been provided to support the inclusion of the gene in MGDB and establish its association with melanoma. MGDB has a user-friendly web interface with multiple browse and search functions. We hoped MGDB will enrich our knowledge about melanoma genetics and serve as a useful complement to the existing public resources. Database URL: http://bioinfo.ahu.edu.cn:8080/Melanoma/index.jsp. © The Author(s) 2015. Published by Oxford University Press.

Pleiotropic and Sex-Specific Effects of Cancer GWAS SNPs on Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study

PubMed Central

Kocarnik, Jonathan M.; Park, S. Lani; Han, Jiali; Dumitrescu, Logan; Cheng, Iona; Wilkens, Lynne R.; Schumacher, Fredrick R.; Kolonel, Laurence; Carlson, Chris S.; Crawford, Dana C.; Goodloe, Robert J.; Dilks, Holli H.; Baker, Paxton; Richardson, Danielle; Matise, Tara C.; Ambite, José Luis; Song, Fengju; Qureshi, Abrar A.; Zhang, Mingfeng; Duggan, David; Hutter, Carolyn; Hindorff, Lucia; Bush, William S.; Kooperberg, Charles; Le Marchand, Loic; Peters, Ulrike

2015-01-01

Background Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. Methods We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. Results We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). Conclusions We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes. PMID:25789475

Biology of advanced uveal melanoma and next steps for clinical therapeutics.

PubMed

Luke, Jason J; Triozzi, Pierre L; McKenna, Kyle C; Van Meir, Erwin G; Gershenwald, Jeffrey E; Bastian, Boris C; Gutkind, J Silvio; Bowcock, Anne M; Streicher, Howard Z; Patel, Poulam M; Sato, Takami; Sossman, Jeffery A; Sznol, Mario; Welch, Jack; Thurin, Magdalena; Selig, Sara; Flaherty, Keith T; Carvajal, Richard D

2015-03-01

Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherapies are reviewed, and next steps in the development of clinical therapeutics are discussed. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Combined BRAF and HSP90 inhibition in patients with unresectable BRAF V600E mutant melanoma.

PubMed

Eroglu, Zeynep; Chen, Yian Ann; Gibney, Geoffrey T; Weber, Jeffrey S; Kudchadkar, Ragini R; Khushalani, Nikhil I; Markowitz, Joseph; Brohl, Andrew S; Tetteh, Leticia F; Ramadan, Howida; Arnone, Gina; Li, Jiannong; Zhao, Xiuhua; Sharma, Ritin; Darville, Lancia N F; Fang, Bin; Smalley, Inna; Messina, Jane L; Koomen, John M; Sondak, Vernon K; Smalley, Keiran S M

2018-04-19

BRAF inhibitors are clinically active in patients with advanced BRAF V600 -mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. Vemurafenib (960 mg PO BID) combined with escalating doses of XL888 (30, 45, 90 or 135 mg PO twice weekly) was investigated in 21 patients with advanced BRAF V600 -mutant melanoma. Primary endpoints were safety and determination of a maximum tolerated dose. Correlative proteomic studies were performed to confirm HSP inhibitor activity. Objective responses were observed in 15/20 evaluable patients (75%; 95% CI: 51-91%), with 3 complete and 12 partial responses. Median progression-free and overall survival were 9.2 months (95% CI: 3.8-not reached) and 34.6 months (6.2-not reached), respectively. The most common grade 3/4 toxicities were skin toxicities such as rash (n=4, 19%) and cutaneous squamous cell carcinomas (n=3, 14%), along with diarrhea (n=3, 14%). Pharmacodynamic analysis of patients' PBMCs showed increased day 8 HSP70 expression compared to baseline in the three cohorts with XL888 doses ≥45 mg. Diverse effects of vemurafenib-XL888 upon intratumoral HSP-client protein expression were noted, with the expression of multiple proteins (including ERBB3 and BAD) modulated on therapy. XL888 in combination with vemurafenib has clinical activity in patients with advanced BRAF V600 -mutant melanoma, with a tolerable side-effect profile. HSP90 inhibitors warrant further evaluation in combination with current standard-of-care BRAF plus MEK inhibitors in BRAF V600 -mutant melanoma. Copyright ©2018, American Association for Cancer Research.

Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

PubMed Central

Simpson, R Mark; Bastian, Boris C; Michael, Helen T; Webster, Joshua D; Prasad, Manju L; Conway, Catherine M; Prieto, Victor M; Gary, Joy M; Goldschmidt, Michael H; Esplin, D Glen; Smedley, Rebecca C; Piris, Adriano; Meuten, Donald J; Kiupel, Matti; Lee, Chyi-Chia R; Ward, Jerrold M; Dwyer, Jennifer E; Davis, Barbara J; Anver, Miriam R; Molinolo, Alfredo A; Hoover, Shelley B; Rodriguez-Canales, Jaime; Hewitt, Stephen M

2014-01-01

Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. PMID:24128326

The effect of multiple primary rules on cancer incidence rates and trends

PubMed Central

Weir, Hannah K.; Johnson, Christopher J.; Ward, Kevin C.; Coleman, Michel P.

2018-01-01

Purpose An examination of multiple primary cancers can provide insight into the etiologic role of genes, the environment, and prior cancer treatment on a cancer patient’s risk of developing a subsequent cancer. Different rules for registering multiple primary cancers (MP) are used by cancer registries throughout the world making data comparisons difficult. Methods We evaluated the effect of SEER and IARC/IACR rules on cancer incidence rates and trends using data from the SEER Program. We estimated age-standardized incidence rate (ASIR) and trends (1975–2011) for the top 26 cancer categories using joinpoint regression analysis. Results ASIRs were higher using SEER compared to IARC/IACR rules for all cancers combined (3 %) and, in rank order, melanoma (9 %), female breast (7 %), urinary bladder (6 %), colon (4 %), kidney and renal pelvis (4 %), oral cavity and pharynx (3 %), lung and bronchus (2 %), and non-Hodgkin lymphoma (2 %). ASIR differences were largest for patients aged 65+ years. Trends were similar using both MP rules with the exception of cancers of the urinary bladder, and kidney and renal pelvis. Conclusions The choice of multiple primary coding rules effects incidence rates and trends. Compared to SEER MP coding rules, IARC/IACR rules are less complex, have not changed over time, and report fewer multiple primary cancers, particularly cancers that occur in paired organs, at the same anatomic site and with the same or related histologic type. Cancer registries collecting incidence data using SEER rules may want to consider including incidence rates and trends using IARC/IACR rules to facilitate international data comparisons. PMID:26809509

CD200 is induced by ERK and is a potential therapeutic target in melanoma

PubMed Central

Petermann, Kimberly B.; Rozenberg, Gabriela I.; Zedek, Daniel; Groben, Pamela; McKinnon, Karen; Buehler, Christin; Kim, William Y.; Shields, Janiel M.; Penland, Shannon; Bear, James E.; Thomas, Nancy E.; Serody, Jonathan S.; Sharpless, Norman E.

2007-01-01

Immune-mediated antitumor responses occur in patients with metastatic melanoma (MM), and therapies designed to augment such responses are clinically beneficial. Despite the immunogenicity of melanoma, immunomodulatory therapies fail in the majority of patients with MM. An inability of DCs to sufficiently activate effector cells may, in part, underlie this failure of the antitumor response seen in most patients. In this work, we show that mutation of N-RAS or B-RAF, signature genetic lesions present in most MMs, potently induced the expression of cell-surface CD200, a repressor of DC function. Employing 2 independent, genome-wide microarray analyses, we identified CD200 as a highly dynamic, downstream target of RAS/RAF/MEK/ERK activation in melanoma. CD200 protein was similarly overexpressed in human melanoma cell lines and primary tumors. CD200 mRNA expression correlated with progression and was higher in melanoma than in other solid tumors or acute leukemia. Melanoma cell lines expressing endogenous CD200 repressed primary T cell activation by DCs, while knockdown of CD200 by shRNA abrogated this immunosuppressive effect. These data indicate that in addition to its effects on growth, survival, and motility, ERK activation in MM attenuates a host antitumor immune response, implicating CD200 and its interaction with the CD200 receptor as a potential therapeutic target for MM. PMID:18008004

CD63 tetraspanin is a negative driver of epithelial-to-mesenchymal transition in human melanoma cells.

PubMed

Lupia, Antonella; Peppicelli, Silvia; Witort, Ewa; Bianchini, Francesca; Carloni, Vinicio; Pimpinelli, Nicola; Urso, Carmelo; Borgognoni, Lorenzo; Capaccioli, Sergio; Calorini, Lido; Lulli, Matteo

2014-12-01

The CD63 tetraspanin is highly expressed in the early stages of melanoma and decreases in advanced lesions, suggesting it as a possible suppressor of tumor progression. We employed loss- and gain-of-gene-function approaches to investigate the role of CD63 in melanoma progression and acquisition of the epithelial-to-mesenchymal transition (EMT) program. We used two human melanoma cell lines derived from primary tumors and one primary human melanoma cell line isolated from a cutaneous metastasis, differing by levels of CD63 expression. CD63-silenced melanoma cells showed enhanced motility and invasiveness with downregulation of E-cadherin and upregulation of N-cadherin and Snail. In parallel experiments, transient and stable ectopic expression of CD63 resulted in a robust reduction of cell motility, invasiveness, and protease activities, which was proportional to the increase in CD63 protein level. Transfected cells overexpressing the highest level of CD63 when transplanted into immunodeficient mice showed a reduced incidence and rate of tumor growth. Moreover, these cells showed a reduction of N-cadherin, Vimentin, Zeb1, and a-SMA, and a significant resistance to undergo an EMT program both in basal condition and in the following stimulation with TGFβ. Thus, our results establish a previously unreported mechanistic link between the tetraspanin CD63 and EMT abrogation in melanoma.

Validating malignant melanoma ICD-9-CM codes in Umbria, ASL Napoli 3 Sud and Friuli Venezia Giulia administrative healthcare databases: a diagnostic accuracy study.

PubMed

Orso, Massimiliano; Serraino, Diego; Abraha, Iosief; Fusco, Mario; Giovannini, Gianni; Casucci, Paola; Cozzolino, Francesco; Granata, Annalisa; Gobbato, Michele; Stracci, Fabrizio; Ciullo, Valerio; Vitale, Maria Francesca; Eusebi, Paolo; Orlandi, Walter; Montedori, Alessandro; Bidoli, Ettore

2018-04-20

To assess the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in identifying subjects with melanoma. A diagnostic accuracy study comparing melanoma ICD-9-CM codes (index test) with medical chart (reference standard). Case ascertainment was based on neoplastic lesion of the skin and a histological diagnosis from a primary or metastatic site positive for melanoma. Administrative databases from Umbria Region, Azienda Sanitaria Locale (ASL) Napoli 3 Sud (NA) and Friuli Venezia Giulia (FVG) Region. 112, 130 and 130 cases (subjects with melanoma) were randomly selected from Umbria, NA and FVG, respectively; 94 non-cases (subjects without melanoma) were randomly selected from each unit. Sensitivity and specificity for ICD-9-CM code 172.x located in primary position. The most common melanoma subtype was malignant melanoma of skin of trunk, except scrotum (ICD-9-CM code: 172.5), followed by malignant melanoma of skin of lower limb, including hip (ICD-9-CM code: 172.7). The mean age of the patients ranged from 60 to 61 years. Most of the diagnoses were performed in surgical departments.The sensitivities were 100% (95% CI 96% to 100%) for Umbria, 99% (95% CI 94% to 100%) for NA and 98% (95% CI 93% to 100%) for FVG. The specificities were 88% (95% CI 80% to 93%) for Umbria, 77% (95% CI 69% to 85%) for NA and 79% (95% CI 71% to 86%) for FVG. The case definition for melanoma based on clinical or instrumental diagnosis, confirmed by histological examination, showed excellent sensitivities and good specificities in the three operative units. Administrative databases from the three operative units can be used for epidemiological and outcome research of melanoma. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Expression of Vitamin D-Activating Enzyme 1α-Hydroxylase (CYP27B1) Decreases during Melanoma Progression**

PubMed Central

Brożyna, Anna A.; Jóźwicki, Wojciech; Janjetovic, Zorica; Slominski, Andrzej T.

2012-01-01

Summary 1α-Hydroxylase (CYP27B1), the enzyme responsible for the synthesis of the biologically active form of vitamin D (1,25(OH)2D3), is expressed in the skin. To assess the correlation between progression of melanocytic tumors and CYP27B1, we analyzed its expression in 29 benign nevi, 75 primary cutaneous melanomas, 40 metastases, and 4 re-excision and 6 normal skin biopsies. Immunoreactivity for CYP27B1 was significantly lower in the vertical growth phase (VGP) and metastatic melanomas (0.6 and 0.5 arbitrary units [AU], respectively) in comparison with nevi and radial growth phase (RGP) tumors (1.2 and 1.1 AU, respectively); and expression was reduced in more advanced lesions (Clark levels III–V, Breslow thickness ≥2.1 mm; 0.8 and 0.7 AU, respectively). There was an inverse correlation between CYP27B1 and Ki-67 expression. Furthermore, CYP27B1 expression was reduced in primary melanomas that created metastases in comparison with non-metastasizing melanomas. Reduced CYP27B1 expression in RGP was related to shorter overall survival (810 vs 982 vs 1151 days in melanomas with absent, low, and high CYP27B1 immunoreactivity), and low CYP27B1 expression in RGP and VGP was related to shorter disease-free survival (114 vs 339 vs 737 days and 129 vs 307 vs 737 days, respectively, in melanomas with absent, low, and high CYP27B1). Also, CYP27B1 expression was inversely related to melanin in melanoma cells in vivo and melanoma cells cultured in vitro. Thus, reduction of CYP27B1 correlates with melanoma phenotype and behavior, and its lack affects the survival of melanoma patients, indicating a role in the pathogenesis and progression of this cancer. PMID:22995334

Validating malignant melanoma ICD-9-CM codes in Umbria, ASL Napoli 3 Sud and Friuli Venezia Giulia administrative healthcare databases: a diagnostic accuracy study

PubMed Central

Orso, Massimiliano; Serraino, Diego; Fusco, Mario; Giovannini, Gianni; Casucci, Paola; Cozzolino, Francesco; Granata, Annalisa; Gobbato, Michele; Stracci, Fabrizio; Ciullo, Valerio; Vitale, Maria Francesca; Orlandi, Walter; Montedori, Alessandro; Bidoli, Ettore

2018-01-01

Objectives To assess the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes in identifying subjects with melanoma. Design A diagnostic accuracy study comparing melanoma ICD-9-CM codes (index test) with medical chart (reference standard). Case ascertainment was based on neoplastic lesion of the skin and a histological diagnosis from a primary or metastatic site positive for melanoma. Setting Administrative databases from Umbria Region, Azienda Sanitaria Locale (ASL) Napoli 3 Sud (NA) and Friuli Venezia Giulia (FVG) Region. Participants 112, 130 and 130 cases (subjects with melanoma) were randomly selected from Umbria, NA and FVG, respectively; 94 non-cases (subjects without melanoma) were randomly selected from each unit. Outcome measures Sensitivity and specificity for ICD-9-CM code 172.x located in primary position. Results The most common melanoma subtype was malignant melanoma of skin of trunk, except scrotum (ICD-9-CM code: 172.5), followed by malignant melanoma of skin of lower limb, including hip (ICD-9-CM code: 172.7). The mean age of the patients ranged from 60 to 61 years. Most of the diagnoses were performed in surgical departments. The sensitivities were 100% (95% CI 96% to 100%) for Umbria, 99% (95% CI 94% to 100%) for NA and 98% (95% CI 93% to 100%) for FVG. The specificities were 88% (95% CI 80% to 93%) for Umbria, 77% (95% CI 69% to 85%) for NA and 79% (95% CI 71% to 86%) for FVG. Conclusions The case definition for melanoma based on clinical or instrumental diagnosis, confirmed by histological examination, showed excellent sensitivities and good specificities in the three operative units. Administrative databases from the three operative units can be used for epidemiological and outcome research of melanoma. PMID:29678984

Targeted Silencing of MART-1 Gene Expression by RNA Interference Enhances the Migration Ability of Uveal Melanoma Cells

PubMed Central

Zhang, Yidan; Jia, Renbing; Wang, Jing; Xu, Xiaofang; Yao, Yuting; Ge, Shengfan; Fan, Xianqun

2013-01-01

Uveal melanoma (UM) is the most common primary intraocular malignancy and the leading potentially fatal primary intraocular disease in adults. Melanoma antigen recognized by T-cells (MART-1) has been studied extensively as a clinically important diagnostic marker for melanoma, however, its biological function remains unclear. In the present study, the UM cell line SP6.5, which showed a high level of MART-1 expression, was subjected to small interfering RNA-mediated silencing of MART-1. Silencing of MART-1 expression increased the migration ability of SP6.5 cells and down-regulated the expression of the metastasis suppressor NM23. Our results suggest that MART-1 is a candidate target for the development of therapeutic strategies for UM and in particular for the suppression of metastasis associated with this malignancy. PMID:23877836

VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers.

PubMed

Bartolomé, Rubén A; Torres, Sofía; Isern de Val, Soledad; Escudero-Paniagua, Beatriz; Calviño, Eva; Teixidó, Joaquín; Casal, J Ignacio

2017-01-03

We have investigated the role of vascular-endothelial (VE)-cadherin in melanoma and breast cancer metastasis. We found that VE-cadherin is expressed in highly aggressive melanoma and breast cancer cell lines. Remarkably, inactivation of VE-cadherin triggered a significant loss of malignant traits (proliferation, adhesion, invasion and transendothelial migration) in melanoma and breast cancer cells. These effects, except transendothelial migration, were induced by the VE-cadherin RGD motifs. Co-immunoprecipitation experiments demonstrated an interaction between VE-cadherin and α2β1 integrin, with the RGD motifs found to directly affect β1 integrin activation. VE-cadherin-mediated integrin signaling occurred through specific activation of SRC, ERK and JNK, including AKT in melanoma. Knocking down VE-cadherin suppressed lung colonization capacity of melanoma or breast cancer cells inoculated in mice, while pre-incubation with VE-cadherin RGD peptides promoted lung metastasis for both cancer types. Finally, an in silico study revealed the association of high VE-cadherin expression with poor survival in a subset of melanoma patients and breast cancer patients showing low CD34 expression. These findings support a general role for VE-cadherin and other RGD cadherins as critical regulators of lung and liver metastasis in multiple solid tumours. These results pave the way for cadherin-specific RGD targeted therapies to control disseminated metastasis in multiple cancers.

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma

NASA Astrophysics Data System (ADS)

Bald, Tobias; Quast, Thomas; Landsberg, Jennifer; Rogava, Meri; Glodde, Nicole; Lopez-Ramos, Dorys; Kohlmeyer, Judith; Riesenberg, Stefanie; van den Boorn-Konijnenberg, Debby; Hömig-Hölzel, Cornelia; Reuten, Raphael; Schadow, Benjamin; Weighardt, Heike; Wenzel, Daniela; Helfrich, Iris; Schadendorf, Dirk; Bloch, Wilhelm; Bianchi, Marco E.; Lugassy, Claire; Barnhill, Raymond L.; Koch, Manuel; Fleischmann, Bernd K.; Förster, Irmgard; Kastenmüller, Wolfgang; Kolanus, Waldemar; Hölzel, Michael; Gaffal, Evelyn; Tüting, Thomas

2014-03-01

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.

Melanoma survivorship: research opportunities.

PubMed

Oliveria, Susan A; Hay, Jennifer L; Geller, Alan C; Heneghan, Maureen K; McCabe, Mary S; Halpern, Allan C

2007-03-01

The rising incidence and mortality rates of melanoma, the most fatal form of skin cancer, are among the greatest increases of all preventable cancers over the past decade. However, because of recent advances in early detection, secondary prevention efforts, and treatment, the number of melanoma survivors is increasing. Little research has been conducted on melanoma survivors and important opportunities exist for research in this understudied population. Here, we outline the important research opportunities related to the study of melanoma survivorship and summarize the paucity of literature currently available. A computerized literature search was performed of the MEDLINE database of the National Library of Medicine from 1966-2005. The scope of the search was limited to those studies published in English. The search was conducted using the following MeSH headings: melanoma, neoplasms, skin neoplasms, survival, and survival rate. The reference lists of relevant book chapters and review articles were further reviewed, and printed materials from recent scientific meetings addressing this topic were obtained. Several factors that affect melanoma survivors warrant further study, including: physiologic long-term effects; psychosocial, behavioral, and cognitive factors; demographic characteristics; surveillance practices; recurrences, secondary primaries, and other cancers; family members of survivors; and economic issues, access to health care/life insurance. Understanding recurrence and second primary cancer risk, psychosocial and cognitive characteristics, behaviors, surveillance patterns, economic sequelae, and family issues of melanoma survivors is important from a public health standpoint to promote the health and well-being of this cohort. Melanoma is an understudied cancer, and the incidence and mortality of this disease are increasing. Describing the long term burden of this cancer and identifying factors that contribute to them will facilitate efforts to develop responsive secondary prevention strategies.

Integrated Cancer Repository for Cancer Research

ClinicalTrials.gov

2017-05-05

Pancreatic Cancer; Thyroid Cancer; Lung Cancer; Esophageal Cancer; Thymus Cancer; Colon Cancer; Rectal Cancer; GIST; Anal Cancer; Bile Duct Cancer; Duodenal Cancer; Gallbladder Cancer; Gastric Cancer; Liver Cancer; Small Intestine Cancer; Peritoneal Surface Malignancies; Familial Adenomatous Polyposis; Lynch Syndrome; Bladder Cancer; Kidney Cancer; Penile Cancer; Prostate Cancer; Testicular Cancer; Ureter Cancer; Urethral Cancer; Hypopharyngeal Cancer; Laryngeal Cancer; Lip Cancer; Oral Cavity Cancer; Nasopharyngeal Cancer; Oropharyngeal Cancer; Paranasal Sinus Cancer; Nasal Cavity Cancer; Salivary Gland Cancer; Skin Cancer; CNS Tumor; CNS Cancer; Mesothelioma; Breastcancer; Leukemia; Melanoma; Sarcoma; Unknown Primary Tumor; Multiple Myeloma; Ovarian Cancer; Endometrial Cancer; Vaginal Cancer

Sun protection and skin self-examination in melanoma survivors.

PubMed

Mujumdar, Urvi J; Hay, Jennifer L; Monroe-Hinds, Yvette C; Hummer, Amanda J; Begg, Colin B; Wilcox, Homer B; Oliveria, Susan A; Berwick, Marianne

2009-10-01

Patients diagnosed with melanoma are at risk for developing recurrent and second primary disease. Skin self-examination (SSE) and sun protection are standard clinical recommendations to minimize risk. In this study we examined performance of these behaviors in individuals with melanoma drawn from the general population. Potential participants (N=148) with a first primary melanoma diagnosed in 2000 were identified through a population-based cancer registry in New Jersey, USA. One hundred and fifteen individuals participated in a 30 min telephone interview concerning behavioral adherence with SSE and sun protection, self-efficacy for performing these behaviors, and perceived risk of developing another skin cancer. We utilized logistic regression to estimate potential associations of demographic, medical, and psychosocial factors with SSE and sun protection, respectively. Seventeen percent of subjects reported performing comprehensive SSE at least once every two months and 23% engaged in regular sun protection. Utilization of SSE was related to the presence of moles (OR=4.2, 95% CI: 1.1-15) and higher SSE self-efficacy (OR=14.4, 95% CI: 1.9-112). Regular sun protection was related to older age (>60 years; OR=3.3, 95% CI: 1.3-8.7), being female (OR=2.8, 95% CI: 1.1-7.3), and higher sun protection self-efficacy (OR=5.0, 95% CI: 1.4-18). These factors remained significant in multivariate models. In this group of primary melanoma survivors, the rates of SSE and sun protection are comparable to, but do not exceed, general population estimates. This study provides justification for further research to address barriers to prevention and control behaviors in melanoma survivors.

Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.

PubMed

Grözinger, Gerd; Mann, Steven; Mehra, Tarun; Klumpp, Bernhard; Grosse, Ulrich; Nikolaou, Konstantin; Garbe, Claus; Clasen, Stephan

2016-06-01

Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

BH3-only protein Bim predicts advanced stage of cutaneous melanoma.

PubMed

Gambichler, T; Rooms, I; Scholl, L; Stockfleth, E; Stücker, M; Sand, M

2016-11-01

Bim having strong pro-apoptotic effects belongs to the BH3-only proteins of the Bcl-2 protein family and contributes to survival pathways in cancer cells. We aimed to investigate Bim protein expression in cutaneous melanoma (CM). Bim protein expression was assessed by immunohistochemistry in primary and metastatic melanomas and correlated with clinical and histopathological features. The Bim immunoreactivity score of the primary melanomas investigated (4.6 ± 1.5) was significantly (P < 0.0001) higher than that observed in metastases (2.8 ± 1.1). Low Bim expression was significantly associated with primary nodular melanoma type (P = 0.005). Moreover, Bim expression was significantly inversely correlated with tumour thickness (r = -0.36; P = 0.0035), advanced stage of disease (stage III and IV; r = -0.60; P < 0.0001), disease relapse (r = -0.18; P = 0.034) and disease-related death (r = -0.19; P = 0.026). Advanced stage of disease was independently predicted by low Bim expression (P = 0.0010, odds ratio: 0.22, 95% CI: 0.10-0.56) on multivariate analysis; however, Bim was not shown to be an independent predictor for disease relapse (P = 0.40) and disease-related death (P = 0.77). Our data demonstrate that Bim protein expression is significantly inversely correlated with melanoma features that are associated with worse prognosis. We have shown that Bim protein expression in CM is an independent predictor for advanced disease confirming that this pro-apoptotic BH3-only protein might be a potent biomarker and promising therapeutic target. © 2016 European Academy of Dermatology and Venereology.

Sentinel lymph node biopsy from the vantage point of an oncologic surgeon.

PubMed

Wilson, Lori L

2009-01-01

Sentinel lymph node biopsy has greatly influenced the surgical management of clinically localized primary melanoma. Lymphatic mapping and sentinel lymph node biopsy have been used for the selective management of the draining regional lymph node basin of primary cutaneous melanoma. Oncologic surgeons have adopted this procedure to selectively identify occult nodal status in melanoma patients who are at a higher risk of regional metastasis. The current standard of treatment of tumor-positive sentinel lymph node metastasis is immediate completion lymphadenectomy, but considerable debate surrounds the utility of this procedure. This contribution reviews development, technical aspects, selective management of the lymph node basin, and sentinel lymph node biopsy techniques.

[A case report of anorectal malignant melanoma showing a complete response after DTIC/ACNU/VCR therapy].

PubMed

Sasaki, Shin; Kojima, Tetsu; Hidemura, Akio; Hatanaka, Kazuhito; Uekusa, Toshimasa; Ishimaru, Masahiro

2010-10-01

We report herein the case of a 64-year-old male who presented with hematochezia. The patient was diagnosed with malignant melanoma of the anorectum using colonoscopy. Preoperative studies revealed no distant metastases, and he underwent Miles operation. Pathological exams revealed that the tumor had invaded the submucosa with lymphatic and venous invasion. Cancer cells were found in regional lymph nodes. Post-operative CT scan demonstrated multiple metastases in the liver, and he received two courses of combined chemotherapy, DAV regimen (dacarbazine: DTIC 100 mg iv days 1-5, nimustine hydrochloride: ACNU 100 mg iv day 1, vincristine sulfate: VCR 1 mg iv day 1), leading to a complete response. However, malignant melanoma cells were found in hernia contents at the operation for left inguinal hernia, which led to a diagnosis of recurrent malignant melanoma. The patient has subsequently been well without any sign of recurrence including liver metastases. To our knowledge, this is the first report of a complete response in a patient with multiple liver metastases of anorectal malignant melanoma after DAV regimen.

Surgical management of sentinel lymph node biopsy outside major nodal basin in patients with cutaneous melanoma.

PubMed

Caracò, Corrado; Marone, Ugo; Di Monta, Gianluca; Aloj, Luigi; Caracò, Corradina; Anniciello, Annamaria; Lastoria, Secondo; Botti, Gerardo; Mozzillo, Nicola

2014-01-01

To assess the incidence of nonmajor lymphatic basin sentinel nodes in patients with cutaneous melanoma in order to propose a correct nomenclature and inform appropriate surgical management. This was a retrospective review of 1,045 consecutive patients with cutaneous melanoma who underwent sentinel lymph node biopsy and dynamic lymphoscintigraphy to identify sentinel node site. Nonmajor drainage sites were classified as uncommon (located in a minor lymphatic basin along the lymphatic drainage to a major classical nodal basin) or interval (located anywhere along the lymphatics between the primary tumor site and the nearest lymphatic basin) sentinel nodes. Nonclassical sentinel nodes were identified in 32 patients (3.0 %). Uncommon sentinel nodes were identified in 3.2 % (n = 17) of trunk melanoma primary disease and in 1.5 % (n = 7) of upper and lower extremity sites. Interval sentinel nodes were identified in 1.3 % (n = 7) of trunk primary lesions, with none from upper and lower extremities melanomas. The incidence of tumor-positive sentinel nodes was 24.1 % (245 of 1,013) in classical sites and 12.5 % (4 of 32) in uncommon/interval sites. The definition of uncommon and interval sentinel nodes allows the identification of different lymphatic pathways and inform appropriate surgical treatment. Wider experience with uncommon/interval sentinel nodes will better clarify the clinical implications and surgical management to be adopted in the management of uncommon and interval sentinel node sites.

Monoclonal antibody (AFH1) immunoreactive on morphologically abnormal basal melanocytes within dysplastic nevi, nevocellular nevus nests, and melanoma.

PubMed

Aronson, P J; Ito, K; Fukaya, T; Hashimoto, K; Mehregan, A H

1988-04-01

The mouse monoclonal antibody AFH1 was produced using formalin-fixed, sham paraffin-embedded human melanoma cell culture line A375 as immunogen. Reactivity of this antibody was assessed by immunohistochemical techniques against formalin- or acid alcohol-fixed paraffin-embedded tissue as well as formalin- or acid alcohol-fixed unembedded lesions. Ninety-seven nevomelanocytic lesions, neurofibromas, epithelial lesions, and a plasmacellular infiltrate were evaluated. AFH1 was immunoreactive on 54 of 55 nevocytic lesions (98.2%), 15 of 16 primary melanomas (93.7%), a lentigo maligna, and nests in 21 of 21 dysplastic nevi (100%). Of 100 consecutive basal melanocytes of intraepidermal melanoma cells counted in each lesion, mean AFH1 immunoreactivity for nonnested basal melanocytes in nevocellular nevi was 3.8%; for dysplastic nevi, 13.8%; and for intraepidermal melanoma cells, 78.0%. When nonnested basal melanocytes were subdivided into cytologically normal and abnormal cell groups, AFH1 immunoreactivity was 9.4% and 72.6%, respectively. AFH1 recognition of the lentiginous portion of dysplastic nevi corresponds statistically to the appearance of abnormal melanocyte cytology, nest formation, or both. Using 50% immunoreactive nonnested melanocytes as the criterion, AFH1 seems to distinguish primary melanoma from dysplastic nevi with a sensitivity of 93.8% and a specificity of 95.8%.

p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

PubMed Central

Terzian, Tamara; Torchia, Enrique C.; Dai, Daisy; Robinson, Steven E.; Murao, Kazutoshi; Stiegmann, Regan A.; Gonzalez, Victoria; Boyle, Glen M.; Powell, Marianne B.; Pollock, Pamela M.; Lozano, Guillermina; Robinson, William A.; Roop, Dennis R.; Box, Neil F.

2011-01-01

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the ‘high-p53’ Mdm4+/− mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/− background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/− mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53. PMID:20849464

Periostin Is a Key Niche Component for Wound Metastasis of Melanoma

PubMed Central

Fukuda, Keitaro; Sugihara, Eiji; Ohta, Shoichiro; Izuhara, Kenji; Funakoshi, Takeru; Amagai, Masayuki; Saya, Hideyuki

2015-01-01

Tissue injury promotes metastasis of several human cancers, although factors associated with wound healing that attract circulating tumor cells have remained unknown. Here, we examined the primary and metastatic lesions that appeared 1 month after trauma in a patient with acral lentiginous melanoma. The levels of mRNA for periostin (POSTN), type 1 collagen, and fibronectin were significantly increased in the metastatic lesion relative to the primary lesion. The increase of these extracellular matrix proteins at the wound site was reproduced in a mouse model of wound healing, with the upregulation of Postn mRNA persisting the longest. POSTN was expressed in the region surrounding melanoma cell nests in metastatic lesions of both wounded mice and the patient. POSTN attenuated the cell adhesion and promoted the migration of melanoma cells without affecting their proliferation in vitro. In the mouse model, the wound site as well as subcutaneously injected osteoblasts that secrete large amounts of POSTN invited the metastasis of remotely-transplanted melanoma cells on the sites. Osteoblasts with suppression of POSTN by shRNA showed a greatly reduced ability to promote such metastasis. Our results suggest that POSTN is a key factor in promoting melanoma cell metastasis to wound sites by providing a premetastatic niche. PMID:26083413

EMMPRIN/CD147 is an independent prognostic biomarker in cutaneous melanoma.

PubMed

Caudron, Anne; Battistella, Maxime; Feugeas, Jean-Paul; Pages, Cécile; Basset-Seguin, Nicole; Mazouz Dorval, Sarra; Funck Brentano, Elisa; Sadoux, Aurélie; Podgorniak, Marie-Pierre; Menashi, Suzanne; Janin, Anne; Lebbé, Céleste; Mourah, Samia

2016-08-01

CD147 has been implicated in melanoma invasion and metastasis mainly through increasing metalloproteinase synthesis and regulating VEGF/VEGFR signalling. In this study, the prognostic value of CD147 expression was investigated in a cohort of 196 cutaneous melanomas including 136 consecutive primary malignant melanomas, 30 lymph nodes, 16 in-transit and 14 visceral metastases. A series of 10 normal skin, 10 blue nevi and 10 dermal nevi was used as control. CD147 expression was assessed by immunohistochemistry, and the association of its expression with the clinicopathological characteristics of patients and survival was evaluated using univariate and multivariate statistical analyses. Univariate analysis showed that high CD147 expression was significantly associated with metastatic potential and with a reduced overall survival (P < 0.05 for both) in primary melanoma patients. CD147 expression level was correlated with histological factors which were associated with prognosis: Clark level, ulceration status and more particularly with Breslow index (r = 0.7, P < 10(-8) ). Multivariate analysis retained CD147 expression level and ulceration status as predicting factors for metastasis and overall survival (P < 0.05 for both). CD147 emerges as an important factor in the aggressive behaviour of melanoma and deserves further evaluation as an independent prognostic biomarker. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Periostin Is a Key Niche Component for Wound Metastasis of Melanoma.

PubMed

Fukuda, Keitaro; Sugihara, Eiji; Ohta, Shoichiro; Izuhara, Kenji; Funakoshi, Takeru; Amagai, Masayuki; Saya, Hideyuki

2015-01-01

Tissue injury promotes metastasis of several human cancers, although factors associated with wound healing that attract circulating tumor cells have remained unknown. Here, we examined the primary and metastatic lesions that appeared 1 month after trauma in a patient with acral lentiginous melanoma. The levels of mRNA for periostin (POSTN), type 1 collagen, and fibronectin were significantly increased in the metastatic lesion relative to the primary lesion. The increase of these extracellular matrix proteins at the wound site was reproduced in a mouse model of wound healing, with the upregulation of Postn mRNA persisting the longest. POSTN was expressed in the region surrounding melanoma cell nests in metastatic lesions of both wounded mice and the patient. POSTN attenuated the cell adhesion and promoted the migration of melanoma cells without affecting their proliferation in vitro. In the mouse model, the wound site as well as subcutaneously injected osteoblasts that secrete large amounts of POSTN invited the metastasis of remotely-transplanted melanoma cells on the sites. Osteoblasts with suppression of POSTN by shRNA showed a greatly reduced ability to promote such metastasis. Our results suggest that POSTN is a key factor in promoting melanoma cell metastasis to wound sites by providing a premetastatic niche.

[Characterization of genetic alterations in primary human melanomas carrying BRAF or NRAS mutation].

PubMed

Lázár, Viktória

2013-06-01

Human malignant melanoma is one of the most aggressive forms of skin cancer with an exceptionally bad prognosis. Melanoma often displays constitutively activated MAPK pathway through BRAF or NRAS mutations. It is also known that these mutations are almost never simultaneously present and that they appear at early stages and preserved throughout tumor progression, although it is proved that these alterations alone are insufficient to cause tumor progression. Therefore the first aim of our study was to evaluate those distinct genetic alterations which can properly differentiate the three important molecular subtypes of primary melanomas with a) BRAF, b) NRAS mutation and c) WT (wild type for both loci). High-resolution array comparative genomic hybridization (array CGH) was used to assess genome-wide analysis of DNA copy number alterations. Primary melanomas with BRAF mutation more frequently exhibited losses on 10q23-10q26 and gains on chromosome 7 and 1q23-1q25 compared to melanomas with NRAS mutation. Loss on the 11q23-11q25 sequence was found mainly in conjunction with NRAS mutation. Based on these results, we proved the existence of marked differences in the genetic pattern of the BRAF and NRAS mutated melanoma subgroups, which might suggest that these mutations contribute to the development of malignant melanoma in conjunction with distinct cooperating oncogenic events. In general, it is an interesting phenomenon suggesting that these mutations provide probably the "guiding force" for these tumors and it also suggests that there are alternative genetic pathways to melanoma. These additional oncogenic events which are associated with BRAF or NRAS mutations can provide rational additional targets for a combination therapy with kinase inhibitors. In this study we also investigated the specific dynamic activities among different signalling pathways highlighting the frequent alterations of genes involved in the signalling interactions between the MAPK-JAK pathways in BRAF mutated melanomas. Using a data mining algorithm we also found a gene alteration signature in the MAPK pathway that was commonly related to the presence of BRAF mutation in our melanoma cohorts. The second aim of this study was to develop an accurate Q-PCR method for determining the co-amplification pattern of six candidate genes that reside in the 11q13 amplicon core. We found that co-amplification of these candidate genes or the CCND1 amplification along with either BRAF or NRAS mutations might be more important for prognosis than the presence of these alterations alone.

Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas P Quinn

2005-11-22

Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patientsmore » with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu-DOTA-Re(Arg11)CCMSH and {sup 212}Pb-DOTA-Re(Arg11)CCMSH complexes were developed and synthesized to investigate its ability to target and deliver an effective dose to small melanoma tumors and metastatic deposits. Dosimetry calculations for {sup 188}Re-CCMSH and {sup 212}Pb/{sup 212}Bi[DOTA]-Re(Arg11)CCMSH were compared in the B16/F1 mouse melanoma flank tumor model to analyze the delivered dose to tumor and normal organs.« less

A novel stilbene-like compound that inhibits melanoma growth by regulating melanocyte differentiation and proliferation.

PubMed

Stueven, Noah A; Schlaeger, Nicholas M; Monte, Aaron P; Hwang, Sheng-Ping L; Huang, Cheng-Chen

2017-12-15

Melanoma is the most aggressive form of skin cancer. Current challenges to melanoma therapy include the adverse effects from immunobiologics, resistance to drugs targeting the MAPK pathway, intricate interaction of many signal pathways, and cancer heterogeneity. Thus combinational therapy with drugs targeting multiple signaling pathways becomes a new promising therapy. Here, we report a family of stilbene-like compounds called A11 that can inhibit melanoma growth in both melanoma-forming zebrafish embryos and mouse melanoma cells. The growth inhibition by A11 is a result of mitosis reduction but not apoptosis enhancement. Meanwhile, A11 activates both MAPK and Akt signaling pathways. Many A11-treated mouse melanoma cells exhibit morphological changes and resemble normal melanocytes. Furthermore, we found that A11 causes down-regulation of melanocyte differentiation genes, including Pax3 and MITF. Together, our results suggest that A11 could be a new melanoma therapeutic agent by inhibiting melanocyte differentiation and proliferation. Copyright © 2017 Elsevier Inc. All rights reserved.

1,3-Bis(3,5-dichlorophenyl) urea compound 'COH-SR4' inhibits proliferation and activates apoptosis in melanoma.

PubMed

Singhal, Sharad S; Figarola, James; Singhal, Jyotsana; Leake, Kathryn; Nagaprashantha, Lokesh; Lincoln, Christopher; Gabriel Gugiu, B; Horne, David; Jove, Richard; Awasthi, Sanjay; Rahbar, Samuel

2012-12-01

The current clinical interventions in malignant melanomas are met with poor response to therapy due to dynamic regulation of multiple melanoma signaling pathways consequent to administration of single target agents. In this context of limited response to single target agents, novel candidate molecules capable of effectively inducing tumor inhibition along with targeting multiple critical nodes of melanoma signaling assume translational significance. In this regard, we investigated the anti-cancer effects of a novel dichlorophenyl urea compound called COH-SR4 in melanoma. The SR4 treatment decreased the survival and inhibited the clonogenic potential of melanomas along with inducing apoptosis in vitro cultures. SR4 treatments lead to inhibition of GST activity along with causing G2/M phase cell cycle arrest. Oral administration of 4 mg/kg SR4 leads to effective inhibition of tumor burdens in both syngeneic and nude mouse models of melanoma. The SR4 treatment was well tolerated and no overt toxicity was observed. The histopathological examination of resected tumor sections revealed decreased blood vessels, decrease in the levels of angiogenesis marker, CD31, and proliferation marker, Ki67, along with an increase in pAMPK levels. Western blot analyses of resected tumor lysates revealed increased PARP cleavage, Bim, pAMPK along with decreased pAkt, vimentin, fibronectin, CDK4 and cyclin B1. Thus, SR4 represents a novel candidate for the further development of mono and combinatorial therapies to effectively target aggressive and therapeutically refractory melanomas. Copyright © 2012 Elsevier Inc. All rights reserved.

Galvanic zinc-copper microparticles inhibit melanogenesis via multiple pigmentary pathways.

PubMed

Won, Yen-Kim; Lin, Connie B; Seiberg, Miri; Chen, Nannan; Hu, Yaping; Rossetti, Dianne; Saliou, Claude; Loy, Chong-Jin

2014-01-01

The endogenous electrical field of human skin plays an important role in many skin functions. However, the biological effects and mechanism of action of externally applied electrical stimulation on skin remain unclear. Recent study showed that galvanic zinc-copper microparticles produce electrical stimulation and reduce inflammatory and immune responses in intact skin, suggesting the important role of electrical stimulation in non-wounded skin. The objective of this study is to investigate the biological effect of galvanic zinc-copper microparticles on skin pigmentation. Our findings showed that galvanic zinc-copper microparticles inhibited melanogenesis in a human melanoma cell line (MNT-1), human keratinocytes and melanoma cells co-cultures, and in pigmented epidermal equivalents. Treatment of galvanic zinc-copper microparticles inhibited melanogenesis by reducing the promoter transactivation of tyrosinase and tyrosinase-related protein-1 in human melanoma cells. In a co-culture Transwell system of keratinocytes and melanoma cells, galvanic zinc-copper microparticles reduced melanin production via downregulation of endothelin-1 secretion from keratinocytes and reduced tyrosinase gene expression in melanoma cells. In addition, exposure of pigmented epidermal equivalents to galvanic zinc-copper microparticles resulted in reduced melanin deposition. In conclusion, our data demonstrated for the first time that galvanic zinc-copper microparticles reduced melanogenesis in melanoma cells and melanin deposition in pigmented epidermal equivalents by affecting multiple pigmentary pathways.

Breslow depth of cutaneous melanoma: impact of factors related to surveillance of the skin, including prior skin biopsies and family history of melanoma.

PubMed

Fisher, Nina M; Schaffer, Julie V; Berwick, Marianne; Bolognia, Jean L

2005-09-01

Because the early detection of cutaneous melanoma can dramatically improve survival, identification and surveillance of persons at risk have received much attention. Our purpose was to examine the influences of personal or family history, patterns of detection, and prior skin biopsies (considered to be a measurement of surveillance by medical personnel) on the Breslow depth of cutaneous melanomas. A retrospective cohort analysis of 218 patients with a history of at least one invasive cutaneous melanoma who visited the Yale Pigmented Lesion Clinic between January 1995 and January 1996 was performed. Data on patterns of detection, melanocytic nevi, and skin biopsies before and after the initial diagnosis of melanoma were collected, and patients with a family history of melanoma were compared with sporadic patients. Initial melanomas discovered by dermatologists were more likely to be 0.75 mm or less in depth than those found by other physicians (P = .03). Although patients detected 45% of the initial primary melanomas (98/218), dermatologists discovered 80% of the second primary tumors (33/41; P = .001). A personal history of melanoma was predictive of a thinner Breslow depth (P = .01), but a family history of melanoma was not. Having a biopsy of any type or combination of types of skin lesion(s) performed in the 5 years, 2 years, or 1 year before the first diagnosis of melanoma did not predict a melanoma of thinner Breslow depth among either familial or sporadic patients. The mean number of skin biopsies performed per patient was 8 times higher in the 5-year period after (5.6) versus the 5-year period before (0.7) the initial diagnosis of melanoma, with a peak in the first year after the diagnosis (2.3 vs 0.25 in the prior year). In 27 patients, one or more skin biopsies were performed in the year before the initial diagnosis of melanoma; 41% of these biopsies (23/56) were of lesions in normally exposed sites (eg, the face, neck, and forearms) compared with 22% of the melanomas (6/27). Since an invasive melanoma (with the possible exception of a nodular melanoma) would likely have been present for at least a year, plausible explanations for why evidence of previous dermatologic care did not appear to result in earlier detection include performance of a limited rather than a total body skin examination as well as subtle clinical features of early melanomas. However, this study cannot give weight to these explanations because at the time new Pigmented Lesion Clinic patients were not routinely asked about previous total body skin examinations. The disappointing trends seen in this study, with neither the well-established risk factor of a family history of melanoma nor previously having a skin biopsy predicting thinner melanomas, highlight the need to establish criteria defining the subset of patients for whom appropriate management requires periodic total body skin examination.

Association between dermoscopic and reflectance confocal microscopy features of cutaneous melanoma with BRAF mutational status.

PubMed

Bombonato, C; Ribero, S; Pozzobon, F C; Puig-Butille, J A; Badenas, C; Carrera, C; Malvehy, J; Moscarella, E; Lallas, A; Piana, S; Puig, S; Argenziano, G; Longo, C

2017-04-01

Melanomas harbouring common genetic mutations might share certain morphological features detectable with dermoscopy and reflectance confocal microscopy. BRAF mutational status is crucial for the management of metastatic melanoma. To correlate the dermoscopic characteristics of primary cutaneous melanomas with BRAF mutational status. Furthermore, a subset of tumours has also been analysed for the presence of possible confocal features that might be linked with BRAF status. Retrospectively acquired dermoscopic and confocal images of patients with melanoma in tertiary referral academic centres: Skin Cancer Unit in Reggio Emilia and at the Melanoma Unit in Barcelona. Kruskal-Wallis test, logistic regressions, univariate and multivariate analyses have been performed to find dermoscopic and confocal features significantly correlated with BRAF mutational status. Dermoscopically, the presence of irregular peripheral streaks and ulceration were positive predictors of BRAF-mutated melanomas with a statistically significance value, while dotted vessels were more represented in wild-type melanomas. None of the evaluated reflectance confocal microscopy features were correlated with genetic profiling. Ulceration and irregular peripheral streaks represent dermoscopic feature indicative for BRAF-mutated melanoma, while dotted vessels are suggestive for wild-type melanoma. © 2016 European Academy of Dermatology and Venereology.

Mitochondrial oxidative stress is the achille's heel of melanoma cells resistant to Braf-mutant inhibitor

PubMed Central

André, Fanny; Jonneaux, Aurélie; Scalbert, Camille; Garçon, Guillaume; Malet-Martino, Myriam; Balayssac, Stéphane; Rocchi, Stephane; Savina, Ariel; Formstecher, Pierre; Mortier, Laurent; Kluza, Jérome; Marchetti, Philippe

2013-01-01

Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition. PMID:24161908

Primary tumor sites in relation to ultraviolet radiation exposure and skin visibility correlate with survival in cutaneous melanoma.

PubMed

Gordon, Daniela; Hansson, Johan; Eloranta, Sandra; Gordon, Max; Gillgren, Peter; Smedby, Karin E

2017-10-01

The prognostic value of detailed anatomic site and ultraviolet radiation (UVR) exposure patterns has not been fully determined in cutaneous melanoma. Thus, we reviewed medical records for detailed site in a population-based retrospective Swedish patient cohort diagnosed with primary invasive melanoma 1976-2003 (n = 5,973). We followed the patients from date of diagnosis until death, emigration or December 31 st 2013, and evaluated melanoma-specific survival by subsite in a multivariable regression model adjusting for established prognostic factors. We found that melanoma on chronic UVR exposure sites (face, dorsum of hands; adjusted HR 0.6; CI 0.4-0.7) and moderately intermittent UVR sites (lateral arms, lower legs, dorsum of feet; HR 0.7; CI 0.6-0.8) were associated with a favorable prognosis compared with highly intermittent sites (chest, back, neck, shoulders and thighs). Further, melanoma on poorly visible skin sites upon self-examination (scalp, retroauricular area, back, posterior upper arms and thighs, buttocks, pubic area; HR 1.3; CI 1.1-1.5) had a worse prognosis than those on easily visible sites (face, chest, abdomen, anterior upper arms and thighs, lower arms and legs, dorsum of hands and feet, palms). In conclusion, highly intermittent UVR exposure sites and poor skin visibility presumably correlate with reduced melanoma survival, independent of established tumor characteristics. A limitation of the study was the lack of information on actual individual UVR exposure. © 2017 UICC.

Vemurafenib Synergizes with Nutlin-3 to Deplete Survivin and Suppress Melanoma Viability and Tumor Growth

PubMed Central

Ji, Zhenyu; Kumar, Raj; Taylor, Michael; Rajadurai, Anpuchchelvi; Marzuka-Alcalá, Alexander; Chen, Y. Erin; Njauw, Ching-Ni Jenny; Flaherty, Keith; Jönsson, Goran; Tsao, Hensin

2013-01-01

Background For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically-informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. Since p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition. Experimental Design Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib. Results Dual targeting of BRAF(V600E) and HDM2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3′s effects fully and vemurafenib’s effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the anti-apoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy. Conclusion These results demonstrate preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target. PMID:23812671

Combination of dacarbazine and dimethylfumarate efficiently reduces melanoma lymph node metastasis.

PubMed

Valero, Teresa; Steele, Silvia; Neumüller, Karin; Bracher, Andreas; Niederleithner, Heide; Pehamberger, Hubert; Petzelbauer, Peter; Loewe, Robert

2010-04-01

Dimethylfumarate (DMF) has been shown to reduce melanoma growth and metastasis in animal models. We addressed the question of whether DMF is as effective in its antitumor activity as the US Food and Drug Administration-approved alkylating agent dacarbazine (DTIC). We also tested the possibility of an improved antitumoral effect when both therapeutics were used together. Using our severe combined immunodeficiency (SCID) mouse model, in which xenografted human melanoma cells metastasize from primary skin sites to sentinel nodes, we show that these treatments, alone or in combination, reduce tumor growth at primary sites. Our main finding was that metastasis to sentinel nodes is significantly delayed only in mice treated with a combination of DTIC and DMF. Subsequent experiments were able to show that a combination of DTIC/DMF significantly reduced lymph vessel density in primary tumors as examined by real-time PCR and immunohistochemistry. In addition, DTIC/DMF treatment significantly impaired melanoma cell migration in vitro. In vivo, DTIC/DMF therapy significantly reduced mRNA expression and protein concentration of the promigratory chemokines CXCL2 and CXCL11. In addition, our data suggest that this xenotransplantation model is suitable for preclinical testing of various combinations of antimelanoma agents.

Multiple mechanisms underlie defective recognition of melanoma cells cultured in three-dimensional architectures by antigen-specific cytotoxic T lymphocytes.

PubMed

Feder-Mengus, C; Ghosh, S; Weber, W P; Wyler, S; Zajac, P; Terracciano, L; Oertli, D; Heberer, M; Martin, I; Spagnoli, G C; Reschner, A

2007-04-10

Cancer cells' growth in three-dimensional (3D) architectures promotes resistance to drugs, cytokines, or irradiation. We investigated effects of 3D culture as compared to monolayers (2D) on melanoma cells' recognition by tumour-associated antigen (TAA)-specific HLA-A(*)0201-restricted cytotoxic T-lymphocytes (CTL). Culture of HBL, D10 (both HLA-A(*)0201+, TAA+) and NA8 (HLA-A(*)0201+, TAA-) melanoma cells on polyHEMA-coated plates, resulted in generation of 3D multicellular tumour spheroids (MCTS). Interferon-gamma (IFN-gamma) production by HLA-A(*)0201-restricted Melan-A/MART-1(27-35) or gp 100(280-288)-specific CTL clones served as immunorecognition marker. Co-culture with melanoma MCTS, resulted in defective TAA recognition by CTL as compared to 2D as witnessed by decreased IFN-gamma production and decreased Fas Ligand, perforin and granzyme B gene expression. A multiplicity of mechanisms were potentially involved. First, MCTS per se limit CTL capacity of recognising HLA class I restricted antigens by reducing exposed cell surfaces. Second, expression of melanoma differentiation antigens is downregulated in MCTS. Third, expression of HLA class I molecules can be downregulated in melanoma MCTS, possibly due to decreased interferon-regulating factor-1 gene expression. Fourth, lactic acid production is increased in MCTS, as compared to 2D. These data suggest that melanoma cells growing in 3D, even in the absence of immune selection, feature characteristics capable of dramatically inhibiting TAA recognition by specific CTL.

iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors

PubMed Central

Crabb, John W.; Hu, Bo; Crabb, John S.; Triozzi, Pierre; Saunthararajah, Yogen; Singh, Arun D.

2015-01-01

Background Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. Methods Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch’s membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors. Results Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens. Conclusions The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and heat shock protein beta-1 as candidate biomarkers of uveal melanoma metastasis and establish a quantitative proteomic database for uveal melanoma primary tumors. PMID:26305875

Intratumoral Heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 Expression in Mucosal Melanoma.

PubMed

Curioni-Fontecedro, A; Pitocco, R; Schoenewolf, N L; Holzmann, D; Soldini, D; Dummer, R; Calvieri, S; Moch, H; Mihic-Probst, D; Fitsche, A

2015-01-01

Mucosal melanoma is a rare disease, which differs from its cutaneous counterpart genetically and for its clinical behaviour. Moreover this is a heterogeneous disease based on the tissue of origin. As CT7 and CT10 are highly expressed in cutaneous melanoma and are immunogenic in this disease, we analysed their expression throughout the different subtypes of mucosal melanoma and tumor development. We detected a frequent expression of CT7 in primaries and corresponding metastases (55%) as well as for CT10 (30%). This expression resulted to be heterogeneous in the same tumor specimen and moreover influenced by the tissue of origin. Our results support the role of these antigens in immunotherapy for mucosal melanoma.

Intratumoral Heterogeneity of MAGE-C1/CT7 and MAGE-C2/CT10 Expression in Mucosal Melanoma

PubMed Central

Curioni-Fontecedro, A.; Pitocco, R.; Schoenewolf, N. L.; Holzmann, D.; Soldini, D.; Dummer, R.; Calvieri, S.; Moch, H.; Mihic-Probst, D.; Fitsche, A.

2015-01-01

Mucosal melanoma is a rare disease, which differs from its cutaneous counterpart genetically and for its clinical behaviour. Moreover this is a heterogeneous disease based on the tissue of origin. As CT7 and CT10 are highly expressed in cutaneous melanoma and are immunogenic in this disease, we analysed their expression throughout the different subtypes of mucosal melanoma and tumor development. We detected a frequent expression of CT7 in primaries and corresponding metastases (55%) as well as for CT10 (30%). This expression resulted to be heterogeneous in the same tumor specimen and moreover influenced by the tissue of origin. Our results support the role of these antigens in immunotherapy for mucosal melanoma. PMID:26161400

ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms.

PubMed

Couts, Kasey L; Bemis, Judson; Turner, Jacqueline A; Bagby, Stacey M; Murphy, Danielle; Christiansen, Jason; Hintzsche, Jennifer D; Le, Anh; Pitts, Todd M; Wells, Keith; Applegate, Allison; Amato, Carol; Multani, Pratik; Chow-Maneval, Edna; Tentler, John J; Shellman, Yiqun G; Rioth, Matthew J; Tan, Aik-Choon; Gonzalez, Rene; Medina, Theresa; Doebele, Robert C; Robinson, William A

2018-01-01

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK ( ALK ATI ) was reported in 11% of melanomas but the response of melanomas expressing ALK ATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALK ATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo , the melanomas expressing wt ALK or ALK ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK ATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALK ATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALK ATI Mol Cancer Ther; 17(1); 222-31. ©2017 AACR . ©2017 American Association for Cancer Research.

Primary mucosal malignant melanoma of the cervix: case report and review of the literature.

PubMed

Cetinkaya, Kadir; Benzer, Emine; Dervisoglu, Haluk

2015-09-09

The incidence of primary mucosal malignant melanoma (PMMM) is 1.3% among all malignant melanomas (MM). Cervical involvement is very rare; the number of cases of cervical PMMM reported so far is around 80. In our patient, a dark color, 2-cm diameter, nonulcerated tumor formation was observed upon examination of the cervix. Tumoral tissue consisted of atypical melanocytic cells containing numerous mitotic figures. In immunochemical studies, S-100, Melan-A, and HMB-45 positivity were observed. The tumor was 20 mm in invasion depth, Breslow IV, and FIGO stage IB1. Radical surgery was followed by adjuvant radiotherapy, and subsequently interferon treatment was applied. Examination and scans 20 months after surgery were free from tumor.

Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node

PubMed Central

Ma, Michelle W.; Medicherla, Ratna C.; Qian, Meng; de Miera, Eleazar Vega-Saenz; Friedman, Erica B.; Berman, Russell S.; Shapiro, Richard L.; Pavlick, Anna C.; Ott, Patrick A.; Bhardwaj, Nina; Shao, Yongzhao; Osman, Iman; Darvishian, Farbod

2013-01-01

The sentinel lymph node is the initial site of metastasis. Down-regulation of anti-tumor immunity plays a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T-cells (Foxp3+) and dendritic cells (conventional: CD11c+, mature: CD86+) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunologic primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared to those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T-cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathologic variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Anti-tumor immunity was down-regulated in the positive sentinel lymph node with an increase in regulatory T-cells compared to the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared to the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T-cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions. PMID:22425909

Melanoma costs: a dynamic model comparing estimated overall costs of various clinical stages.

PubMed

Alexandrescu, Doru Traian

2009-11-15

The rapidly increasing incidence of melanoma occurs at the same time as an increase in general healthcare costs, particularly the expenses associated with cancer care. Previous cost estimates in melanoma have not utilized a dynamic model considering the evolution of the disease and have not integrated the multiple costs associated with different aspects of medical interventions and patient-related factors. Futhermore, previous calculations have not been updated to reflect the modern tendencies in healthcare costs. We designed a comprehensive model of expenses in melanoma that considers the dynamic costs generated by the natural progression of the disease, which produces costs associated with treatment, surveillance, loss of income, and terminal care. The complete range of initial clinical (TNM) stages of the disease and initial tumor stages were analyzed in this model and the total healthcare costs for the five years following melanoma presentation at each particular stage were calculated. We have observed dramatic incremental total costs associated with progressively higher initial stages of the disease, ranging from a total of $4,648.48 for in situ tumors to $159,808.17 for Stage IV melanoma. By stage, early lesions associate 30-55 percent of their costs for the treatment of the primary tumor, due to a low rate of recurrence (local, regional, or distant), which limits the need for additional interventions. For in situ melanoma, T1a, and T1b, surveillance is an important contributor to the medical costs, accounting for more than 25 percent of the total cost over 5 years. In contrast, late lesions incur a much larger proportion of their associated costs (up to 80-85%) from the diagnosis and treatment of metastatic disease because of the increased propensity of those lesions to disseminate. This cost increases with increasing tumor stage (from $2,442.17 for T1a to $6,678.00 for T4b). The most expensive items in the medical care of patients with melanoma consist of adjuvant treatment with IFN-alpha ($75,955.18), palliative care ($14,500), and administration of chemotherapy ($1,967.10 for a triple combination of agents); there are even higher costs for biochemotherapy, the new tyrosine kinase and antiangiogenic drugs, and hospital treatment of neutropenic fever ($1,535.00 to $1,800.00/day). There is a significant cost decrement when melanoma is diagnosed at an earlier stage, with a T4b lesion being approximately 2200 percent more expensive to diagnose and treat than an early in situ melanoma and 1000 percent more expensive than a stage T1a tumor. Although a direct comparison with other cancers would require the use of the same dynamic model, it is apparent that the high costs of melanoma care places it at the top of the most expensive cancers to diagnose, follow, and treat. These high costs for advanced-stage melanoma warrant an increased emphasis on developing effective strategies for its early diagnosis and treatment.

Primary Localization and Tumor Thickness as Prognostic Factors of Survival in Patients with Mucosal Melanoma

PubMed Central

Mehra, Tarun; Grözinger, Gerd; Mann, Steven; Guenova, Emmanuella; Moos, Rudolf; Röcken, Martin; Claussen, Claus Detlef; Dummer, Reinhard; Clasen, Stephan

2014-01-01

Background Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations. Methodology 116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages. Principal Findings We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T1, T2, T3 or T4 stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas. Conclusion Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006). It also depends on T-stage at the time of diagnosis (p<0.0001). PMID:25383553

Primary localization and tumor thickness as prognostic factors of survival in patients with mucosal melanoma.

PubMed

Mehra, Tarun; Grözinger, Gerd; Mann, Steven; Guenova, Emmanuella; Moos, Rudolf; Röcken, Martin; Claussen, Claus Detlef; Dummer, Reinhard; Clasen, Stephan; Naumann, Aline; Garbe, Claus

2014-01-01

Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations. 116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages. We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T1, T2, T3 or T4 stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas. Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006). It also depends on T-stage at the time of diagnosis (p < 0.0001).

DNA from BK Virus and JC Virus and from KI, WU, and MC Polyomaviruses as Well as from Simian Virus 40 Is Not Detected in Non-UV-Light-Associated Primary Malignant Melanomas of Mucous Membranes ▿

PubMed Central

Giraud, Géraldine; Ramqvist, Torbjörn; Ragnarsson-Olding, Boel; Dalianis, Tina

2008-01-01

The single most important causative factor for malignant melanomas of the skin is UV radiation. However, this is not true for melanomas on body surfaces sheltered from the sun; thus, it is important to seek new causative factors of melanoma genesis. Human papillomaviruses and gammaherpesviruses are associated with human skin cancer; for example, human papillomavirus types 5 and 8 are associated with epidermodysplasia verruciformis, and human herpesvirus 8 is associated with Kaposi's sarcoma. Recently, a newly described human polyomavirus, Merkel cell polyomavirus (MCPyV), has been associated with Merkel cell carcinoma, an unusual form of neurotropic skin cancer. Moreover, melanocytes are of neuroepithelial origin. This background impelled us to investigate if human polyomavirus DNA could play a role in the development of extracutaneous melanomas. Sixty-four extracutaneous melanomas were initially collected and dissected. Of these, 38 could be successfully used for further testing for the presence of the five human polyomaviruses known so far—BK virus (BKV), JC virus (JCV), KI polyomavirus (KIPyV), WU polyomavirus (WUPyV), and MCPyV—and of simian virus 40 (SV40). No polyomavirus DNA could be detected in any of the samples tested by use of a nested PCR detecting BKV, JCV, and SV40; a newly designed PCR detecting KIPyV and WUPyV; or a newly designed PCR for MCPyV. We conclude that since no human polyomavirus DNA was detected in primary malignant melanomas on non-sun-exposed body surfaces, these polyomaviruses presumably are not major factors for the development of extracutaneous melanomas. PMID:18768658

Frequent Nuclear/Cytoplasmic Localization of β-Catenin without Exon 3 Mutations in Malignant Melanoma

PubMed Central

Rimm, David L.; Caca, Karel; Hu, Gang; Harrison, Frank B.; Fearon, Eric R.

1999-01-01

β-Catenin has a critical role in E-cadherin-mediated cell-cell adhesion, and it also functions as a downstream signaling molecule in the wnt pathway. Mutations in the putative glycogen synthase kinase 3β phosphorylation sites near the β-catenin amino terminus have been found in some cancers and cancer cell lines. The mutations render β-catenin resistant to regulation by a complex containing the glycogen synthase kinase 3β, adenomatous polyposis coli, and axin proteins. As a result, β-catenin accumulates in the cytosol and nucleus and activates T-cell factor/lymphoid enhancing factor transcription factors. Previously, 6 of 27 melanoma cell lines were found to have β-catenin exon 3 mutations affecting the N-terminal phosphorylation sites (Rubinfeld B, Robbins P, Elgamil M, Albert I, Porfiri E, Polakis P: Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 1997, 275:1790–1792). To assess the role of β-catenin defects in primary melanomas, we undertook immunohistochemical and DNA sequencing studies in 65 melanoma specimens. Nuclear and/or cytoplasmic localization of β-catenin, a potential indicator of wnt pathway activation, was seen focally within roughly one third of the tumors, though a clonal somatic mutation in β-catenin was found in only one case (codon 45 Ser→Pro). Our findings demonstrate that β-catenin mutations are rare in primary melanoma, in contrast to the situation in melanoma cell lines. Nonetheless, activation of β-catenin, as indicated by its nuclear and/or cytoplasmic localization, appears to be frequent in melanoma, and in some cases, it may reflect focal and transient activation of the wnt pathway within the tumor. PMID:10027390

Assessment of the presence of mucosal human papillomaviruses in malignant melanomas using combined fluorescent in situ hybridization and chemiluminescent immunohistochemistry.

PubMed

Ambretti, S; Venturoli, S; Mirasoli, M; La Placa, M; Bonvicini, F; Cricca, M; Zerbini, M; Roda, A; Musiani, M

2007-01-01

The vast majority of studies aimed at detecting human papillomavirus (HPV) DNA in skin cancer have used sensitive polymerase chain reaction (PCR) methods but the PCR technique, despite its high sensitivity, is not suitable to ascertain whether (i) the presence of HPV can be related only to few cells harbouring the virus, (ii) the presence of HPV is due to a tumour surface contamination and (iii) the presence of HPV is localized in cancer cells, rather than in normal keratinocytes present in the tumour biopsy. In a recent work we have found mucosal high-risk (HR) HPV genotypes in primary melanoma by PCR. To localize mucosal HR-HPV nucleic acids and tumoural melanocytic marker in the same sections of primary melanoma samples in order to understand the relationship between HPVs and melanoma cells. We have developed a very sensitive method that combines an enzyme-amplified fluorescent in situ hybridization (ISH) for the detection of HPV nucleic acids (types 16 and 18) with a chemiluminescent immunohistochemistry (IHC) method for the detection of the tumoural melanocytic marker HMB-45 sequentially in the same section. Digital images of fluorescent ISH and chemiluminescent IHC were separately recorded, assigned different colours and merged using specific software for image analysis. The combined fluorescent ISH and chemiluminescent IHC demonstrated a sharp colocalization (in the range 60-80%) of HPV nucleic acids and melanoma marker inside the same sections of melanoma biopsies, with a strong specificity and sensitivity. The strong colocalization of mucosal HR-HPV nucleic acids and HMB-45 melanocytic marker emphasized that viral nucleic acids were specifically present in melanoma cells and supported a possible active role of HPV in malignant melanoma.

Nevoid melanoma of the vagina: report of one case diagnosed on thin layer cytological preparations.

PubMed

Fulciniti, Franco; Ascierto, Paolo Antonio; Simeone, Ester; Bove, Patrizia; Losito, Simona; Russo, Serena; Gallo, Maria Stella; Greggi, Stefano

2007-07-03

Primary melanoma of the vagina is an extremely rare neoplasm with approximately 250 reported cases in the world literature 1234. In its amelanotic variant this lesion may raise several differential diagnostic problems in cytological specimens 5. In this setting, the usage of thin layer cytopathological techniques (Liquid Based Preparations = LBP) may enhance the diagnostic sensitivity by permitting immunocytochemical study without having to repeat the sampling procedure. The aim of this paper is to describe the cytomorphological presentation of primary vaginal melanoma on LBP since it has not previously been reported up to now, to our knowledge. a 79-y-o female complaining of vulvar itching and yellowish vaginal discharge underwent a complete gynaecological evaluation during which a LBP cytological sample was taken from a suspicious whitish mass protruding into the vaginal lumen. A cytopathological diagnosis of amelanotic melanoma was rendered. The mass was radically excised and the patient was treated with alpha-Interferon. amelanotic melanoma may be successfully diagnosed on LBP cytological preparations. Thin layer preparations may enhance the diagnostic cytomorphological clues to its diagnosis and may permit an adequate immunocytochemical characterization of the neoplasm.

Metastatic pathways in patients with cutaneous melanoma.

PubMed

Adler, Nikki R; Haydon, Andrew; McLean, Catriona A; Kelly, John W; Mar, Victoria J

2017-01-01

Metastasis represents the end product of an elaborate biological process, which is determined by a complex interplay between metastatic tumour cells, host factors and homoeostatic mechanisms. Cutaneous melanoma can metastasize haematogenously or lymphogenously. The three predominant models that endeavour to explain the patterns of melanoma progression are the stepwise spread model, the simultaneous spread model and the model of differential spread. The time course to the development of metastases differs between the different metastatic routes. There are several clinical and histopathological risk factors for the different metastatic pathways. In particular, patient sex and the anatomical location of the primary tumour influence patterns of disease progression. There is limited existing evidence regarding the relationship between tumour mutation status, other diagnostic and prognostic biomarkers and the metastatic pathways of primary cutaneous melanoma. This knowledge gap needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Preclinical evaluation of radiation and systemic, RGD-targeted, adeno-associated virus phage-TNF gene therapy in a mouse model of spontaneously metastatic melanoma.

PubMed

Quinn, T J; Healy, N; Sara, A; Maggi, E; Claros, C S; Kabarriti, R; Scandiuzzi, L; Liu, L; Gorecka, J; Adem, A; Basu, I; Yuan, Z; Guha, C

2017-01-01

The incidence of melanoma in the United States continues to rise, with metastatic lesions notoriously recalcitrant to therapy. There are limited effective treatment options available and a great need for more effective therapies that can be rapidly integrated in the clinic. In this study, we demonstrate that the combination of RGD-targeted adeno-associated virus phage (RGD-AAVP-TNF) with hypofractionated radiation therapy results in synergistic inhibition of primary syngeneic B16 melanoma in a C57 mouse model. Furthermore, this combination appeared to modify the tumor microenvironment, resulting in decreased Tregs in the draining LN and increased tumor-associated macrophages within the primary tumor. Finally, there appeared to be a reduction in metastatic potential and a prolongation of overall survival in the combined treatment group. These results indicate the use of targeted TNF gene therapy vector with radiation treatment could be a valuable treatment option for patients with metastatic melanoma.

Immunohistochemical expression of cyclooxygenase-2 (COX-2) in oral nevi and melanoma.

PubMed

de Souza do Nascimento, Juliana; Carlos, Román; Delgado-Azañero, Wilson; Mosqueda Taylor, Adalberto; de Almeida, Oslei Paes; Romañach, Mário José; de Andrade, Bruno Augusto Benevenuto

2016-07-01

Cyclooxygenase-2 (COX-2) catalyses the conversion of arachidonic acid to prostaglandin, and its overexpression has been demonstrated in different malignant tumors, including cutaneous melanoma. However, no data about the expression of this protein in oral melanocytic lesions are available to date. The aim of this study was to evaluate the immunohistochemical expression of COX-2 in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. COX-2 was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 36 intramucosal nevi and 13 primary oral melanomas, and in four cutaneous nevi and eight melanomas. All cases of oral and cutaneous melanomas were positive for COX-2. On the other hand, all oral and cutaneous melanocytic nevi were negative. COX-2 is highly positive in oral melanomas and negative in oral nevi and might represent a useful marker to distinguish melanocytic lesions of the oral cavity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mucosal Malignant Melanoma of Nasal Cavity Recurring a Year After Radiotherapy.

PubMed

Çomunoğlu, Cem; Kuzey, Gamze Mocan; Inançli, Mete; Baba, Füsun; Özkayalar, Hanife

2017-01-01

Sinonasal mucosal malignant melanoma is a rare entity. In this report we present a nasal mucosal malignant melanoma case with its histopathological and clinical features. An 88-year-old female patient presented with epistaxis a month ago. Examination revealed a polypoid mass lesion of right nasal cavity originating from the middle concha. Her medical history revealed that she had been found to have a mass lesion in the right nasal cavity 15 months ago. She then underwent a punch biopsy from that lesion. A definitive histopathological diagnosis was not made but it was declared that the lesion had been a malignant epithelial tumor. The patient then had radiotherapy and the lesion showed complete regression. One year after completion of radiotherapy, the lesion recurred. Her last PET-CT showed multiple metastatic foci. Endoscopic excisional biopsy was performed for her recurrent lesion. Fragmented tumoral tissues were measured as 3,6x3x0,5 cm. Macroscopically the tumor was brownish in color. Histopathologically the tumor consisted of spindled and epitheloid cells. Immunohistochemically the tumor cells displayed positivity for S-100, HMB-45 and Melan-A. Findings were consistent with malignant melanoma. Mucosal malignant melanomas have a poor prognosis despite chemotherapy and radiotherapy. Five-year survival for sinonasal melanoma is reported to be lower than 35%. Sinonasal melanomas show a high recurrence rate. The immunohistochemical markers showing high specificity for malignant melanoma such as S-100, HMB-45 and Melan-A are used in order to reach a correct diagnosis. In our case the tumor showed recurrence and multiple metastases 1 year after completion of radiotherapy. For this recurrent tumor, chemotherapy and radiotherapy have been planned.

Noncutaneous malignant melanoma: a prognostic model from a retrospective multicenter study

PubMed Central

2010-01-01

Background We performed multicenter study to define clinical characteristics of noncutaneous melanomas and to establish prognostic factors patients who received curative resection. Methods Of the 141 patients who were diagnosed of non-cutaneous melanoma at 4 institutions in Korea between June 1992 and May 2005, 129 (91.5%) satisfied the selection criteria. Results Of the 129 noncutaneous melanoma patients, 14 patients had ocular melanoma and 115 patients had mucosal melanoma. For mucosal melanoma, anorectum was the most common anatomic site (n = 39, 30.2%) which was followed by nasal cavity (n = 30, 23.3%), genitourinary (n = 21, 16.3%), oral cavity (n = 14, 10.9%), upper gastrointestinal tract (n = 6, 4.7%) and maxillary sinus (n = 5, 3.9%) in the order of frequency. With the median 64.5 (range 4.3-213.0) months follow-up, the median overall survival were 24.4 months (95% CI 13.2-35.5) for all patients, and 34.6 (95% CI 24.5-44.7) months for curatively resected mucosal melanoma patients. Adverse prognostic factors of survival for 87 curatively resected mucosal melanoma patients were complete resection (R1 resection margin), and age > 50 years. For 14 ocular melanoma, Survival outcome was much better than mucosal melanoma with 73.3% of 2 year OS and 51.2 months of median OS (P = .04). Conclusion Prognosis differed according to primary sites of noncutaneous melanoma. Based on our study, noncutaneous melanoma patients should be treated differently to improve survival outcome. PMID:20426858

Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sustarsic, Elahu G.; Department of Biological Sciences, Ohio University, Athens, OH; Junnila, Riia K.

2013-11-08

Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includesmore » 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation. Based on this data, GH could be a new therapeutic target in melanoma.« less

ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity

PubMed Central

Landreville, Solange; Agapova, Olga A.; Kneass, Zachary T.; Salesse, Christian; Harbour, J. William

2011-01-01

SUMMARY Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1− bulk tumor cells. ABCB1+ cells also exhibited enhanced clonogenicity, anchorage independent growth, tumorigenicity and mitochondrial activity compared to ABCB1− cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1+ cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others, and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma. PMID:21575142

Dissecting the Mutational Landscape of Cutaneous Melanoma: An Omic Analysis Based on Patients from Greece

PubMed Central

Piroti, Georgia; Papadodima, Olga

2018-01-01

Melanoma is a lethal type of skin cancer, unless it is diagnosed early. Formalin-fixed, paraffin-embedded (FFPE) tissue is a valuable source for molecular assays after diagnostic examination, but isolated nucleic acids often suffer from degradation. Here, for the first time, we examine primary melanomas from Greek patients, using whole exome sequencing, so as to derive their mutational profile. Application of a bioinformatic framework revealed a total of 10,030 somatic mutations. Regarding the genes containing putative protein-altering mutations, 73 were common in at least three patients. Sixty-five of these 73 top common genes have been previously identified in melanoma cases. Biological processes related to melanoma were affected by varied genes in each patient, suggesting differences in the components of a pathway possibly contributing to pathogenesis. We performed a multi-level analysis highlighting a short list of candidate genes with a probable causative role in melanoma. PMID:29596374

Clinical study of noninvasive in vivo melanoma and nonmelanoma skin cancers using multimodal spectral diagnosis

PubMed Central

Lim, Liang; Nichols, Brandon; Migden, Michael R.; Rajaram, Narasimhan; Reichenberg, Jason S.; Markey, Mia K.; Ross, Merrick I.; Tunnell, James W.

2014-01-01

Abstract. The goal of this study was to determine the diagnostic capability of a multimodal spectral diagnosis (SD) for in vivo noninvasive disease diagnosis of melanoma and nonmelanoma skin cancers. We acquired reflectance, fluorescence, and Raman spectra from 137 lesions in 76 patients using custom-built optical fiber-based clinical systems. Biopsies of lesions were classified using standard histopathology as malignant melanoma (MM), nonmelanoma pigmented lesion (PL), basal cell carcinoma (BCC), actinic keratosis (AK), and squamous cell carcinoma (SCC). Spectral data were analyzed using principal component analysis. Using multiple diagnostically relevant principal components, we built leave-one-out logistic regression classifiers. Classification results were compared with histopathology of the lesion. Sensitivity/specificity for classifying MM versus PL (12 versus 17 lesions) was 100%/100%, for SCC and BCC versus AK (57 versus 14 lesions) was 95%/71%, and for AK and SCC and BCC versus normal skin (71 versus 71 lesions) was 90%/85%. The best classification for nonmelanoma skin cancers required multiple modalities; however, the best melanoma classification occurred with Raman spectroscopy alone. The high diagnostic accuracy for classifying both melanoma and nonmelanoma skin cancer lesions demonstrates the potential for SD as a clinical diagnostic device. PMID:25375350

Clinical study of noninvasive in vivo melanoma and nonmelanoma skin cancers using multimodal spectral diagnosis

NASA Astrophysics Data System (ADS)

Lim, Liang; Nichols, Brandon; Migden, Michael R.; Rajaram, Narasimhan; Reichenberg, Jason S.; Markey, Mia K.; Ross, Merrick I.; Tunnell, James W.

2014-11-01

The goal of this study was to determine the diagnostic capability of a multimodal spectral diagnosis (SD) for in vivo noninvasive disease diagnosis of melanoma and nonmelanoma skin cancers. We acquired reflectance, fluorescence, and Raman spectra from 137 lesions in 76 patients using custom-built optical fiber-based clinical systems. Biopsies of lesions were classified using standard histopathology as malignant melanoma (MM), nonmelanoma pigmented lesion (PL), basal cell carcinoma (BCC), actinic keratosis (AK), and squamous cell carcinoma (SCC). Spectral data were analyzed using principal component analysis. Using multiple diagnostically relevant principal components, we built leave-one-out logistic regression classifiers. Classification results were compared with histopathology of the lesion. Sensitivity/specificity for classifying MM versus PL (12 versus 17 lesions) was 100%;/100%;, for SCC and BCC versus AK (57 versus 14 lesions) was 95%;/71%, and for AK and SCC and BCC versus normal skin (71 versus 71 lesions) was 90%/85%. The best classification for nonmelanoma skin cancers required multiple modalities; however, the best melanoma classification occurred with Raman spectroscopy alone. The high diagnostic accuracy for classifying both melanoma and nonmelanoma skin cancer lesions demonstrates the potential for SD as a clinical diagnostic device.

Nodular melanoma is less likely than superficial spreading melanoma to be histologically associated with a naevus.

PubMed

Pan, Yan; Adler, Nikki R; Wolfe, Rory; McLean, Catriona A; Kelly, John W

2017-10-16

To determine the frequency of naevus-associated melanoma among superficial spreading and nodular subtypes; and to investigate associations between naevus-associated melanoma and other clinico-pathological characteristics. Cross-sectional study of all patients with nodular and superficial spreading melanomas diagnosed between 1994 and 2015 at the Victorian Melanoma Service, Melbourne. Clinical and pathological characteristics of naevus-associated and de novo melanomas were assessed in univariable and multivariable logistic regression analyses. Of 3678 primary melanomas, 1360 (37.0%) were histologically associated with a naevus and 2318 (63.0%) were de novo melanomas; 71 of 621 nodular (11.4%) and 1289 of 3057 superficial spreading melanomas (42.2%) were histologically associated with a naevus. In multivariable analyses, the odds of being associated with a naevus were higher for melanomas located on the trunk (v head and neck: adjusted odds ratio [OR], 2.27; 95% CI, 1.73-2.96; P < 0.001), while the odds were lower for thicker tumours (adjusted OR, 0.75 per millimetre increase in Breslow thickness; 95% CI, 0.69-0.81; P < 0.001), amelanotic/hypomelanotic melanomas (adjusted OR, 0.68; 95% CI, 0.48-0.97; P = 0.035), and older age (patients 70 years or older v patients under 30 at diagnosis: adjusted OR, 0.28; 95% CI, 0.20-0.40; P < 0.001). After adjusting for confounders, the odds of an associated naevus was three times as high for superficial spreading melanomas as for nodular melanomas (adjusted OR, 3.05; 95% CI, 2.24-4.17; P < 0.001). Melanomas are most likely to arise in the absence of a pre-existing naevus, particularly nodular melanomas. Public health campaigns should therefore emphasise the detection of suspicious de novo lesions, as well as of changing lesions.

Modelling uveal melanoma

PubMed Central

Foss, A.; Cree, I.; Dolin, P.; Hungerford, J.

1999-01-01

BACKGROUND/AIM—There has been no consistent pattern reported on how mortality for uveal melanoma varies with age. This information can be useful to model the complexity of the disease. The authors have examined ocular cancer trends, as an indirect measure for uveal melanoma mortality, to see how rates vary with age and to compare the results with their other studies on predicting metastatic disease.
METHODS—Age specific mortality was examined for England and Wales, the USA, and Canada. A log-log model was fitted to the data. The slopes of the log-log plots were used as measure of disease complexity and compared with the results of previous work on predicting metastatic disease.
RESULTS—The log-log model provided a good fit for the US and Canadian data, but the observed rates deviated for England and Wales among people over the age of 65 years. The log-log model for mortality data suggests that the underlying process depends upon four rate limiting steps, while a similar model for the incidence data suggests between three and four rate limiting steps. Further analysis of previous data on predicting metastatic disease on the basis of tumour size and blood vessel density would indicate a single rate limiting step between developing the primary tumour and developing metastatic disease.
CONCLUSIONS—There is significant underreporting or underdiagnosis of ocular melanoma for England and Wales in those over the age of 65 years. In those under the age of 65, a model is presented for ocular melanoma oncogenesis requiring three rate limiting steps to develop the primary tumour and a fourth rate limiting step to develop metastatic disease. The three steps in the generation of the primary tumour involve two key processes—namely, growth and angiogenesis within the primary tumour. The step from development of the primary to development of metastatic disease is likely to involve a single rate limiting process.

 PMID:10216060

The impact of surgery on survival of patients with cutaneous melanoma: revisiting the role of primary tumor excision margins.

PubMed

Mocellin, Simone; Pasquali, Sandro; Nitti, Donato

2011-02-01

To quantify the impact of excision margins on disease-specific survival of patients with primary cutaneous melanoma. Current guidelines recommend narrow margins for the treatment of primary melanoma, although available evidence on this subject is not unequivocal and not always appropriately analyzed. A systematic review of randomized controlled trials (RCT) addressing the issue of wide versus narrow excision margins was performed. Meta-analysis methods for time-to-event data were used to extract hazard ratios(HR) and their 95% confidence intervals (CI) from eligible studies, and ultimately to estimate the summary effect of excision margins on patients' survival. The 5 eligible RCT enrolled a total of 3295 patients who were allocated to wide (3-5 cm) or narrow (1-2 cm) excision of their primary tumor. The data of locoregional disease-free (LDFS), disease-free (DFS),disease-specific (DSS), and overall (OS) survival were available for 3, 5, 3, and 5 RCT, respectively. The meta-analysis suggested that narrow margins might be associated with an increased risk of both locoregional disease recurrence (HR: 1.30, CI: 1.07-1.57; P = 0.01) and death by disease (HR: 1.28, CI:1.07-1.53, P = 0.01). As regards DFS, the borderline disadvantage (HR:1.13, CI: 0.995-1.28; P = 0.06) becomes significant when considering RCT that enrolled patients with thicker melanoma (HR: 1.19, CI: 1.02-1.39, P =0.03). When death by any cause (OS) was analyzed, no risk difference was found. The lack of DSS data from all the available RCT does not allow to draw definitive conclusions. However, current evidence appears sufficient to question the common belief that narrow excision margins are as safe as wide margins in the management of primary melanoma, that calls for further investigation in this field.

[Primary pigmented breast adenocarcinoma in a male patient].

PubMed

Dauendorffer, J-N; Pages, C; Abd Alsamad, I; Bagot, M; Fraitag, S

2013-01-01

Pigmented mammary tumours are rare. Herein, we report the third case of primary pigmented breast adenocarcinoma in a male patient with clinical mimicking of nodular melanoma of the nipple. A male patient presented with a pigmented nodule of the right nipple. Histological examination of the lesion showed dermal and subcutaneous adenocarcinomatous proliferation. The perilesional stroma contained melanin both inside and outside macrophages, leading us to conclude on primary pigmented breast adenocarcinoma clinically mimicking nodular melanoma of the nipple. Local production of melanin by neoplastic cells in the mammary carcinoma was postulated as the cause of hyperpigmentation of the tumour. Other possible causes are transfer of melanin from overlying melanocytes of the pigmented areolar epidermis to the underlying neoplastic cells, or melanin synthesis by intratumoral melanocytes migrating from the epidermis (which strikes us as the most convincing interpretation for the reported case). Breast adenocarcinoma is a rare tumour in men and may present clinically as a pigmented lesion of the nipple, resulting in the problem of differential diagnosis with primary or metastasised nodular melanoma. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells.

PubMed

Manca, Antonella; Sini, Maria Cristina; Izzo, Francesco; Ascierto, Paolo A; Tatangelo, Fabiana; Botti, Gerardo; Gentilcore, Giusy; Capone, Marilena; Mozzillo, Nicola; Rozzo, Carla; Cossu, Antonio; Tanda, Francesco; Palmieri, Giuseppe

2011-06-01

Arginine deiminase (ADI), an arginine-degrading enzyme, has been used in the treatment of tumours sensitive to arginine deprivation, such as malignant melanoma (MM) and hepatocellular carcinoma (HCC). Endogenous production of arginine is mainly dependent on activity of ornithine transcarbamylase (OTC) and argininosuccinate synthetase (ASS) enzymes. We evaluated the effect of ADI treatment on OTC and ASS expression in a series of melanoma cell lines. Twenty-five primary melanoma cell lines and normal fibroblasts as controls underwent cell proliferation assays and Western blot analyses in the presence or absence of ADI. Tissue sections from primary MMs (N = 20) and HCCs (N = 20) were investigated by immunohistochemistry for ASS expression. Overall, 21/25 (84%) MM cell lines presented a cell growth inhibition by ADI treatment; none of them presented constitutive detectable levels of the ASS protein. However, 7/21 (33%) ADI-sensitive melanoma cell lines presented markedly increased expression levels of the ASS protein following ADI treatment, with a significantly higher IC50 median value. Growth was not inhibited and the IC50 was not reached among the remaining 4/25 (16%) MM cell lines; all of them showed constitutive ASS expression. The OTC protein was found expressed in all melanoma cell lines before and after the ADI treatment. Lack of ASS immunostaining was observed in all analyzed in vivo specimens. Our findings suggest that response to ADI treatment in melanoma is significantly correlated with the ability of cells to express ASS either constitutively at basal level (inducing drug resistance) or after the treatment (reducing sensitivity to ADI).

Immunotherapy of patients with metastatic melanoma.

PubMed

Yu, Zhe; Si, Lu

2017-04-01

Malignant melanoma (MM) is the primary cause of skin cancer related death and the incidence is increasing in the past years. Advanced MM still has a poor prognosis, but in recent years, the development of immunotherapy has changed its poor prognosis. Immune checkpoints show the revolutionary treatment of metastatic melanoma. Ipilimumab and pembrolizumab, monoclonal antibodies against the CTLA-4 and PD-1 respectively, have been shown to prolong overall survival (OS) in patients with advanced melanoma. The combination immunotherapy seems to be superior to monotherapy. In this review, recently immunotherapy clinical trial results are presented. The combination of immunotherapy provides new options for the treatment of MM patients. However, further studies are necessary to answer such question as optimal treatment, combination of immunotherapies, crowd selection and risk balance in patients with melanoma.

Monitoring the Systemic Human Memory B Cell Compartment of Melanoma Patients for Anti-Tumor IgG Antibodies

PubMed Central

Gilbert, Amy E.; Karagiannis, Panagiotis; Dodev, Tihomir; Koers, Alexander; Lacy, Katie; Josephs, Debra H.; Takhar, Pooja; Geh, Jenny L. C.; Healy, Ciaran; Harries, Mark; Acland, Katharine M.; Rudman, Sarah M.; Beavil, Rebecca L.; Blower, Philip J.; Beavil, Andrew J.; Gould, Hannah J.; Spicer, James; Nestle, Frank O.; Karagiannis, Sophia N.

2011-01-01

Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer. PMID:21559411

One Step Melanoma Surgery for Patient with Thick Primary Melanomas: "To Break the Rules, You Must First Master Them!"

PubMed

Tchernev, Georgi

2018-02-15

We present to the attention of the medical, dermatological and oncosurgical community data that serves to indicate the indispensability of optimisation of the algorithm and recommendations for diagnosis and surgical treatment of cutaneous melanoma. These recommendations could be referred to different subgroups of patients in different clinical stages as well as to patients with different initial characterisation (histological morphology) of the primary tumours. One step surgery is not a myth, even more, it could prove to be one of the best solutions for some patient collectives with advanced stages of melanoma. We present a case of a 74 - year old patient with a congenital medium sized melanocytic nevus, located directly above the lateral part of the elbow joint. In one month and a half, an achromatic nodular formation evolves with a diameter of 2.7 x 2.3 cm, prominent over the skin level, painful by palpation and spontaneously bleeding. By the anamnestic, clinical and dermoscopic findings the patient was diagnosed with nodular melanoma associated with a congenital medium sized melanocytic nevus. A primary excision with a field of safety 0.5 cm in all directions was performed. After confirmation of the primary diagnosis (tumour thickness 8 mm with no ultrasonographic detection of enlarged lymph nodes), seven days later are - excision was performed with an additional field of surgical safety of 1.5 cm in all directions. In this case remains unclear the following question: For what reason a preoperative high - frequent ultrasonography (HFUS) is not recommended to be used as it will allow only one surgical excision with the elimination of a tumour with a safety field of 2cm in all directions? The enigma about the obstacles preventing such a rational optimisation of the current diagnostic and therapeutic algorithm in patients with melanomas remains unresolved. One step surgery for cutaneous melanoma is widely used in many countries although it continues to be considered as a matter of dispute for some experts. Once again, by a clinical case and the following analysis, we would like to focus the attention of the dermatosurgical community on this crucial and highly significant problem. Innovations are very often resulting from the simplicity of logic, which unfortunately is not always accepted appropriately.

Multifocal amelanotic conjunctival melanoma and acquired melanosis sine pigmento.

PubMed Central

Paridaens, A D; McCartney, A C; Hungerford, J L

1992-01-01

Clinical and histopathological features of four cases of multifocal amelanotic malignant melanoma of the conjunctiva in association with 'acquired melanosis sine pigmento' are reported. The absence of conjunctival pigmentation in this extremely rare combination of lesions prevented early diagnosis and clinical monitoring. As a result orbital exenteration was required in three cases. This multicentric non-pigmented variety of conjunctival malignant melanoma tends to present later than pigmented forms and may require exenteration of the orbit as a primary procedure. Images PMID:1540561

Conjunctival malignant melanoma: A rare variant and review of important diagnostic and therapeutic considerations

PubMed Central

Albreiki, Danah H.; Gilberg, Steven M.; Farmer, James P.

2012-01-01

Malignant melanoma of the conjunctiva is a relatively infrequent neoplasm that can be associated with significant morbidity and cause diagnostic difficulty to both the ophthalmologist and pathologist. We herein describe the first reported case in North American and European databases of a rare variant-signet ring cell melanoma – arising in the background of primary acquired melanosis (PAM) and use this case as a review of important diagnostic and therapeutic considerations when faced with this condition. PMID:23960986

Multifocal amelanotic conjunctival melanoma and acquired melanosis sine pigmento.

PubMed

Paridaens, A D; McCartney, A C; Hungerford, J L

1992-03-01

Clinical and histopathological features of four cases of multifocal amelanotic malignant melanoma of the conjunctiva in association with 'acquired melanosis sine pigmento' are reported. The absence of conjunctival pigmentation in this extremely rare combination of lesions prevented early diagnosis and clinical monitoring. As a result orbital exenteration was required in three cases. This multicentric non-pigmented variety of conjunctival malignant melanoma tends to present later than pigmented forms and may require exenteration of the orbit as a primary procedure.

Mutation analysis of metastatic melanomas in the central nervous system: results of a panel of 5 genes in 48 cases.

PubMed

Gamsizkan, Mehmet; Yilmaz, Ismail; Simsek, Hasan Aktug; Onguru, Onder; Griffin, Ann; Tihan, Tarik

2016-01-01

Melanocytic lesions in the central nervous system (CNS) may be primary to the site but are more commonly metastases from cutaneous primaries. In fact, melanomas are one of the most common malignancies that can metastasize to the brain, and some patients may not have a diagnosis of melanoma prior to the discovery of the CNS lesion. In such cases, identifying the primary site may be challenging. We reviewed the archives of a large referral center for melanocytic tumors involving the CNS and selected 48 patients for this study based on our inclusion criteria. We used sequencing to identify mutation status of these tumors and compared these with clinicopathological features. Mutations in exon 9, 11, 13, 17, and 18 of KIT gene, exon 15 of BRAF gene, exon 2 and 3 of NRAS gene, exon 4 and 5 of GNAQ and GNA11 genes were analyzed. Mutations in BRAF-exon 15 were the most common among tumors (58.3%). NRAS-exon 2 and NRAS-exon 3 mutations were detected in 3 and 7 cases, respectively. GNAQ-exon 4, GNAQ-exon 5 and GNA11-exon 5 mutation were present in 1 tumor each. Eight tumors were wild type for all 5 genes, and 6 of these were not known primary despite a work-up and clinical follow-up. Only 1 of these tumors showed a mutation in exon 11 of KIT gene. When compared to primary melanocytic lesions of the CNS, metastatic melanomas were characterized by BRAF gene mutations and wild-type GNAQ and GNA11 genes.

Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Bevacizumab in Treating Patients With Stage IV Melanoma That Cannot Be Removed by Surgery or Gynecological Cancers

ClinicalTrials.gov

2018-02-05

Cervical Adenosarcoma; Cervical Adenosquamous Carcinoma; Cervical Carcinosarcoma; Cervical Squamous Cell Carcinoma, Not Otherwise Specified; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Fallopian Tube Adenocarcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Epithelial Tumor; Malignant Peritoneal Neoplasm; Ovarian Carcinosarcoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IV Skin Melanoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma; Uterine Corpus Carcinosarcoma

Multiple mechanisms underlie defective recognition of melanoma cells cultured in three-dimensional architectures by antigen-specific cytotoxic T lymphocytes

PubMed Central

Feder-Mengus, C; Ghosh, S; Weber, W P; Wyler, S; Zajac, P; Terracciano, L; Oertli, D; Heberer, M; Martin, I; Spagnoli, G C; Reschner, A

2007-01-01

Cancer cells' growth in three-dimensional (3D) architectures promotes resistance to drugs, cytokines, or irradiation. We investigated effects of 3D culture as compared to monolayers (2D) on melanoma cells' recognition by tumour-associated antigen (TAA)-specific HLA-A*0201-restricted cytotoxic T-lymphocytes (CTL). Culture of HBL, D10 (both HLA-A*0201+, TAA+) and NA8 (HLA-A*0201+, TAA−) melanoma cells on polyHEMA-coated plates, resulted in generation of 3D multicellular tumour spheroids (MCTS). Interferon-gamma (IFN-γ) production by HLA-A*0201-restricted Melan-A/MART-127–35 or gp100280–288-specific CTL clones served as immunorecognition marker. Co-culture with melanoma MCTS, resulted in defective TAA recognition by CTL as compared to 2D as witnessed by decreased IFN-γ production and decreased Fas Ligand, perforin and granzyme B gene expression. A multiplicity of mechanisms were potentially involved. First, MCTS per se limit CTL capacity of recognising HLA class I restricted antigens by reducing exposed cell surfaces. Second, expression of melanoma differentiation antigens is downregulated in MCTS. Third, expression of HLA class I molecules can be downregulated in melanoma MCTS, possibly due to decreased interferon-regulating factor-1 gene expression. Fourth, lactic acid production is increased in MCTS, as compared to 2D. These data suggest that melanoma cells growing in 3D, even in the absence of immune selection, feature characteristics capable of dramatically inhibiting TAA recognition by specific CTL. PMID:17342088

Human Papilloma Virus in Melanoma Biopsy Specimens and Its Relation to Melanoma Progression

PubMed Central

Dréau, Didier; Culberson, Cathy; Wyatt, Sharon; Holder, Walter D.

2000-01-01

Objectives To evaluate melanoma biopsy specimens for human papilloma virus (HPV) and determine the relation between the presence of HPV, in vitro growth, and clinical progression of melanoma in the patients from whom the biopsy specimens were derived. Summary Background Data Ultraviolet radiation from sun exposure appears to be the primary causal agent in the development of cutaneous melanoma. However, other agents, including HPV, as observed in different epithelial carcinomas, may also play a role in melanoma development and progression. Methods Twelve melanoma biopsy specimens obtained from 12 patients with AJCC stage III and IV melanoma were stained with antibodies against gp-100 (HMB-45) and S-100 protein to confirm melanoma diagnosis and with a polyclonal HPV antibody. After mechanical dissociation, the melanoma specimen cells’ ability to grow in vitro was assessed. Patients were evaluated for melanoma progression with physical examination, complete blood count, and liver function tests every 3 months and a chest radiograph every 6 months. Results All biopsy specimens were positive for S-100, and nine (75%) were positive for gp-100. Seven of 12 (58%) were positive for HPV by immunohistochemistry. In vitro, none of the HPV-negative tumor cells grew from the tumor biopsies, whereas five of seven (71%) of the HPV-positive melanoma tumor cells grew very well. All patients with HPV-positive tumor cells had recurrences and died of melanoma progression, whereas four of five (80%) patients with HPV-negative tumor cells remained alive and without melanoma recurrence. Conclusions The presence of HPV was found in 58% of the biopsy specimens obtained from patients with stage III and IV melanoma and correlated with rapid melanoma progression. HPV may serve as a cofactor in the development of melanoma and may modulate a more aggressive phenotype in HPV-containing melanoma cells. PMID:10767787

Incidence of complications in dermatological surgery of melanoma and non-melanoma skin cancer in patients with multiple comorbidity and/or antiplatelet-anticoagulants. Five year experience in our Hospital.

PubMed

Arguello-Guerra, Lilia; Vargas-Chandomid, Estefanía; Díaz-González, Jose Manuel; Méndez-Flores, Silvia; Ruelas-Villavicencio, Ana; Domínguez-Cherit, Judith

2018-01-01

Surgery is performed more frequently now at days, due to the increasing incidence of melanoma and no-melanoma skin cancer. There are different opinions among dermatologic surgeons between to continue or discontinue antithrombotic therapy prior to the procedure, which increases the risk of thromboembolic events. Prophylaxis with oral antibiotics in the postsurgical period is controversial. To report the safety of surgery without suspending antithrombotic therapy and without oral antibiotic prophylaxis in dermatology surgery of patients with multiple comorbidities and polypharmacy. We designed a retrospective study. We included a total of 655 patients; 96.6% had at least one comorbidity; 27.7% used aspirin and 4.3% some type of antithrombotic therapy. The most common type of skin tumor was basal cell carcinoma with 69.8% . The complication rate was 4.2%; the most was wound dehiscence (1.1%), followed by partial necrosis (0.9%), infection (0.9%), reaction to foreign body (0.6%), complete necrosis (0.3%), bleeding (0.2%) and fistulae (0.2%). Based on the literature and our experience, dermatologic surgery is safe without suspending antithrombotic therapy or antibiotic prophylaxis in patients with multiple comorbidity. Copyright: © 2018 Permanyer.

The detection of melanoma cells in peripheral blood by reverse transcription-polymerase chain reaction.

PubMed Central

Foss, A. J.; Guille, M. J.; Occleston, N. L.; Hykin, P. G.; Hungerford, J. L.; Lightman, S.

1995-01-01

Both cutaneous and uveal melanoma undergo haematogenous dissemination. Detection of tyrosinase mRNA by reverse transcription-polymerase chain reaction (RT-PCR) has been described as an extremely sensitive way of detecting circulating viable melanoma cells in the peripheral venous blood, and this technique may be of value in the early detection of dissemination. Also, it has been suggested that surgical manipulation of the eye, such as occurs during enucleation, can provoke uveal melanoma dissemination. The purpose of this study was to evaluate whether tyrosinase mRNA is detectable in the peripheral blood of patients with uveal and cutaneous melanoma and in patients with uveal melanoma undergoing surgical procedures on the eye harbouring the tumour. Venous blood samples from 36 patients diagnosed as having active uveal melanoma and from six patients with advanced metastatic cutaneous melanoma were analysed. In addition, blood samples were spiked with known numbers of cells from three cell lines and four primary uveal melanoma cultures. The reported sensitivity of the technique was confirmed, with an ability to detect down to one cell per ml of blood. All 51 blood samples from the 36 patients with uveal melanoma were negative, and this included 20 perioperative blood samples. The test was also negative for the six patients with advanced cutaneous melanoma. There were two positives among 31 control samples analysed. This study demonstrates that there are far fewer circulating viable melanocytes than has been previously supposed in patients with melanoma and that the RT-PCR is of no clinical value in detecting metastatic melanoma disease. There was no evidence for surgery causing a bolus of melanoma cells to enter the peripheral circulation. Images Figure 1 Figure 2 PMID:7599046

KIT amplification and gene mutations in acral/mucosal melanoma in Korea.

PubMed

Yun, Jina; Lee, Jeeyun; Jang, Jiryeon; Lee, Eui Jin; Jang, Kee Taek; Kim, Jung Han; Kim, Kyoung-Mee

2011-06-01

Mucosal and acral melanomas have demonstrated different genetic alterations and biological behavior compared with more common cutaneous melanomas. It was recently reported that gain-of-function KIT mutations and/or copy number increases are more common in mucosal and acral melanomas. Thus, we studied the frequency and pattern of KIT aberrations in mucosal and acral melanomas in Korea. We analyzed 97 patients who were pathologically confirmed with mucosal or acral melanoma between 1997 and 2010 at Samsung Medical Center. Of the 97 melanoma patients, 92 were screened for mutations in KIT exons 11, 13, 17, and 18, BRAF and NRAS genes. KIT copy number was assessed by quantitative, real-time PCR. Of the 97 patients, 55 (56.7%) were mucosal, 40 (41.2%) were acral melanoma, and two were of unknown primary origin. Among seven cases with KIT mutation, five (60.0%) occurred in exon 11, one (20.0%) in exon 17, and one (20.0%) in exon 13. Point mutations were the most common, resulting in substitutions in exon 11 (K558R, T574A, L576P, and V559A), exon 13 (N655K), and exon 17 (N822K). A novel Thr574Ala (c.1720A>G) KIT mutation, which has not been reported in melanoma or other tumor types, was identified in one genital melanoma case. Of the 97 mucosal or acral melanoma specimens, 49 were tested for KIT gene copy number changes using quantitative PCR. Increased KIT copy number was identified in 15 patients: seven (40%) of 20 acral melanomas and eight (31%) of 26 mucosal melanomas. Our study implicates that a significant proportion of acral and mucosal melanomas have KIT mutations in Asian population. © 2011 The Authors. APMIS © 2011 APMIS.

Sun exposure and protection behaviors among long-term melanoma survivors and non-cancer controls

PubMed Central

Vogel, Rachel Isaksson; Strayer, Lori G.; Engelman, Leah; Nelson, Heather H.; Blaes, Anne H.; Anderson, Kristin E.; Lazovich, DeAnn

2016-01-01

Introduction Melanoma is considered a generally preventable cancer, with excessive ultraviolet radiation (UVR) exposure being a strong causal factor. UVR exposure following a melanoma diagnosis can be modified to reduce risk of second primary melanomas. The goal of this study was to compare measures of UVR exposure and protection behaviors between long-term melanoma survivors and controls. Methods Participants from a previously conducted case-control study were recruited for a cross-sectional survey. Melanoma cases were 25–59 years old at diagnosis; controls were age and sex matched. Participants were asked about UVR exposure and protection measures used in the past year and comparisons between melanoma survivors and controls were conducted using logistic regression models, adjusting for potential confounders. Results A total of 726 (67.7%) long-term melanoma survivors and 657 (60.9%) controls completed the follow-up survey. Melanoma survivors were significantly less likely to report high sun exposure on a typical weekday (OR=0.72 [0.55–0.94]), sunburns (OR=0.40 [0.30–0.53]), or indoor tanning (OR=0.20 [0.09–0.44]) than controls; however high sun exposure on a typical weekend day was similar. Report of optimal sun protection behaviors were higher in melanoma survivors compared to controls. However, a few melanoma survivors reported indoor tanning, 10% reported intentionally seeking sun to tan, and 20% reported sunburns. Conclusion Although long term melanoma survivors reported healthier UVR exposure and protection behaviors compared to controls, a sizeable proportion still reported elevated sun exposure, sunburns, and suboptimal UVR protection behaviors. Impact Opportunities remain for improving sun protection to reduce future melanoma risk among melanoma survivors. PMID:28254810

Melanin content in melanoma metastases affects the outcome of radiotherapy.

PubMed

Brożyna, Anna A; Jóźwicki, Wojciech; Roszkowski, Krzysztof; Filipiak, Jan; Slominski, Andrzej T

2016-04-05

Melanin possess radioprotective and scavenging properties, and its presence can affect the behavior of melanoma cells, its surrounding environment and susceptibility to the therapy, as showed in vitro experiments. To determine whether melanin presence in melanoma affects the efficiency of radiotherapy (RTH) we evaluated the survival time after RTH treatment in metastatic melanoma patients (n = 57). In another cohort of melanoma patients (n = 84), the relationship between melanin level and pT and pN status was determined. A significantly longer survival time was found in patients with amelanotic metastatic melanomas in comparison to the melanotic ones, who were treated with either RTH or chemotherapy (CHTH) and RTH. These differences were more significant in a group of melanoma patients treated only with RTH. A detailed analysis of primary melanomas revealed that melanin levels were significantly higher in melanoma cells invading reticular dermis than the papillary dermis. A significant reduction of melanin pigmentation in pT3 and pT4 melanomas in comparison to pT1 and T2 tumors was observed. However, melanin levels measured in pT3-pT4 melanomas developing metastases (pN1-3, pM1) were higher than in pN0 and pM0 cases. The presence of melanin in metastatic melanoma cells decreases the outcome of radiotherapy, and melanin synthesis is related to higher disease advancement. Based on our previous cell-based and clinical research and present research we also suggest that inhibition of melanogenesis can improve radiotherapy modalities. The mechanism of relationship between melanogenesis and efficacy of RTH requires additional studies, including larger melanoma patients population and orthotopic, imageable mouse models of metastatic melanoma.

Dermoscopy for melanoma detection in family practice

PubMed Central

Herschorn, Andrea

2012-01-01

Abstract Objective To assess the diagnostic accuracy and clinical utility of dermoscopy for melanoma detection in family practice. Quality of evidence Ovid MEDLINE (1946 to June 2011), EMBASE, PubMed, and Cochrane databases were searched using the following terms: dermoscopy, dermatoscopy, epiluminescence microscopy, family practice, general practice, primary health care, melanoma, skin neoplasms, and pigmented nevus. To be included, studies had to be primary research articles with family physicians as the subjects and dermoscopy training and use as the intervention. Four papers met all inclusion criteria and provided level I evidence according to the Canadian Task Force on Preventive Health Care definition. Main message Among family physicians, dermoscopy has higher sensitivity for melanoma detection than naked-eye examination with generally no decrease in specificity. Dermoscopy also helps to increase family physicians’ confidence in their preliminary diagnosis of lesions. When using dermoscopy, compared with naked-eye examination, there is a higher likelihood that a lesion assessed as being malignant is in fact malignant and that a lesion assessed as being benign is in fact benign. Conclusion Dermoscopy has been shown to be a useful and fairly inexpensive tool for melanoma detection in family practice. This technique can increase family physicians’ confidence in their referral accuracy to dermatologists and can assist in decreasing unnecessary biopsies. Dermoscopy might be especially useful in examining patients at high risk of melanoma, as the current Canadian clinical practice guideline recommends yearly screening in these individuals. PMID:22859635

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4.

PubMed

Pinheiro, Céline; Miranda-Gonçalves, Vera; Longatto-Filho, Adhemar; Vicente, Anna L S A; Berardinelli, Gustavo N; Scapulatempo-Neto, Cristovam; Costa, Ricardo F A; Viana, Cristiano R; Reis, Rui M; Baltazar, Fátima; Vazquez, Vinicius L

2016-06-02

BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi. Samples included 20 benign nevi, 282 primary melanomas, 117 lymph node and 54 distant metastases samples. BRAF mutation was observed in 29/92 (31.5%) melanoma patients and 17/20 (85%) benign nevi samples. NRAS mutation was observed in 4/36 (11.1%) melanoma patients and 1/19 (5.3%) benign nevi samples. MCT4 and GLUT1 expression was significantly increased in metastatic samples, and MCT1, MCT4 and GLUT1 were significantly associated with poor prognostic variables. Importantly, MCT1 and MCT4 were associated with shorter overall survival. In conclusion, the present study brings new insights on metabolic aspects of melanoma, paving the way for the development of new-targeted therapies.

The magic of numbers: malignant melanoma between science and pseudoscience.

PubMed

Weyers, Wolfgang

2011-06-01

In 2009, a new system for staging and classification of malignant melanoma has been proposed by the American Joint Committee on Cancer (AJCC). The AJCC recommends that staging of primary melanoma be based on 3 criteria, namely, thickness, ulceration, and mitotic rate, the latter substituting Clark levels in the previous classification. In melanomas measuring ≤1 mm in thickness, ulceration or finding of single mitotic figure in the dermis defines stage T1b. According to the AJCC, sentinel lymph node dissection should be considered for those melanomas because of a significantly impaired prognosis. As with other prognostic parameters, however, assessment of mitotic rate, with one mitotic figure being the cutoff point, is highly unreliable, and statistics based on such data lack validity. Despite the large database being employed, they may be pseudoscience rather than science.

Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS.

PubMed

Zuidervaart, W; van Nieuwpoort, F; Stark, M; Dijkman, R; Packer, L; Borgstein, A-M; Pavey, S; van der Velden, P; Out, C; Jager, M J; Hayward, N K; Gruis, N A

2005-06-06

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma.

Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS

PubMed Central

Zuidervaart, W; van Nieuwpoort, F; Stark, M; Dijkman, R; Packer, L; Borgstein, A-M; Pavey, S; van der Velden, P; Out, C; Jager, M J; Hayward, N K; Gruis, N A

2005-01-01

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma. PMID:15928660

Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and β1-integrin activation

PubMed Central

Balistreri, Giuseppe; Gramolelli, Silvia; Tatti-Bugaeva, Olga; Paatero, Ilkka; Niiranen, Otso; Tuohinto, Krista; Perälä, Nina; Taiwo, Adewale; Zinovkina, Nadezhda; Repo, Pauliina; Icay, Katherine; Ivaska, Johanna; Saharinen, Pipsa; Hautaniemi, Sampsa; Lehti, Kaisa

2018-01-01

Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and β1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident β1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype. PMID:29712618

Impact of scalp location on survival in head and neck melanoma: A retrospective cohort study.

PubMed

Xie, Charles; Pan, Yan; McLean, Catriona; Mar, Victoria; Wolfe, Rory; Kelly, John

2017-03-01

Scalp melanomas have more aggressive clinicopathological features than other melanomas and mortality rates more than twice that of melanoma located elsewhere. We sought to describe the survival of patients with scalp melanoma versus other cutaneous head and neck melanoma (CHNM), and explore a possible independent negative impact of scalp location on CHNM survival. A retrospective cohort study was performed of all invasive primary CHNM cases seen at a tertiary referral center over a 20-year period. Melanoma-specific survival (MSS) was compared between scalp melanoma and other invasive CHNM. Multivariable Cox proportional hazards regression was performed to determine associations with survival. On univariate analysis, patients with scalp melanoma had worse MSS than other CHNM (hazard ratio 2.22, 95% confidence interval 1.59-3.11). Scalp location was not associated with MSS in CHNM on multivariable analysis (hazard ratio 1.11, 95% confidence interval 0.77-1.61) for all tumors together, but remained independently associated with MSS for the 0.76- to 1.50-mm thickness stratum (hazard ratio 5.51, 95% confidence interval 1.55-19.59). Disease recurrence was not assessed because of unavailable data. The poorer survival of scalp melanoma is largely explained by greater Breslow thickness and a higher proportion of male patients. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma.

PubMed

Hintzsche, Jennifer D; Gorden, Nicholas T; Amato, Carol M; Kim, Jihye; Wuensch, Kelsey E; Robinson, Steven E; Applegate, Allison J; Couts, Kasey L; Medina, Theresa M; Wells, Keith R; Wisell, Joshua A; McCarter, Martin D; Box, Neil F; Shellman, Yiqun G; Gonzalez, Rene C; Lewis, Karl D; Tentler, John J; Tan, Aik Choon; Robinson, William A

2017-06-01

Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (P<0.05). KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%). Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients. Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas. Alternative splicing in four genes were observed in SF3B1-mutant samples compared with the wild-type samples. This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1. This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date. The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes. These findings expand our knowledge of this rare disease.

Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma

PubMed Central

Hintzsche, Jennifer D.; Gorden, Nicholas T.; Amato, Carol M.; Kim, Jihye; Wuensch, Kelsey E.; Robinson, Steven E.; Applegate, Allison J.; Couts, Kasey L.; Medina, Theresa M.; Wells, Keith R.; Wisell, Joshua A.; McCarter, Martin D.; Box, Neil F.; Shellman, Yiqun G.; Gonzalez, Rene C.; Lewis, Karl D.; Tentler, John J.

2017-01-01

Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available. Mutational profiles were compared between mucosal subgroups and sun-exposed cutaneous melanomas. Comparisons of molecular profiles identified 161 genes enriched in mucosal melanoma (P<0.05). KIT and NF1 were frequently comutated (32%) in the mucosal subgroup, with a significantly higher incidence than that in cutaneous melanoma (4%). Recurrent SF3B1 R625H/S/C mutations were identified and validated in 7 of 19 (37%) mucosal melanoma patients. Mutations in the spliceosome pathway were found to be enriched in mucosal melanomas when compared with cutaneous melanomas. Alternative splicing in four genes were observed in SF3B1-mutant samples compared with the wild-type samples. This study identified potential new therapeutic targets for mucosal melanoma, including comutation of NF1 and KIT, and recurrent R625 mutations in SF3B1. This is the first report of SF3B1 R625 mutations in vulvovaginal mucosal melanoma, with the largest whole-exome sequencing project of mucosal melanomas to date. The results here also indicated that the mutations in SF3B1 lead to alternative splicing in multiple genes. These findings expand our knowledge of this rare disease. PMID:28296713

Comparison of Clinicopathologic Features and Survival of Histopathologically Amelanotic and Pigmented Melanomas: A Population-Based Study

PubMed Central

Thomas, Nancy E.; Kricker, Anne; Waxweiler, Weston T.; Dillon, Patrick M.; Busam, Klaus J.; From, Lynn; Groben, Pamela A.; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; Marrett, Loraine D.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A.; Orlow, Drs. Irene; Paine, Susan; Ollila, David W.; Reiner, Anne S.; Luo, Li; Hao, Honglin; Frank, Jill S.; Begg, Colin B.; Berwick, Marianne

2014-01-01

Importance Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathology review, or no adjustment for stage limit interpretation or generalization of results from prior studies. Objective To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study. Design Survival analysis with median follow-up of 7.6 years. Setting The Genes, Environment, and Melanoma study enrolled incident cases of melanoma diagnosed in 1998-2003 from international population-based cancer registries. Participants A total of 2,995 patients with 3,486 invasive primary melanomas centrally scored for histologic pigmentation. Main Outcomes and Measurements Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively. Results Eight percent of melanomas (275 of 3,467) were histopathologically amelanotic. Female sex, nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a co-existing nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally of a higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (P for trend <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than pigmented melanoma [hazard ratio (HR), 2.0; 95% confidence interval (CI), 1.4-3.0; P< .001], adjusted for age, sex anatomic site, and study design variables; but survival did not differ once AJCC tumor stage was also taken into account, (HR, 0.8; 95% CI, 0.5-1.2; P = .36). Conclusions and Relevance At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biology of amelanotic melanoma are warranted. PMID:25162299

Invasive Scalp Melanoma: Role for Enhanced Detection Through Professional Training.

PubMed

Lovasik, Brendan P; Sharma, Ishna; Russell, Maria C; Carlson, Grant W; Delman, Keith A; Rizzo, Monica

2016-11-01

Scalp and neck melanomas (SNMs) have a relatively poor prognosis compared to other sites, and represent an anatomically challenging area for detection. The aim of this study was to identify the role of the hairdresser in detection of SNMs. A tertiary surgical oncology institutional database was retrospectively reviewed for all patients undergoing resection of a scalp, posterior neck, or retro auricular invasive primary melanoma between 2008 and 2014. SNMs accounted for 128 melanoma patients during the study period, with median age 66 years, 88 % male, and median Breslow thickness 1.55 mm. Hairdressers detected 10 % of all SNMs, with hairdresser-detected SNMs presenting 13 years younger (53 vs. 66 years, P = 0.015), and with a trend towards lower Breslow depth (1.15 vs. 1.63) and more frequent discovery in AJCC Stage Ia or Ib (66.7 % vs. 44.8 %) than otherwise-detected SNMs. Women with SNMs were 1.8-fold more likely than men to have their SNMs detected by a hairdresser (P = 0.001), and presented at higher AJCC clinical stage than men and required wider surgical resection margins (P = 0.011). Women with hairdresser-detected SNMs were younger, with lower Breslow thickness and lower AJCC Clinical Stage than women with otherwise-detected SNM. This study suggests that hairdressers play a critical role in detection of invasive primary scalp and neck melanoma, accounting for 10 % of all melanomas referred to a tertiary surgical oncology center. Quality improvement initiatives aimed at increasing early detection of scalp and neck melanoma should include members of the cosmetology community.

Multiplicity of skin cancers in Queensland and their cost burden to government and patients.

PubMed

Gordon, Louisa G; Elliott, Thomas M; Olsen, Catherine M; Pandeya, Nirmala; Whiteman, David C

2018-02-01

To determine the cost burden to government and patients for individuals with multiple skin cancers. We used self-reported baseline data on socio-demographics, phenotype and sun exposure behaviours from participants in the QSkin Sun and Health Study with at least one histopathologically confirmed keratinocyte cancer or melanoma (n=5,673). Linkage to Australian Medicare data (2011-2014) provided resource data and government and out-of-pocket patient costs. Generalised linear models examined costs by frequency of skin cancer groups separately for melanoma and keratinocyte cancer. Over three years, 539 participants were diagnosed with melanoma (11% had ≥2 melanomas) and 5,134 participants were treated for keratinocyte cancers (10% had ≥6). Median Medicare costs per person were $1,325 (maximum $6,117) for ≥2 melanomas and $2,126 (maximum $54,618) for ≥6 keratinocyte cancers. Increased costs were associated with private health insurance. Individuals who are multiply affected by skin cancers are relatively common and the accompanying individual and government cost burden can be substantial. These findings support skin cancer being classified as a chronic disease. Implications for public health: Over time, the economic burden for skin cancer for individuals and health providers is high and investment in prevention remains important from an economic viewpoint. © 2017 The Authors.

Single-center retrospective series of fourteen patients with mucosal melanoma of the nasal cavity and paranasal sinuses.

PubMed

Letievant, J-C; Poupart, M; Ambrun, A; Colin, C; Pignat, J-C

2016-12-01

Mucosal melanoma of the nasal cavity and paranasal sinuses is a rare and highly aggressive tumor. We report our experience over 20 years in management of this tumor. A retrospective study included 14 patients with primary sinonasal mucosal melanoma. The series comprised 8 male and 6 female patients, with a median age at diagnosis of 67 years. Staging on the American Joint Committee on Cancer classification of sinus cancer was 14% T2, 22% T3, 75% T4a and 7% T4b. All patients underwent primary surgical treatment; 71% received adjuvant external radiotherapy. Median recurrence-free interval was 28.7 months. Two- and 5-year overall survival was 43% and 32%, respectively. Median follow-up was 43 months. Mucosal melanomas of the nasal cavity and paranasal sinuses are very specific entities. Limited pathophysiological knowledge still precludes effective medium- and long-term management. Future treatment will probably be based on global adjuvant or neoadjuvant-targeted chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Mucosal melanoma of the head and neck: a systematic review of the literature.

PubMed

Lazarev, Stanislav; Gupta, Vishal; Hu, Kenneth; Harrison, Louis B; Bakst, Richard

2014-12-01

Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN. Copyright © 2014 Elsevier Inc. All rights reserved.

Mucosal Melanoma of the Head and Neck: A Systematic Review of the Literature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lazarev, Stanislav; Gupta, Vishal; Hu, Kenneth

2014-12-01

Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear marginsmore » remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN.« less

CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.

PubMed

Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

2016-10-04

Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma.

CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma

PubMed Central

Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

2016-01-01

Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma. PMID:27556188

Immunohistochemical mismatch in a case of rhabdomyoblastic metastatic melanoma.

PubMed

Dumitru, Adrian Vasile; Tampa, Mircea Ştefan; Georgescu, Simona Roxana; Păunică, Stana; Matei, Clara Nicoleta; Nica, Adriana Elena; Costache, Mariana; Motofei, Ion; Sajin, Maria; Păunică, Ioana; Georgescu, Tiberiu Augustin

2018-01-01

Melanomas can exhibit a wide range of unusual morphologies due to the neural crest origin of melanocytes. Several authors have documented variations in size and shape of cells, cytoplasmic features and inclusions, nuclear features and cell architecture. Metastatic melanoma with rhabdomyoblastic differentiation is an extremely rare condition with poor prognosis. Few studies concerning rhabdoid or rhabdomyoblastic differentiation in melanoma are currently available and the current report highlights some of the most important immunohistochemical features of this rare entity. We report on a case of a rhabdomyoblastic metastatic melanoma showing intense positivity for both melanocytic and rhabdoid markers in two cell populations dissociated within the tumor with multiple mismatches in immunomarker expression. Improved recognition of this rare morphological pattern may provide the means for developing new techniques to identify novel therapeutic targets, which would improve the prognostic outlook for these patients.

DEK oncogene is overexpressed during melanoma progression.

PubMed

Riveiro-Falkenbach, Erica; Ruano, Yolanda; García-Martín, Rosa M; Lora, David; Cifdaloz, Metehan; Acquadro, Francesco; Ballestín, Claudio; Ortiz-Romero, Pablo L; Soengas, María S; Rodríguez-Peralto, José L

2017-03-01

DEK is an oncoprotein involved in a variety of cellular functions, such as DNA repair, replication, and transcriptional control. DEK is preferentially expressed in actively proliferating and malignant cells, including melanoma cell lines in which DEK was previously demonstrated to play a critical role in proliferation and chemoresistance. Still, the impact of this protein in melanoma progression remains unclear. Thus, we performed a comprehensive analysis of DEK expression in different melanocytic tumors. The immunostaining results of 303 tumors demonstrated negligible DEK expression in benign lesions. Conversely, malignant lesions, particularly in metastatic cases, were largely positive for DEK expression, which was partially associated with genomic amplification. Importantly, DEK overexpression was correlated with histological features of aggressiveness in primary tumors and poor prognosis in melanoma patients. In conclusion, our study provides new insight into the involvement of DEK in melanoma progression, as well as proof of concept for its potential application as a marker and therapeutic target of melanoma. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Diagnosis of metastatic melanoma by fine-needle biopsy: analysis of 2,204 cases.

PubMed

Murali, Rajmohan; Doubrovsky, Anna; Watson, Geoffrey F; McKenzie, Paul R; Lee, C Soon; McLeod, Duncan J; Uren, Roger F; Stretch, Jonathan R; Saw, Robyn P M; Thompson, John F; Scolyer, Richard A

2007-03-01

Fine-needle biopsy (FNB) has been reported as a rapid, minimally invasive technique for the diagnosis of metastatic melanoma. The diagnostic accuracy of FNB was assessed in a consecutive series of 2,204 FNBs of clinically suspicious lesions from patients with previous primary melanomas treated at the Sydney Melanoma Unit, Sydney, Australia, between January 1992 and December 2002. The sensitivity and specificity of FNB were 96.3% and 98.9%, respectively. There were 5 false-positive cases (0.6%), which were verified as metastatic adenocarcinoma (3 cases) or reactive processes (organizing hematoma and chronic osteomyelitis, 1 each). False-negative diagnoses (6.7% of cases) were associated with a variety of clinicopathologic factors, including difficult-to-access anatomic sites (eg, high axilla or deep inguinal), small lesions, and lesional characteristics such asfibrosis, necrosis, or cystic change. FNB is a highly accurate, rapid, and cost-effective procedure for the diagnosis of metastatic melanoma and should be considered as the initial diagnostic procedure of choice in patients with melanoma with clinically suspected metastases.

Primary mucosal sinonasal melanoma—Case report and review of the literature. The role of complex treatment-surgery and adjuvant radiotherapy

PubMed Central

Marinova, Lena; Yordanov, Kaloyan; Sapundgiev, Nikolay

2010-01-01

Aim The place of adjuvant radiotherapy in the treatment of sinonasal melanoma. Background Sinonasal mucosal melanoma is a rare disease with poor prognosis and requires a complex treatment. Elective neck dissection in patients with N0 and adjuvant radiotherapy has been a source of controversy. High late regional recurrence rates rise questions about elective irradiation of the neck nodes in patients with N0 stage disease. Methods We present our two years’ follow up in a case of locally advanced sinonasal melanoma and literature review of the treatment options for mucosal melanoma. Results In locally advanced sinonasal melanoma treated with surgical resection, postoperative radiotherapy and chemotherapy we had local tumor control. Two years later, a regional contralateral recurrence without distant metastasis occurred. Conclusions Literature data for frequent neck lymph nodes recurrences justify elective neck dissection. Postoperative elective neck radiotherapy for patients with locally advanced sinonasal melanoma and clinically N0 appears to decrease the rate of late regional recurrences. PMID:24376954

Melanoma-specific mortality and competing mortality in patients with non-metastatic malignant melanoma: a population-based analysis.

PubMed

Shen, Weidong; Sakamoto, Naoko; Yang, Limin

2016-07-07

The objectives of this study were to evaluate and model the probability of melanoma-specific death and competing causes of death for patients with melanoma by competing risk analysis, and to build competing risk nomograms to provide individualized and accurate predictive tools. Melanoma data were obtained from the Surveillance Epidemiology and End Results program. All patients diagnosed with primary non-metastatic melanoma during the years 2004-2007 were potentially eligible for inclusion. The cumulative incidence function (CIF) was used to describe the probability of melanoma mortality and competing risk mortality. We used Gray's test to compare differences in CIF between groups. The proportional subdistribution hazard approach by Fine and Gray was used to model CIF. We built competing risk nomograms based on the models that we developed. The 5-year cumulative incidence of melanoma death was 7.1 %, and the cumulative incidence of other causes of death was 7.4 %. We identified that variables associated with an elevated probability of melanoma-specific mortality included older age, male sex, thick melanoma, ulcerated cancer, and positive lymph nodes. The nomograms were well calibrated. C-indexes were 0.85 and 0.83 for nomograms predicting the probability of melanoma mortality and competing risk mortality, which suggests good discriminative ability. This large study cohort enabled us to build a reliable competing risk model and nomogram for predicting melanoma prognosis. Model performance proved to be good. This individualized predictive tool can be used in clinical practice to help treatment-related decision making.

Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma

PubMed Central

Schadendorf, Dirk; Hodi, F. Stephen; Robert, Caroline; Weber, Jeffrey S.; Margolin, Kim; Hamid, Omid; Patt, Debra; Chen, Tai-Tsang; Berman, David M.; Wolchok, Jedd D.

2015-01-01

Purpose To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies. Methods The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method. Results Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3. Conclusion To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma. PMID:25667295

State of the Science on Prevention and Screening to Reduce Melanoma Incidence and Mortality: The Time is Now

PubMed Central

Tripp, Mary K.; Watson, Meg; Balk, Sophie J.; Swetter, Susan M.; Gershenwald, Jeffrey E.

2016-01-01

Although overall cancer incidence rates are decreasing, melanoma incidence rates continue to increase about 3% annually. Melanoma is a significant public health problem that exacts a substantial financial burden. Years of potential life lost from melanoma deaths contribute to the social, economic and human toll of this disease. However, most cases are potentially preventable. Research has clearly established that exposure to ultraviolet (UV) radiation increases melanoma risk. Unprecedented anti-tumor activity and evolving survival benefit from novel targeted therapies and immunotherapies are now available for patients with unresectable and/or metastatic melanoma. Still, prevention (minimizing sun exposure that may result in tanned or sunburned skin and avoiding indoor tanning) and early detection (identifying lesions before they become invasive, or at an earlier stage) have significant potential to reduce melanoma incidence and melanoma-associated deaths. This paper reviews the state of the science on prevention and early detection of melanoma, and current areas of scientific uncertainty and ongoing debate. The US Surgeon General’s Call to Action to Prevent Skin Cancer and US Preventive Services Task Force reviews on skin cancer have propelled a national discussion on melanoma prevention and screening that makes this an extraordinary and exciting time for diverse disciplines in multiple sectors – health care, government, education, business, advocacy and community – to coordinate efforts and leverage existing knowledge to make major strides in reducing the public health burden of melanoma in the US. PMID:27232110

Detection of desmoplastic melanoma with dermoscopy and reflectance confocal microscopy.

PubMed

Maher, N G; Solinas, A; Scolyer, R A; Puig, S; Pellacani, G; Guitera, P

2017-12-01

Desmoplastic melanoma (DM) is frequently misdiagnosed clinically and often associated with melanoma in situ (MIS). To improve the detection of DM using dermoscopy and reflectance confocal microscopy (RCM). A descriptive analysis of DM dermoscopy features and a case-control study within a melanoma population for RCM feature evaluation was performed blindly, using data obtained between 2005 and 2015. After retrospectively identifying all DM cases with RCM data over the study period (n = 16), a control group of non-DM melanoma patients with RCM data, in a ratio of at least 3 : 1, was selected. The control group was matched by age and primary tumour site location, divided into non-DM invasive melanomas (n = 27) and MIS (n = 27). Invasive melanomas were selected according to the melanoma subtypes associated with the DM cases. The main outcomes were the frequency of melanoma-specific features on dermoscopy for DM; and the odds ratios of RCM features to distinguish DM from MIS and/or other invasive melanomas; or MIS from the combined invasive melanoma group. At least one of the 14 melanoma-specific features evaluated on dermoscopy was found in 100% of DMs (n = 15 DM with dermoscopy). Known RCM melanoma predictors were commonly found in the DMs, such as pagetoid cells (100%) and cell atypia (100%). The RCM feature of spindle cells in the superficial dermis was more common in DM compared with the entire melanoma control group (OR 3.82, 95% CI 1.01-14.90), and particularly compared to MIS (OR 5.48, 95% CI 1.11-32.36). Nucleated cells in the dermis and the RCM correlate of dermal inflammation were also significant RCM features favouring DM over MIS, as well as invasive melanoma over MIS. Dermoscopy and RCM may be useful tools for the identification of DM. Certain RCM features may help distinguish DM from MIS and other invasive melanomas. Larger studies are warranted. © 2017 European Academy of Dermatology and Venereology.

Vemurafenib: in unresectable or metastatic melanoma.

PubMed

Keating, Gillian M

2012-10-01

Vemurafenib is a first-in-class, small molecule BRAFV600E inhibitor. It is indicated in the US for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation, and in the EU as monotherapy in adults with BRAFV600 mutation-positive unresectable or metastatic melanoma. Oral vemurafenib improved overall survival (OS) [co-primary endpoint] in patients with unresectable, previously untreated, BRAFV600E mutation-positive, stage IIIC or IV melanoma, according to the results of a randomized, open-label, multicenter, phase III trial (BRIM-3). With vemurafenib versus dacarbazine, the risk of death was significantly reduced by 63% in the interim OS analysis, and by 56%, 38%, and 30% in subsequent updated OS analyses. The median OS duration was 13.6 months in vemurafenib recipients and 9.7 months in dacarbazine recipients in the most recent OS analysis. In the phase III trial, progression-free survival (PFS) [co-primary endpoint] was also significantly improved in vemurafenib versus dacarbazine recipients (median PFS of 5.3 vs 1.6 months), with a significant reduction in the risk of death or disease progression of 74% in the final PFS analysis. Vemurafenib was also associated with a high overall response rate in patients with previously treated, BRAFV600 mutation-positive, stage IV melanoma, according to the results of a noncomparative, multicenter, phase II trial. Patients had received at least one prior systemic treatment for advanced disease (excluding BRAF inhibitors other than sorafenib or MEK inhibitors). The overall response rate (primary endpoint) was 53% (complete response rate of 6% and partial response rate of 47%), with a median duration of response of 6.7 months, and a median OS duration of 15.9 months. Oral vemurafenib was generally well tolerated in patients with metastatic melanoma, with cutaneous adverse events among the most commonly occurring adverse events. Cutaneous squamous cell carcinoma and/or keratoacanthoma were reported in 18% of vemurafenib recipients in the BRIM-3 trial.

TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma.

PubMed

Griewank, Klaus G; Murali, Rajmohan; Puig-Butille, Joan Anton; Schilling, Bastian; Livingstone, Elisabeth; Potrony, Miriam; Carrera, Cristina; Schimming, Tobias; Möller, Inga; Schwamborn, Marion; Sucker, Antje; Hillen, Uwe; Badenas, Celia; Malvehy, Josep; Zimmer, Lisa; Scherag, André; Puig, Susana; Schadendorf, Dirk

2014-09-01

Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

ARMS depletion facilitates UV irradiation induced apoptotic cell death in melanoma.

PubMed

Liao, Yi-Hua; Hsu, Su-Ming; Huang, Pei-Hsin

2007-12-15

Tumor cells often aberrantly reexpress molecules that mediate proper embryonic development for advantageous growth or survival. Here, we report that ankyrin repeat-rich membrane spanning (ARMS), a transmembrane protein abundant in the developing and adult neural tissues, is overexpressed in melanoma, a tumor ontogenetically originating from neural crest. Immunohistochemical study of 79 melanocytic lesions showed significantly increased expression of ARMS in primary malignant melanomas (92.9%) and metastatic melanoma (60.0%) in comparison with benign nevocellular nevi (26.7%). To investigate the role of ARMS in melanoma formation, murine B16F0 melanoma cells with stable knockdown of ARMS were established by RNA interference. Down-regulation of ARMS resulted in significant inhibition of anchorage-independent growth in soft agar and restrictive growth of melanoma in severe combined immunodeficient mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVB-induced apoptosis, whereas constitutively active MEK rescued ARMS-depleted cells from apoptosis. We further showed that BRAF, a downstream signaling molecule of ARMS in ERK pathway, is not mutated as a constitutively active form in acral lentiginous melanoma; in contrast, BRAF(T1799A) mutation, which leads to constitutive activation of ERK signaling, was detected in 57.1% of superficial spreading melanoma. Our study suggests that overexpression of ARMS per se serves as one mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway, especially in acral lentiginous melanoma, most of which does not harbor BRAF mutation.

Mutations in GNA11 in Uveal Melanoma

PubMed Central

Van Raamsdonk, Catherine D.; Griewank, Klaus G.; Crosby, Michelle B.; Garrido, Maria C.; Vemula, Swapna; Wiesner, Thomas; Obenauf, Anna C.; Wackernagel, Werner; Green, Gary; Bouvier, Nancy; Sozen, M. Mert; Baimukanova, Gail; Roy, Ritu; Heguy, Adriana; Dolgalev, Igor; Khanin, Raya; Busam, Klaus; Speicher, Michael R.; O’Brien, Joan; Bastian, Boris C.

2011-01-01

BACKGROUND Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. METHODS We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. RESULTS We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. CONCLUSIONS Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.) PMID:21083380

The Clinical Management of Multiple Melanoma Brain Metastases: A Systematic Review

PubMed Central

Goyal, Sharad; Silk, Ann W.; Tian, Sibo; Mehnert, Janice; Danish, Shabbar; Ranjan, Sinthu; Kaufman, Howard L.

2017-01-01

Importance The treatment of multiple brain metastases (MBM) from melanoma is controversial and includes surgical resection, stereotactic radiosurgery and whole brain radiation. Several new classes of agents have revolutionized the treatment of metastatic melanoma allowing for subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving. Objective To review the current evidence regarding the treatment of MBM from melanoma. Evidence Review The Pubmed database was searched using combinations of search terms and synonyms for melanoma, brain metastases, radiation, chemotherapy, immunotherapy and targeted therapy published between January 1, 1995 and January 1, 2015. Articles were selected for inclusion based on targeted keyword searches, manual review of bibliographies, and whether the article was a clinical trial, large observational study, or retrospective study focusing on melanoma brain metastases. Of 2243 articles initially identified, 110 were selected for full review. Of these, the most pertinent 76 articles were included. Findings Patients with newly diagnosed MBM can be treated with various modalities, either alone or in combination. Level 1 evidence supports the use of radiosurgery alone, whole brain radiation therapy (WBRT), and radiosurgery with WBRT. Though the addition of WBRT to SRS improves the overall brain relapse rate, WBRT has no significant impact on overall survival and has detrimental neurocognitive outcomes. Cytotoxic chemotherapy has largely been ineffective; targeted therapies and immunotherapies have reported to have high response rates and deserve further attention in the setting of larger clinical trials. Further studies are needed to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Conclusions and Relevance At this time, the standard management for patients with MBM from melanoma includes SRS, WBRT, or combination of both. Emerging data exists to support the notion that SRS in combination with targeted therapies or immune therapy may obviate the need for whole brain radiation and prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. PMID:26181286

Atypical Clinical Presentation of Xeroderma Pigmentosum in a Patient Harboring a Novel Missense Mutation in the XPC Gene: The Importance of Clinical Suspicion.

PubMed

Meneses, Marina; Chavez-Bourgeois, Marion; Badenas, Celia; Villablanca, Salvador; Aguilera, Paula; Bennàssar, Antoni; Alos, Llucia; Puig, Susana; Malvehy, Josep; Carrera, Cristina

2015-01-01

Xeroderma pigmentosum (XP) is a genodermatosis caused by abnormal DNA repair. XP complementation group C (XPC) is the most frequent type in Mediterranean countries. We describe a case with a novel mutation in the XPC gene. A healthy Caucasian male patient was diagnosed with multiple primary melanomas. Digital follow-up and molecular studies were carried out. During digital follow-up 8 more additional melanomas were diagnosed. Molecular studies did not identify mutations in CDKN2A, CDK4 or MITF genes. Two heterozygous mutations in the XPC gene were detected: c.2287delC (p.Leu763Cysfs*4) frameshift and c.2212A>G (p.Thr738Ala) missense mutations. The p.Thr738Ala missense mutation has not been previously described. Missense mutations in the XPC gene may allow partial functionality that could explain this unusual late onset XP. Atypical clinical presentation of XPC could be misdiagnosed when genetic aberrations allow partial DNA repair capacity. © 2015 S. Karger AG, Basel.

Bone marrow metastasis of malignant melanoma in childhood arising within a congenital melanocytic nevus.

PubMed

Volejnikova, Jana; Bajciova, Viera; Sulovska, Lucie; Geierova, Marie; Buriankova, Eva; Jarosova, Marie; Hajduch, Marian; Sterba, Jaroslav; Mihal, Vladimir

2016-09-01

Malignant melanoma in childhood is infrequent and can arise within congenital melanocytic nevi. Spread of malignant melanoma to the bone marrow, especially in children, is extremely rare. Reported is a case of a 5-year-old boy with a congenital large melanocytic nevus of the head and neck who presented with a short history of low back and leg pain, fever and cervical lymphadenopathy. Despite regular follow-up by a dermatologist and plastic surgeon and repeatedly negative histology of previous partial excisions, diffuse bone marrow infiltration with malignant melanoma was diagnosed. The primary site was identified in the post-excision area. The disease progressed rapidly on ipilimumab immunotherapy and led to death at four months from the diagnosis. Surveillance is indispensable in children with a predisposition to melanoma and nonspecific symptoms such as bone pain, gait impairment or cytopenia, should always be taken into account.

Coexistence of amelanotic melanoma and liposarcoma.

PubMed

Jeong, Taek Jo; Lee, Eun Ju; Haw, Sik; Shin, Min Kyung; Haw, Choong Rim

2009-11-01

An amelanotic malignant melanoma is characterized by little or no pigment. It is frequently misdiagnosed because it is a rare entity in general, and because of its unusual clinical features. Liposarcoma is one of the most common adult soft tissue sarcomas. We encountered a case of amelanotic melanoma with a concurrent liposarcoma. A 68-year-old man presented with a single, 1.5x1.5 cm round erythematous, eroded nodule on the left heel. A biopsy specimen showed atypical, pleomorphic tumor cells with little melanin pigment. The tumor cells were positive for S-100, HMB-45 and negative for cytokeratins. These findings were consistent with amelanotic melanoma. On positron emission tomography/computed tomography (PET/CT), a hypermetabolic lesion was found in the left buttock. This lesion was excised and diagnosed as a well-differentiated liposarcoma. An association between sarcomas and other primary malignancies has been reported. However, an association between melanoma and liposarcoma is rare.

Malignant melanoma misdiagnosed as diabetic foot ulcer: A case report.

PubMed

Gao, Wei; Chen, Dawei; Ran, Xingwu

2017-07-01

Acral lentiginous melanoma (AML) does not exhibit the classic signs of malignant melanoma. ALM is frequently misdiagnosed because of its unusual sites and atypical clinical morphologies, which lead to poor prognosis. A female patient aged 78 years was presented to our center with two ulcers on her right foot. Diabetic foot ulcer was considered as the primary diagnosis. The ulcers failed to improve after 2 weeks' therapy. An incisional biopsy of the lesion revealed malignant melanoma. The patient received wide excision, skin grafting as well as biotherapy. The lesion was healed and no other metastasis has been founded until now. Clinicians must maintain a high level of suspicion in distinguishing malignant melanoma from other more benign skin lesions of the foot. The need for early biopsy of ulcer, even when clinical suspicion is low, can not be overemphasized. Only in this way can we reduce misdiagnosis rate and improve survival rate in patients with foot ulcer.

Screening and Prevention Measures for Melanoma: Is There a Survival Advantage?

PubMed Central

Chen, Suephy C.; Swetter, Susan M.

2012-01-01

Controversy has emerged over the past decades regarding the value and impact of melanoma screening to detect early stage disease for improved prognosis. Those questioning the benefits of prevention efforts base their arguments on the absence of prospective, randomized studies demonstrating decreased melanoma mortality to justify the cost associated with screening and educational campaigns. For those in favor of melanoma screening, the lack of proven survival benefit is not a justification to abandon this approach, but rather a reflection of the lack of resources necessary to conduct a long-term trial. In 2009, the US Preventive Services Task Force (USPSTF)report did not recommend routine primary care screening for the general population given the absence of evidence. However, since the USPSTF report, a series of new studies are available, which support the potential benefit of screening and have the potential to significantly impact current policies regarding skin cancer screening, particularly for melanoma. PMID:22907282

Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts.

PubMed

Weiss, Sarah A; Han, Joseph; Darvishian, Farbod; Tchack, Jeremy; Han, Sung Won; Malecek, Karolina; Krogsgaard, Michelle; Osman, Iman; Zhong, Judy

2016-10-19

Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts. We queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as ≤45 (young), 46-65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis. We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas. Older age at time of melanoma diagnosis is associated with shorter MSS, however age's association with clinicopathologic features is dependent upon specific characteristics of the study population. TIL as a read-out of the host immune response may have greater prognostic impact in patients older than age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly.

Tumor vascularity and hematogenous metastasis in experimental murine intraocular melanoma.

PubMed Central

Grossniklaus, H E

1998-01-01

PURPOSE: The purpose of this study is to test the hypothesis that primary tumor vascularity in a murine model of intraocular melanoma positively correlates with the development and hematogenous spread of metastasis. METHODS: Forty 12-week-old C57BL6 mice were inoculated in either the anterior chamber (AC) or posterior compartment (PC) of 1 eye with 5 x 10(5) cells/microL of Queens tissue culture melanoma cells. The inoculated eye was enucleated at 2 weeks; the mice were sacrificed at 4 weeks postinoculation, and necropsies were performed. The enucleated eyes were examined for histologic and ultrastructural features, including relationship of tumor cells to tumor vascular channels, vascular pattern, and mean vascular density. RESULTS: Melanoma grew and was confined to the eye in 12 of 20 AC eyes and 10 of 20 PC eyes. Histologic and electron microscopic examination showed tumor invasion into vascular channels. Five of 12 AC tumors (42%) and 8 of 10 PC tumors (80%) metastasized. All of the AC tumors, but none of the PC tumors, that distantly metastasized also metastasized to ipsilateral cervical lymph nodes (P = .00535). There was no statistically significant difference of vascular pattern between the melanomas that did and did not metastasize to lungs in the PC group (P = .24), although there was a significant difference in the AC group (P = .02). Tumors with high-grade vascular patterns were more likely to metastasize than tumors with low-grade vascular patterns in the AC group. The mean vascular density positively correlated with the presence and number of metastases in both groups (P = .0000 and P < .001, respectively). There was no statistically significant difference of vascular pattern and mean vascular density for AC versus PC melanoma (P = .97). CONCLUSIONS: The rate of metastasis in this murine intraocular melanoma model positively correlates with primary tumor vascularity. The melanoma metastasizes via invasion of tumor vascular channels. AC melanoma also metastasizes through regional lymphatics. Images FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 11 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 PMID:10360307

Survival According to BRAF-V600 Tumor Mutations – An Analysis of 437 Patients with Primary Melanoma

PubMed Central

Meckbach, Diana; Bauer, Jürgen; Pflugfelder, Annette; Meier, Friedegund; Busch, Christian; Eigentler, Thomas K.; Capper, David; von Deimling, Andreas; Mittelbronn, Michel; Perner, Sven; Ikenberg, Kristian; Hantschke, Markus; Büttner, Petra; Garbe, Claus; Weide, Benjamin

2014-01-01

The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies. PMID:24475086

Ber-H2 (CD30) immunohistochemical staining in malignant melanoma.

PubMed

Polski, J M; Janney, C G

1999-09-01

Malignant melanoma can be included in the differential diagnosis of Hodgkin's disease, anaplastic large cell lymphoma, or embryonal carcinoma These malignancies express CD30, a marker of diagnostic value. A retrospective immunohistochemical study was undertaken to determine the frequency of immunoreactivity of Ber-H2 (anti-CD30 monoclonal antibody) in malignant melanoma Archival paraffin-embedded tissue from 24 primary and metastatic lesions was used. No Ber-H2 labeling was observed in the majority of the studied cases. Variable weak cytoplasmic staining was present in only one case. The findings are compared with the previous reports claiming frequent CD30 expression in malignant melanoma. We discuss issues pertaining to the interpretation of the Ber-H2 IHC staining in formalin-fixed, paraffin-embedded tissue.

Anorectal mucosal melanoma

PubMed Central

Malaguarnera, Giulia; Madeddu, Roberto; Catania, Vito Emanuele; Bertino, Gaetano; Morelli, Luca; Perrotta, Rosario Emanuele; Drago, Filippo; Malaguarnera, Michele; Latteri, Saverio

2018-01-01

Anorectal melanoma is an uncommon and aggressive mucosal melanocytic malignancy. Due to its rarity, the pre-operative diagnosis remains difficult. The first symptoms are non-specific such as anal bleeding, anal mass or pain. Although anorectal melanoma carries a poor prognosis; optimal therapeutics strategies are unclear. Surgical resection remains the mainstay of treatment. The optimal surgical procedure for primary tumours is controversial and can vary from wide local excision or endoscopic mucosal resection (EMR) to an abdomino-perineal resection. A high degree of uncertainly exists regarding the benefit of radiation therapy or chemotherapy. The treatment of advanced melanoma is evolving rapidly with better understanding of the disease biology and immunology. Considerable effort has been devoted to the identification of molecular determinants of response to target therapies and immunotherapy. PMID:29492238

Late prostatic metastasis of an uveal melanoma in a miniature Schnauzer dog.

PubMed

Delgado, Esmeralda; Silva, João X; Pissarra, Hugo; Peleteiro, Maria C; Dubielzig, Richard R

2016-07-01

This manuscript describes a previously unreported clinical case of canine uveal melanoma in a miniature Schnauzer dog with an unusual location of metastasis (prostate) and delayed occurrence (3 years after primary tumor diagnosis and enucleation). Immunohistochemical labeling of both tumors with Melan A, Ki-67, and c-kit added some valuable information.

A signet-ring cell melanoma arising from a medium-sized congenital melanocytic nevus in an adult: A case report and literature review.

PubMed

Tajima, Shogo; Koda, Kenji

2015-07-01

Patients with congenital nevus, especially giant congenital melanocytic nevus (CMN) measuring >20 cm, are known to be at elevated risk of developing melanomas, especially during the first and second decades of life. Melanomas rarely develop in patients with small and medium-sized CMNs, but if they do, they occur during the fourth and fifth decades of life. We present a case of a rapidly enlarging signet-ring cell melanoma (over 3 months) that arose from a medium-sized CMN in a 57-year-old Japanese man. Only 11 other cases of signet-ring cell melanomas at the primary site have been reported. On the basis of morphology alone, it is difficult to diagnose a nodule appearing in a CMN as a signet-ring cell melanoma, because even a benign melanocytic nevus can appear as signet-ring cell morphology. Moreover, a rapidly growing proliferative nodule (PN) more often develops in a CMN than melanoma; PNs may at times exhibit enough atypia to be comparable to melanomas. In our case, loss of p16 expression in the melanoma distinguished it from the nevus cells and was helpful in making the correct diagnosis. Clinical information, such as the patient's age, was also useful in establishing the diagnosis. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

Mucosal melanomas in the elderly: challenging cases and review of the literature

PubMed Central

Baderca, Flavia; Vincze, Dana; Balica, Nicolae; Solovan, Caius

2014-01-01

Melanomas are malignant tumors that originate from melanocytes. They are most frequently localized in the skin, but 5% of all melanomas interest also extracutaneous sites as mucosal surfaces, parenchymatous organs, the retroperitoneum area, and the ocular ball. The purpose of this study was to investigate the epidemiologic and morphologic data of mucosal melanomas diagnosed at Emergency City Hospital (Timisoara, Romania) during a period of 12 years. The study included 17 cases of extracutaneous, extraocular melanomas, with 16 primary melanomas and one secondary melanoma. All our patients were older than 53 years and were mostly men. Most of the patients presented with localized disease; only one case had regional lymph node metastases, and another one had systemic metastases at the time of diagnosis. Regarding localization, nine of 16 melanomas were in the head and neck region, six were diagnosed in the gastrointestinal and urogenital tracts (three cases each), and one case had a rare localization (retroperitoneum). The most common histologic type was represented by epithelioid cells, and the majority of the tumors were achromic. Mucosal melanoma is a tumor associated with aging, all our patients being older than 53 years. Because of unspecific symptoms and low incidence, the diagnosis is often delayed and requires teamwork among the clinician, pathologist, radiologist, and oncologist. Different genetic fingerprints impose a correct diagnosis to offer the patient the best novel, personalized therapy. PMID:24959073

Mucosal melanomas in the elderly: challenging cases and review of the literature.

PubMed

Baderca, Flavia; Vincze, Dana; Balica, Nicolae; Solovan, Caius

2014-01-01

Melanomas are malignant tumors that originate from melanocytes. They are most frequently localized in the skin, but 5% of all melanomas interest also extracutaneous sites as mucosal surfaces, parenchymatous organs, the retroperitoneum area, and the ocular ball. The purpose of this study was to investigate the epidemiologic and morphologic data of mucosal melanomas diagnosed at Emergency City Hospital (Timisoara, Romania) during a period of 12 years. The study included 17 cases of extracutaneous, extraocular melanomas, with 16 primary melanomas and one secondary melanoma. All our patients were older than 53 years and were mostly men. Most of the patients presented with localized disease; only one case had regional lymph node metastases, and another one had systemic metastases at the time of diagnosis. Regarding localization, nine of 16 melanomas were in the head and neck region, six were diagnosed in the gastrointestinal and urogenital tracts (three cases each), and one case had a rare localization (retroperitoneum). The most common histologic type was represented by epithelioid cells, and the majority of the tumors were achromic. Mucosal melanoma is a tumor associated with aging, all our patients being older than 53 years. Because of unspecific symptoms and low incidence, the diagnosis is often delayed and requires teamwork among the clinician, pathologist, radiologist, and oncologist. Different genetic fingerprints impose a correct diagnosis to offer the patient the best novel, personalized therapy.

IRF4 rs12203592 functional variant and melanoma survival.

PubMed

Potrony, Miriam; Rebollo-Morell, Aida; Giménez-Xavier, Pol; Zimmer, Lisa; Puig-Butille, Joan Anton; Tell-Marti, Gemma; Sucker, Antje; Badenas, Celia; Carrera, Cristina; Malvehy, Josep; Schadendorf, Dirk; Puig, Susana

2017-04-15

Inherited genetic factors may modulate clinical outcome in melanoma. Some low-to-medium risk genes in melanoma susceptibility play a role in melanoma outcome. Our aim was to assess the role of the functional IRF4 SNP rs12203592 in melanoma prognosis in two independent sets (Barcelona, N = 493 and Essen, N = 438). Genotype association analyses showed that the IRF4 rs12203592 T allele increased the risk of dying from melanoma in both sets (Barcelona: odds ratio [OR] = 6.53, 95% CI 1.38-30.87, Adj p = 0.032; Essen: OR = 1.68, 95% CI 1.04-2.72, Adj p = 0.035). Survival analyses only showed significance for the Barcelona set (hazard ratio = 4.58, 95% CI 1.11-18.92, Adj p = 0.036). This SNP was also associated with tumour localization, increasing the risk of developing melanoma in head or neck (OR = 1.79, 95% CI 1.07-2.98, Adj p = 0.032) and protecting from developing melanoma in the trunk (OR = 0.59, 95% CI 0.41-0.85, Adj p = 0.004). These findings suggest for the first time that IRF4 rs12203592 plays a role in the modulation of melanoma outcome and confirms its contribution to the localization of the primary tumour. © 2017 UICC.

Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

PubMed Central

Smith, S L; Damato, B E; Scholes, A G M; Nunn, J; Field, J K; Heighway, J

2002-01-01

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT–PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours. British Journal of Cancer (2002) 87, 1308–1313. doi:10.1038/sj.bjc.6600620 www.bjcancer.com © 2002 Cancer Research UK PMID:12439722

Enhanced immunohistochemical detection of neural infiltration in primary melanoma: is there a clinical value?

PubMed

Scanlon, Patrick; Tian, Jaiying; Zhong, Judy; Silva, Ines; Shapiro, Richard; Pavlick, Anna; Berman, Russell; Osman, Iman; Darvishian, Farbod

2014-08-01

Neural infiltration in primary melanoma is a histopathologic feature that has been associated with desmoplastic histopathologic subtype and local recurrence in the literature. We tested the hypothesis that improved detection and characterization of neural infiltration into peritumoral or intratumoral location and perineural or intraneural involvement could have a prognostic relevance. We studied 128 primary melanoma cases prospectively accrued and followed at New York University using immunohistochemical detection with antihuman neurofilament protein and routine histology with hematoxylin and eosin. Neural infiltration, defined as the presence of tumor cells involving or immediately surrounding nerve foci, was identified and characterized using both detection methods. Neural infiltration rate of detection was enhanced by immunohistochemistry for neurofilament in matched-pair design (47% by immunohistochemistry versus 25% by routine histology). Immunohistochemical detection of neural infiltration was significantly associated with ulceration (P = .021), desmoplastic and acral lentiginous histologic subtype (P = .008), and head/neck/hands/feet tumor location (P = .037). Routinely detected neural infiltration was significantly associated with local recurrence (P = .010). Immunohistochemistry detected more intratumoral neural infiltration cases compared with routine histology (30% versus 3%, respectively). Peritumoral and intratumoral nerve location had no impact on clinical outcomes. Using a multivariate model controlling for stage, neither routinely detected neural infiltration nor enhanced immunohistochemical characterization of neural infiltration was significantly associated with disease-free or overall survival. Our data demonstrate that routinely detected neural infiltration is associated with local recurrence in all histologic subtypes but that improved detection and characterization of neural infiltration with immunohistochemistry in primary melanoma does not add to prognostic relevance. Copyright © 2014 Elsevier Inc. All rights reserved.

Sphincter-sparing local excision and hypofractionated radiation therapy for anorectal melanoma: a 20-year experience.

PubMed

Kelly, Patrick; Zagars, Gunar K; Cormier, Jancie N; Ross, Merrick I; Guadagnolo, B Ashleigh

2011-10-15

Anorectal melanoma is a rare disease with a poor prognosis. Because survival is determined by distant failure, many centers have adopted sphincter-sparing excision for primary tumor control. However, this approach is associated with high rates of local failure (∼50%). In this study, the authors report their 20-year experience with sphincter-sparing excision combined with radiation therapy (RT) for the treatment of localized anorectal melanoma. The authors reviewed the records of 54 patients with localized anorectal melanoma who were treated at the University of Texas MD Anderson Cancer Center from 1989 to 2008. All patients underwent definitive local excision with or without sentinel lymph node biopsy or lymph node dissection. RT (25-36 grays in 5-6 fractions) was delivered to extended fields that targeted the primary site and draining pelvic/inguinal lymphatics in 39 patients and to limited fields that targeted only the primary site in 15 patients. The 5-year rates of local control (LC), lymph node control (NC), and sphincter preservation were 82%, 88%, and 96%, respectively. However, because of the high rate of distant metastasis, the overall survival (OS) rate at 5 years was only 30%. Although there were no significant differences in LC, NC, or OS based on RT field extent, patients who received extended-field RT had higher rates of lymphedema than patients who received limited-field RT. The current results indicated that combined sphincter-sparing local excision and RT is a well tolerated approach that provides effective LC for patients with anorectal melanoma. Inclusion of the inguinal lymph node basins in the RT fields did not improve outcomes and was associated with an increased risk of lymphedema. Copyright © 2011 American Cancer Society.

Poliosis circumscripta unmasking a scalp melanoma.

PubMed

Yeo, L; Husain, E; Rajpara, S

2015-12-01

A 28-year-old man presented with a 1-year history of a localized patch of grey hair and an underlying darkly pigmented lesion on his right occipital area. Clinical appearance revealed poliosis overlying an asymmetrical plaque with variable degrees of brown pigmentation and white discolouration. Owing to the suspicious nature of the lesion, excision with a 2 mm margin was performed. Histology revealed an invasive melanoma with extensive regression and prominent involvement of multiple hair follicles. Scalp melanoma with associated poliosis is extremely rare, and has only been reported once in the literature to date. There have been two reports in the opthalmology literature regarding eyelash poliosis associated with orbital melanoma. The pathogenesis of poliosis still remains unclear. This is the second reported case of poliosis circmscripta unmasking a scalp melanoma, and highlights the importance of being vigilant when examining patients with poliosis of the scalp. © 2014 British Association of Dermatologists.

[Anorectal Malignant Melanoma Is a Very Rare Disease and Has a Poor Prognosis].

PubMed

Yoshida, Yuta; Noura, Shingo; Matsumura, Tae; Hirota, Masaki; Shuto, Takashi; Muratsu, Arisa; Yasuyama, Harunobu; Takata, Akihiro; Koga, Chikato; Kameda, Chizu; Murakami, Masahiro; Kawabata, Ryohei; Shimizu, Junzo; Miwa, Hideaki; Hasegawa, Junichi

2017-11-01

We performed abdomino-perineal-resection(APR)on 2 cases of anorectal malignant melanoma. The first case was a 70- year-old woman suffering from bloody stool. Colonoscopy showed a black tumor in the rectum. Biopsy revealed a malignant melanoma. A CT scan showed multiple lung metastases and liver metastasis. She underwent surgery for the purpose of bleeding control, but died shortly thereafter because her liver and lung metastases had worsened. The second case was a 43- years-old man suffering from bloody stool. He had a black type 3 tumor in the rectum. A biopsy revealed malignant melanoma. A CT scan showed lateral lymph node swelling. He underwent APR with right side-lateral dissection. An established treatment for anorectal malignant melanoma has not been agreed upon and it is controversial. We experienced 2 cases that underwent surgery and we report them along with relevant information from the literature.

Tumor Cell Plasticity in Uveal Melanoma

PubMed Central

Folberg, Robert; Arbieva, Zarema; Moses, Jonas; Hayee, Amin; Sandal, Tone; Kadkol, ShriHari; Lin, Amy Y.; Valyi-Nagy, Klara; Setty, Suman; Leach, Lu; Chévez-Barrios, Patricia; Larsen, Peter; Majumdar, Dibyen; Pe’er, Jacob; Maniotis, Andrew J.

2006-01-01

The histological detection of laminin-rich vasculogenic mimicry patterns in human primary uveal melanomas is associated with death from metastases. We therefore hypothesized that highly invasive uveal melanoma cells forming vasculogenic mimicry patterns after exposure to a laminin-rich three-dimensional microenvironment would differentially express genes associated with invasive and metastatic behavior. However, we discovered that genes associated with differentiation (GDF15 and ATF3) and suppression of proliferation (CDKNa1/p21) were up-regulated in highly invasive uveal melanoma cells forming vasculogenic mimicry patterns, and genes associated with promotion of invasive and metastatic behavior such as CD44, CCNE2 (cyclin E2), THBS1 (thrombospondin 1), and CSPG2 (chondroitin sulfate proteoglycan; versican) were down-regulated. After forming vasculogenic mimicry patterns, uveal melanoma cells invaded only short distances, failed to replicate, and changed morphologically from the invasive epithelioid to the indolent spindle A phenotype. In human tissue samples, uveal melanoma cells within vasculogenic mimicry patterns assumed the spindle A morphology, and the expression of Ki67 was significantly reduced in adjacent melanoma cells. Thus, the generation of vasculogenic mimicry patterns is accompanied by dampening of the invasive and metastatic uveal melanoma genotype and phenotype and underscores the plasticity of these cells in response to cues from the microenvironment. PMID:17003493

Percutaneous Hepatic Perfusion with Melphalan for Unresectable Metastatic Melanoma or Sarcoma to the Liver: A Single Institution Experience

PubMed Central

Forster, Meghan R.; Rashid, Omar M.; Perez, Matthew; Choi, Junsung; Chaudhry, Tariq; Zager, Jonathan S.

2015-01-01

Background Patients with unresectable melanoma or sarcoma hepatic metastasis have a poor prognosis with few therapeutic options. Percutaneous hepatic perfusion (PHP), isolating and perfusing the liver with chemotherapy, provides a promising minimally invasive management option. We reviewed our institutional experience with PHP. Methods We retrospectively reviewed patients with unresectable melanoma or sarcoma hepatic metastasis treated with PHP from 2008 to 2013 and evaluated therapeutic response, morbidity, hepatic progression free survival (hPFS), and overall survival (OS). Results Ten patients were treated with 27 PHPs (median 3). Diagnoses were ocular melanoma (n=5), cutaneous melanoma (n=3), unknown primary melanoma (n=1), and sarcoma (n=1). Median hPFS was 240 days, 9 of 10 patients (90%) demonstrated stable disease or partial response to treatment. At a median follow up of 11.5 months, 4 of 10 (40%) remain alive. There were no perioperative mortalities. Myelosuppresion was the most common morbidity, managed on an outpatient basis with growth factors. The median hospital stay was 3 days. Conclusions Patients with metastatic melanoma and sarcoma to the liver have limited treatment options. Our experience with PHP demonstrates promising results with minimal morbidity and should be considered (pending FDA approval) as a management option for unresectable melanoma or sarcoma hepatic metastasis. PMID:24249545

HOTAIR role in melanoma progression and its identification in the blood of patients with advanced disease.

PubMed

Cantile, Monica; Scognamiglio, Giosuè; Marra, Laura; Aquino, Gabriella; Botti, Chiara; Falcone, Maria Rosaria; Malzone, Maria Gabriella; Liguori, Giuseppina; Di Bonito, Maurizio; Franco, Renato; Ascierto, Paolo Antonio; Botti, Gerardo

2017-12-01

The molecular mechanisms responsible for the metastatic progression of melanoma have not been fully defined yet. We have recently shown that an important role in this process is certainly played by HOX genes, whose regulation is under control of particular non-coding RNAs, some of which are present within the HOX locus. HOTAIR is the most studied among them, whose aberrant expression is associated with the metastatic progression of many malignancies. The aim of this study was to verify the role played by HOTAIR in metastatic progression of melanoma and to evaluate the circulating levels of HOTAIR in the blood of patients with metastatic melanoma. A series of melanocytic lesions were selected to evaluate the potential changes in the expression of HOTAIR during the evolution of the disease through in situ and molecular approaches. None of the benign melanocytic lesions showed the presence of HOTAIR. The staining of HOTAIR resulted very weak in the primary pT1 lesions, while it was very strong in all pairs of primary tissues and corresponding metastases. Surprisingly, we found the presence of HOTAIR in some intratumoral lymphocytes, while this positivity decreased in lymphocyte component further away from the tumor. HOTAIR was also detected in the serum of selected metastatic patients. These data allowed us to speculate on the fundamental role played by HOTAIR in tumor evolution of melanoma. Its presence in intratumoral lymphocytes might suggest that its involvement in the modulation of tumor microenvironment and the detection in the serum could be used in the management of melanoma patients. © 2017 Wiley Periodicals, Inc.

[The related factors of head and neck mocosal melanoma with lymph node metastasis].

PubMed

Yin, G F; Guo, W; Chen, X H; Huang, Z G

2017-12-05

Objective: To investigate the related factors of mucosal melanoma of head and neck with lymph node metastasis for early diagnosis and further treatments. Method: A retrospective analysis of 117 cases of head and neck mucosal malignant melanoma patients which received surgical treatment was performed. Eleven cases of patients with pathologically confirmed lymph node metastasis and 33 cases without lymph node metastasis (1∶3) were randomly selected to analyze. The related factors of lymph node metastasis of head and neck mucosal melanoma patients including age, gender, whether the existence of recurrence, bone invasion, lesion location were analyzed. The single factor and logistic regression analysis were performed, P <0.05 difference was statistically significant. Result: The lymph node metastasis rate of head and neck mucosal melanoma was 9.40%(11/117), the single factor analysis showed that there were 3 factors to be associated with lymph node metastasis, which was recurrence ( P =0.0000), bone invasion ( P =0.001), primary position ( P =0.007). Recurrence ( P =0.021) was a risk factor for lymph node metastasis according to the Logistic regression analysis, and the impact of bone invasion ( P =0.487) and primary location ( P =0.367) remained to be further explored. Conclusion: The patients of head and neck mucosal melanoma with the presence of recurrent usually accompanied by a further progression of the disease, such as lymph node metastasis, so for recurrent patients should pay special attention to the situation of lymph node and choose the reasonable treatment. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

AIM1 and LINE-1 Epigenetic Aberrations In Tumor and Serum Relate to Melanoma Progression and Disease Outcome

PubMed Central

Hoshimoto, Sojun; Kuo, Christine; Chong, Kelly; Takeshima, Ling; Takei, Yoshiki; Li, Michelle; Huang, Sharon; Sim, Myung-Shin; Morton, Donald L.; Hoon, Dave S.B.

2012-01-01

Aberrations in the methylation status of non-coding genomic repeat DNA sequences and specific gene promoter region are important epigenetic events in melanoma progression. Promoter methylation status in LINE-1 and Absent in melanoma-1(AIM1;6q21) associated with melanoma progression and disease outcome was assessed. LINE-1 and AIM1 methylation status was assessed in paraffin-embedded archival tissues(PEAT)(n=133) and melanoma patients’ serum(n=56). LINE-1 U-Index(hypomethylation) and AIM1 were analyzed in microdissected melanoma PEAT sections. The LINE-1 U-Index of melanoma(n=100) was significantly higher than that of normal skin(n=14) and nevi(n=12)(P=0.0004). LINE-1 U-Index level was elevated with increasing AJCC stage(P<0.0001). AIM1 promoter hypermethylation was found in higher frequency(P=0.005) in metastatic melanoma(65%) than in primary melanomas(38%). When analyzed, high LINE-1 U-Index and/or AIM1 methylation in melanomas were associated with disease-free survival(DFS) and overall survival(OS) in Stage I/II patients (P=0.017, 0.027; respectively). In multivariate analysis, melanoma AIM1 methylation status was a significant prognostic factor of OS(P=0.032). Furthermore, serum unmethylated LINE-1 was at higher levels in both stage III(n=20) and stage IV(n=36) patients compared to healthy donors(n=14)(P=0.022). Circulating methylated AIM1 was detected in patients’ serum and was predictive of OS in Stage IV patients (P=0.009). LINE-1 hypomethylation and AIM1 hypermethylation have prognostic utility in both melanoma patients’ tumors and serum. PMID:22402438

A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene.

PubMed

Gobeil, Stephane; Zhu, Xiaochun; Doillon, Charles J; Green, Michael R

2008-11-01

Metastasis suppressor genes inhibit one or more steps required for metastasis without affecting primary tumor formation. Due to the complexity of the metastatic process, the development of experimental approaches for identifying genes involved in metastasis prevention has been challenging. Here we describe a genome-wide RNAi screening strategy to identify candidate metastasis suppressor genes. Following expression in weakly metastatic B16-F0 mouse melanoma cells, shRNAs were selected based upon enhanced satellite colony formation in a three-dimensional cell culture system and confirmed in a mouse experimental metastasis assay. Using this approach we discovered 22 genes whose knockdown increased metastasis without affecting primary tumor growth. We focused on one of these genes, Gas1 (Growth arrest-specific 1), because we found that it was substantially down-regulated in highly metastatic B16-F10 melanoma cells, which contributed to the high metastatic potential of this mouse cell line. We further demonstrated that Gas1 has all the expected properties of a melanoma tumor suppressor including: suppression of metastasis in a spontaneous metastasis assay, promotion of apoptosis following dissemination of cells to secondary sites, and frequent down-regulation in human melanoma metastasis-derived cell lines and metastatic tumor samples. Thus, we developed a genome-wide shRNA screening strategy that enables the discovery of new metastasis suppressor genes.

Regulator of G protein signaling 4 inhibits human melanoma cells proliferation and invasion through the PI3K/AKT signaling pathway

PubMed Central

Xue, Xiaotong; Wang, Lihua; Meng, Xianguang; Jiao, Jing; Dang, Ningning

2017-01-01

Melanoma is a tumor produced by skin melanocytes, which has a high metastatic rate and poor prognosis. So far, plenty of work has been done on melanoma, but mechanisms underlying melanoma development have not been fully elucidated. Here we identified regulator of G protein signaling 4(RGS4) as novel therapeutic target for malignant melanoma and its regulating effect on melanoma. We found that endogenous RGS4 expression was much lower in melanoma tissues and cells. In A375 cell line with low endogenous RGS4 expression, the function of RGS4 was detected by up-regulation its expression with pcDNA3.1-RGS4 and knockdown its expression with siRNA. Our results showed that RGS4 could significantly reduce the proliferation, migration and invasion of melanoma cells. RGS4 is an important regulator for the apoptosis of melanocyte, and the apoptosis rate is significantly decreased in low RGS4 enviroment. RGS4 induced non-activation of PI3K/AKT pathway, resulting in decreased expression of E2F1 and Cyclin D1, thus constraining cell proliferation and invasion. These results were further confirmed in M14 cell lines. Collectively, our findings show that RGS4 plays an important role in multiple cellular functions of melanoma development and is valuable to be a therapeutic target. PMID:29108247

[Multiple post-chemotherapy plantar nevi].

PubMed

Hueso, Luis; Requena, Celia; Serra-Guillén, Carlos; Alfaro, Alberto; Nagore, Eduardo; Llombart, Beatriz; Botella-Estrada, Rafael; Sanmartín, Onofre; Guillén, Carlos

2006-06-01

The induction of multiple melanocytic nevi in children after chemotherapy has been documented in the literature. This situation apparently has more to do with the state of immunosuppression that is produced than with any specific agent used. We present the case of a 12-year-old girl who presented with multiple plantar melanocytic nevi after multidrug chemotherapy for acute lymphocytic leukemia. None of the lesions showed any alarming clinical signs. Although the degeneration of post-chemotherapy melanocytic nevi to melanoma has not been documented in any of the cases described, the presence of a high number of melanocytic nevi is an accepted risk factor for melanoma; thus, close clinical follow-up of these patients seems advisable.

Non-melanoma Skin Cancer in Canada Chapter 2: Primary Prevention of Non-melanoma Skin Cancer.

PubMed

Barber, Kirk; Searles, Gordon E; Vender, Ronald; Teoh, Hwee; Ashkenas, John

2015-01-01

Non-melanoma skin cancer (NMSC), including basal and squamous cell carcinoma (BCC and SCC), represents the most common malignancy. To provide guidance to Canadian health care practitioners regarding primary prevention of NMSC. Structured literature searches were conducted, using search terms including prevention, sunscreen, and sun prevention factor. All recommendations concern guidance that physicians should regularly discuss with their patients to help establish photoprotection habits. The GRADE system was used to assign strength to each recommendation. Ultraviolet exposure is the major modifiable risk factor for NMSC. Aspects of photoprotection, including effective sunscreen use and avoidance of both the midday sun and artificial tanning, are discussed. Several widespread misunderstandings that undermine responsible public health measures related to sun safety are addressed. Photoprotection represents both an individual priority and a public health imperative. By providing accurate information during routine patient visits, physicians reinforce the need for ongoing skin cancer prevention. © The Author(s) 2015.

Aberrant Cx43 Expression and Mislocalization in Metastatic Human Melanomas.

PubMed

Alaga, Katanya C; Crawford, Melissa; Dagnino, Lina; Laird, Dale W

2017-01-01

At present, it is unclear if melanocytes contain Cx43 gap junctions and whether Cx43 expression is regulated in melanoma onset and progression. To this end, we cultured pure populations of mouse melanocytes and found that they had no detectable Cx43 and exhibited an inability for dye transfer indicating they were devoid of functional gap junctions. Given the evidence that melanomas acquire the expression of other connexin isoforms during tumor progression, we assessed if Cx43 was also expressed and assembled into gap junctions at any stage of human melanoma onset and progression to distant metastases. Nearly all primary melanomas within the epidermis lacked Cx43. In contrast, nodal metastases expressed low levels of Cx43 which was markedly higher in distant metastases that had invaded vital organs. Importantly, in all stages of melanoma progression, Cx43 could be detected in intracellular compartments but was rarely assembled into gap junctions indicative of functional gap junction channels. Overall, these studies suggest that melanocytes do not form Cx43 homocellular gap junctions and even though Cx43 levels increase during melanoma progression, this connexin rarely assembles into gap junction structures.

Aberrant Cx43 Expression and Mislocalization in Metastatic Human Melanomas

PubMed Central

Alaga, Katanya C.; Crawford, Melissa; Dagnino, Lina; Laird, Dale W.

2017-01-01

At present, it is unclear if melanocytes contain Cx43 gap junctions and whether Cx43 expression is regulated in melanoma onset and progression. To this end, we cultured pure populations of mouse melanocytes and found that they had no detectable Cx43 and exhibited an inability for dye transfer indicating they were devoid of functional gap junctions. Given the evidence that melanomas acquire the expression of other connexin isoforms during tumor progression, we assessed if Cx43 was also expressed and assembled into gap junctions at any stage of human melanoma onset and progression to distant metastases. Nearly all primary melanomas within the epidermis lacked Cx43. In contrast, nodal metastases expressed low levels of Cx43 which was markedly higher in distant metastases that had invaded vital organs. Importantly, in all stages of melanoma progression, Cx43 could be detected in intracellular compartments but was rarely assembled into gap junctions indicative of functional gap junction channels. Overall, these studies suggest that melanocytes do not form Cx43 homocellular gap junctions and even though Cx43 levels increase during melanoma progression, this connexin rarely assembles into gap junction structures. PMID:28607585

Adjuvant Treatment of Melanoma

PubMed Central

Moreno Nogueira, J. A.; Valero Arbizu, M.; Pérez Temprano, R.

2013-01-01

Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50–80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-α2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas. PMID:23476798

A multivariate analysis of prognostic factors for melanoma patients with lesions greater than or equal to 3.65 mm in thickness. The importance of revealing alternative Cox models.

PubMed Central

Day, C L; Lew, R A; Mihm, M C; Sober, A J; Harris, M N; Kopf, A W; Fitzpatrick, T B; Harrist, T J; Golomb, F M; Postel, A; Hennessey, P; Gumport, S L; Raker, J W; Malt, R A; Cosimi, A B; Wood, W C; Roses, D F; Gorstein, F; Rigel, D; Friedman, R J; Mintzis, M M; Grier, R W

1982-01-01

Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%). PMID:7055383

Resveratrol Overcomes Cellular Resistance to Vemurafenib Through Dephosphorylation of AKT in BRAF-mutated Melanoma Cells.

PubMed

Luo, Hao; Umebayashi, Masayo; Doi, Keiko; Morisaki, Takashi; Shirasawa, Senji; Tsunoda, Toshiyuki

2016-07-01

The serine/threonine-protein kinase B-Raf (BRAF) V600E mutant (BRAF(V600E)) inhibitor vemurafenib, has improved clinical outcomes for patients with BRAF(V600E) melanoma, but acquired cellular resistance mediated by AKT serine/threonine kinase 1 (AKT) phosphorylation limits its efficacy. We examined the effect of resveratrol on vemurafenib-resistant melanoma cells. A vemurafenib-resistant human metastatic melanoma cell line positive for the BRAF V600E mutation was established. The anti-tumorigenic effects of vemurafenib and resveratrol, both alone and in combination, were examined through analysis of cell proliferation and protein expression. The level of phosphorylated AKT (p-AKT) was increased in the primary melanoma cells after treatment with vemurafenib, and the basal level of p-AKT was increased in vemurafenib-resistant melanoma cells. Notably, resveratrol both alone and in combination with vemurafenib effectively suppressed cell proliferation and AKT phosphorylation in both parental and vemurafenib-resistant melanoma cells. Vemurafenib resistance can be reversed by addition of resveratrol in patients undergoing treatment with BRAF inhibitors. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

POLE mutations in families predisposed to cutaneous melanoma.

PubMed

Aoude, Lauren G; Heitzer, Ellen; Johansson, Peter; Gartside, Michael; Wadt, Karin; Pritchard, Antonia L; Palmer, Jane M; Symmons, Judith; Gerdes, Anne-Marie; Montgomery, Grant W; Martin, Nicholas G; Tomlinson, Ian; Kearsey, Stephen; Hayward, Nicholas K

2015-12-01

Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.

Real-time Supervised Detection of Pink Areas in Dermoscopic Images of Melanoma: Importance of Color Shades, Texture and Location

PubMed Central

Kaur, Ravneet; Albano, Peter P.; Cole, Justin G.; Hagerty, Jason; LeAnder, Robert W.; Moss, Randy H.; Stoecker, William V.

2015-01-01

Background/Purpose Early detection of malignant melanoma is an important public health challenge. In the USA, dermatologists are seeing more melanomas at an early stage, before classic melanoma features have become apparent. Pink color is a feature of these early melanomas. If rapid and accurate automatic detection of pink color in these melanomas could be accomplished, there could be significant public health benefits. Methods Detection of three shades of pink (light pink, dark pink, and orange pink) was accomplished using color analysis techniques in five color planes (red, green, blue, hue and saturation). Color shade analysis was performed using a logistic regression model trained with an image set of 60 dermoscopic images of melanoma that contained pink areas. Detected pink shade areas were further analyzed with regard to the location within the lesion, average color parameters over the detected areas, and histogram texture features. Results Logistic regression analysis of a separate set of 128 melanomas and 128 benign images resulted in up to 87.9% accuracy in discriminating melanoma from benign lesions measured using area under the receiver operating characteristic curve. The accuracy in this model decreased when parameters for individual shades, texture, or shade location within the lesion were omitted. Conclusion Texture, color, and lesion location analysis applied to multiple shades of pink can assist in melanoma detection. When any of these three details: color location, shade analysis, or texture analysis were omitted from the model, accuracy in separating melanoma from benign lesions was lowered. Separation of colors into shades and further details that enhance the characterization of these color shades are needed for optimal discrimination of melanoma from benign lesions. PMID:25809473

The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy

PubMed Central

Dar, Altaf A.; Nosrati, Mehdi; Bezrookove, Vladimir; de Semir, David; Majid, Shahana; Thummala, Suresh; Sun, Vera; Tong, Schuyler; Leong, Stanley P. L.; Minor, David; Billings, Paul R.; Soroceanu, Liliana; Debs, Robert; Miller, James R.; Sagebiel, Richard W.

2015-01-01

Background: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. Methods: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided. Results: shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents. Conclusions: These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF. PMID:25713167

Real-time supervised detection of pink areas in dermoscopic images of melanoma: importance of color shades, texture and location.

PubMed

Kaur, R; Albano, P P; Cole, J G; Hagerty, J; LeAnder, R W; Moss, R H; Stoecker, W V

2015-11-01

Early detection of malignant melanoma is an important public health challenge. In the USA, dermatologists are seeing more melanomas at an early stage, before classic melanoma features have become apparent. Pink color is a feature of these early melanomas. If rapid and accurate automatic detection of pink color in these melanomas could be accomplished, there could be significant public health benefits. Detection of three shades of pink (light pink, dark pink, and orange pink) was accomplished using color analysis techniques in five color planes (red, green, blue, hue, and saturation). Color shade analysis was performed using a logistic regression model trained with an image set of 60 dermoscopic images of melanoma that contained pink areas. Detected pink shade areas were further analyzed with regard to the location within the lesion, average color parameters over the detected areas, and histogram texture features. Logistic regression analysis of a separate set of 128 melanomas and 128 benign images resulted in up to 87.9% accuracy in discriminating melanoma from benign lesions measured using area under the receiver operating characteristic curve. The accuracy in this model decreased when parameters for individual shades, texture, or shade location within the lesion were omitted. Texture, color, and lesion location analysis applied to multiple shades of pink can assist in melanoma detection. When any of these three details: color location, shade analysis, or texture analysis were omitted from the model, accuracy in separating melanoma from benign lesions was lowered. Separation of colors into shades and further details that enhance the characterization of these color shades are needed for optimal discrimination of melanoma from benign lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

HMB-45 may be a more sensitive maker than S-100 or Melan-A for immunohistochemical diagnosis of primary oral and nasal mucosal melanomas.

PubMed

Yu, Chuan-Hang; Chen, Huang-Hsu; Liu, Chia-Ming; Jeng, Yung-Ming; Wang, Jeng-Tzung; Wang, Yi-Ping; Liu, Bu-Yuan; Sun, Andy; Chiang, Chun-Pin

2005-10-01

Primary mucosal melanomas (MMs) of the head and neck are a rare entity. Melanomas with characteristic melanin-pigmented tumor cells are easy to diagnose, but those without melanin-pigmented tumor cells, amelanotic melanomas, are difficult to identify and need immunohistochemistry (IHC) to confirm the final diagnosis. In this study, we examined the expression of three melanocytic differentiation markers, HMB-45, S-100, and Melan-A in primary oral and nasal MMs. We tried to evaluate whether HMB-45, S-100, and Melan-A were useful for diagnosis of primary oral and nasal MMs and to find out which marker was the best of the three. This study used IHC to examine the expression of HMB-45, S-100, and Melan-A in 17 formalin-fixed paraffin-embedded specimens of primary oral and nasal MMs. The staining intensities (SIs) and labeling indices (LIs) of HMB-45, S-100, and Melan-A in 17 MMs were calculated and compared between any two markers. Immunostaining results showed that the positive rate was 94% (16 of 17) for HMB-45, 88% (15 of 17) for S-100, and 71% (12 of 17) for Melan-A in 17 MMs. The SI of HMB-45 was significantly higher than that of S-100 (P = 0.0011) or of Melan-A (P = 0.0034). In addition, the mean LI of Melan-A (59 +/- 43%) was significantly lower than that of HMB-45 (83 +/- 28%, P = 0.0065) or of S-100 (79 +/- 33%, P = 0.0237). Our results indicate that both HMB-45 and S-100 show a high positive rate and LI in MMs and therefore may be good markers for immunohistochemical diagnosis of primary oral and nasal MMs. In addition, HMB-45 may be a more sensitive marker than S-100 because HMB-45 shows a significantly higher SI than S-100 in this study.

SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells.

PubMed

Santini, R; Pietrobono, S; Pandolfi, S; Montagnani, V; D'Amico, M; Penachioni, J Y; Vinci, M C; Borgognoni, L; Stecca, B

2014-09-18

Melanoma is one of the most aggressive types of human cancer, characterized by enhanced heterogeneity and resistance to conventional therapy at advanced stages. We and others have previously shown that HEDGEHOG-GLI (HH-GLI) signaling is required for melanoma growth and for survival and expansion of melanoma-initiating cells (MICs). Recent reports indicate that HH-GLI signaling regulates a set of genes typically expressed in embryonic stem cells, including SOX2 (sex-determining region Y (SRY)-Box2). Here we address the function of SOX2 in human melanomas and MICs and its interaction with HH-GLI signaling. We find that SOX2 is highly expressed in melanoma stem cells. Knockdown of SOX2 sharply decreases self-renewal in melanoma spheres and in putative melanoma stem cells with high aldehyde dehydrogenase activity (ALDH(high)). Conversely, ectopic expression of SOX2 in melanoma cells enhances their self-renewal in vitro. SOX2 silencing also inhibits cell growth and induces apoptosis in melanoma cells. In addition, depletion of SOX2 progressively abrogates tumor growth and leads to a significant decrease in tumor-initiating capability of ALDH(high) MICs upon xenotransplantation, suggesting that SOX2 is required for tumor initiation and for continuous tumor growth. We show that SOX2 is regulated by HH signaling and that the transcription factors GLI1 and GLI2, the downstream effectors of HH-GLI signaling, bind to the proximal promoter region of SOX2 in primary melanoma cells. In functional studies, we find that SOX2 function is required for HH-induced melanoma cell growth and MIC self-renewal in vitro. Thus SOX2 is a critical factor for self-renewal and tumorigenicity of MICs and an important mediator of HH-GLI signaling in melanoma. These findings could provide the basis for novel therapeutic strategies based on the inhibition of SOX2 for the treatment of a subset of human melanomas.

Estimation of Fractal Dimension in Differential Diagnosis of Pigmented Skin Lesions

NASA Astrophysics Data System (ADS)

Aralica, Gorana; Milošević, Danko; Konjevoda, Paško; Seiwerth, Sven; Štambuk, Nikola

Medical differential diagnosis is a method of identifying the presence of a particular entity (disease) within a set of multiple possible alternatives. The significant problem in dermatology and pathology is the differential diagnosis of malignant melanoma and other pigmented skin lesions, especially of dysplastic nevi. Malignant melanoma is the most malignant skin neoplasma, with increasing incidence in various parts of the world. It is hoped that the methods of quantitative pathology, i.e. morphometry, can help objectification of the diagnostic process, since early discovery of melanoma results in 10-year survival rate of 90%. The aim of the study was to use fractal dimension calculated from the perimeter-area relation of the cell nuclei as a tool for the differential diagnosis of pigmented skin lesions. We analyzed hemalaun-eosin stained pathohistological slides of pigmented skin lesions: intradermal naevi (n = 45), dysplastic naevi (n = 47), and malignant melanoma (n = 50). It was found that fractal dimension of malignant melanoma cell nuclei differs significantly from the intradermal and dysplastic naevi (p ≤ 0. 001, Steel-Dwass Multiple Comparison Test). Additionaly, ROC analysis confirmed the value of fractal dimension based evaluation. It is suggested that the estimation of fractal dimension from the perimeter-area relation of the cell nuclei may be a potentially useful morphometric parameter in the medical differential diagnosis of pigmented skin lesions.

Phytochemicals for the Management of Melanoma

PubMed Central

Pal, Harish Chandra; Hunt, Katherine Marchiony; Diamond, Ariana; Elmets, Craig A.; Afaq, Farrukh

2016-01-01

Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma. PMID:26864554

A web platform for the network analysis of high-throughput data in melanoma and its use to investigate mechanisms of resistance to anti-PD1 immunotherapy.

PubMed

Dreyer, Florian S; Cantone, Martina; Eberhardt, Martin; Jaitly, Tanushree; Walter, Lisa; Wittmann, Jürgen; Gupta, Shailendra K; Khan, Faiz M; Wolkenhauer, Olaf; Pützer, Brigitte M; Jäck, Hans-Martin; Heinzerling, Lucie; Vera, Julio

2018-06-01

Cellular phenotypes are established and controlled by complex and precisely orchestrated molecular networks. In cancer, mutations and dysregulations of multiple molecular factors perturb the regulation of these networks and lead to malignant transformation. High-throughput technologies are a valuable source of information to establish the complex molecular relationships behind the emergence of malignancy, but full exploitation of this massive amount of data requires bioinformatics tools that rely on network-based analyses. In this report we present the Virtual Melanoma Cell, an online tool developed to facilitate the mining and interpretation of high-throughput data on melanoma by biomedical researches. The platform is based on a comprehensive, manually generated and expert-validated regulatory map composed of signaling pathways important in malignant melanoma. The Virtual Melanoma Cell is a tool designed to accept, visualize and analyze user-generated datasets. It is available at: https://www.vcells.net/melanoma. To illustrate the utilization of the web platform and the regulatory map, we have analyzed a large publicly available dataset accounting for anti-PD1 immunotherapy treatment of malignant melanoma patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Phytochemicals for the Management of Melanoma.

PubMed

Pal, Harish Chandra; Hunt, Katherine Marchiony; Diamond, Ariana; Elmets, Craig A; Afaq, Farrukh

2016-01-01

Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

Metastatic Blue Nevus-Like Melanoma Detected by Liquid-Based Catheterized Urine Cytology.

PubMed

Kim, Sue Kyung; Yang, Ji Young; Han, Jae Ho; Kwon, Ji Eun

2018-06-01

Primary or metastatic malignant melanoma can mimic benign blue nevus in rare cases, making the diagnosis challenging. Herein, we report an exceptionally rare case of blue nevus-like melanoma and its blue nevus-like metastasis which was detected by catheterized urine cytology. The patient presented with blue-colored papuloplaques on his temple which were diagnosed as blue nevus-like melanoma on punch biopsies. While he was admitted for administration of chemotherapy, hematuria was detected. Catheterized urine cytology revealed singly scattered oval to spindle-shaped pigmented cells with a moderate degree of variation in shape and size. Many of them had small nuclei with indiscernible to inconspicuous nucleoli while only a few cells showed nuclear enlargement and nuclear hyperchromasia, which could be diagnostic pitfalls. Most of the cells on the smear were positive for HMB45 immunostaining, which confirmed the diagnosis of metastatic blue nevus-like melanoma. To the best of our knowledge, the present case is the first report describing cytomorphologic findings of blue nevus-like metastasis of melanoma in the urine specimen.

Sunbeds and sunlamps: who used them and their risk for melanoma

PubMed Central

Fears, Thomas R.; Sagebiel, Richard W.; Halpern, Allan; Elder, David E.; Holly, Elizabeth A.; Guerry, DuPont; Tucker, Margaret A.

2011-01-01

Summary Sunbed/sunlamp use was recently classified as carcinogenic. This report considers characteristics of those who use sunbeds/sunlamps and the effect of sunbed/sunlamp use on their risk for melanoma within a large case-control study carried out in 1991–2. Females were more likely than males to have used sunbeds/sunlamps. Use by females increased strongly and significantly with younger ages and with the perceived ability to tan. For females the individual risk for melanoma increased with typical session time and frequency of sessions. Use before age 20, current use and years of use were not significant. The use patterns of occasional and frequent users were very different. We estimate that typical 5 minute sessions would increase the risk for melanoma by 19% for frequent users (10+ sessions) and by 3% for occasional users (1–9 sessions). Body sites that are not generally exposed to sunlight were more common sites of primary melanomas for frequent sunbed/sunlamp users. For males, measures of sunbed/sunlamp use were not significantly associated with melanoma risk. PMID:21362155

Communication by Mothers with Breast Cancer or Melanoma with Their Children

PubMed Central

Gaber, Rikki; Desai, Sapna; Smith, Maureen; Eilers, Steve; Blatt, Hanz; Guevara, Yanina; Robinson, June K.

2013-01-01

Communication of familial risk of breast cancer and melanoma has the potential to educate relatives about their risk, and may also motivate them to engage in prevention and early detection practices. With the Health Insurance Portability and Accountability Act (HIPAA) privacy laws, the patient often becomes the sole communicator of such risks to family members. This study surveys mothers diagnosed with either breast cancer or melanoma and their adult children about their family communication style, knowledge of increased risk, and early detection practices. In both cancer groups, most mothers alerted their children of the risk and need for early detection practices. Breast cancer mothers communicated risk and secondary prevention with early detection by breast self-examination and mammograms whereas the melanoma mothers communicated risk and primary prevention strategies like applying sunscreen and avoiding deliberate tanning. Open communication about health matters significantly increased the likelihood that children engaged in early detection and/or primary prevention behaviors. Examining the information conveyed to at-risk family members, and whether such information motivated them to engage in early detection/prevention behaviors, is key to guiding better cancer prevention communication between doctors and patients. PMID:23965923

Communication by mothers with breast cancer or melanoma with their children.

PubMed

Gaber, Rikki; Desai, Sapna; Smith, Maureen; Eilers, Steve; Blatt, Hanz; Guevara, Yanina; Robinson, June K

2013-08-08

Communication of familial risk of breast cancer and melanoma has the potential to educate relatives about their risk, and may also motivate them to engage in prevention and early detection practices. With the Health Insurance Portability and Accountability Act (HIPAA) privacy laws, the patient often becomes the sole communicator of such risks to family members. This study surveys mothers diagnosed with either breast cancer or melanoma and their adult children about their family communication style, knowledge of increased risk, and early detection practices. In both cancer groups, most mothers alerted their children of the risk and need for early detection practices. Breast cancer mothers communicated risk and secondary prevention with early detection by breast self-examination and mammograms whereas the melanoma mothers communicated risk and primary prevention strategies like applying sunscreen and avoiding deliberate tanning. Open communication about health matters significantly increased the likelihood that children engaged in early detection and/or primary prevention behaviors. Examining the information conveyed to at-risk family members, and whether such information motivated them to engage in early detection/prevention behaviors, is key to guiding better cancer prevention communication between doctors and patients.

Facial resurfacing with a monoblock full-thickness skin graft after multiple malignant melanomas excision in xeroderma pigmentosum.

PubMed

Ozmen, Selahattin; Uygur, Safak; Eryilmaz, Tolga; Ak, Betul

2012-09-01

Xeroderma pigmentosum is an autosomal recessive disease, characterized by vulnerability of the skin to solar radiation. Increase in sunlight-induced cancer is a direct consequence of an increase in mutated cells of the skin of patients with xeroderma pigmentosum. There is no specific technique for facial resurfacing in patients with xeroderma pigmentosum. In this article, a patient with xeroderma pigmentosum with multiple malignant melanomas on her face and radical excision of total facial skin followed by facial resurfacing with monoblock full-thickness skin graft from the abdomen is presented.

KIT pathway alterations in mucosal melanomas of the vulva and other sites.

PubMed

Omholt, Katarina; Grafström, Eva; Kanter-Lewensohn, Lena; Hansson, Johan; Ragnarsson-Olding, Boel K

2011-06-15

A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens. Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry. KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P = 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (≥4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P = 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis. Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens. ©2011 AACR.

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance.

PubMed

Krumm, Andrea; Barckhausen, Christina; Kücük, Pelin; Tomaszowski, Karl-Heinz; Loquai, Carmen; Fahrer, Jörg; Krämer, Oliver Holger; Kaina, Bernd; Roos, Wynand Paul

2016-05-15

DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O(6)-methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. ©2016 AACR. ©2016 American Association for Cancer Research.

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells.

PubMed

Martin, Shaun; Dudek-Peric, Aleksandra M; Garg, Abhishek D; Roose, Heleen; Demirsoy, Seyma; Van Eygen, Sofie; Mertens, Freya; Vangheluwe, Peter; Vankelecom, Hugo; Agostinis, Patrizia

2017-09-02

The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF V600E . Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF V600E inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanoma cells. Compromising the heightened autophagy in these BRAF V600E inhibitor-resistant melanoma cells through the knockdown of different autophagy genes (ATG5, ATG7, ULK1), reduced their invasive and eATP-secreting capacity. Furthermore, eATP promoted the aggressive nature of the BRAF V600E inhibitor-resistant melanoma cells by signaling through the purinergic receptor P2RX7. This autophagy-propelled eATP-dependent autocrine-paracrine pathway supported the maintenance and expansion of a drug-resistant melanoma phenotype. In conclusion, we have identified an autophagy-driven response that relies on the secretion of ATP to drive P2RX7-based migration and expansion of the Vemurafenib-resistant phenotype. This emphasizes the potential of targeting autophagy in the treatment and management of metastatic melanoma.

Stem cell media culture of melanoma results in the induction of a nonrepresentative neural expression profile.

PubMed

Anaka, Matthew; Freyer, Claudia; Gedye, Craig; Caballero, Otavia; Davis, Ian D; Behren, Andreas; Cebon, Jonathan

2012-02-01

The ability of cell lines to accurately represent cancer is a major concern in preclinical research. Culture of glioma cells as neurospheres in stem cell media (SCM) has been shown to better represent the genotype and phenotype of primary glioblastoma in comparison to serum cell lines. Despite the use of neurosphere-like models of many malignancies, there has been no robust analysis of whether other cancers benefit from a more representative phenotype and genotype when cultured in SCM. We analyzed the growth properties, transcriptional profile, and genotype of melanoma cells grown de novo in SCM, as while melanocytes share a common precursor with neural cells, melanoma frequently demonstrates divergent behavior in cancer stem cell assays. SCM culture of melanoma cells induced a neural lineage gene expression profile that was not representative of matched patient tissue samples and which could be induced in serum cell lines by switching them into SCM. There was no enrichment for expression of putative melanoma stem cell markers, but the SCM expression profile did overlap significantly with that of SCM cultures of glioma, suggesting that the observed phenotype is media-specific rather than melanoma-specific. Xenografts derived from either culture condition provided the best representation of melanoma in situ. Finally, SCM culture of melanoma did not prevent ongoing acquisition of DNA copy number abnormalities. In conclusion, SCM culture of melanoma does not provide a better representation of the phenotype or genotype of metastatic melanoma, and the resulting neural bias could potentially confound therapeutic target identification. Copyright © 2011 AlphaMed Press.

[Dermoscopy in cutaneous melanoma].

PubMed

Gallegos-Hernández, José Francisco; Ortiz-Maldonado, Alma Lilia; Minauro-Muñoz, Gerardo Gabriel; Arias-Ceballos, Héctor; Hernández-Sanjuan, Martín

2015-01-01

The mortality of cutaneous melanoma has not declined over the past 50 years. The only interventions that can reduce mortality are primary prevention and early diagnosis, and the dermoscopic evaluation is essential to achieve this. Dermoscopy identifies characteristics of melanoma that would go unnoticed to the naked eye. The aim of this paper is to report the most frequent dermoscopic findings in patients diagnosed with in situ and invasive melanoma. An observational and retrospective study of contact dermoscopy was performed using LED DermliteTM and camera DermliteTM dermoscope. The findings evaluated were: asymmetry in two axes, association of colours, lack of pigment, irregular points, atypical network, pseudopods, blue veil, ulceration, and peri-lesional pink ring. These dermoscopic findings were compared with the histological diagnosis. The study included 65 patients with cutaneous melanoma; 10 in situ, and 55 invasive. The mean Breslow in invasive melanoma was 3 mm. Most patients (35) had localization in extremities. In all patients, the most frequent dermoscopic finding was asymmetry in two axes, followed by association of two or more colours; in melanoma in situ, asymmetry was the most frequent, followed by atypical-irregular points. In invasive melanoma asymmetry in two axes, the association of two or more colours, and pseudopods, were the most frequent findings. Asymmetry in two axes is the most common dermoscopic finding in in situ and invasive melanoma. The presence of two or more colours in a pigmented lesion should be suspected in an invasive melanoma. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Patient with confirmed LEOPARD syndrome developing multiple melanoma

PubMed Central

Colmant, Caroline; Franck, Deborah; Marot, Liliane; Matthijs, Gert; Sznajer, Yves; Blomme, Sandrine

2018-01-01

LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis. PMID:29445579

Patient with confirmed LEOPARD syndrome developing multiple melanoma.

PubMed

Colmant, Caroline; Franck, Deborah; Marot, Liliane; Matthijs, Gert; Sznajer, Yves; Blomme, Sandrine; Tromme, Isabelle

2018-01-01

LEOPARD syndrome, also known as Gorlin syndrome II, cardiocutaneous syndrome, lentiginosis profusa syndrome, Moynahan syndrome, was more recently coined as Noonan syndrome with multiple lentigines (NSML), inside the RASopathies. Historically, the acronym LEOPARD refers to the presence of distinctive clinical features such as: lentigines (L), electrocardiographic/conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), genital abnormalities (A), retardation of growth (R), and sensorineural deafness (D). This condition is identified in 85% of patients with phenotype hallmarks caused by presence a germline point mutation in PTPN11 gene. Association of melanoma to NSML seems to be rare: to our knowledge, two patients so far were reported in the literature. We herein present a patient diagnosed with LEOPARD syndrome, in whom molecular investigation confirmed the presence of the c.1403C>T mutation in exon 12 of the PTPN11 gene, who developed four superficial spreading melanomas and three atypical lentiginous hyperplasias. Three of the melanomas were achromic or hypochromic, three were in situ, and one had a Breslow index under 0.5 mm. Dermoscopic examination showed some characteristic white structures in most of the lesions, which were a signature pattern and a key for the diagnosis.

microRNA-216b inhibits cell proliferation and migration in human melanoma by targeting FOXM1 in vitro and in vivo.

PubMed

Sun, Mengyao; Wang, Xiaopeng; Tu, Chen; Wang, Shuang; Qu, Jianqiang; Xiao, Shengxiang

2017-12-01

MicroRNAs (miRNAs) play an increasingly important role in cancer growth by coordinately suppressing genes that control cell migration, proliferation, and invasion. The above results can be achieved through the regulation of gene expression by miRNAs by suppressing translation or the direct sequence-specific degradation of the targeted mRNA. In the present study, we indicate that the expression of miR-216b could be effectively repressed both in human melanoma tissues through a comparison with primary melanoma and in human melanoma cell lines through a comparison with a normal human keratinocyte line. Moreover, miR-216b induced a clear decrease in melanoma cell proliferation and migration in vitro. Forkhead box M1 (FOXM1) was confirmed as a target gene of miR-216b, and the overexpression of miR-216b markedly repressed the luciferase activity of reporter plasmids containing the FOXM1 3'-UTR (untranslated region). Furthermore, miR-216b suppressed melanoma cell growth in nude mice in vivo, with the effects of miR-216b overexpression on melanoma cell growth and proliferation reversed by FOXM1 overexpression. The results demonstrated that miR-216b is a tumor suppressor in melanoma, identified the FOXM1 signaling pathway as a target of miR-216b action, and suggested a potential therapeutic role for miR-216b in melanoma. © 2017 International Federation for Cell Biology.

RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells

PubMed Central

Mezzanotte, Jessica J; Hill, Victoria; Schmidt, M Lee; Shinawi, Thoraia; Tommasi, Stella; Krex, Dietmar; Schackert, Gabriele; Pfeifer, Gerd P; Latif, Farida; Clark, Geoffrey J

2014-01-01

Brain metastasis is a major contributor to cancer mortality, yet, the genetic changes underlying the development of this capacity remain poorly understood. RASSF proteins are a family of tumor suppressors that often suffer epigenetic inactivation during tumorigenesis. However, their epigenetic status in brain metastases has not been well characterized. We have examined the promoter methylation of the classical RASSF members (RASSF1A-RASSF6) in a panel of metastatic brain tumor samples. RASSF1A and RASSF2 have been shown to undergo promoter methylation at high frequency in primary lung and breast tumors and in brain metastases. Other members exhibited little or no methylation in these tumors. In examining melanoma metastases, however, we found that RASSF6 exhibits the highest frequency of inactivation in melanoma and in melanoma brain metastases. Most melanomas are driven by an activating mutation in B-Raf. Introduction of RASSF6 into a B-RafV600E-containing metastatic melanoma cell line inhibited its ability to invade through collagen and suppressed MAPK pathway activation and AKT. RASSF6 also appears to increase the association of mutant B-Raf and MST1, providing a potential mechanism by which RASSF6 is able to suppress MAPK activation. Thus, we have identified a novel potential role for RASSF6 in melanoma development. Promoter methylation leading to reduced expression of RASSF6 may play an important role in melanoma development and may contribute to brain metastases. PMID:25482183

Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness.

PubMed

Saladi, Srinivas Vinod; Keenen, Bridget; Marathe, Himangi G; Qi, Huiling; Chin, Khew-Voon; de la Serna, Ivana L

2010-10-22

Metastatic melanoma is an aggressive malignancy that is resistant to therapy and has a poor prognosis. The progression of primary melanoma to metastatic disease is a multi-step process that requires dynamic regulation of gene expression through currently uncharacterized epigenetic mechanisms. Epigenetic regulation of gene expression often involves changes in chromatin structure that are catalyzed by chromatin remodeling enzymes. Understanding the mechanisms involved in the regulation of gene expression during metastasis is important for developing an effective strategy to treat metastatic melanoma. SWI/SNF enzymes are multisubunit complexes that contain either BRG1 or BRM as the catalytic subunit. We previously demonstrated that heterogeneous SWI/SNF complexes containing either BRG1 or BRM are epigenetic modulators that regulate important aspects of the melanoma phenotype and are required for melanoma tumorigenicity in vitro. To characterize BRG1 expression during melanoma progression, we assayed expression of BRG1 in patient derived normal skin and in melanoma specimen. BRG1 mRNA levels were significantly higher in stage IV melanomas compared to stage III tumors and to normal skin. To determine the role of BRG1 in regulating the expression of genes involved in melanoma metastasis, we expressed BRG1 in a melanoma cell line that lacks BRG1 expression and examined changes in extracellular matrix and adhesion molecule expression. We found that BRG1 modulated the expression of a subset of extracellular matrix remodeling enzymes and adhesion proteins. Furthermore, BRG1 altered melanoma adhesion to different extracellular matrix components. Expression of BRG1 in melanoma cells that lack BRG1 increased invasive ability while down-regulation of BRG1 inhibited invasive ability in vitro. Activation of metalloproteinase (MMP) 2 expression greatly contributed to the BRG1 induced increase in melanoma invasiveness. We found that BRG1 is recruited to the MMP2 promoter and directly activates expression of this metastasis associated gene. We provide evidence that BRG1 expression increases during melanoma progression. Our study has identified BRG1 target genes that play an important role in melanoma metastasis and we show that BRG1 promotes melanoma invasive ability in vitro. These results suggest that increased BRG1 levels promote the epigenetic changes in gene expression required for melanoma metastasis to proceed.

Correlations of EGF G1380A, bFGF C754G and VEGF T460C polymorphisms with malignant melanoma susceptibility and prognosis: A case-control study.

PubMed

Wang, Xin-Hua; Long, Zi-Wen

2017-06-20

This case-control study aims to investigate the correlations of EGF G1380A, bFGF C754G and VEGF T460C polymorphisms with the susceptibility and prognosis of malignant melanoma. A total of 153 patients with multiple primary melanomas were collected as the case group and another 170 healthy individuals were selected as the control group. ELISA and PCR-RFLP were performed to test the serum level of VEGF and to analyze the genotype as well as allele frequencies of VEGF T460C, EGF G1380A, and bFGF C754G, respectively. The patients were assigned into complete remission (CR), partial remission (PR) and non-remission groups after treatment. HE and CD34 staining were conducted in tissue samples of CR and PR patients. Event-free survival (EFS) and overall survival (OS) were measured. AA genotype of EGF G1380A and GG genotype of bFGF C754G had higher frequency distribution in the case group than the control group. Patients with AA genotype of EGF G1380 and GG genotype of bFGF C754G had an elevated VEGF level in comparison to other genotypes. Patients with GA+GG genotypes of EGF G1380A and CG+CC genotypes of bFGF C754G had higher EFS and OS than those with AA genotype and those with GG genotype, respectively. According to the haplotype analysis, the case group had a notably higher frequency of TAG and CAG along with while lower frequency of TGG and CGC compared with the control group. Logistic regression analysis revealed that the polymorphisms of EGF G1380A and bFGF C754G as well as the haploid TAG increased the susceptibility of malignant melanoma. The results indicated that EGF G1380A and bFGF C754G gene polymorphisms were associated with the susceptibility and prognosis of malignant melanoma, and that the polymorphisms of EGF G1380A and bFGF C754G as well as the haploid TAG increased the susceptibility of malignant melanoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study.

PubMed

Thomas, Nancy E; Kricker, Anne; Waxweiler, Weston T; Dillon, Patrick M; Busman, Klaus J; From, Lynn; Groben, Pamela A; Armstrong, Bruce K; Anton-Culver, Hoda; Gruber, Stephen B; Marrett, Loraine D; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A; Orlow, Irene; Paine, Susan; Ollila, David W; Reiner, Anne S; Luo, Li; Hao, Honglin; Frank, Jill S; Begg, Colin B; Berwick, Marianne

2014-12-01

IMPORTANCE Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.OBJECTIVE To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.DESIGN, SETTING, AND PARTICIPANTS Survival analysis with a median follow-up of 7.6 years.The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma(GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.MAIN OUTCOMES AND MEASURES Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.RESULTS Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex,nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally ofa higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios[ORs] [95%CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95%CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a;P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95%CI, 1.4-3.0)(P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95%CI, 0.5-1.2)(P = .36).CONCLUSIONS AND RELEVANCE At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.

Futility of fluorodeoxyglucose F 18 positron emission tomography in initial evaluation of patients with T2 to T4 melanoma.

PubMed

Clark, Paige B; Soo, Victoria; Kraas, Jonathan; Shen, Perry; Levine, Edward A

2006-03-01

Evaluation of newly diagnosed patients with melanoma for metastasis is requisite to treatment planning. The reported diagnostic yield of whole-body conventional radiological imaging in initial staging of patients with melanoma is low. However, the diagnostic yield of positron emission tomography (PET) for distant metastases is unclear. There is no utility of PET as part of a routine metastatic survey in patients with T2 to T4 melanoma. Retrospective review of a cohort study between December 1998 and July 2004. University hospital tertiary care center. There were 64 patients with T2 to T4 melanomas who underwent PET for detection of occult metastases at our institution. All patients underwent surgical excision of the primary lesion and sentinel lymph node dissection. Data included were pathologic findings of the primary lesion and sentinel lymph nodes, laboratory data, and radiological reports. None of the patients had clinically suspected regional or distant metastases prior to PET. The diagnostic yield of PET was evaluated through retrospective analysis. Positive scans were then correlated for accuracy with follow-up imaging, biopsy, and clinical information when available. Positron emission tomography did not reveal occult distant metastases in any of the patients. Positron emission tomographic scans showed no abnormalities in 94% of these patients. In 2 patients (3%), false-positive findings were reported on PET (muscular activity and intranodal melanocytic nevocellular inclusion). Further, PET was not useful in predicting regional lymph node metastases. Nineteen of 64 patients had positive sentinel lymph nodes, and only 2 (11%) were identified on PET. Overall, PET did not change clinical management in any of the patients. This study suggests no utility for PET in the detection of occult metastases in patients at initial diagnosis of melanoma. Omission of PET imaging from preoperative evaluations for patients with melanoma is recommended.

Protective CD8 Memory T Cell Responses to Mouse Melanoma Are Generated in the Absence of CD4 T Cell Help

PubMed Central

Steinberg, Shannon M.; Zhang, Peisheng; Turk, Mary Jo

2011-01-01

Background We have previously demonstrated that temporary depletion of CD4 T cells in mice with progressive B16 melanoma, followed by surgical tumor excision, induces protective memory CD8 T cell responses to melanoma/melanocyte antigens. We also showed that persistence of these CD8 T cells is supported, in an antigen-dependent fashion, by concurrent autoimmune melanocyte destruction. Herein we explore the requirement of CD4 T cell help in priming and maintaining this protective CD8 T cell response to melanoma. Methodology and Principal Findings To induce melanoma/melanocyte antigen-specific CD8 T cells, B16 tumor bearing mice were depleted of regulatory T cells (Treg) by either temporary, or long-term continuous treatment with anti-CD4 (mAb clone GK1.5). Total depletion of CD4 T cells led to significant priming of IFN-γ-producing CD8 T cell responses to TRP-2 and gp100. Surprisingly, treatment with anti-CD25 (mAb clone PC61), to specifically deplete Treg cells while leaving help intact, was ineffective at priming CD8 T cells. Thirty to sixty days after primary tumors were surgically excised, mice completely lacking CD4 T cell help developed autoimmune vitiligo, and maintained antigen-specific memory CD8 T cell responses that were highly effective at producing cytokines (IFN-γ, TNF-α, and IL-2). Mice lacking total CD4 T cell help also mounted protection against re-challenge with B16 melanoma sixty days after primary tumor excision. Conclusions and Significance This work establishes that CD4 T cell help is dispensable for the generation of protective memory T cell responses to melanoma. Our findings support further use of CD4 T cell depletion therapy for inducing long-lived immunity to cancer. PMID:22046294

Recurrence and Survival Outcomes After Percutaneous Thermal Ablation of Oligometastatic Melanoma.

PubMed

White, Mariah L; Atwell, Thomas D; Kurup, A Nicholas; Schmit, Grant D; Carter, Rickey E; Geske, Jennifer R; Kottschade, Lisa A; Pulido, Jose S; Block, Matthew S; Jakub, James W; Callstrom, Matthew R; Markovic, Svetomir N

2016-03-01

To evaluate focal treatment of melanoma metastases and to explore whether any potential extended survival benefit exists in a select patient population. All patients who underwent image-guided local thermal ablation of metastatic melanoma over an 11-year period (January 1, 2002, to December 31, 2013) were retrospectively identified using an internally maintained clinical registry. Only patients with oligometastatic stage IV disease amenable to complete ablation of all clinical disease at the time of ablation were included in the analysis. Overall survival and median progression-free survival periods were calculated. Thirty-three patients with primary ocular or nonocular melanoma had 66 metastases treated in the lungs, liver, bones, or soft tissues. Eleven (33%) patients were on systemic medical therapy at the time of the procedure. The median survival time was 3.8 years (range, 0.5-10.5 years), with a 4-year estimated survival of 44.1% (95% CI, 28%-68%). Local recurrence at the ablation site developed in 15.1% (5 of 33) of the patients and 13.6% of the tumors (9 of 66). The median progression-free survival time was 4.4 months (95% CI, 1.4 months to 10.5 years), with an estimated 1-year progression-free survival of 30.3% (95% CI, 18%-51%). A subgroup analysis identified 11 patients with primary ocular melanoma and 22 with nonocular melanoma, with a median survival time of 3.9 years (range, 0.9-4.7 years) and 3.8 years (range, 0.5-10.5 years), respectively (P=.58). There were no major complications and no deaths within 30 days of the procedure. Selective use of image-guided thermal ablation of oligometastatic melanoma may provide results similar to surgical resection in terms of technical effectiveness and oncologic outcomes with minimal risk. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

ClinicalTrials.gov

2018-04-02

Glioma; Lymphoma; Metastatic Malignant Solid Neoplasm; Neuroendocrine Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Stage III Breast Cancer AJCC v7; Stage III Colorectal Cancer AJCC v7; Stage III Cutaneous Melanoma AJCC v7; Stage III Lung Cancer AJCC v7; Stage III Pancreatic Cancer AJCC v6 and v7; Stage III Prostate Cancer AJCC v7; Stage III Renal Cell Cancer AJCC v7; Stage III Soft Tissue Sarcoma AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Colorectal Cancer AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Lung Cancer AJCC v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage IV Prostate Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7; Stage IV Soft Tissue Sarcoma AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7; Unresectable Solid Neoplasm

Sentinel lymph node biopsy in cutaneous melanoma of the head and neck using the indocyanine green SPY Elite system.

PubMed

Vahabzadeh-Hagh, Andrew M; Blackwell, Keith E; Abemayor, Elliot; St John, Maie A

2018-05-17

Lymph node status is the single most important prognostic factor for patients with early-stage cutaneous melanoma. Sentinel lymph node biopsy (SLNB) has become the standard of care for intermediate depth melanomas. Modern SLNB implementation includes technetium-99 lymphoscintigraphy combined with local administration of a vital blue dye. However, sentinel lymph nodes may fail to localize in some cases and false-negative rates range from 0 to 34%. Here we demonstrate the feasibility of a new sentinel lymph node biopsy technique using indocyanine green (ICG) and the SPY Elite near-infrared imaging system. Cases of primary cutaneous melanoma of the head and neck without locoregional metastasis, underwent SLNB at a single quaternary care institution between May 2016 and June 2017. Intraoperatively, 0.25 mL of ICG was injected intradermal in 4 quadrants around the primary lesion. 10-15 minute circulation time was permitted. SPY Elite identified the sentinel lymph node within the nodal basin marked by lymphoscintigraphy. Target first echelon lymph nodes were confirmed with a gamma probe and ICG fluorescence. 14 patients were included with T1a to T4b cutaneous melanomas. Success rates for sentinel lymph node identification using lymphoscintigraphy and the SPY Elite system were both 86%. Zero false negatives occurred. Median length of follow-up was 323 days. In this pilot study, Indocyanine green near-infrared fluorescence demonstrates a safe, and facile method of sentinel lymph node biopsy for cutaneous melanoma of the head and neck compared with lymphoscintigraphy and vital blue dyes. Copyright © 2018 Elsevier Inc. All rights reserved.

Metastatic Melanoma Induced Metabolic Changes in C57BL/6J Mouse Stomach Measured by 1H NMR Spectroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, M; Wang, Xiliang

Melanoma is a malignant tumor of melanocytes with high capability of invasion and rapid metastasis to other organs. Malignant melanoma is the most common metastatic malignancy found in gastrointestinal tract (GI). To the best of our knowledge, previous studies of melanoma in gastrointestinal tract are all clinical case reports. In this work, 1H NMR-based metabolomics approach is used to investigate the metabolite profiles differences of stomach tissue extracts of metastatic B16-F10 melanoma in C57BL/6J mouse and search for specific metabolite biomarker candidates. Principal Component Analysis (PCA), an unsupervised multivariate data analysis method, is used to detect possible outliers, while Orthogonalmore » Projection to Latent Structure (OPLS), a supervised multivariate data analysis method, is employed to evaluate important metabolites responsible for discriminating the control and the melanoma groups. Both PCA and OPLS results reveal that the melanoma group can be well separated from its control group. Among the 50 identified metabolites, it is found that the concentrations of 19 metabolites are statistically and significantly changed with the levels of O-phosphocholine and hypoxanthine down-regulated while the levels of isoleucine, leucine, valine, isobutyrate, threonine, cadaverine, alanine, glutamate, glutamine, methionine, citrate, asparagine, tryptophan, glycine, serine, uracil, and formate up-regulated in the melanoma group. These significantly changed metabolites are associated with multiple biological pathways and may be potential biomarkers for metastatic melanoma in stomach.« less

Metastatic Melanoma Induced Metabolic Changes in C57BL/6J Mouse Stomach Measured by 1H NMR Spectroscopy

DOE PAGES

Hu, M; Wang, Xiliang

2014-12-05

Melanoma is a malignant tumor of melanocytes with high capability of invasion and rapid metastasis to other organs. Malignant melanoma is the most common metastatic malignancy found in gastrointestinal tract (GI). To the best of our knowledge, previous studies of melanoma in gastrointestinal tract are all clinical case reports. In this work, 1H NMR-based metabolomics approach is used to investigate the metabolite profiles differences of stomach tissue extracts of metastatic B16-F10 melanoma in C57BL/6J mouse and search for specific metabolite biomarker candidates. Principal Component Analysis (PCA), an unsupervised multivariate data analysis method, is used to detect possible outliers, while Orthogonalmore » Projection to Latent Structure (OPLS), a supervised multivariate data analysis method, is employed to evaluate important metabolites responsible for discriminating the control and the melanoma groups. Both PCA and OPLS results reveal that the melanoma group can be well separated from its control group. Among the 50 identified metabolites, it is found that the concentrations of 19 metabolites are statistically and significantly changed with the levels of O-phosphocholine and hypoxanthine down-regulated while the levels of isoleucine, leucine, valine, isobutyrate, threonine, cadaverine, alanine, glutamate, glutamine, methionine, citrate, asparagine, tryptophan, glycine, serine, uracil, and formate up-regulated in the melanoma group. These significantly changed metabolites are associated with multiple biological pathways and may be potential biomarkers for metastatic melanoma in stomach.« less

A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children.

PubMed

Yélamos, Oriol; Arva, Nicoleta C; Obregon, Roxana; Yazdan, Pedram; Wagner, Annette; Guitart, Joan; Gerami, Pedram

2015-03-01

Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6.

Profiling of ABC transporters ABCB5, ABCF2 and nestin-positive stem cells in nevi, in situ and invasive melanoma.

PubMed

Setia, Namrata; Abbas, Ossama; Sousa, Yessica; Garb, Jane L; Mahalingam, Meera

2012-08-01

Distinct ABCB5 forms and ABCF2, members of the ATP-binding cassette (ABC) superfamily of transporters, are normally expressed in various tissues and cells, and enhanced expression of both has been demonstrated in select cancers. In melanoma cell lines, gene expression profiling of ABC transporters has revealed enhanced expression of melanocyte-specific ABCB5 and ABCF2 proteins. Given this, our primary aim was to ascertain immunohistochemical expression of the ABC transporters ABCB5 and ABCF2 and, the stem cell marker, nestin in a spectrum of benign and malignant nevomelanocytic proliferations, including nevi (n=30), in situ (n=31) and invasive (n=24) primary cutaneous melanomas to assess their role in the stepwise development of malignancy. In addition, their expression was compared with established melanoma prognosticators to ascertain their utility as independent prognosticators. A semiquantitative scoring system was utilized by deriving a cumulative score (based on percentage positivity cells and intensity of expression) and statistical analyses was carried out using analysis of variance with linear contrasts. Mean cumulative score in nevi, in situ and invasive melanoma were as follows: 3.8, 4.4 and 5.3 for ABCB5, respectively (P<0.005 for all), and 4.6, 4.6 and 5.3 for nestin, respectively (P=not significant for all). No appreciable expression of ABCF2 was noted in any of the groups. While ulcerated lesions of melanoma demonstrated lower levels of expression of ABCB5 and nestin than non-ulcerated lesions, and nestin expression was lower in lesions with mitoses >1, after controlling for the presence of ulceration and mitotic activity, the expression of both proteins did not significantly correlate with known melanoma prognosticators. The gradual increase in the expression of ABCB5 from benign nevus to in situ to invasive melanoma suggests that it plays a role in melanomagenesis. On the basis of our findings, a prospective study with follow-up data is required to ascertain the utility of ABCB5 as a therapeutic target.

Promoter Methylation of PTEN Is a Significant Prognostic Factor in Melanoma Survival.

PubMed

Roh, Mi Ryung; Gupta, Sameer; Park, Kyu-Hyun; Chung, Kee Yang; Lauss, Martin; Flaherty, Keith T; Jönsson, Göran; Rha, Sun Young; Tsao, Hensin

2016-05-01

Structural compromise of the tumor suppressor gene, phosphatase and tensin homolog (PTEN), occurs in 10% of melanoma specimens, and loss of PTEN expression through DNA methylation of the PTEN promoter region has also been reported in a number of other malignancies. However, the role of PTEN promoter methylation in melanoma is not well understood. We thus sought to elucidate the prevalence of PTEN promoter methylation in melanoma specimens, its relationship to clinical features, and its impact on the outcome of patients with melanoma. PTEN promoter methylation data were acquired from an archived primary Korean melanoma cohort (KMC) of 158 patients and, for validation, 234 patients from The Cancer Genome Atlas melanoma (TCGA-MEL) cohort. Hierarchical clustering was performed to identify PTEN "high methylated" and "low methylated" samples. Subsequently, differences in clinical features and outcomes based on PTEN promoter methylation status were then analyzed using SPSS and R. In the KMC, all tumors were acquired from primary tumors and 65.7% (n = 105) were acral or mucosal by site, whereas in the TCGA-MEL cohort, 90.5% of the tumors were from regional lymph node and distant metastatic lesions. Overall, 17.7% and 45.7% of the specimens harbored BRAF mutations in the KMC and TCGA-MEL cohort, respectively. Neuroblastoma RAS viral oncogene homolog was mutated in 12.2% and 26.9% of the tumors in the KMC and TCGA-MEL cohort, respectively. In the KMC, 31 cases (19.6%) were included in the high methylated group versus 142 cases (60.7%) in the TCGA-MEL cohort (P < 0.001). Multivariate Cox-regression analysis revealed promoter methylation of PTEN to be an independent negative prognostic factor for survival in both the KMC (hazard ratio 3.76, 95% confidence interval = 1.24-11.12, P = 0.017) and TCGA-MEL cohort (HR 1.88, 95% confidence interval = 1.13-3.12, P = 0.015). Our results indicate that PTEN promoter methylation is an independent predictor for impaired survival in patients with melanoma. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

SVM classifier on chip for melanoma detection.

PubMed

Afifi, Shereen; GholamHosseini, Hamid; Sinha, Roopak

2017-07-01

Support Vector Machine (SVM) is a common classifier used for efficient classification with high accuracy. SVM shows high accuracy for classifying melanoma (skin cancer) clinical images within computer-aided diagnosis systems used by skin cancer specialists to detect melanoma early and save lives. We aim to develop a medical low-cost handheld device that runs a real-time embedded SVM-based diagnosis system for use in primary care for early detection of melanoma. In this paper, an optimized SVM classifier is implemented onto a recent FPGA platform using the latest design methodology to be embedded into the proposed device for realizing online efficient melanoma detection on a single system on chip/device. The hardware implementation results demonstrate a high classification accuracy of 97.9% and a significant acceleration factor of 26 from equivalent software implementation on an embedded processor, with 34% of resources utilization and 2 watts for power consumption. Consequently, the implemented system meets crucial embedded systems constraints of high performance and low cost, resources utilization and power consumption, while achieving high classification accuracy.

Factors Associated with Inconsistent Sun Protection in First-Degree Relatives of Melanoma Survivors

PubMed Central

Shuk, Elyse; Burkhalter, Jack; Baguer, Carlos; Holland, Susan; Pinkhasik, Alisa; Brady, Mary Sue; Coit, Daniel; Ariyan, Charlotte; Hay, Jennifer

2014-01-01

First-degree relatives (FDRs) of melanoma survivors are at heightened risk for developing melanoma, but sporadically use sun protection. To develop appropriate interventions, in this article we identify factors related to sun protection inconsistency in melanoma FDRs using ethnographic decision tree modeling. We conducted in-home interviews with 25 melanoma FDRs balanced across gender and sunbathing attitudes and identified factors related to daily decision making about use of sunscreen, shade seeking, hats, and clothing. Results indicated primary facilitators for sun protection involved water settings and sunny weather. Physical activities such as exercise served to promote as well as inhibit sun protection. If participants anticipated shade cover, they tended to forgo other sun protection. The use of hats and clothing was often dictated by non-sun protection goals. Understanding factors related to inconsistent sun protection with detail and nuance is an important prerequisite to interventions aimed to improve sun protection maintenance in this population. PMID:22645220

A report of amelanotic malignant melanoma of the esophagus diagnosed appropriately with novel markers: A case report.

PubMed

Kobayashi, Junya; Fujimoto, Daisuke; Murakami, Makoto; Hirono, Yasuo; Goi, Takanori

2018-06-01

The present case study reported of amelanotic malignant melanoma of the esophagus. A 68-year-old man underwent laparoscopic distal gastrectomy for early gastric cancer diagnosis. After gastrectomy, endoscopic examination revealed a protruded lesion lying adjacent to the melanosis area of the esophagus. Histology of the biopsy specimen suggested malignancy, but the diagnosis could not be made. The patient underwent trans-thoraco-abdominal curative subtotal esophagectomy. Immunohistochemical examination of the resected specimen was negative for HBM-45 and Melan-A. However, immunohistochemical examinations of SOX10 (Sry-related HMg-Box gene 10) and KBA.62, which are not associated with melanosome, were strongly positive, and tyrosinase was notably positive. A diagnosis primary of amelanotic malignant melanoma of the esophagus that consisted of only premelanosomes was made. The present findings suggest that, in the diagnosis of malignant melanoma, SOX10 and KBA.62 may be useful, particularly in diagnosing amelanotic malignant melanoma.

Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade

PubMed Central

Taube, Janis M.; Young, Geoffrey D.; McMiller, Tracee L.; Chen, Shuming; Salas, January T.; Pritchard, Theresa S.; Xu, Haiying; Meeker, Alan K.; Fan, Jinshui; Cheadle, Chris; Berger, Alan E.; Pardoll, Drew M.; Topalian, Suzanne L.

2015-01-01

Purpose Blocking the immunosuppressive PD-1/PD-L1 pathway has anti-tumor activity in multiple cancer types, and PD-L1 expression on tumor cells and infiltrating myeloid cells correlates with the likelihood of response. We previously found that IFNG (interferon-gamma) was over-expressed by TILs in PD-L1+ vs. PD-L1(−) melanomas, creating adaptive immune resistance by promoting PD-L1 display. The current study was undertaken to identify additional factors in the PD-L1+ melanoma microenvironment coordinately contributing to immunosuppression. Experimental design Archived, formalin-fixed paraffin-embedded melanoma specimens were assessed for PD-L1 protein expression at the tumor cell surface with immunohistochemistry (IHC). Whole genome expression analysis, quantitative (q)RT-PCR, immunohistochemistry, and functional in vitro validation studies were employed to assess factors differentially expressed in PD-L1+ versus PD-L1(−) melanomas. Results Functional annotation clustering based on whole genome expression profiling revealed pathways up-regulated in PD-L1+ melanomas, involving immune cell activation, inflammation, and antigen processing and presentation. Analysis by qRT-PCR demonstrated over-expression of functionally related genes in PD-L1+ melanomas, involved in CD8+ T cell activation (CD8A, IFNG, PRF1, CCL5), antigen presentation (CD163, TLR3, CXCL1, LYZ), and immunosuppression [PDCD1 (PD-1), CD274(PD-L1), LAG3, IL10]. Functional studies demonstrated that some factors, including IL-10 and IL-32-gamma, induced PD-L1 expression on monocytes but not tumor cells. Conclusions These studies elucidate the complexity of immune checkpoint regulation in the tumor microenvironment, identifying multiple factors likely contributing to coordinated immunosuppression. These factors may provide tumor escape mechanisms from anti-PD-1/PD-L1 therapy, and should be considered for co-targeting in combinatorial immunomodulation treatment strategies. PMID:25944800

Prognostic Role of Multiple Lymphatic Basin Drainage in Sentinel Lymph Node-Negative Trunk Melanoma Patients: A Multicenter Study from the Italian Melanoma Intergroup.

PubMed

Ribero, Simone; Osella-Abate, Simona; Pasquali, Sandro; Rossi, Carlo Riccardo; Borgognoni, Lorenzo; Piazzalunga, Dario; Solari, Nicola; Schiavon, Mauro; Brandani, Paola; Ansaloni, Luca; Ponte, Erica; Silan, Francesco; Sommariva, Antonio; Bellucci, Francesco; Macripò, Giuseppe; Quaglino, Pietro

2016-05-01

Multiple lymphatic basin drainage (MLBD) is frequently observed in patients with trunk melanoma undergoing sentinel lymph node (SLN) biopsy. Conflicting data regarding the prognostic association of MLBD in SLN-negative patients have been reported. This study aimed to investigate the prognostic role of MLBD in patients with negative SLN biopsy. Retrospective data from 656 melanoma patients who underwent a SLN biopsy (1991-2012) at six Italian centers were gathered in a multicenter database. MLBD was defined as lymphoscintigraphic and intraoperative identification of an SLN in more than one nodal basin. Clinical and pathologic variables were recorded and analyzed for their impact on survival. SLN-negative patients with MLBD were at lower risk of melanoma recurrence [hazard ratio (HR) 0.73, P = 0.05) and melanoma-related death (HR 0.68, P = 0.001) independent of common staging features. Multivariable Cox analyses of disease-free interval (DFI) and disease-specific survival (DSS) showed that MLBD maintained a favorable role and ulceration an unfavorable role. Histologic regression was independently associated only with DFI. When survival was stratified according to presence of MLBD, histologic regression and Breslow thickness <2 mm were associated with improved DFI (5-year DFI: 96.9 vs. 66,1 %, respectively; HR 0.48, P < 0.001) and DSS (5-year DSS: 96.7 vs. 71.8 %, respectively; HR 0.52, P = 0.005) compared to patients without these three favorable parameters. Patients with negative SLN biopsy results have better prognosis when two or more lymphatic basins are identified and analyzed. Further research is required to investigate the mechanisms behind this evidence.

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq

PubMed Central

Loeffler-Wirth, Henry; Hopp, Lydia; Schadendorf, Dirk; Schartl, Manfred; Anderegg, Ulf; Camp, Gray; Treutlein, Barbara; Binder, Hans; Kunz, Manfred

2017-01-01

Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy. PMID:27903987

The radial growth phase of malignant melanoma: multi-phase modelling, numerical simulations and linear stability analysis.

PubMed

Ciarletta, P; Foret, L; Ben Amar, M

2011-03-06

Cutaneous melanoma is disproportionately lethal despite its relatively low incidence and its potential for cure in the early stages. The aim of this study is to foster understanding of the role of microstructure on the occurrence of morphological changes in diseased skin during melanoma evolution. The authors propose a biomechanical analysis of its radial growth phase, investigating the role of intercellular/stromal connections on the initial stages of epidermis invasion. The radial growth phase of a primary melanoma is modelled within the multi-phase theory of mixtures, reproducing the mechanical behaviour of the skin layers and of the epidermal-dermal junction. The theoretical analysis takes into account those cellular processes that have been experimentally observed to disrupt homeostasis in normal epidermis. Numerical simulations demonstrate that the loss of adhesiveness of the melanoma cells both to the basal laminae, caused by deregulation mechanisms of adherent junctions, and to adjacent keratynocytes, consequent to a downregulation of E-cadherin, are the fundamental biomechanical features for promoting tumour initiation. Finally, the authors provide the mathematical proof of a long wavelength instability of the tumour front during the early stages of melanoma invasion. These results open the perspective to correlate the early morphology of a growing melanoma with the biomechanical characteristics of its micro-environment.

Anorectal melanoma: not a haemorrhoid.

PubMed

Turner, Greg; Abbott, Sarah; Eglinton, Tim; Wakeman, Chris; Frizelle, Frank

2014-06-06

Melanoma of the anorectum is a rare malignancy which is particularly aggressive compared to cutaneous melanoma. Due to its presenting symptoms, location and rarity there is often a delay in diagnosis. The purpose of this paper is to raise awareness of anorectal melanoma in New Zealand by presenting our institution's experience of four cases. The presentation, management and outcomes of four cases are described. A review of the literature surrounding anorectal melanoma was also carried out. The four cases (3 male, 1 female, aged 30-87 years) all presented with haemorrhoidal symptoms of anal discomfort and/or outlet rectal bleeding. Three patients had metastatic disease at presentation, and the remaining patient was found to have a concurrent lymphoma which was treated with chemotherapy before he underwent excision of the melanoma. Surgical excision is the mainstay of treatment and recent literature suggests transanal excision of the primary tumour to have equivalent overall survival to abdominoperineal resection. Anorectal melanoma is rare tumour with a poor prognosis. Patients are commonly misdiagnosed as having haemorrhoids; therefore a high index of suspicion is needed to enable early diagnosis. Metastatic disease is common at presentation, and the key prognostic indicator. Local control can be obtained with transanal excision, avoiding the morbidity of abdominoperineal resection. Adjuvant therapies available at present provide little survival advantage.

Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation.

PubMed

Bald, Tobias; Landsberg, Jennifer; Lopez-Ramos, Dorys; Renn, Marcel; Glodde, Nicole; Jansen, Philipp; Gaffal, Evelyn; Steitz, Julia; Tolba, Rene; Kalinke, Ulrich; Limmer, Andreas; Jönsson, Göran; Hölzel, Michael; Tüting, Thomas

2014-06-01

Infiltration of human melanomas with cytotoxic immune cells correlates with spontaneous type I IFN activation and a favorable prognosis. Therapeutic blockade of immune-inhibitory receptors in patients with preexisting lymphocytic infiltrates prolongs survival, but new complementary strategies are needed to activate cellular antitumor immunity in immune cell-poor melanomas. Here, we show that primary melanomas in Hgf-Cdk4(R24C) mice, which imitate human immune cell-poor melanomas with a poor outcome, escape IFN-induced immune surveillance and editing. Peritumoral injections of immunostimulatory RNA initiated a cytotoxic inflammatory response in the tumor microenvironment and significantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibody-mediated blockade of the IFN-induced immune-inhibitory interaction between PD-L1 and PD-1 receptors further prolonged the survival. These results highlight important interconnections between type I IFNs and immune-inhibitory receptors in melanoma pathogenesis, which serve as targets for combination immunotherapies. Using a genetically engineered mouse melanoma model, we demonstrate that targeted activation of the type I IFN system with immunostimulatory RNA in combination with blockade of immune-inhibitory receptors is a rational strategy to expose immune cell-poor tumors to cellular immune surveillance. ©2014 American Association for Cancer Research.

The radial growth phase of malignant melanoma: multi-phase modelling, numerical simulations and linear stability analysis

PubMed Central

Ciarletta, P.; Foret, L.; Ben Amar, M.

2011-01-01

Cutaneous melanoma is disproportionately lethal despite its relatively low incidence and its potential for cure in the early stages. The aim of this study is to foster understanding of the role of microstructure on the occurrence of morphological changes in diseased skin during melanoma evolution. The authors propose a biomechanical analysis of its radial growth phase, investigating the role of intercellular/stromal connections on the initial stages of epidermis invasion. The radial growth phase of a primary melanoma is modelled within the multi-phase theory of mixtures, reproducing the mechanical behaviour of the skin layers and of the epidermal–dermal junction. The theoretical analysis takes into account those cellular processes that have been experimentally observed to disrupt homeostasis in normal epidermis. Numerical simulations demonstrate that the loss of adhesiveness of the melanoma cells both to the basal laminae, caused by deregulation mechanisms of adherent junctions, and to adjacent keratynocytes, consequent to a downregulation of E-cadherin, are the fundamental biomechanical features for promoting tumour initiation. Finally, the authors provide the mathematical proof of a long wavelength instability of the tumour front during the early stages of melanoma invasion. These results open the perspective to correlate the early morphology of a growing melanoma with the biomechanical characteristics of its micro-environment. PMID:20656740

Cytomorphology of cervicovaginal melanoma: ThinPrep versus conventional Papanicolaou tests.

PubMed

Setia, Namrata; Goulart, Robert A; Leiman, Gladywn; Otis, Christopher N; Modem, Rukmini; Pantanowtiz, Liron

2010-12-31

Primary cervicovaginal melanoma is a rare malignancy associated with a high risk of recurrence. Prior studies discussing the cytomorphology of cervicovaginal melanoma have been based primarily on review of conventional Papanicolaou (Pap) smears. The aim of this study was to evaluate cervicovaginal melanomas identified in liquid-based Pap tests, in comparison with features seen on conventional Pap smear preparation. Cases of cervicovaginal melanoma identified on Pap tests with concurrent or subsequent histopathologic confirmation were collected from the Baystate Medical Center cytopathology files and personal archives of the authors over a total period of 34 years. All cytopathology (n = 6) and the available histology slides (n = 5) were reviewed. Cases were analyzed regarding clinical, histopathologic and cytomorphological findings. A total of six cases with invasive cervicovaginal melanoma diagnosed on Pap tests were identified. Most patients were postmenopausal with contact bleeding, correlating with surface ulceration (identified in biopsy/excision material in 5/5 cases). Most cases had deeply invasive tumors (5/5: modified Breslow's thickness > 5 mm and Chung's level of invasion IV/V). Pap tests included four ThinPrep and two conventional smears. Overall, ThinPrep Pap tests exhibited a higher ratio of tumor cells to background squamous cells. While all Pap tests were bloodstained, tumor diathesis was prominent only within conventional smears. Melanoma cells were present both as clusters and scattered single cells in each Pap test type. Both the preparations contained epithelioid tumor cells, whereas spindled tumor cells were seen in only two ThinPrep cases. Prominent nucleoli and binucleation of tumor cells were seen in both the preparations. Melanin pigment was identified in only ThinPrep (3/4) cases and nuclear pseudo-inclusions in one conventional Pap smear. Cell blocks were made in three ThinPrep cases and immunocytochemistry (S-100, HMB45, Melan-A) performed on additional vial material (one ThinPrep slide and one cell block) was immunoreactive in melanoma cells. Primary cervicovaginal melanoma, a rare malignancy seen predominantly in postmenopausal women, may be successfully diagnosed in either ThinPrep Pap tests or conventional Pap smears. While ThinPrep Pap tests did not demonstrate morphological advantage over conventional smears, liquid-based cytology specimens did provide additional material for cellblock preparation and immunocytochemical evaluation in a subset of cases.

Cytomorphology of cervicovaginal melanoma: ThinPrep versus conventional Papanicolaou tests

PubMed Central

Setia, Namrata; Goulart, Robert A; Leiman, Gladywn; Otis, Christopher N; Modem, Rukmini; Pantanowtiz, Liron

2010-01-01

Background: Primary cervicovaginal melanoma is a rare malignancy associated with a high risk of recurrence. Prior studies discussing the cytomorphology of cervicovaginal melanoma have been based primarily on review of conventional Papanicolaou (Pap) smears. The aim of this study was to evaluate cervicovaginal melanomas identified in liquid-based Pap tests, in comparison with features seen on conventional Pap smear preparation. Materials and Methods: Cases of cervicovaginal melanoma identified on Pap tests with concurrent or subsequent histopathologic confirmation were collected from the Baystate Medical Center cytopathology files and personal archives of the authors over a total period of 34 years. All cytopathology (n = 6) and the available histology slides (n = 5) were reviewed. Cases were analyzed regarding clinical, histopathologic and cytomorphological findings. Results: A total of six cases with invasive cervicovaginal melanoma diagnosed on Pap tests were identified. Most patients were postmenopausal with contact bleeding, correlating with surface ulceration (identified in biopsy/excision material in 5/5 cases). Most cases had deeply invasive tumors (5/5: modified Breslow's thickness > 5 mm and Chung's level of invasion IV/V). Pap tests included four ThinPrep and two conventional smears. Overall, ThinPrep Pap tests exhibited a higher ratio of tumor cells to background squamous cells. While all Pap tests were bloodstained, tumor diathesis was prominent only within conventional smears. Melanoma cells were present both as clusters and scattered single cells in each Pap test type. Both the preparations contained epithelioid tumor cells, whereas spindled tumor cells were seen in only two ThinPrep cases. Prominent nucleoli and binucleation of tumor cells were seen in both the preparations. Melanin pigment was identified in only ThinPrep (3/4) cases and nuclear pseudo-inclusions in one conventional Pap smear. Cell blocks were made in three ThinPrep cases and immunocytochemistry (S-100, HMB45, Melan-A) performed on additional vial material (one ThinPrep slide and one cell block) was immunoreactive in melanoma cells. Conclusion: Primary cervicovaginal melanoma, a rare malignancy seen predominantly in postmenopausal women, may be successfully diagnosed in either ThinPrep Pap tests or conventional Pap smears. While ThinPrep Pap tests did not demonstrate morphological advantage over conventional smears, liquid-based cytology specimens did provide additional material for cellblock preparation and immunocytochemical evaluation in a subset of cases. PMID:21298024

Pigmentary characteristics and moles in relation to melanoma risk.

PubMed

Titus-Ernstoff, Linda; Perry, Ann E; Spencer, Steven K; Gibson, Jennifer J; Cole, Bernard F; Ernstoff, Marc S

2005-08-10

Although benign and atypical moles are considered key melanoma risk factors, previous studies of their influence were small and/or institution-based. We conducted a population-based case-control study in the state of New Hampshire. Individuals of ages 20-69 with an incident diagnosis of first primary cutaneous melanoma were ascertained through the New Hampshire State Cancer Registry. Controls were identified through New Hampshire driver's license lists and frequency-matched by age and gender to cases. We interviewed 423 eligible cases and 678 eligible controls. Host characteristics, including mole counts, were evaluated using logistic regression analyses. Our results showed that pigmentary factors, including eye color (OR = 1.57 for blue eyes compared to brown), hair color (OR = 1.85 for blonde/red hair color compared to brown/black), freckles before age 15 (OR = 2.39 for freckles present compared to absent) and sun sensitivity (OR = 2.25 for peeling sunburn followed by no tan or a light tan and 2.42 for sunburn followed by tan compared to tanning immediately), were related to melanoma risk; these associations held after adjustment for sun-related factors and for moles. In analyses confined to skin examination participants, the covariate-adjusted effects of benign and atypical moles were moderately strong. Compared to 0-4 benign moles, risk increased steadily for 5-14 moles (OR = 1.71), 15-24 moles (OR = 3.55) and >or= 25 moles (OR = 4.33). Risk also increased with the number of atypical moles; compared to none, the ORs for having 1, 2-3, or >or= 4 atypical moles were 2.08, 1.84 and 3.80, respectively. Although risk was highest for those with multiple benign and atypical moles, the interaction was not of statistical significance. Our findings, arising from the first population- and incidence-based study to evaluate atypical moles in relation to melanoma risk, confirm the importance of host susceptibility, represented by pigmentary factors and the tendency to develop benign or atypical moles, in the etiology of this disease. (c) 2005 Wiley-Liss, Inc.

Local and systemic effect of transfection-reagent formulated DNA vectors on equine melanoma.

PubMed

Mählmann, Kathrin; Feige, Karsten; Juhls, Christiane; Endmann, Anne; Schuberth, Hans-Joachim; Oswald, Detlef; Hellige, Mareu; Doherr, Marcus; Cavalleri, Jessika-M V

2015-05-14

Equine melanoma has a high incidence in grey horses. Xenogenic DNA vaccination may represent a promising therapeutic approach against equine melanoma as it successfully induced an immunological response in other species suffering from melanoma and in healthy horses. In a clinical study, twenty-seven, grey, melanoma-bearing, horses were assigned to three groups (n = 9) and vaccinated on days 1, 22, and 78 with DNA vectors encoding for equine (eq) IL-12 and IL-18 alone or in combination with either human glycoprotein (hgp) 100 or human tyrosinase (htyr). Horses were vaccinated intramuscularly, and one selected melanoma was locally treated by intradermal peritumoral injection. Prior to each injection and on day 120, the sizes of up to nine melanoma lesions per horse were measured by caliper and ultrasound. Specific serum antibodies against hgp100 and htyr were measured using cell based flow-cytometric assays. An Analysis of Variance (ANOVA) for repeated measurements was performed to identify statistically significant influences on the relative tumor volume. For post-hoc testing a Tukey-Kramer Multiple-Comparison Test was performed to compare the relative volumes on the different examination days. An ANOVA for repeated measurements was performed to analyse changes in body temperature over time. A one-way ANOVA was used to evaluate differences in body temperature between the groups. A p-value < 0.05 was considered significant for all statistical tests applied. In all groups, the relative tumor volume decreased significantly to 79.1 ± 26.91% by day 120 (p < 0.0001, Tukey-Kramer Multiple-Comparison Test). Affiliation to treatment group, local treatment and examination modality had no significant influence on the results (ANOVA for repeated measurements). Neither a cellular nor a humoral immune response directed against htyr or hgp100 was detected. Horses had an increased body temperature on the day after vaccination. This is the first clinical report on a systemic effect against equine melanoma following treatment with DNA vectors encoding eqIL12 and eqIL18 and formulated with a transfection reagent. Addition of DNA vectors encoding hgp100 respectively htyr did not potentiate this effect.

Local and systemic effect of transfection-reagent formulated DNA vectors on equine melanoma.

PubMed

Mählmann, Kathrin; Feige, Karsten; Juhls, Christiane; Endmann, Anne; Schuberth, Hans-Joachim; Oswald, Detlef; Hellige, Maren; Doherr, Marcus; Cavalleri, Jessika-M V

2015-06-11

Equine melanoma has a high incidence in grey horses. Xenogenic DNA vaccination may represent a promising therapeutic approach against equine melanoma as it successfully induced an immunological response in other species suffering from melanoma and in healthy horses. In a clinical study, twenty-seven, grey, melanoma-bearing, horses were assigned to three groups (n = 9) and vaccinated on days 1, 22, and 78 with DNA vectors encoding for equine (eq) IL-12 and IL-18 alone or in combination with either human glycoprotein (hgp) 100 or human tyrosinase (htyr). Horses were vaccinated intramuscularly, and one selected melanoma was locally treated by intradermal peritumoral injection. Prior to each injection and on day 120, the sizes of up to nine melanoma lesions per horse were measured by caliper and ultrasound. Specific serum antibodies against hgp100 and htyr were measured using cell based flow-cytometric assays. An Analysis of Variance (ANOVA) for repeated measurements was performed to identify statistically significant influences on the relative tumor volume. For post-hoc testing a Tukey-Kramer Multiple-Comparison Test was performed to compare the relative volumes on the different examination days. An ANOVA for repeated measurements was performed to analyse changes in body temperature over time. A one-way ANOVA was used to evaluate differences in body temperature between the groups. A p-value < 0.05 was considered significant for all statistical tests applied. In all groups, the relative tumor volume decreased significantly to 79.1 ± 26.91% by day 120 (p < 0.0001, Tukey-Kramer Multiple-Comparison Test). Affiliation to treatment group, local treatment and examination modality had no significant influence on the results (ANOVA for repeated measurements). Neither a cellular nor a humoral immune response directed against htyr or hgp100 was detected. Horses had an increased body temperature on the day after vaccination. This is the first clinical report on a systemic effect against equine melanoma following treatment with DNA vectors encoding eqIL12 and eqIL18 and formulated with a transfection reagent. Addition of DNA vectors encoding hgp100 respectively htyr did not potentiate this effect.

Cholangiocarcinoma…Or Not?

PubMed Central

Kenny, Patrick; Kerns, Tamie

2013-01-01

Introduction Cholangiocarcinoma includes all tumors originating in the epithelium of the bile duct and is the ninth most common gastrointestinal tract cancer. Metastatic disease may also rarely be present in the common bile duct. We present a case of metastatic malignant melanoma presenting as obstructive hepatitis and initially was thought to be and was almost treated as cholangiocarcinoma prior to adequate tissue sampling. Case Report A 76-year-old man presented with nausea, vomiting, and painless jaundice. He had a mixed hepatocellular pattern with transaminases and alkaline phosphatase greater than 1000 and total bilirubin of 12. A three-phase liver CT showed an enhancing mass within a dilated common bile duct and extension of the mass into the right and left intrahepatic bile ducts. He subsequently underwent ERCP with bile duct brushings and stent placement. Bile duct brushings showed benign reactive ductal epithelial cells. An endoscopic ultrasound with fine needle aspiration of the bile duct mass was performed. Pathology was negative for CK7, CK20, and positive for S100, Pan-melanoma, and negative for BRAF. No suspicious skin lesions were seen on close inspection by a dermatologist. However, two years prior the patient was diagnosed with cutaneous malignant melanoma in situ that was surgically resected. Thus, it was felt that this case represented metastatic melanoma to the bile duct. Due to significant comorbidities the patient was determined to be a poor surgical candidate. He has completed first line therapy for unresectable multiple melanoma with four rounds of ipilimumab. Discussion Pathologic diagnosis of cholangiocarcinoma is often difficult to obtain from ERCP secondary to paucicellularity of these tumors and with no imaging modality that is specific for cholangiocarcinma. The hepatobiliary tract is a possible, though relatively rare, location for metastatic focus of malignant melanoma and should be considered in a patient with a history of melanoma and no tissue diagnosis after ERCP. There are multiple case reports of metastatic melanoma to the ampula of Vater causing obstructive hepatitis, but only 10 reports of disease found in the common bile duct. This case highlights the importance of obtaining tissue from suspected malignant lesions using various forms of endoscopy to ensure proper treatment and prolonged survival.

Emerging insights into resistance to BRAF inhibitors in melanoma.

PubMed

Bucheit, Amanda D; Davies, Michael A

2014-02-01

Melanoma is the most aggressive form of skin cancer. The treatment of patients with advanced melanoma is rapidly evolving due to an improved understanding of molecular drivers of this disease. Somatic mutations in BRAF are the most common genetic alteration found in these tumors. Recently, two different mutant-selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, have gained regulatory approval based on positive results in randomized phase III trials. While the development of these agents represents a landmark in the treatment of melanoma, the benefit of these agents is limited by the frequent and rapid onset of resistance. The identification of several molecular mechanisms of resistance to BRAF inhibitors is rapidly leading to the clinical testing of combinatorial strategies to improve the clinical benefit of these agents. These mechanisms, and the lessons learned from the initial testing of the BRAF inhibitors, provide multiple insights that may facilitate the development of targeted therapies against other oncogenic mutations in melanoma, as well as in other cancers. Copyright © 2013 Elsevier Inc. All rights reserved.

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

PubMed Central

Kong, Xiangju; Hong, Aayoung; Koya, Richard C.; Moriceau, Gatien; Chodon, Thinle; Guo, Rongqing; Johnson, Douglas B.; Dahlman, Kimberly B.; Kelley, Mark C.; Kefford, Richard F.; Chmielowski, Bartosz; Glaspy, John A.; Sosman, Jeffrey A.; van Baren, Nicolas; Long, Georgina V.; Ribas, Antoni; Lo, Roger S.

2013-01-01

BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses. PMID:24265155

Epidemiologic evidence for different roles of ultraviolet A and B radiation in melanoma mortality rates.

PubMed

Garland, Cedric F; Garland, Frank C; Gorham, Edward D

2003-07-01

The action spectrum of ultraviolet radiation mainly responsible for melanoma induction is unknown, but evidence suggests it could be ultraviolet A (UVA), which has a different geographic distribution than ultraviolet B (UVB). This study assessed whether melanoma mortality rates are more closely related to the global distribution of UVA or UVB. UVA and UVB radiation and age-adjusted melanoma mortality rates were obtained for all 45 countries reporting cancer data to the World Health Organization. Stratospheric ozone data were obtained from NASA satellites. Average population skin pigmentation was obtained from skin reflectometry measurements. Paradoxically, melanoma mortality rates decreased with increasing UVB in men (r = -0.48, p < 0.001), and women (r = -0.57, p < 0.001), and with increasing UVA in both sexes. By contrast, rates were positively associated with increasing UVA/UVB ratio in men (r = + 0.49, p < 0.001) and women (r = + 0.55, p < 0.001). After multiple adjustment that included controlling for skin pigmentation, only UVA was associated with melanoma mortality rates in men (p < 0.02) with a suggestive but non-significant trend present in women (p = 0.12). UVA radiation was associated with melanoma mortality rates after controlling for UVB and average pigmentation. The results require confirmation in observational studies.

Regulation of hematogenous tumor metastasis by acid sphingomyelinase

PubMed Central

Carpinteiro, Alexander; Becker, Katrin Anne; Japtok, Lukasz; Hessler, Gabriele; Keitsch, Simone; Požgajovà, Miroslava; Schmid, Kurt W; Adams, Constantin; Müller, Stefan; Kleuser, Burkhard; Edwards, Michael J; Grassmé, Heike; Helfrich, Iris; Gulbins, Erich

2015-01-01

Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1−/− mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. PMID:25851537

Improving Primary Care Residents' Proficiency in the Diagnosis of Skin Cancer

PubMed Central

Gerbert, Barbara; Bronstone, Amy; Wolff, Mimi; Maurer, Toby; Berger, Timothy; Pantilat, Steven; McPhee, Stephen J

1998-01-01

OBJECTIVE To determine whether a brief, multicomponent intervention could improve the skin cancer diagnosis and evaluation planning performance of primary care residents to a level equivalent to that of dermatologists. PARTICIPANTS Fifty-two primary care residents (26 in the control group and 26 in the intervention group) and 13 dermatologists completed a pretest and posttest. DESIGN A randomized, controlled trial with pretest and posttest measurements of residents' ability to diagnose and make evaluation plans for lesions indicative of skin cancer. INTERVENTION The intervention included face-to-face feedback sessions focusing on residents' performance deficiencies; an interactive seminar including slide presentations, case examples, and live demonstrations; and the Melanoma Prevention Kit including a booklet, magnifying tool, measuring tool, and skin color guide. MEASUREMENTS AND MAIN RESULTS We compared the abilities of a control and an intervention group of primary care residents, and a group of dermatologists to diagnose and make evaluation plans for six categories of skin lesions including three types of skin cancer—malignant melanoma, squamous cell carcinoma, and basal cell carcinoma. At posttest, both the intervention and control group demonstrated improved performance, with the intervention group revealing significantly larger gains. The intervention group showed greater improvement than the control group across all six diagnostic categories (a gain of 13 percentage points vs 5, p < .05), and in evaluation planning for malignant melanoma (a gain of 46 percentage points vs 36, p < .05) and squamous cell carcinoma (a gain of 42 percentage points vs 21, p < .01). The intervention group performed as well as the dermatologists on five of the six skin cancer diagnosis and evaluation planning scores with the exception of the diagnosis of basal cell carcinoma. CONCLUSIONS Primary care residents can diagnose and make evaluation plans for cancerous skin lesions, including malignant melanoma, at a level equivalent to that of dermatologists if they receive relevant, targeted education. PMID:9502368

Causes of infertility as predictors of subsequent cancer risk.

PubMed

Brinton, Louise A; Westhoff, Carolyn L; Scoccia, Bert; Lamb, Emmet J; Althuis, Michelle D; Mabie, Jerome E; Moghissi, Kamran S

2005-07-01

Although studies have found elevated risks of certain cancers linked to infertility, the underlying reasons remain unclear. In a retrospective cohort study of 12,193 U.S. women evaluated for infertility between 1965 and 1988, 581 cases of cancer were identified through 1999. We used standardized incidence ratios (SIRs) to compare cancer risk with the general population. Analyses within the cohort estimated rate ratios (RRs) associated with infertility after adjusting for other risk predictors. Infertility patients demonstrated a higher cancer risk than the general population (SIR = 1.23; 95% confidence interval [CI] = 1.1-1.3), with nulligravid (primary infertility) patients at even higher risk (1.43; 1.3-1.6). Particularly elevated risks among primary infertility patients were observed for cancers of the uterus (1.93) and ovaries (2.73). Analyses within the cohort revealed increased RRs of colon, ovarian, and thyroid cancers, and of melanomas associated with endometriosis. Melanomas were linked with anovulatory problems, whereas uterine cancers predominated among patients with tubal disorders. When primary infertility patients with specific causes of infertility were compared with unaffected patients who had secondary infertility, endometriosis was linked with distinctive excesses of cancers of the colon (RR = 2.40; 95% CI = 0.7-8.4), ovaries (2.88; 1.2-7.1), and thyroid (4.65; 0.8-25.6) cancers, as well as melanomas (2.32; 0.8-6.7). Primary infertility due to anovulation particularly predisposed to uterine cancer (2.42; 1.0-5.8), and tubal disorders to ovarian cancer (1.61; 0.7-3.8). Primary infertility associated with male-factor problems was associated with unexpected increases in colon (2.85; 0.9-9.5) and uterine (3.15; 1.0-9.5) cancers. The effects of infertility may extend beyond gynecologic cancers. Thyroid cancers and melanomas deserve specific attention, particularly with respect to endometriosis.

Congenital nevi versus metastatic melanoma in a newborn to a mother with malignant melanoma - diagnosis supported by sex chromosome analysis and Imaging Mass Spectrometry.

PubMed

Alomari, Ahmed K; Glusac, Earl J; Choi, Jennifer; Hui, Pei; Seeley, Erin H; Caprioli, Richard M; Watsky, Kalman L; Urban, Jennifer; Lazova, Rossitza

2015-10-01

A 37-year-old pregnant woman presented with a 2-cm irregular reddish nodule on her left upper arm during pregnancy. A biopsy from the lesion showed a 2.2-mm thick malignant melanoma with intravascular invasion, 25 mitosis/mm(2) and no ulceration. Following induction of labor, the patient underwent re-excision with sentinel lymph node biopsy. This showed no residual melanoma and no lymph node metastasis. The newborn boy had multiple pigmented lesions on the trunk, some of which were large and irregular. Two were biopsied and histologic examination showed dense dermal proliferation of medium sized melanocytes with multiple mitotic figures and no maturation with their descent into the dermis, raising suspicion of transplacental metastases. Examination of the placenta failed to show metastatic lesions. Multiplex polymerase chain reaction (PCR)-based genotyping, including testing for amelogenin locus for sex chromosome determination, demonstrated the presence of Y chromosome material in the melanocytes of the newborn's lesions excluding maternal origin. A diagnosis of congenital nevi was rendered. Subsequently, Imaging Mass Spectrometric analysis of the mother's lesion showed proteomic signature expression indicative of malignant melanoma, whereas the two lesions in the newborn showed changes indicative of nevi. This case demonstrates the utility of genotyping and Mass Spectrometry analysis in this challenging clinical scenario. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sunny holidays before and after melanoma diagnosis are respectively associated with lower Breslow thickness and lower relapse rates in Italy.

PubMed

Gandini, Sara; De Vries, Esther; Tosti, Giulio; Botteri, Edoardo; Spadola, Giuseppe; Maisonneuve, Patrick; Martinoli, Chiara; Joosse, Arjen; Ferrucci, Pier Francesco; Baldini, Federica; Cocorocchio, Emilia; Pennacchioli, Elisabetta; Cataldo, Francesco; Bazolli, Barbara; Clerici, Alessandra; Barberis, Massimo; Bataille, Veronique; Testori, Alessandro

2013-01-01

Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.

Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

PubMed Central

Gandini, Sara; De Vries, Esther; Tosti, Giulio; Botteri, Edoardo; Spadola, Giuseppe; Maisonneuve, Patrick; Martinoli, Chiara; Joosse, Arjen; Ferrucci, Pier Francesco; Baldini, Federica; Cocorocchio, Emilia; Pennacchioli, Elisabetta; Cataldo, Francesco; Bazolli, Barbara; Clerici, Alessandra; Barberis, Massimo

2013-01-01

Background Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. Methods A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Results Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results. PMID:24223851

Proton beam radiotherapy of uveal melanoma

PubMed Central

Damato, Bertil; Kacperek, Andrzej; Errington, Doug; Heimann, Heinrich

2013-01-01

Proton beam radiotherapy of uveal melanoma can be administered as primary treatment, as salvage therapy for recurrent tumor, and as neoadjuvant therapy prior to surgical resection. The physical properties of proton beams make it possible to deliver high-doses of radiation to the tumor with relative sparing of adjacent tissues. This form of therapy is effective for a wider range of uveal melanoma than any other modality, providing exceptionally-high rates of local tumor control. This is particularly the case with diffuse iris melanomas, many of which are unresectable. The chances of survival, ocular conservation, visual preservation and avoidance of iatrogenic morbidity depend greatly on the tumor size, location and extent. When treating any side-effects and/or complications, it is helpful to consider whether these are the result of collateral damage or persistence of the irradiated tumor (‘toxic tumor syndrome’). PMID:24227980

[Recurrence rate following adjuvant strontium-90 brachytherapy after excision of conjunctival melanoma].

PubMed

Krause, L; Ritter, C; Wachtlin, J; Kreusel, K-M; Höcht, S; Foerster, M H; Bechrakis, N E

2008-07-01

Because of the high local recurrence rates after excision of conjunctival melanomas, adjuvant local chemotherapy or irradiation is recommended. Strontium-90 brachytherapy is one radiotherapeutic option due to its low penetration depth. 15 patients with conjunctival melanoma were treated with adjuvant strontium-90 brachytherapy after tumour excision. The treatment was fractionated into 9 irradiation sessions with 6 Gy each. The mean follow-up was 35 months (12-60 months). Seven patients (46%) had no recurrence during the follow-up. Three patients (20%) had a recurrence in the treated or adjacent area. Eight patients (53%) developed new tumours in non-treated areas. Strontium-90 brachytherapy is a useful adjuvant in the treatment of conjunctival melanomas. Regular ophthalmoscopic controls are necessary because of the high rate of new tumours in non-irradiated areas, especially in cases with primary acquired melanosis.

Quantitative comparison of the spreading and invasion of radial growth phase and metastatic melanoma cells in a three-dimensional human skin equivalent model.

PubMed

Haridas, Parvathi; McGovern, Jacqui A; McElwain, Sean D L; Simpson, Matthew J

2017-01-01

Standard two-dimensional (2D) cell migration assays do not provide information about vertical invasion processes, which are critical for melanoma progression. We provide information about three-dimensional (3D) melanoma cell migration, proliferation and invasion in a 3D melanoma skin equivalent (MSE) model. In particular, we pay careful attention to compare the structure of the tissues in the MSE with similarly-prepared 3D human skin equivalent (HSE) models. The HSE model is identically prepared to the MSE model except that melanoma cells are omitted. Using the MSE model, we examine melanoma migration, proliferation and invasion from two different human melanoma cell lines. One cell line, WM35, is associated with the early phase of the disease where spreading is thought to be confined to the epidermis. The other cell line, SK-MEL-28, is associated with the later phase of the disease where spreading into the dermis is expected. 3D MSE and HSE models are constructed using human de-epidermised dermis (DED) prepared from skin tissue. Primary fibroblasts and primary keratinocytes are used in the MSE and HSE models to ensure the formation of a stratified epidermis, with a well-defined basement membrane. Radial spreading of cells across the surface of the HSE and MSE models is observed. Vertical invasion of melanoma cells downward through the skin is observed and measured using immunohistochemistry. All measurements of invasion are made at day 0, 9, 15 and 20, providing detailed time course data. Both HSE and MSE models are similar to native skin in vivo , with a well-defined stratification of the epidermis that is separated from the dermis by a basement membrane. In the HSE and MSE we find fibroblast cells confined to the dermis, and differentiated keratinocytes in the epidermis. In the MSE, melanoma cells form colonies in the epidermis during the early part of the experiment. In the later stage of the experiment, the melanoma cells in the MSE invade deeper into the tissues. Interestingly, both the WM35 and SK-MEL-28 melanoma cells lead to a breakdown of the basement membrane and eventually enter the dermis. However, these two cell lines invade at different rates, with the SK-MEL-28 melanoma cells invading faster than the WM35 cells. The MSE and HSE models are a reliable platform for studying melanoma invasion in a 3D tissue that is similar to native human skin. Interestingly, we find that the WM35 cell line, that is thought to be associated with radial spreading only, is able to invade into the dermis. The vertical invasion of melanoma cells into the dermal region appears to be associated with a localised disruption of the basement membrane. Presenting our results in terms of time course data, along with images and quantitative measurements of the depth of invasion extends previous 3D work that has often been reported without these details.

Quantitative comparison of the spreading and invasion of radial growth phase and metastatic melanoma cells in a three-dimensional human skin equivalent model

PubMed Central

Haridas, Parvathi; McGovern, Jacqui A.; McElwain, Sean D.L.

2017-01-01

Background Standard two-dimensional (2D) cell migration assays do not provide information about vertical invasion processes, which are critical for melanoma progression. We provide information about three-dimensional (3D) melanoma cell migration, proliferation and invasion in a 3D melanoma skin equivalent (MSE) model. In particular, we pay careful attention to compare the structure of the tissues in the MSE with similarly-prepared 3D human skin equivalent (HSE) models. The HSE model is identically prepared to the MSE model except that melanoma cells are omitted. Using the MSE model, we examine melanoma migration, proliferation and invasion from two different human melanoma cell lines. One cell line, WM35, is associated with the early phase of the disease where spreading is thought to be confined to the epidermis. The other cell line, SK-MEL-28, is associated with the later phase of the disease where spreading into the dermis is expected. Methods 3D MSE and HSE models are constructed using human de-epidermised dermis (DED) prepared from skin tissue. Primary fibroblasts and primary keratinocytes are used in the MSE and HSE models to ensure the formation of a stratified epidermis, with a well-defined basement membrane. Radial spreading of cells across the surface of the HSE and MSE models is observed. Vertical invasion of melanoma cells downward through the skin is observed and measured using immunohistochemistry. All measurements of invasion are made at day 0, 9, 15 and 20, providing detailed time course data. Results Both HSE and MSE models are similar to native skin in vivo, with a well-defined stratification of the epidermis that is separated from the dermis by a basement membrane. In the HSE and MSE we find fibroblast cells confined to the dermis, and differentiated keratinocytes in the epidermis. In the MSE, melanoma cells form colonies in the epidermis during the early part of the experiment. In the later stage of the experiment, the melanoma cells in the MSE invade deeper into the tissues. Interestingly, both the WM35 and SK-MEL-28 melanoma cells lead to a breakdown of the basement membrane and eventually enter the dermis. However, these two cell lines invade at different rates, with the SK-MEL-28 melanoma cells invading faster than the WM35 cells. Discussion The MSE and HSE models are a reliable platform for studying melanoma invasion in a 3D tissue that is similar to native human skin. Interestingly, we find that the WM35 cell line, that is thought to be associated with radial spreading only, is able to invade into the dermis. The vertical invasion of melanoma cells into the dermal region appears to be associated with a localised disruption of the basement membrane. Presenting our results in terms of time course data, along with images and quantitative measurements of the depth of invasion extends previous 3D work that has often been reported without these details. PMID:28890854

Lifetime prevalence of non-melanoma and melanoma skin cancer in Australian recreational and competitive surfers.

PubMed

Climstein, Mike; Furness, James; Hing, Wayne; Walsh, Joe

2016-07-01

Surfing is one of the most popular outdoor aquatic activities in Australia with an estimated 2.7 million recreational surfers; however, Australia has long been recognized as having the highest incidence of melanoma in the world, and it is the most common type of cancer in young Australians. The aim of this study was to investigate the lifetime prevalence of non-melanoma [basal cell carcinoma (BCC), squamous cell carcinoma (SCC)] and melanoma skin cancers in Australian recreational and competitive surfers. Australian surfers were invited to complete an online surveillance survey to determine the lifetime prevalence of non-melanoma and melanoma skin cancers. A total of 1348 surfers (56.9% recreational) participated in this study, of which 184 surfers reported a skin cancer (competitive n = 96, recreational n = 87). Of non-melanoma and melanoma cancers reported, BCC was the most common (6.8%), followed by melanoma (1.4%) and SCC (0.6%). The relative risk was higher (P < 0.001) in competitive vs. recreational surfers [OR 1.74 (CI 1.28-2.31)]. There was a higher (P < 0.05) number of skin cancers reported on the face (23.5%), back (16.4%) and arms (12.4%). There were significant trends (P < 0.001) in reported skin cancers between competitive and recreational surfers, as well as significantly (P < 0.001) more skin cancers reported in males (14.6%) than females (9.4%). Based upon these findings, individuals who surf are advised to regularly utilize sun protection strategies (avoid peak ultraviolet radiation (10 am-3 pm), rashvest, hat and sunscreen) and primary care physicians are recommended to regularly screen their patients who surf. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Can Melan-A replace S-100 and HMB-45 in the evaluation of sentinel lymph nodes from patients with malignant melanoma?

PubMed

Kucher, Cynthia; Zhang, Paul J; Acs, Geza; Roberts, Shelley; Xu, Xiaowei

2006-09-01

The sentinel lymph node (SLN) biopsy has become an increasingly important procedure used in the primary staging of malignant melanoma. However, micrometastases in a lymph node can be easily missed on routine H&E-stained sections. Therefore, S-100 and HMB-45 IHC stains are standardly performed on grossly negative SLNs for detection of metastatic melanoma. Each of these IHC markers, however, is not ideal. The authors investigated whether the newer IHC marker Melan-A would improve the detection of metastatic melanoma in SLN biopsies. Forty lymph nodes previously diagnosed with metastatic melanoma were retrospectively evaluated for S-100, HMB-45, and Melan-A expression. In addition, 42 SLN biopsies for metastatic melanoma detection were prospectively collected and evaluated for S-100, HMB-45, and Melan-A expression. All lymph nodes with metastatic melanoma from the retrospective study demonstrated S-100 reactivity. Five of the lymph nodes with metastatic melanoma from the retrospective study failed to express either HMB-45 or Melan-A, all of which displayed a desmoplastic morphology. One of the metastases positive for S-100 and HMB-45 failed to show reactivity with Melan-A (3%). The prospective study found 10 lymph nodes from 42 cases to be positive for metastatic melanoma, which were positive for S-100 (100%). Nine of the involved lymph nodes were positive for HMB-45(90%), and nine were positive for Melan-A (90%). Melan-A, although very specific, cannot replace the use of S-100 and HMB-45 for the detection of metastatic melanoma in SLNs. It can, however, substitute for HMB-45 with equally good results.

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

PubMed Central

Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

2014-01-01

The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up- regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16 days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMPK-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity. PMID:25016296

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma.

PubMed

Syed, Deeba N; Lall, Rahul K; Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

2014-12-01

The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

Whole Body Melanoma Transcriptome Response in Medaka

PubMed Central

Schartl, Manfred; Shen, Yingjia; Maurus, Katja; Walter, Ron; Tomlinson, Chad; Wilson, Richard K.; Postlethwait, John; Warren, Wesley C.

2015-01-01

The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model. PMID:26714172

Whole Body Melanoma Transcriptome Response in Medaka.

PubMed

Schartl, Manfred; Shen, Yingjia; Maurus, Katja; Walter, Ron; Tomlinson, Chad; Wilson, Richard K; Postlethwait, John; Warren, Wesley C

2015-01-01

The incidence of malignant melanoma continues to increase each year with poor prognosis for survival in many relapse cases. To reverse this trend, whole body response measures are needed to discover collaborative paths to primary and secondary malignancy. Several species of fish provide excellent melanoma models because fish and human melanocytes both appear in the epidermis, and fish and human pigment cell tumors share conserved gene expression signatures. For the first time, we have examined the whole body transcriptome response to invasive melanoma as a prelude to using transcriptome profiling to screen for drugs in a medaka (Oryzias latipes) model. We generated RNA-seq data from whole body RNA isolates for controls and melanoma fish. After testing for differential expression, 396 genes had significantly different expression (adjusted p-value <0.02) in the whole body transcriptome between melanoma and control fish; 379 of these genes were matched to human orthologs with 233 having annotated human gene symbols and 14 matched genes that contain putative deleterious variants in human melanoma at varying levels of recurrence. A detailed canonical pathway evaluation for significant enrichment showed the top scoring pathway to be antigen presentation but also included the expected melanocyte development and pigmentation signaling pathway. Results revealed a profound down-regulation of genes involved in the immune response, especially the innate immune system. We hypothesize that the developing melanoma actively suppresses the immune system responses of the body in reacting to the invasive malignancy, and that this mal-adaptive response contributes to disease progression, a result that suggests our whole-body transcriptomic approach merits further use. In these findings, we also observed novel genes not yet identified in human melanoma expression studies and uncovered known and new candidate drug targets for further testing in this malignant melanoma medaka model.

Relationship of cutaneous malignant melanoma to individual sunlight-exposure habits.

PubMed

Holman, C D; Armstrong, B K; Heenan, P J

1986-03-01

The relationships of different histologic types of cutaneous malignant melanoma to occupational and recreational sunlight exposure, habits of clothing, sunburn histories, and use of sunscreening agents were examined in a case-control study of 507 patients and 507 matched controls in Western Australia. Variations in relationships according to the primary site of melanoma were also examined. An increased incidence rate of superficial spreading melanoma was associated with low total outdoor exposure in early adulthood and frequent participation in boating and fishing. Superficial spreading melanoma of the trunk was also related to frequency of sunbathing at ages 15-24 years and of exposure of the trunk while working outdoors. In women the rate ratio for all types of melanoma occurring on the trunk was estimated at 13.0 (95% confidence interval, 2.0-83.9) in those who wore a bikini or bathed nude at ages 15-24 years compared with those wearing a conservative one-piece bathing suit. There was little evidence that sunbathing or wearing a bikini within 10 years of case diagnosis were risk factors for melanoma of the trunk. After control of confounding due to constitutional factors, only Hutchinson's melanotic freckle melanoma showed a relationship to severe sunburn. For nodular melanoma, sunburn appeared to be protective. Although many of the results supported the hypothesis that melanomas other than the Hutchinson's melanotic freckle type are related to occasional bursts of recreational sun exposure during a susceptible period in early adult life, little support for the hypothesis was obtained when recreational sun exposure was expressed as a proportion of total outdoor exposure, which had been considered a priori to be an index of intermittent sunlight exposure.

Regulation of cell cycle checkpoint kinase WEE1 by miR-195 in malignant melanoma.

PubMed

Bhattacharya, A; Schmitz, U; Wolkenhauer, O; Schönherr, M; Raatz, Y; Kunz, M

2013-06-27

WEE1 kinase has been described as a major gate keeper at the G2 cell cycle checkpoint and to be involved in tumour progression in different malignant tumours. Here we analysed the expression levels of WEE1 in a series of melanoma patient samples and melanoma cell lines using immunoblotting, quantitative real-time PCR and immunohistochemistry. WEE1 expression was significantly downregulated in patient samples of metastatic origin as compared with primary melanomas and in melanoma cell lines of high aggressiveness as compared with cell lines of low aggressiveness. Moreover, there was an inverse correlation between the expression of WEE1 and WEE1-targeting microRNA miR-195. Further analyses showed that transfection of melanoma cell lines with miR-195 indeed reduced WEE1 mRNA and protein expression in these cells. Reporter gene analysis confirmed direct targeting of the WEE1 3' untranslated region (3'UTR) by miR-195. Overexpression of miR-195 in SK-Mel-28 melanoma cells was accompanied by WEE1 reduction and significantly reduced stress-induced G2-M cell cycle arrest, which could be restored by stable overexpression of WEE1. Moreover, miR-195 overexpression and WEE1 knockdown, respectively, increased melanoma cell proliferation. miR-195 overexpression also enhanced migration and invasiveness of melanoma cells. Taken together, the present study shows that WEE1 expression in malignant melanoma is directly regulated by miR-195. miR-195-mediated downregulation of WEE1 in metastatic lesions may help to overcome cell cycle arrest under stress conditions in the local tissue microenvironment to allow unrestricted growth of tumour cells.

Chemotherapy-induced bystander effect in response to several chloroethylnitrosoureas: an origin independent of DNA damage?

PubMed

Merle, Patrick; Morvan, Daniel; Caillaud, Denis; Demidem, Aicha

2008-01-01

Chloroethylnitrosourea (CENU) chemotherapy is used for the treatment of melanoma tumors. The main mechanism of action of this anticancer agent is via DNA damage. We recently showed in murine experiments using a parental double B16 melanoma tumor model that, after treatment of primary tumors with cystemustine (CENU agent), untreated secondary tumors exhibited growth inhibition and metabolism disorders. The response of secondary untreated tumor was called the chemotherapy-induced bystander effect. To see whether chemotherapy-induced bystander effects were induced with other members of the CENU family, we compared three CENU(s) used in melanoma treatment: cystemustine, carmustine and fotemustine. Our results demonstrate that fotemustine, like cystemustine, but not carmustine induced a protective effect against secondary untreated tumors including alterations in phospholipid derivative and glutathione which are the metabolic signature of the bystander effect. From these data we may conclude that DNA damage to the primary tumor is not sufficient to explain chemotherapy-induced bystander effects.

Expression and structural features of endoglin (CD105), a transforming growth factor beta1 and beta3 binding protein, in human melanoma.

PubMed Central

Altomonte, M.; Montagner, R.; Fonsatti, E.; Colizzi, F.; Cattarossi, I.; Brasoveanu, L. I.; Nicotra, M. R.; Cattelan, A.; Natali, P. G.; Maio, M.

1996-01-01

Human endoglin (CD105) is a member of the transforming growth factor beta (TGF-beta) receptor family that binds TGF-beta1 and -beta3, but not TGF-beta2, on human endothelial cells. Immunohistochemical analyses demonstrated that CD105 is expressed on normal and neoplastic cells of the melanocytic lineage. The anti-CD105 MAb, MAEND3, stained 50, 25 and 34% of intradermal naevi, primary and metastatic melanomas investigated, respectively, and nine out of 12 melanoma cell lines. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed that CD105 expressed by melanoma cells consists of a homodimeric protein with an apparent molecular weight of 180 and 95 kDa under non-reducing and reducing conditions. Cross-linking of 125I-labelled TGF-beta1 to melanoma cells, Mel 97, by disuccinimidyl suberate (DSS) demonstrated that CD105 expressed on pigmented cells binds TGF-beta1; the pattern of binding of TGF-beta1 to melanoma cells was found to be similar to that of human umbilical vein endothelial cells. The addition of exogenous, bioactive TGF-beta1 significantly (P<0.05) inhibited the growth of CD105-positive melanoma cells, Mel 97, but did not affect that of CD105-negative melanoma cells, F0-1. These data, altogether, demonstrate that CD105 is expressed on pigmented cells and might play a functionally relevant role in the biology of human melanoma cells by regulating their sensitivity to TGF-betas. Images Figure 1 Figure 3 Figure 4 PMID:8932339

What's new in skin cancer? An analysis of guidelines and systematic reviews published in 2008-2009.

PubMed

Macbeth, A E; Grindlay, D J C; Williams, H C

2011-07-01

This review summarizes clinically important findings from 17 systematic reviews and 2 guidelines on skin cancer indexed between April 2008 and April 2009. Melanoma primary-prevention measures, such as education, are more likely to be successful in younger children than adolescents, and general population screening for melanoma by whole-body examination is not currently supported by the evidence. A large systematic review of melanoma and pregnancy concluded that pregnancy does not affect prognosis. Two systematic reviews imply that sunburn later in life also increases the risk of melanoma, and that it is just as important as sunburn early in life. Three systematic reviews discussed the role of positron emission tomography and sentinel lymph-node biopsy for melanoma staging, but produced conflicting results. Superior diagnostic accuracy of dermatoscopy over naked-eye examination for melanoma was found in one review, while a second implied nonsignificantly higher sensitivity of computer-based diagnostic methods over dermatoscopy for melanoma but with reduced specificity. There were no identified randomized controlled trials of treatments for unresectable recurrent melanoma, and a review of immunotherapy with vaccines for melanoma failed to prove improved overall and disease-free survival. Guidelines for the management of basal cell carcinoma call for risk stratification, based on numerous factors including tumour size, site and histological subtype. Squamous cell carcinoma of the ear has been shown to spread to regional lymph nodes more commonly than to other sites, and may be predicted by depth of invasion, tumour size, cellular differentiation and completeness of excision. © The Author(s). CED © 2011 British Association of Dermatologists.

Melanoma Cells Can Adopt the Phenotype of Stromal Fibroblasts and Macrophages by Spontaneous Cell Fusion in Vitro.

PubMed

Kemény, Lajos V; Kurgyis, Zsuzsanna; Buknicz, Tünde; Groma, Gergely; Jakab, Ádám; Zänker, Kurt; Dittmar, Thomas; Kemény, Lajos; Németh, István B

2016-06-02

After the removal of primary cutaneous melanoma some patients develop local recurrences, even after having histologically tumor-free re-excision. A potential explanation behind this phenomenon is that tumor cells switch their phenotype, making their recognition via standard histopathological assessments extremely difficult. Tumor-stromal cell fusion has been proposed as a potential mechanism for tumor cells to acquire mesenchymal traits; therefore, we hypothesized that melanoma cells could acquire fibroblast- and macrophage-like phenotypes via cell fusion. We show that melanoma cells spontaneously fuse with human dermal fibroblasts and human peripheral blood monocytes in vitro. The hybrid cells' nuclei contain chromosomes from both parental cells and are indistinguishable from the parental fibroblasts or macrophages based on their morphology and immunophenotype, as they could lose the melanoma specific MART1 marker, but express the fibroblast marker smooth muscle actin or the macrophage marker CD68. Our results suggest that, by spontaneous cell fusion in vitro, tumor cells can adopt the morphology and immunophenotype of stromal cells while still carrying oncogenic, tumor-derived genetic information. Therefore, melanoma-stromal cell fusion might play a role in missing tumor cells by routine histopathological assessments.

Loco-Regional Control With Complete Resection and Tongue Reconstruction on the Malignant Melanoma in the Tongue.

PubMed

Alkaff, Tuqa; Jeong, Woo Shik; Nam, Soon Yuhl; Choi, Jong Woo

2017-07-01

Primary malignant melanoma in the tongue is very uncommon disease that is considered low in comparison to cutaneous melanoma. In this report, the authors described a case of the hemitongue reconstruction with fasciocutaneous free flap on the patient who suffered from the malignant melanoma primarily originating from the base of the tongue that was treated with surgery and radiotherapy but developed a lung metastasis. A 76-year-old man was referred to the otorhinolaryngology clinic after complaining of a painful mass present for 3 months on the right side of the tongue. A punch biopsy was revealed atypical cells with pigmentation that is consistent with malignant melanoma. After wide excision and bilateral neck dissection performed, hemipartial tongue reconstruction was done using a radial forearm free flap. The patient had an uneventful recovery and received a course of radiotherapy along with follow-up examinations for 3 years. The authors report this rare patient for providing the other surgeons with the useful information regarding the management of the malignant melanoma on the tongue with free flap reconstruction which turned out to be successful in loco-regional control.

On the role of classical and novel forms of vitamin D in melanoma progression and management.

PubMed

Slominski, Andrzej T; Brożyna, Anna A; Skobowiat, Cezary; Zmijewski, Michal A; Kim, Tae-Kang; Janjetovic, Zorica; Oak, Allen S; Jozwicki, Wojciech; Jetten, Anton M; Mason, Rebecca S; Elmets, Craig; Li, We; Hoffman, Robert M; Tuckey, Robert C

2018-03-01

Melanoma represents a significant clinical problem affecting a large segment of the population with a relatively high incidence and mortality rate. Ultraviolet radiation (UVR) is an important etiological factor in malignant transformation of melanocytes and melanoma development. UVB, while being a full carcinogen in melanomagenesis, is also necessary for the cutaneous production of vitamin D3 (D3). Calcitriol (1,25(OH) 2 D3) and novel CYP11A1-derived hydroxyderivatives of D3 show anti-melanoma activities and protective properties against damage induced by UVB. The former activities include inhibitory effects on proliferation, plating efficiency and anchorage-independent growth of cultured human and rodent melanomas in vitro, as well as the in vivo inhibition of tumor growth by 20(OH)D3 after injection of human melanoma cells into immunodeficient mice. The literature indicates that low levels of 25(OH)D3 are associated with more advanced melanomas and reduced patient survivals, while single nucleotide polymorphisms of the vitamin D receptor or the D3 binding protein gene affect development or progression of melanoma, or disease outcome. An inverse correlation of VDR and CYP27B1 expression with melanoma progression has been found, with low or undetectable levels of these proteins being associated with poor disease outcomes. Unexpectedly, increased expression of CYP24A1 was associated with better melanoma prognosis. In addition, decreased expression of retinoic acid orphan receptors α and γ, which can also bind vitamin D3 hydroxyderivatives, showed positive association with melanoma progression and shorter disease-free and overall survival. Thus, inadequate levels of biologically active forms of D3 and disturbances in expression of the target receptors, or D3 activating or inactivating enzymes, can affect melanomagenesis and disease progression. We therefore propose that inclusion of vitamin D into melanoma management should be beneficial for patients, at least as an adjuvant approach. The presence of multiple hydroxyderivatives of D3 in skin that show anti-melanoma activity in experimental models and which may act on alternative receptors, will be a future consideration when planning which forms of vitamin D to use for melanoma therapy. Published by Elsevier Ltd.

Characterizations of 9p21 candidate genes in familial melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, G.J.; Flores, J.F.; Glendening, J.M.

We have previously collected and characterized 16 melanoma families for the inheritance of a familial melanoma predisposition gene on 9p21. Clear evidence for genetic linkage has been detected in 8 of these families with the 9p21 markers D9S126 and 1FNA, while linkage of the remaining families to this region is less certain. A candidate for the 9p21 familial melanoma gene, the cyclin kinase inhibitor gene p16 (also known as the multiple tumor suppressor 1 (MTS1) gene), has been recently indentified. Notably, a nonsense mutation within the p16 gene has been detected in the lymphoblastoid cell line DNA from a dysplasticmore » nevus syndrome (DNS), or familial melanoma, patient. The p16 gene is also known to be frequently deleted or mutated in a variety of tumor cell lines (including melanoma) and resides within a region that has been defined as harboring the 9p21 melanoma predisposition locus. This region is delineated on the distal side by the marker D9S736 (which resides just distal to the p16 gene) and extends in a proximal direction to the marker D9S171. Overall, the entire distance between these two loci is estimated at 3-5Mb. Preliminary analysis of our two largest 9p21-linked melanoma kindreds (by direct sequencing of PCR products) has not yet revealed mutations within the coding region of the p16 gene. Others have reported that 8/11 unrelated 9p21-linked melanoma families do not appear to carry p16 mutations; thus the possibility exists that p16 is not a melanoma susceptibility gene per se, although it appears to play some role in melanoma tumor progression. Our melanoma kindred DNAs are currently being analyzed by SSCP using primers that amplify exons of other candidate genes from the 9p21 region implicated in familial melanoma. These novel genes reside within a distinct critical region of homozygous loss in melanoma which is located >2 Mb from the p16 gene on 9p21.« less

Study of LOXO-101 (Larotrectinib) in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE)

ClinicalTrials.gov

2017-09-05

Carcinoma, Non-Small-Cell Lung; Thyroid Neoplasms; Sarcoma; Colorectal Neoplasms; Salivary Gland Neoplasms; Biliary Tract Neoplasms; Brain Neoplasm, Primary; Carcinoma, Ductal, Breast; Melanoma; Solid Tumors; Glioblastoma; Bile Duct Neoplasms; Astrocytoma; Head and Neck Squamous Cell Carcinoma; Pontine Glioma; Pancreatic Neoplasms; Ovarian Neoplasms; Carcinoma, Renal Cell; Cholangiocarcinoma; Carcinoma; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas

Irreversible Electroporation of Human Primary Uveal Melanoma in Enucleated Eyes

PubMed Central

Mandel, Yossi; Laufer, Shlomi; Belkin, Michael; Rubinsky, Boris; Pe'er, Jacob; Frenkel, Shahar

2013-01-01

Uveal melanoma (UM) is the most common primary intraocular tumor in adults and is characterized by high rates of metastatic disease. Although brachytherapy is the most common globe-sparing treatment option for small- and medium-sized tumors, the treatment is associated with severe adverse reactions and does not lead to increased survival rates as compared to enucleation. The use of irreversible electroporation (IRE) for tumor ablation has potential advantages in the treatment of tumors in complex organs such as the eye. Following previous theoretical work, herein we evaluate the use of IRE for uveal tumor ablation in human ex vivo eye model. Enucleated eyes of patients with uveal melanoma were treated with short electric pulses (50–100 µs, 1000–2000 V/cm) using a customized electrode design. Tumor bioimpedance was measured before and after treatment and was followed by histopathological evaluation. We found that IRE caused tumor ablation characterized by cell membrane disruption while sparing the non-cellular sclera. Membrane disruption and loss of cellular capacitance were also associated with significant reduction in total tumor impedance and loss of impedance frequency dependence. The effect was more pronounced near the pulsing electrodes and was dependent on time from treatment to fixation. Future studies should further evaluate the potential of IRE as an alternative method of uveal melanoma treatment. PMID:24039721

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi.

PubMed

Clarke, Loren E; Flake, Darl D; Busam, Klaus; Cockerell, Clay; Helm, Klaus; McNiff, Jennifer; Reed, Jon; Tschen, Jaime; Kim, Jinah; Barnhill, Raymond; Elenitsas, Rosalie; Prieto, Victor G; Nelson, Jonathan; Kimbrell, Hillary; Kolquist, Kathryn A; Brown, Krystal L; Warf, M Bryan; Roa, Benjamin B; Wenstrup, Richard J

2017-02-15

Recently, a 23-gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617-628. © 2016 American Cancer Society. © 2016 Myriad Genetics, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Histopathology report of cutaneous melanoma and sentinel lymph node in Europe: a web-based survey by the Dermatopathology Working Group of the European Society of Pathology.

PubMed

Batistatou, Anna; Cook, Martin G; Massi, Daniela

2009-05-01

In order to survey the diagnostic reporting of melanomas by European pathologists and assess their current practice and opinions on the information required in the final report, a web-based questionnaire was diffused through the members of the Dermatopathology Working Group of the European Society of Pathology. Forty replies from different pathology laboratories were collected (49%). Main prognostic parameters related to the primary tumor, including Breslow thickness, presence of ulceration, and Clark's level, as well as additional features, are reported by a large majority of laboratories. Presence of regression is reported by 90% of respondents but with different recording items. For sentinel lymph node (SLN) biopsy for melanoma, the conventional panel of antibodies includes S-100, Melan A, and HMB45. Dissection of the SLN is performed by "bivalve" or "bread loaf" approach. The number of sections cut and stained varies. Forty-four percent of respondents report depths of metastases from the capsule, while the majority report maximum dimension of the largest deposit. Results indicate that pathology reports for primary cutaneous melanoma and SLN vary between laboratories across Europe. Although the most important prognostic features are universally reported, key features which impact on prognosis and treatment are often omitted and others still require standardization.

Heterogeneity and frequency of BRAF mutations in primary melanoma: Comparison between molecular methods and immunohistochemistry

PubMed Central

Bruno, William; Martinuzzi, Claudia; Andreotti, Virginia; Pastorino, Lorenza; Spagnolo, Francesco; Dalmasso, Bruna; Cabiddu, Francesco; Gualco, Marina; Ballestrero, Alberto; Bianchi-Scarrà, Giovanna; Queirolo, Paola

2017-01-01

Finding the best technique to identify BRAF mutations with a high sensitivity and specificity is mandatory for accurate patient selection for target therapy. BRAF mutation frequency ranges from 40 to 60% depending on melanoma clinical characteristics and detection technique used. Intertumoral heterogeneity could lead to misinterpretation of BRAF mutational status; this is especially important if testing is performed on primary specimens, when metastatic lesions are unavailable. Aim of this study was to identify the best combination of methods for detecting BRAF mutations (among peptide nucleic acid – PNA-clamping real-time PCR, immunohistochemistry and capillary sequencing) and investigate BRAF mutation heterogeneity in a series of 100 primary melanomas and a subset of 25 matched metastatic samples. Overall, we obtained a BRAF mutation frequency of 62%, based on the combination of at least two techniques. Concordance between mutation status in primary and metastatic tumor was good but not complete (67%), when agreement of at least two techniques were considered. Next generation sequencing was used to quantify the threshold of detected mutant alleles in discordant samples. Combining different methods excludes that the observed heterogeneity is technique-based. We propose an algorithm for BRAF mutation testing based on agreement between immunohistochemistry and PNA; a third molecular method could be added in case of discordance of the results. Testing the primary tumor when the metastatic sample is unavailable is a good option if at least two methods of detection are used, however the presence of intertumoral heterogeneity or the occurrence of additional primaries should be carefully considered. PMID:28039443

Photoacoustic detection of induced melanoma in vitro using a mouse model

NASA Astrophysics Data System (ADS)

Gupta, Sagar; Bhattacharya, Kiran; Newton, Jessica R.; Quinn, Thomas P.; Viator, John A.

2012-03-01

Metastasis is a life threatening complex physiological phenomenon that involves the movement of cancer cells from one organ to another by means of blood and lymph. An understanding about metastasis is extremely important to device diagnostic systems to detect and monitor its spread within the body. For the first time we report rapid photoacoustic detection of the induced metastatic melanoma in mice in vitro using photoacoustic flowmetry. A new photoacoustic flow system is developed, that employs photoacoustic excitation coupled with an ultrasound transducer capable of determining the presence of individual, induced mouse melanoma cells (B16/F10) within the circulating system in vitro. Tumor was induced in mice by injecting mouse melanoma cells through tail vein into the C57BL/6 mice. A luciferase based in vivo bioluminescence imaging is performed to confirm the tumor load and multiple metastases in the tumor-induced mice. 1ml of blood obtained through cardiac puncture of the induced metastasized mice was treated to lyse the red blood cells (RBC) and enriched, leaving the induced melanoma in the peripheral blood mononuclear suspension (PBMC). A photoacoustic flowsystem coupled with an ultrasound transducer is used to detect the individual circulating metastatic melanoma cells from the enriched cell suspension.

Vemurafenib: an evidence-based review of its clinical utility in the treatment of metastatic melanoma.

PubMed

Swaika, Abhisek; Crozier, Jennifer A; Joseph, Richard W

2014-01-01

The discovery of BRAF mutations in the majority of patients with metastatic melanoma combined with the identification of highly selective BRAF inhibitors have revolutionized the treatment of patients with metastatic melanoma. The first highly specific BRAF inhibitor, vemurafenib, began clinical testing in 2008 and moved towards a rapid approval in 2011. Vemurafenib induced responses in ~50% of patients with metastatic BRAF-mutant melanoma and demonstrated improved overall survival in a randomized Phase III trial. Furthermore, vemurafenib is well-tolerated with a low toxicity profile and rapid onset of action. Finally, vemurafenib is active even in patients with widely metastatic disease. Despite the success of vemurafenib in treating patients with BRAF-mutant metastatic melanoma, most, if not all, patients ultimately develop resistance resulting in disease progression at a median time of ~6 months. Multiple mechanisms of resistance have been described and rationale strategies are underway to combat resistance. This review highlights the development, clinical utility, resistance mechanisms, and future use of vemurafenib both in melanoma and other malignancies. We consulted PubMed, Scopus, MEDLINE, ASCO annual symposium abstracts, and http://clinicaltrials.gov/ for the purpose of this review.

Vemurafenib: an evidence-based review of its clinical utility in the treatment of metastatic melanoma

PubMed Central

Swaika, Abhisek; Crozier, Jennifer A; Joseph, Richard W

2014-01-01

The discovery of BRAF mutations in the majority of patients with metastatic melanoma combined with the identification of highly selective BRAF inhibitors have revolutionized the treatment of patients with metastatic melanoma. The first highly specific BRAF inhibitor, vemurafenib, began clinical testing in 2008 and moved towards a rapid approval in 2011. Vemurafenib induced responses in ~50% of patients with metastatic BRAF-mutant melanoma and demonstrated improved overall survival in a randomized Phase III trial. Furthermore, vemurafenib is well-tolerated with a low toxicity profile and rapid onset of action. Finally, vemurafenib is active even in patients with widely metastatic disease. Despite the success of vemurafenib in treating patients with BRAF-mutant metastatic melanoma, most, if not all, patients ultimately develop resistance resulting in disease progression at a median time of ~6 months. Multiple mechanisms of resistance have been described and rationale strategies are underway to combat resistance. This review highlights the development, clinical utility, resistance mechanisms, and future use of vemurafenib both in melanoma and other malignancies. We consulted PubMed, Scopus, MEDLINE, ASCO annual symposium abstracts, and http://clinicaltrials.gov/ for the purpose of this review. PMID:24966667

Clinicopathological features and clinical outcomes associated with TP53 and BRAFNon-V600 mutations in cutaneous melanoma patients.

PubMed

Kim, Dae Won; Haydu, Lauren E; Joon, Aron Y; Bassett, Roland L; Siroy, Alan E; Tetzlaff, Michael T; Routbort, Mark J; Amaria, Rodabe N; Wargo, Jennifer A; McQuade, Jennifer L; Kemnade, Jan; Hwu, Patrick; Woodman, Scott E; Roszik, Jason; Kim, Kevin B; Gershenwald, Jeffrey E; Lazar, Alexander J; Davies, Michael A

2017-04-15

BRAF V600 , NRAS, TP53, and BRAF Non-V600 are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAF V600 and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAF Non-V600 mutations. This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926). The prevalence of BRAF V600 , NRAS, TP53, and BRAF Non-V600 mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAF Non-V600 mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAF Non-V600 mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAF Non-V600 mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy. These results add to the understanding of the clinical features associated with TP53 and BRAF Non-V600 mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society. © 2016 American Cancer Society.

Use of support services in a sample of patients with high-risk primary melanomas in urban, regional and rural Queensland.

PubMed

von Schuckmann, Lena A; Smithers, Bernhard M; Khosrotehrani, Kiarash; Beesley, Vanessa L; van der Pols, Jolieke C; Hughes, Maria B; Green, Adele C

2017-06-01

To characterise use of support services in patients diagnosed with high-risk primary melanoma by their location of residence. In a cross-sectional study of 787 patients with histologically-confirmed clinical stage 1B-2 melanoma, we estimated odds ratios (ORs) using regression models to assess the association of support service use with residence in rural, regional or urban areas. We also evaluated demographic and clinical correlates of support service use. Among 113 rural patients, 33 (29%) used support services around time of diagnosis compared to 88 (39%) of 224 regional participants and 164 of 448 (37%) urban participants. Regional participants more commonly used support services compared to rural participants (OR 1.84; CI 1.09-3.10), but there was no association with urban versus rural residence (OR 1.32; CI 0.82-2.13). As well, females (OR 1.58; CI 1.15-2.18), those <65 years (OR 1.96; CI 1.42-2.71), or with higher education (OR 2.30; CI 1.53-3.44), or those with T-stage 4B (OR 2.69; CI 1.36-5.32) were more likely to use support services than other patients. Use of support services is lower among rural patients and other sub-groups of primary melanoma patients who have poorer prognoses than others. Implications for public health: Appropriate triage to support services is required for rural and other vulnerable patient groups to ensure optimal patient care. © 2017 The Authors.

Direct targeting of MEK1/2 and RSK2 by silybin induces cell cycle arrest and inhibits melanoma cell growth

PubMed Central

Lee, Mee-Hyun; Huang, Zunnan; Kim, Dong Joon; Kim, Sung-Hyun; Kim, Myoung Ok; Lee, Sung-Young; Xie, Hua; Park, Si Jun; Kim, Jae Young; Kundu, Joydeb Kumar; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

2013-01-01

Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of nuclear factor-kappaB, activator protein-1 and signal transducer and activator of transcription-3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways. PMID:23447564

LncRNA MEG3 repressed malignant melanoma progression via inactivating Wnt signaling pathway.

PubMed

Li, Peng; Gao, Ying; Li, Jun; Zhou, Yu; Yuan, Jing; Guan, Huiwen; Yao, Peng

2018-05-21

Accumulating evidence has indicated that MEG3 can serve as a tumor suppressive lncRNA in various tumors. It is aberrantly expressed in multiple cancers. However, the biological roles of MEG3 in melanoma are poorly understood. Therefore, in our study, we concentrated on the biological mechanism of MEG3 in melanoma progression. First, we observed that MEG3 was obviously decreased in melanoma cells including A375, SK-MEL-1, B16, and A2058 cells compared to human epidermal melanocytes HEMa-LP. MEG3 was restored by transfecting LV-MEG3 in to A375 and A2058 cells. Subsequently, we found that overexpression of MEG3 was able to inhibit cell proliferation and colony formation capacity. Meanwhile, melanoma cell apoptosis was induced by up-regulation of MEG3. Overexpression of MEG3 greatly repressed melanoma cell migration and invasion ability. In addition, Wnt signaling pathway has been identified in the progression of various cancers. Here, in our study, it was indicated that Wnt signaling was highly activated in melanoma cells with β-catenin expression significantly increased and GSK-3β decreased. Interestingly, MEG restoration strongly inactivated Wnt signaling pathway by reducing β-catenin and CyclinD1, elevating GSK-3β levels in vitro. Finally, in vivo experiments were carried out to confirm the inhibitory roles of MEG3 in vivo. Taken these together, we suggested that MEG3 can inhibit melanoma development through blocking Wnt signaling pathway. © 2018 Wiley Periodicals, Inc.

CD82 suppresses CD44 alternative splicing-dependent melanoma metastasis by mediating U2AF2 ubiquitination and degradation

PubMed Central

Fu, Ailing; Zhu, Huifeng; Ren, Qiao; Wang, Bochu; Xu, Xingran; Bai, Huiyuan; Dong, Cheng

2016-01-01

Melanoma is one of the most lethal forms of skin cancer due to its early metastatic spread. The variant form of CD44 (CD44v), a cell surface glycoprotein, is highly expressed on metastatic melanoma. The mechanisms of regulation of CD44 alternative splicing in melanoma and its pathogenic contributions are so far poorly understood. Here, we investigated the expression level of CD44 in a large set of melanocytic lesions at different stages. We found that the expression of CD44v8-10 and a splicing factor, U2AF2, is significantly increased during melanoma progression, while CD82/KAI1, a tetraspanin family of tumor suppressor, is reduced in metastatic melanoma. CD44v8-10 and U2AF2 expressions which are negatively correlated with CD82 levels are dramatically elevated in primary melanoma compared with dysplastic nevi and further increased in metastatic melanoma. We also showed that patients with higher CD44v8-10 and U2AF2 expression levels tended to have shorter survival. By using both in vivo and in vitro assays, we demonstrated that CD82 inhibits the production of CD44v8-10 on melanoma. Mechanistically, U2AF2 is a downstream target of CD82 and in malignant melanoma facilitates CD44v8-10 alternative splicing. U2AF2-mediated CD44 isoform switch is required for melanoma migration in vitro and lung and liver metastasis in vivo. Notably, overexpression of CD82 suppresses U2AF2 activity by inducing U2AF2 ubiquitination. In addition, our data suggested that enhancement of melanoma migration by U2AF2-dependent CD44v8-10 splicing is mediated by Src/FAK/RhoA activation and formation of stress fibers as well as CD44-E-selectin binding reinforcement. These findings uncovered a hitherto unappreciated function of CD82 in severing the linkage between U2AF2-mediated CD44 alternative splicing and cancer aggressiveness, with potential prognostic and therapeutic implications in melanoma. PMID:27041584

Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma.

PubMed

Keating, Gillian M

2016-04-01

The MEK inhibitor cobimetinib (Cotellic(®)) is indicated for the treatment of patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma, in combination with the BRAF inhibitor vemurafenib (Zelboraf(®)). In the pivotal coBRIM trial, previously untreated patients with BRAF (V600) mutation-positive unresectable, stage IIIC or stage IV melanoma received cobimetinib 60 mg once daily for the first 21 days of each 28-day cycle plus vemurafenib 960 mg twice daily or vemurafenib alone. Compared with vemurafenib alone, cobimetinib plus vemurafenib significantly prolonged progression-free survival (primary endpoint) and was associated with a significantly higher overall response rate and significantly prolonged overall survival. Cobimetinib plus vemurafenib had a manageable tolerability profile. In conclusion, cobimetinib plus vemurafenib is a valuable option for use in BRAF (V600) mutation-positive unresectable or metastatic melanoma.

Selective expression of inhibitory Fcgamma receptor by metastatic melanoma impairs tumor susceptibility to IgG-dependent cellular response.

PubMed

Cassard, Lydie; Cohen-Solal, Joel F G; Fournier, Emilie M; Camilleri-Broët, Sophie; Spatz, Alain; Chouaïb, Salem; Badoual, Cécile; Varin, Audrey; Fisson, Sylvain; Duvillard, Pierre; Boix, Charlotte; Loncar, Shannon M; Sastre-Garau, Xavier; Houghton, Alan N; Avril, Marie-Françoise; Gresser, Ion; Fridman, Wolf H; Sautès-Fridman, Catherine

2008-12-15

During melanoma progression, patients develop anti-tumor immunity including the production of anti-tumor antibodies. Although the strategies developed by malignant cells to escape anti-tumor cellular immunity have been extensively investigated, little is known about tumor resistance to humoral immunity. The main effect of IgG antibodies is to activate the immune response by binding to host Fc gamma receptors (FcgammaR) expressed by immune cells. We previously reported in a limited study that some human metastatic melanoma cells ectopically express the FcgammaRIIB1, an inhibitory isoform of FcgammaR. By analyzing a large panel of different types of human primary and metastatic solid tumors, we report herein that expression of FcgammaRIIB is restricted to melanoma and is acquired during tumor progression. We show that FcgammaRIIB expression prevents the lysis of human metastatic melanoma cells by NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, independently of the intracytoplasmic region of FcgammaRIIB. Using experimental mouse models, we demonstrate that expression of FcgammaRIIB protects B16F0 melanoma tumors from the ADCC induced by monoclonal and polyclonal anti-tumor IgG in vivo. Thus, our results identify FcgammaRIIB as a marker of human metastatic melanoma that impairs the tumor susceptibility to FcgammaR-dependent innate effector responses. (c) 2008 Wiley-Liss, Inc.

Humanistic burden of disease for patients with advanced melanoma in Canada.

PubMed

Cheung, Winson Y; Bayliss, Martha S; White, Michelle K; Stroupe, Angela; Lovley, Andrew; King-Kallimanis, Bellinda L; Lasch, Kathryn

2018-06-01

Metastatic melanoma is a highly aggressive cancer, often striking in the prime of life. This study provides new information directly from advanced melanoma (stage III and IV) patients on how their disease impacts their health-related quality of life (HRQL). Twenty-nine in-depth, qualitative interviews were conducted with adult patients with advanced melanoma in Canada. A semi-structured interview guide was used. Interviews were transcribed verbatim and key concepts were identified using a grounded theory analytic approach. Many patients' journeys began with the startling diagnosis of an invasive disease and a vastly shortened life expectancy. By the time they reached an advanced stage of melanoma, these patients' overall functioning and quality of life had been greatly diminished by this quickly progressing cancer. The impact was described in terms of physical pain and disability, emotional distress, diminished interactions with friends and family, and burden on caregivers. Our findings provide evidence of signs, symptoms, and functional impacts of advanced melanoma. Signs and symptoms reported (physical, mental, and social) confirm and expand on those reported in the existing clinical literature. Primary care physicians should be better trained to identify melanomas early. Oncology care teams can improve on their current approaches for helping patients navigate treatment options, with information about ancillary services to mitigate disease impacts on HRQL, such as mental health and social supports, as well as employment or financial support services.

Epidemiology, management and survival outcomes of primary cutaneous melanoma: a ten-year overview.

PubMed

Aubuchon, M M F; Bolt, L J J; Janssen-Heijnen, M L G; Verleisdonk-Bolhaar, S T H P; van Marion, A; van Berlo, C L H

2017-02-01

Malignant melanoma (MM) is the most aggressive type of skin cancer, accounting for 90% of all the skin cancer mortality. The objective of this study was providing an overview of current patient- and tumour characteristics, treatment strategies, complications and survival in patients with MM over the past ten years. Hereby, an up-to-date view of every day clinical practice is obtained. Files of patients treated for primary cutaneous melanoma (n = 686) in the VieCuri Medical Centre in the Netherlands between January 2002 and December 2013 were retrospectively reviewed. Relevant patient features, tumour characteristics, and (surgical) outcomes were evaluated. The majority of all the patients presented thin tumours (59.1% stage 1A/in situ melanoma). Men showed more ulceration (17.7% vs. 8.4%, p < .01) and a significantly higher Breslow thickness than women (1.2 mm vs. 0.9 mm, p < .01). 14.6% (40/273) underwent sentinel lymph node biopsy (SLNB); 10/40 (25%) showed nodal metastasis, 50 patients (7.3%) developed distant metastases (M: 10.6%, F: 5%, p < .01). One-, 5- and 10- year disease specific survival rates were 96%, 86% and 84%, respectively. Median survival for stage 4 MM was 3 months. Extensive surgery was uncommon (n = 3). Patients generally presented with thin melanomas. Lymph node disease and distant metastases remained infrequently observed during following years, and general 1- and 5-year overall disease-specific survival rates exceeded 85%. Small numbers of rescue surgery and palliative medical treatment warrant further centralisation and investigation.

Fisetin Inhibits Human Melanoma Cell Invasion through Promotion of Mesenchymal to Epithelial Transition and by Targeting MAPK and NFκB Signaling Pathways

PubMed Central

Pal, Harish Chandra; Sharma, Samriti; Strickland, Leah Ray; Katiyar, Santosh K.; Ballestas, Mary E.; Athar, Mohammad; Elmets, Craig A.; Afaq, Farrukh

2014-01-01

Malignant melanoma is responsible for approximately 75% of skin cancer-related deaths. BRAF plays an important role in regulating the mitogen-activated protein kinase (MAPK) signaling cascade in melanoma with activating mutations in the serine/threonine kinase BRAF occurring in 60–70% of malignant melanomas. The BRAF-MEK-ERK (MAPK) pathway is a key regulator of melanoma cell invasion. In addition, activation of NFκB via the MAPK pathway is regulated through MEK-induced activation of IKK. These pathways are potential targets for prevention and treatment of melanoma. In this study, we investigated the effect of fisetin, a phytochemical present in fruits and vegetables, on melanoma cell invasion and epithelial-mesenchymal transition, and delineated the underlying molecular mechanism. Treatment of multiple human malignant melanoma cell lines with fisetin (5–20 µM) resulted in inhibition of cell invasion. BRAF mutated melanoma cells were more sensitive to fisetin treatment, and this was associated with a decrease in the phosphorylation of MEK1/2 and ERK1/2. In addition, fisetin inhibited the activation of IKK leading to a reduction in the activation of the NFκB signaling pathway. Treatment of cells with an inhibitor of MEK1/2 (PD98059) or of NFκB (caffeic acid phenethyl ester) also reduced melanoma cell invasion. Furthermore, treatment of fisetin promoted mesenchymal to epithelial transition in melanoma cells, which was associated with a decrease in mesenchymal markers (N-cadherin, vimentin, snail and fibronectin) and an increase in epithelial markers (E-cadherin and desmoglein). Employing three dimensional skin equivalents consisting of A375 cells admixed with normal human keratinocytes embedded onto a collagen-constricted fibroblast matrix, we found that treatment of fisetin reduced the invasive potential of melanoma cells into the dermis and increased the expression of E-cadherin with a concomitant decrease in vimentin. These results indicate that fisetin inhibits melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFκB signaling pathways. PMID:24466036

Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death.

PubMed

Lv, Da-Lun; Chen, Lei; Ding, Wei; Zhang, Wei; Wang, He-Li; Wang, Shuai; Liu, Wen-Bei

2018-01-01

Melanoma is a leading cause of cancer death worldwide, and SMI-4a and G-Rh2 exert anti-tumor activity in multiple cancer. However, SMI-4a as well as a synergistic relationship between SMI-4a and G-Rh2 in anti-melanoma capacity are still unknown. Therefore, we investigated the effects of SMI-4a and combined SMI-4a with G-Rh2 on the viability, apoptosis and autophagy of melanoma, and to preliminarily explore the underlying mechanism of SMI-4a and combined SMI-4a with G-Rh2 in inhibiting tumor growth. Cell viability was examined with cell counting Kit 8 assay and colony formation assay; Apoptosis was evaluated by flow cytometry and Caspase 3/7 activity assay; Western blotting was used to test proteins related to autophagy and the AKT/mammalian target of rapamycin (mTOR) signaling pathway; Tumor xenograft model in BALB/c nude mice was performed to evaluate the effects of SMI-4a and combined SMI-4a with G-Rh2 in anti-melanoma in vivo. SMI-4a, a pharmacological inhibitor of PIM-1, could decrease cell viability, induce apoptosis, and promote Caspase 3/7 activity in both A375 and G361 melanoma cells, and SMI-4a inhibited tumor growth by inducing autophagy via down-regulating AKT/mTOR axis in melanoma cells. Furthermore, G-Rh2 amplified the anti-tumor activity of SMI-4a in melanoma cells via strengthening autophagy. Our results suggested that SMI-4a could enhance autophagy-inducing apoptosis by inhibiting AKT/mTOR signaling pathway in melanoma cells, and G-Rh2 could enhance the effects of SMI-4a against melanoma cancer via amplifying autophagy induction. This study demonstrates that combined SMI-4a and G-Rh2 might be a novel alternative strategy for melanoma treatment.

Variables that influence BRAF mutation probability: A next-generation sequencing, non-interventional investigation of BRAFV600 mutation status in melanoma.

PubMed

Gaiser, Maria Rita; Skorokhod, Alexander; Gransheier, Diana; Weide, Benjamin; Koch, Winfried; Schif, Birgit; Enk, Alexander; Garbe, Claus; Bauer, Jürgen

2017-01-01

The incidence of melanoma, particularly in older patients, has steadily increased over the past few decades. Activating mutations of BRAF, the majority occurring in BRAFV600, are frequently detected in melanoma; however, the prognostic significance remains unclear. This study aimed to define the probability and distribution of BRAFV600 mutations, and the clinico-pathological factors that may affect BRAF mutation status, in patients with advanced melanoma using next-generation sequencing. This was a non-interventional, retrospective study of BRAF mutation testing at two German centers, in Heidelberg and Tübingen. Archival tumor samples from patients with histologically confirmed melanoma (stage IIIB, IIIC, IV) were analyzed using PCR amplification and deep sequencing. Clinical, histological, and mutation data were collected. The statistical influence of patient- and tumor-related characteristics on BRAFV600 mutation status was assessed using multiple logistic regression (MLR) and a prediction profiler. BRAFV600 mutation status was assessed in 453 samples. Mutations were detected in 57.6% of patients (n = 261), with 48.1% (n = 102) at the Heidelberg site and 66.0% (n = 159) at the Tübingen site. The decreasing influence of increasing age on mutation probability was quantified. A main effects MLR model identified age (p = 0.0001), center (p = 0.0004), and melanoma subtype (p = 0.014) as significantly influencing BRAFV600 mutation probability; ultraviolet (UV) exposure showed a statistical trend (p = 0.1419). An interaction model of age versus other variables showed that center (p<0.0001) and melanoma subtype (p = 0.0038) significantly influenced BRAF mutation probability; age had a statistically significant effect only as part of an interaction with both UV exposure (p = 0.0110) and melanoma subtype (p = 0.0134). This exploratory study highlights that testing center, melanoma subtype, and age in combination with UV exposure and melanoma subtype significantly influence BRAFV600 mutation probability in patients with melanoma. Further validation of this model, in terms of reproducibility and broader relevance, is required.

Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts

PubMed Central

2013-01-01

One of the key oncogenic pathways involved in melanoma aggressiveness, development and progression is the RAS/BRAF/MEK pathway, whose alterations are found in most patients. These molecular anomalies are promising targets for more effective anti-cancer therapies. Some Mek inhibitors showed promising antitumor activity, although schedules and doses associated with low systemic toxicity need to be defined. In addition, it is now accepted that cancers can arise from and be maintained by the cancer stem cells (CSC) or tumor-initiating cells (TIC), commonly expanded in vitro as tumorspheres from several solid tumors, including melanoma (melanospheres). Here, we investigated the potential targeting of MEK pathway by exploiting highly reliable in vitro and in vivo pre-clinical models of melanomas based on melanospheres, as melanoma initiating cells (MIC) surrogates. MEK inhibition, through PD0325901, provided a successful strategy to affect survival of mutated-BRAF melanospheres and growth of wild type-BRAF melanospheres. A marked citotoxicity was observed in differentated melanoma cells regardless BRAF mutational status. PD0325901 treatment, dramatically inhibited growth of melanosphere-generated xenografts and determined impaired tumor vascularization of both mutated- and wild type-BRAF tumors, in the absence of mice toxicity. These results suggest that MEK inhibition might represent a valid treatment option for patients with both mutated- or wild type-BRAF melanomas, affecting tumor growth through multiple targets. PMID:24238212

Outcomes of mucosal melanoma of the head and neck.

PubMed

Frakes, Jessica M; Strom, Tobin J; Naghavi, Arash O; Trotti, Andy; Rao, Nikhil G; McCaffrey, Judith C; Otto, Kristen J; Padhya, Tapan; Caudell, Jimmy J

2016-04-01

Mucosal melanoma of the head and neck is a rare disease with limited data available on outcomes; therefore, we reviewed our institutional experience. An institutional database was queried and 38 patients with head and neck mucosal melanoma were identified. Charts were abstracted and local control (LC), progression-free survival (PFS) and overall survival (OS) were calculated. Most patients had T4 disease (86%), although nodes were positive in 11%. En bloc or endoscopic resection was performed on 93%. Adjuvant or definitive radiotherapy to a median dose of 60 Gy was utilized in 90%. Chemotherapy was given in 21%, and 16% received interferon. Three-year LC, PFS and OS were 90%, 48% and 59%, respectively. Median OS was 4.6 years. Site of first failure was distant in 52% of cases. With aggressive therapy median OS was 4.6 years in this cohort. Distant recurrence remains the primary mode of failure. It may be reasonable to include mucosal melanoma patients in trials of systemic agents along with high-risk cutaneous melanomas. © 2015 The Royal Australian and New Zealand College of Radiologists.

DNA from human polyomaviruses, TSPyV, MWPyV, HPyV6, 7 and 9 was not detected in primary mucosal melanomas.

PubMed

Ramqvist, Torbjörn; Nordfors, Cecilia; Dalianis, Tina; Ragnarsson-Olding, Boel

2014-02-01

Mucosal melanomas arise in non UV-light exposed areas and causative factors are yet unknown. Human polyomaviruses (HPyVs) are rapidly increasing in numbers and are potentially oncogenic, as has been established for MCPyV in Merkel cell carcinoma, an unusual skin cancer type. The aim of the present study was to investigate the association between TSPyV, MWPyV, HPyV6, 7 and 9 and mucosal melanoma. Fifty-five mucosal melanomas, were analyzed by a Luminex assay, for the presence of 10 HPyVs (BKPyV, JCPyV, KIPyV, WUPyV, TSPyV, MWPyV, HPyV6, 7 and 9) and two primate viruses (SV40 and LPyV). In 37 samples the DNA quality was satisfactory for analysis. However, none of the samples analyzed were positive for any of the examined viruses. None of the above-analyzed HPyVs were detected in mucosal melanoma samples, and they are for this reason unlikely to play a major role in the development of this tumor type.

Photoacoustic imaging of single circulating melanoma cells in vivo

NASA Astrophysics Data System (ADS)

Wang, Lidai; Yao, Junjie; Zhang, Ruiying; Xu, Song; Li, Guo; Zou, Jun; Wang, Lihong V.

2015-03-01

Melanoma, one of the most common types of skin cancer, has a high mortality rate, mainly due to a high propensity for tumor metastasis. The presence of circulating tumor cells (CTCs) is a potential predictor for metastasis. Label-free imaging of single circulating melanoma cells in vivo provides rich information on tumor progress. Here we present photoacoustic microscopy of single melanoma cells in living animals. We used a fast-scanning optical-resolution photoacoustic microscope to image the microvasculature in mouse ears. The imaging system has sub-cellular spatial resolution and works in reflection mode. A fast-scanning mirror allows the system to acquire fast volumetric images over a large field of view. A 500-kHz pulsed laser was used to image blood and CTCs. Single circulating melanoma cells were imaged in both capillaries and trunk vessels in living animals. These high-resolution images may be used in early detection of CTCs with potentially high sensitivity. In addition, this technique enables in vivo study of tumor cell extravasation from a primary tumor, which addresses an urgent pre-clinical need.

CDKN2B loss promotes progression from benign melanocytic nevus to melanoma

PubMed Central

McNeal, Andrew S.; Liu, Kevin; Nakhate, Vihang; Natale, Christopher A.; Duperret, Elizabeth K.; Capell, Brian C.; Dentchev, Tzvete; Berger, Shelley L.; Herlyn, Meenhard; Seykora, John T.; Ridky, Todd W.

2015-01-01

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. PMID:26183406

Intratumor and Intertumor Heterogeneity in Melanoma.

PubMed

Grzywa, Tomasz M; Paskal, Wiktor; Włodarski, Paweł K

2017-12-01

Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

An ecologic study of cancer mortality rates in Spain with respect to indices of solar UVB irradiance and smoking.

PubMed

Grant, William B

2007-03-01

There is increasing evidence that vitamin D reduces the risk of many types of cancer. Geographic variations in cancer mortality rates in Spain are apparently linked to variations in solar ultraviolet (UV) irradiances and other factors. Cancer mortality rates for 48 continental Spanish provinces for 1978-1992 were used in linear regression analyses with respect to mortality rates for latitude (an index of solar UVB levels), skin cancer (an index of high cumulative UVB irradiance), melanoma (an index related to solar UV irradiance and several other factors) and lung cancer (an index of cumulative effects of smoking). The 9 cancers with mortality rates significantly correlated with latitude for 1 or both sexes were brain, gastric, melanoma, nonmelanoma skin cancer (NMSC), non-Hodgkin's lymphoma (NHL), pancreatic, pleural, rectal and thyroid cancer. Inverse correlations with latitude were found for laryngeal, lung and uterine corpus cancer. The 17 cancers inversely correlated with NMSC are bladder, brain, breast, colon, esophageal, gallbladder, Hodgkin's lymphoma, lung, melanoma, multiple myeloma, NHL, ovarian, pancreatic, pleural, rectal, thyroid and uterine corpus cancer. The 16 correlated with melanoma are bladder, brain, breast, colon, gallbladder, leukemia, lung, multiple myeloma, NHL, ovarian, pancreatic, pleural, prostate, rectal, renal and uterine corpus cancer. The results for lung cancer were in accordance with the literature. These results provide more support for the UVB/vitamin D/cancer hypothesis and indicate a new way to investigate the role of solar UV irradiance on cancer risk. They also provide more evidence that melanoma and NMSC have different etiologies. Copyright 2006 Wiley-Liss, Inc.

Molecular markers to complement sentinel node status in predicting survival in patients with high-risk locally invasive melanoma.

PubMed

Rowe, Casey J; Tang, Fiona; Hughes, Maria Celia B; Rodero, Mathieu P; Malt, Maryrose; Lambie, Duncan; Barbour, Andrew; Hayward, Nicholas K; Smithers, B Mark; Green, Adele C; Khosrotehrani, Kiarash

2016-08-01

Sentinel lymph node status is a major prognostic marker in locally invasive cutaneous melanoma. However, this procedure is not always feasible, requires advanced logistics and carries rare but significant morbidity. Previous studies have linked markers of tumour biology to patient survival. In this study, we aimed to combine the predictive value of established biomarkers in addition to clinical parameters as indicators of survival in addition to or instead of sentinel node biopsy in a cohort of high-risk melanoma patients. Patients with locally invasive melanomas undergoing sentinel lymph node biopsy were ascertained and prospectively followed. Information on mortality was validated through the National Death Index. Immunohistochemistry was used to analyse proteins previously reported to be associated with melanoma survival, namely Ki67, p16 and CD163. Evaluation and multivariate analyses according to REMARK criteria were used to generate models to predict disease-free and melanoma-specific survival. A total of 189 patients with available archival material of their primary tumour were analysed. Our study sample was representative of the entire cohort (N = 559). Average Breslow thickness was 2.5 mm. Thirty-two (17%) patients in the study sample died from melanoma during the follow-up period. A prognostic score was developed and was strongly predictive of survival, independent of sentinel node status. The score allowed classification of risk of melanoma death in sentinel node-negative patients. Combining clinicopathological factors and established biomarkers allows prediction of outcome in locally invasive melanoma and might be implemented in addition to or in cases when sentinel node biopsy cannot be performed. © 2016 UICC.

Tumor location predicts survival in cutaneous head and neck melanoma.

PubMed

Tseng, Warren H; Martinez, Steve R

2011-05-15

Prior studies documented poorer outcomes in patients with cutaneous head and neck melanoma (CHNM) relative to those with melanoma at other sites. We evaluated survival differences attributable to tumor location in patients with CHNM. We queried the Surveillance, Epidemiology, and End Results (SEER) database for patients undergoing surgery for CHNM from 1988 to 2006, excluding patients without biopsy-proven diagnoses, those diagnosed at autopsy, and patients with distant metastases. Using the Kaplan-Meier method, we assessed patient, tumor, and treatment-specific factors on overall survival (OS) and melanoma specific survival (MSS). Cox proportional hazards models assessed the role of tumor location (ear, eyelid, face, lip, scalp/neck) on OS and MSS, while controlling for patient age, gender, race, tumor thickness, tumor ulceration, lymph node status, histologic subtype, type of surgery, and use of radiation. Risks of overall and melanoma-specific mortality were reported as hazard ratios (HR) with 95% confidence intervals (CI). Among 27,097 patients, 10-y rates of OS and MSS were 56.1% and 84.7%, respectively. On multivariate analysis, scalp/neck primary site was associated with an increased risk of overall (HR 1.20, CI 1.14-1.26; P < 0.001) and melanoma-specific mortality (HR 1.64, CI 1.49-1.80, P < 0.001) relative to melanomas of the face. Tumors of the lip had poorer MSS (HR 1.55; CI 1.05-2.28, P = 0.03) but not OS (HR 1.03, CI 0.80-1.34; P = 0.80). Patients with melanomas of the scalp/neck have poorer OS and MSS and those with lip melanomas have poorer MSS. These anatomic areas should not be overlooked when performing skin examinations. Copyright © 2011 Elsevier Inc. All rights reserved.

Comparison of the in vitro and in vivo effects of retinoids either alone or in combination with cisplatin and 5-fluorouracil on tumor development and metastasis of melanoma.

PubMed

Liu, Xin; Chan, Sui Yung; Ho, Paul Chi-Lui

2008-12-01

Retinoids have previously been reported to inhibit proliferation of melanoma cell lines in vitro. However, the relative antimetastatic efficacy of various retinoids on melanoma in vivo is unknown. Therefore, we investigated the effects of different retinoids on the invasion and metastasis of murine melanoma B16-F10 cells in vitro and in vivo. Based on the findings, the antitumor effects of a selected retinoid either alone or in combination with cisplatin were also investigated in a preclinical mouse melanoma model. Cell proliferation and invasion analyses of murine melanoma B16-F10 cells were assessed in the presence of different retinoids, either alone or in combination with cisplatin (CDDP) or 5-fluorouracil (5-FU). Experimental lung metastasis assay was performed in this study to investigate the antimetastatic efficacy of retinoids. Additionally, a mouse melanoma model was used to assess the antitumor efficacy of a selected retinoid in combination with cisplatin. Retinoids showed significant antiproliferation and anti-invasion effects on murine melanoma B16-F10 cells. Pretreatment with retinoids increased the sensitivity to CDDP but not to 5-FU in in-vitro. Moreover, the number of metastatic colonies formed in the lungs of mice injected intravenously with B16-F10 cells was significantly reduced by injecting the respective retinoid once a day for 10 days. Treatment with a combination of cisplatin and 13-cis-retinoic acid resulted in a significant reduction in primary tumor size and the number of lung metastatic nodules in melanoma-bearing mice. These results suggest that retinoids not only exhibit antimetastatic effect, but also enhance the antitumor activity of cisplatin in vivo.

Sentinel node biopsy in thin and thick melanoma.

PubMed

Mozzillo, Nicola; Pennacchioli, Elisabetta; Gandini, Sara; Caracò, Corrado; Crispo, Anna; Botti, Gerardo; Lastoria, Secondo; Barberis, Massimo; Verrecchia, Francesco; Testori, Alessandro

2013-08-01

Although sentinel node biopsy (SNB) has become standard of care in patients with melanoma, its use in patients with thin or thick melanomas remains a matter of debate. This was a retrospective analysis of patients with thin (≤1 mm) or thick (≥4 mm) melanomas who underwent SNB at two Italian centers between 1998 and 2011. The associations of clinicopathologic features with sentinel lymph node positive status and overall survival (OS) were analyzed. In 492 patients with thin melanoma, sentinel node was positive for metastatic melanoma in 24 (4.9 %) patients. No sentinel node positivity was detected in patients with primary tumor thickness <0.3 mm. Mitotic rate was the only factor significantly associated with sentinel node positivity (p = 0.0001). Five-year OS was 81 % for patients with positive sentinel node and 93 % for negative sentinel node (p = 0.001). In 298 patients with thick melanoma, 39 % of patients had positive sentinel lymph nodes (median Breslow thickness 5 mm). In patients with positive sentinel node, 93 % had mitotic rate >1/mm(2). Five-year OS was 49 % for patients with positive sentinel lymph nodes and 56 % for patients with negative sentinel nodes (p = 0.005). The rate of sentinel node positivity in patients with thin melanoma was 4.9 %. The only clinicopathologic factor related to node positivity was mitotic rate. Given its prognostic importance, SNB should be considered in such patients. SNB should also be the standard method for melanoma ≥4 mm, not only for staging, but also for guiding therapeutic decisions.

AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma.

PubMed

Namiki, Takeshi; Tanemura, Atsushi; Valencia, Julio C; Coelho, Sergio G; Passeron, Thierry; Kawaguchi, Masakazu; Vieira, Wilfred D; Ishikawa, Masashi; Nishijima, Wataru; Izumo, Toshiyuki; Kaneko, Yasuhiko; Katayama, Ichiro; Yamaguchi, Yuji; Yin, Lanlan; Polley, Eric C; Liu, Hongfang; Kawakami, Yutaka; Eishi, Yoshinobu; Takahashi, Eishi; Yokozeki, Hiroo; Hearing, Vincent J

2011-04-19

The identification of genes that participate in melanomagenesis should suggest strategies for developing therapeutic modalities. We used a public array comparative genomic hybridization (CGH) database and real-time quantitative PCR (qPCR) analyses to identify the AMP kinase (AMPK)-related kinase NUAK2 as a candidate gene for melanomagenesis, and we analyzed its functions in melanoma cells. Our analyses had identified a locus at 1q32 where genomic gain is strongly associated with tumor thickness, and we used real-time qPCR analyses and regression analyses to identify NUAK2 as a candidate gene at that locus. Associations of relapse-free survival and overall survival of 92 primary melanoma patients with NUAK2 expression measured using immunohistochemistry were investigated using Kaplan-Meier curves, log rank tests, and Cox regression models. Knockdown of NUAK2 induces senescence and reduces S-phase, decreases migration, and down-regulates expression of mammalian target of rapamycin (mTOR). In vivo analysis demonstrated that knockdown of NUAK2 suppresses melanoma tumor growth in mice. Survival analysis showed that the risk of relapse is greater in acral melanoma patients with high levels of NUAK2 expression than in acral melanoma patients with low levels of NUAK2 expression (hazard ratio = 3.88; 95% confidence interval = 1.44-10.50; P = 0.0075). These data demonstrate that NUAK2 expression is significantly associated with the oncogenic features of melanoma cells and with the survival of acral melanoma patients. NUAK2 may provide a drug target to suppress melanoma progression. This study further supports the importance of NUAK2 in cancer development and tumor progression, while AMPK has antioncogenic properties.

Melanoma in-situ arising in seborrheic keratosis: a case report

PubMed Central

Repertinger, Susan; Wang, Jeff; Adickes, Edward; Sarma, Deba P

2008-01-01

Background Seborrheic keratosis is a very common benign skin tumor in man. Melanoma is rare but is the most dreaded of all malignant skin tumors. A melanoma arising in a seborrheic keratosis is distinctly rare. We are reporting such a case occurring in an 86-year-old man. Case presentation An-86-year-old male with a history of multiple actinic keratoses and seborrheic keratoses of the head and trunk presented with a mid-back skin lesion. The lesion was poorly circumscribed, flat, and gray, with a pink-tan, well-circumscribed scaly nodule within it. The biopsied lesion was composed of the usual features of hyperkeratotic seborrheic keratosis, but with focal atypical melanocytic proliferation with nesting along the dermal-epidermal junction. We interpreted this lesion as a melanoma in-situ arising within a seborrheic keratosis. Conclusion It is not uncommon for many physicians to remove a typical seborrheic keratosis without a confirmatory microscopic confirmation. We urge that all such lesions be examined by the pathologist to avoid missing another concomitant malignant lesion such as melanoma which needs adequate resection and close follow-up. PMID:18947402

A Randomized Trial on the Efficacy of Mastery Learning for Primary Care Provider Melanoma Opportunistic Screening Skills and Practice.

PubMed

Robinson, June K; Jain, Namita; Marghoob, Ashfaq A; McGaghie, William; MacLean, Michael; Gerami, Pedram; Hultgren, Brittney; Turrisi, Rob; Mallett, Kimberly; Martin, Gary J

2018-06-01

Early detection of melanoma represents an opportunity to reduce the burden of disease among people at increased risk for melanoma. To develop and demonstrate the efficacy of online training. Randomized educational trial. Primary care providers (PCPs). Mastery learning course with visual and dermoscopic assessment, diagnosis and management, and deliberate practice with feedback to reach a minimum passing standard. Pre-test/post-test diagnostic accuracy. Referral of concerning lesions for 3 months before and after the educational intervention. Among the 89 PCPs, 89.8% were internal medicine physicians, and the remainder were physician assistants embedded in internists' practices. There were no differences between control and intervention groups regarding gender, age, race, or percentage of full-time PCPs. The control group had more PCPs who reported less than 5 years of practice (n = 18) than the intervention group (n = 6) (χ 2 [6, n = 89] = 14.34, p = 0.03). PCPs in the intervention group answered more melanoma detection questions correctly on the post-test (M = 10.05, SE = 1.24) compared to control group PCPs (M = 7.11, SE = 0.24), and had fewer false-positive and no false-negative melanoma diagnoses (intervention, M = 1.09, SE = 0. 20; control, M = 3.1, SE = 0.23; ANCOVA, F[1,378] =27.86, p < 0.001; η p 2  = 0.26). PCPs who underwent training referred fewer benign lesions, including nevi, seborrheic keratoses, and dermatofibromas, than control PCPs (F[1,79] = 72.89, p < 0.001; η p 2  = 0.489; F[1,79] = 25.82, p < 0.001; η p 2  = 0.246; F[1,79] = 34.25, p < 0.001; η p 2  = 0.302; respectively). Those receiving training referred significantly more melanomas than controls (F[1,79] = 24.38, p < 0.001; η p 2  = 0.236). Referred melanomas (0.8  ± 0.07 per month for intervention, 0.17 ± 0.06 for control) were mostly located on the head and neck. Mastery learning improved PCPs' ability to detect melanoma on a standardized post-test and may improve referral of patients with suspected melanoma. Further studies are needed to confirm this finding. ClinicalTrials.gov NCT02385253.

Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma.

PubMed

Mustapha, Nadia; Mokdad-Bzéouich, Imèn; Maatouk, Mouna; Ghedira, Kamel; Hennebelle, Thierry; Chekir-Ghedira, Leila

2016-06-01

The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species in B16F10 and primary human keratinocyte cells. Our results indicate that hawthorn could be considered as a promising agent for the treatment of melanoma as it shows antitumor activity in vitro and in vivo. Moreover, hawthorn constituents are shown to be highly effective at inhibiting tyrosinase-mediated melanogenesis in vitro on melanoma cells by preventing oxidation in these cells and without affecting the viability of normal human keratinocyte cells. Then, hawthorn might also be used as a new candidate of natural skin depigmenting agents in skin care products.

In Vivo Imaging of Experimental Melanoma Tumors using the Novel Radiotracer 68Ga-NODAGA-Procainamide (PCA).

PubMed

Kertész, István; Vida, András; Nagy, Gábor; Emri, Miklós; Farkas, Antal; Kis, Adrienn; Angyal, János; Dénes, Noémi; Szabó, Judit P; Kovács, Tünde; Bai, Péter; Trencsényi, György

2017-01-01

The most aggressive form of skin cancer is the malignant melanoma. Because of its high metastatic potential the early detection of primary melanoma tumors and metastases using non-invasive PET imaging determines the outcome of the disease. Previous studies have already shown that benzamide derivatives, such as procainamide (PCA) specifically bind to melanin pigment. The aim of this study was to synthesize and investigate the melanin specificity of the novel 68 Ga-labeled NODAGA-PCA molecule in vitro and in vivo using PET techniques. Procainamide (PCA) was conjugated with NODAGA chelator and was labeled with Ga-68 ( 68 Ga-NODAGA-PCA). The melanin specificity of 68 Ga-NODAGA-PCA was tested in vitro , ex vivo and in vivo using melanotic B16-F10 and amelanotic Melur melanoma cell lines. By subcutaneous and intravenous injection of melanoma cells tumor-bearing mice were prepared, on which biodistribution studies and small animal PET/CT scans were performed for 68 Ga-NODAGA-PCA and 18 FDG tracers. 68 Ga-NODAGA-PCA was produced with high specific activity (14.9±3.9 GBq/µmol) and with excellent radiochemical purity (98%<), at all cases. In vitro experiments showed that 68 Ga-NODAGA-PCA uptake of B16-F10 cells was significantly ( p ≤0.01) higher than Melur cells. Ex vivo biodistribution and in vivo PET/CT studies using subcutaneous and metastatic tumor models showed significantly ( p ≤0.01) higher 68 Ga-NODAGA-PCA uptake in B16-F10 primary tumors and lung metastases in comparison with amelanotic Melur tumors. In experiments where 18 FDG and 68 Ga-NODAGA-PCA uptake of B16-F10 tumors was compared, we found that the tumor-to-muscle (T/M) and tumor-to-lung (T/L) ratios were significantly ( p ≤0.05 and p ≤0.01) higher using 68 Ga-NODAGA-PCA than the 18 FDG accumulation. Our novel radiotracer 68 Ga-NODAGA-PCA showed specific binding to the melanin producing experimental melanoma tumors. Therefore, 68 Ga-NODAGA-PCA is a suitable diagnostic radiotracer for the detection of melanoma tumors and metastases in vivo .

In Vivo Imaging of Experimental Melanoma Tumors using the Novel Radiotracer 68Ga-NODAGA-Procainamide (PCA)

PubMed Central

Kertész, István; Vida, András; Nagy, Gábor; Emri, Miklós; Farkas, Antal; Kis, Adrienn; Angyal, János; Dénes, Noémi; Szabó, Judit P.; Kovács, Tünde; Bai, Péter; Trencsényi, György

2017-01-01

Purpose: The most aggressive form of skin cancer is the malignant melanoma. Because of its high metastatic potential the early detection of primary melanoma tumors and metastases using non-invasive PET imaging determines the outcome of the disease. Previous studies have already shown that benzamide derivatives, such as procainamide (PCA) specifically bind to melanin pigment. The aim of this study was to synthesize and investigate the melanin specificity of the novel 68Ga-labeled NODAGA-PCA molecule in vitro and in vivo using PET techniques. Methods: Procainamide (PCA) was conjugated with NODAGA chelator and was labeled with Ga-68 (68Ga-NODAGA-PCA). The melanin specificity of 68Ga-NODAGA-PCA was tested in vitro, ex vivo and in vivo using melanotic B16-F10 and amelanotic Melur melanoma cell lines. By subcutaneous and intravenous injection of melanoma cells tumor-bearing mice were prepared, on which biodistribution studies and small animal PET/CT scans were performed for 68Ga-NODAGA-PCA and 18FDG tracers. Results: 68Ga-NODAGA-PCA was produced with high specific activity (14.9±3.9 GBq/µmol) and with excellent radiochemical purity (98%<), at all cases. In vitro experiments showed that 68Ga-NODAGA-PCA uptake of B16-F10 cells was significantly (p≤0.01) higher than Melur cells. Ex vivo biodistribution and in vivo PET/CT studies using subcutaneous and metastatic tumor models showed significantly (p≤0.01) higher 68Ga-NODAGA-PCA uptake in B16-F10 primary tumors and lung metastases in comparison with amelanotic Melur tumors. In experiments where 18FDG and 68Ga-NODAGA-PCA uptake of B16-F10 tumors was compared, we found that the tumor-to-muscle (T/M) and tumor-to-lung (T/L) ratios were significantly (p≤0.05 and p≤0.01) higher using 68Ga-NODAGA-PCA than the 18FDG accumulation. Conclusion: Our novel radiotracer 68Ga-NODAGA-PCA showed specific binding to the melanin producing experimental melanoma tumors. Therefore, 68Ga-NODAGA-PCA is a suitable diagnostic radiotracer for the detection of melanoma tumors and metastases in vivo. PMID:28382139

Chemokine Receptor CXCR4 Expression in Patients With Melanoma and Colorectal Cancer Liver Metastases and the Association With Disease Outcome

PubMed Central

Kim, Joseph; Mori, Takuji; Chen, Steven L.; Amersi, Farin F.; Martinez, Steve R.; Kuo, Christine; Turner, Roderick R.; Ye, Xing; Bilchik, Anton J.; Morton, Donald L.; Hoon, Dave S. B.

2006-01-01

Objective: To determine the role of chemokine receptor (CR) expression in patients with melanoma and colorectal cancer (CRC) liver metastases. Summary Background Data: Murine and in vitro models have identified CR as potential factors in organ-specific metastasis of multiple cancers. Chemokines via their respective receptors have been shown to promote cell migration to distant organs. Methods: Patients who underwent hepatic surgery for melanoma or CRC liver metastases were assessed. Screening cDNA microarrays of melanoma/CRC cell lines and tumor specimens were analyzed to identify CR. Microarray data were validated by quantitative real-time RT-PCR (qRT) in paraffin-embedded liver metastases. Migration assays and immunohistochemistry were performed to verify CR function and confirm CR expression, respectively. Results: Microarray analysis identified CXCR4 as the most common CR expressed by both cancers. qRT demonstrated CXCR4 expression in 24 of 27 (89%) melanoma and 28 of 29 (97%) CRC liver metastases. In vitro treatment of melanoma or CRC cells with CXCL12, the ligand for CXCR4, significantly increased cell migration (P < 0.001). Low versus high CXCR4 expression in CRC liver metastases correlated with a significant difference in overall survival (median 27 months vs. 10 months, respectively; P = 0.036). In melanoma, low versus high CXCR4 expression in liver metastases demonstrated no difference in overall survival (median 11 months vs. 8 months, respectively; P = not significant). Conclusions: CXCR4 is expressed and functional on melanoma and CRC cells. The ligand for CXCR4 is highly expressed in liver and may specifically attract melanoma and CRC CXCR4 (+) cells. Quantitative analysis of CXCR4 gene expression in patients with liver metastases has prognostic significance for disease outcome. PMID:16794396

Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway.

PubMed

Yeramian, Andree; Sorolla, Anabel; Velasco, Ana; Santacana, Maria; Dolcet, Xavier; Valls, Joan; Abal, Leandre; Moreno, Sara; Egido, Ramón; Casanova, Josep M; Puig, Susana; Vilella, Ramón; Llombart-Cussac, Antonio; Matias-Guiu, Xavier; Martí, Rosa M

2012-02-15

Despite the use of multiple therapeutic strategies, metastatic melanoma remains a challenge for oncologists. Thus, new approaches using combinational treatment may be used to try to improve the prognosis of this disease. In this report, we have analyzed the expression of receptor tyrosine kinases (RTKs) in melanoma specimens and in four metastatic melanoma cell lines. Both melanoma specimens and cell lines expressed RTKs, suggesting that they may represent eventual targets for multitargeted tyrosine kinase inhibitor, Suntinib. Sunitinib reduced the proliferation of two melanoma cell lines (M16 and M17) and increased apoptosis in one of them (M16). Moreover, the two metastatic melanoma cell lines harbored an activated receptor (PDGFRα and VEGFR, respectively), and Sunitinib suppressed the phosphorylation of the RTKs and their downstream targets Akt and ribosomal protein S6, in these two cell lines. Similar results were obtained when either PDGFRα or VEGFR2 expression was silenced by lentiviral-mediated short-hairpin RNA delivery in M16 and M17, respectively. To evaluate the interaction between Sunitinib and Bortezomib, median dose effect analysis using MTT assay was performed, and combination index was calculated. Bortezomib synergistically enhanced the Sunitinib-induced growth arrest in Sunitinib-sensitive cells (combination index < 1). Moreover, LY294002, a PI3K inhibitor, sensitized melanoma cells to Bortezomib treatment, suggesting that downregulation of phospho-Akt by Sunitinib mediates the synergy obtained by Bortezomib + Sunitinib cotreatment. Altogether, our results suggest that melanoma cells harboring an activated RTK may be clinically responsive to pharmacologic RTK inhibition by Sunitinib, and a strategy combining Sunitinib and Bortezomib, may provide therapeutic benefit. Copyright © 2011 UICC.

Novel alpha-MSH peptide analogs for melanoma targeting

NASA Astrophysics Data System (ADS)

Flook, Adam Michael

Skin cancer is the one of the most diagnosed cancers in the United States with increasing incidence over the past two decades. There are three major forms of skin cancer but melanoma is the deadliest. It is estimated that 76,690 new diagnoses of melanoma and 9,480 deaths will occur in 2013. Melanoma accounts for approximately 1.6% of all cancer related deaths and is the 5 th leading diagnosed cancer in the United States. The mean survival rate of patients diagnosed with metastatic melanoma is six months, with five year survival rates of less than 5%. In this project, we describe the design and characterization of novel melanoma-targeting peptide analogs for use in diagnostic imaging of both primary and metastatic melanoma lesions. Novel alpha-MSH peptide conjugates were designed to target the melanocortin-1 receptor present and over-expressed on melanoma cells. These peptides were synthesized and their in-vitro melanocortin-1 receptor binding affinities were established in murine melanoma cells. Once binding affinities were determined, the peptides were radiolabeled with 99mTc utilizing a novel direct radiolabeling technique developed in our laboratory. The peptides were purified via reverse-phase high performance liquid chromatography and in-vivo melanoma targeting and pharmacokinetic properties were determined in B16/F1 melanoma-bearing female C57BL/6 mice. Biodistribution and SPECT/CT imaging studies were performed with the promising 99m Tc-labeled peptide conjugates. All alpha-MSH peptide conjugates tested showed low nanomolar binding affinity for the melanocortin-1 receptor. All peptides were readily radiolabeld with 99mTc with greater than 95% radiochemical purity. All 99mTc-labeled peptides displayed high specific in-vivo melanoma tumor uptake while maintaining low normal organ accumulation, and were excreted through the urinary system in a timely fashion. In addition, all tested 99mTc-labeld alpha-MSH peptides demonstrated clear visualization of in-vivo tumor lesions with SPECT/CT. While all peptides exhibited high melanoma uptake, extremely high non-specific renal uptake was of concern. After synthesis of alpha-MSH peptide conjugates containing a different amino acid linker, renal uptake was drastically reduced and a lead compound had emerged, showing favorable in-vivo melanoma targeting and uptake properties with limited amounts of non-specific renal accumulation.

Epidemiological and clinical characteristics of malignant melanoma in Southeast Anatolia in Turkey.

PubMed

Sula, Bilal; Uçmak, Feyzullah; Kaplan, Mehmet Ali; Urakçi, Zuhat; Arica, Mustafa; Isikdogan, Abdurrahman

2016-01-01

The present study aimed to establish the epidemiological and clinical characteristics of patients who were histopathologically diagnosed with malignant melanoma (MM). The present study retrospectively analyzed the data of 78 patients who were histopathologically diagnosed with MM in Dicle University Medical Faculty, Dermatology and Medical Oncology departments between 2005 and 2014. The study included 78 patients in total with 44 (56.4%) male and 34 (43.6%) female. Median age of the patients was 62.50 years (range: 27 - 84 years). Of the patients, 78.2% (n = 61) had cutaneous melanoma, 8.9% had solid organ melanoma, and 2.5% had ocular and mucosal melanoma. The most common tumor localization among the patients was the lower extremities with 29.4% (n = 23). The most common histopathological type was nodular malignant melanoma with 35.8% (n = 28). Based on TNM, Clark and Breslow classifications, 26.9% (n = 21) of the patients were stage 4, 26.9% (n = 21) were Clark stage 4, and 37.1% (n = 29) were Breslow stage 4. Median overall survival in all patients was 14.9 months (95% CI 10.9 - 18.8 months). In the multivariate Cox analysis, only stage statistically significantly affecting survival [odds ratio (OR): 0.54; (95% CI 0.16-1.82, p = 0.02)]. Malignant melanoma data are also important for the optimal utilization of effective methods and healthcare resources to prevent the disease. In order to minimize MM mortality and morbidity, not only the society but also physicians from primary and secondary care hospitals should become familiar with melanoma.

Melanoma knowledge, perception, and awareness in ethnic minorities in Chicago: recommendations regarding education.

PubMed

Robinson, June K; Joshi, Komal M; Ortiz, Sara; Kundu, Roopal V

2011-03-01

To assess the level of melanoma awareness and risk perception among ethnic minorities and to identify ways to enhance the relevance of melanoma educational materials for ethnic minorities.   Twelve focus groups composed of participants from a single ethnicity [African-American (n=40), Hispanic (n=40), and Asian (n=40)], participated in a 2 h discussion on melanoma and skin cancer and commented on an educational brochure by the American Cancer Society and reacted to photographs of melanoma on ethnic skin. Participants also evaluated the ability to sunburn and tan and the skin cancer risk of images of celebrities before and after the discussion. Additionally, participants assessed the skin tone of celebrities as very fair, fair, olive, light brown, dark brown, and very dark. The audiotape recordings of the 12 focus groups were transcribed and analyzed with the Non-numerical Unstructured Data Indexing Searching and Theorizing software for common themes. The common themes were (1) lack of relevance of skin cancer to ethnic people, (2) understanding of skin cancer risk terminology is based on personal experience and what is acquired from the media, and (3) sources of health information for ethnic minorities are fragmented and physicians are not the primary source of information. Celebrity images representing the six skin tones were selected. Relevance of melanoma education to ethnic people may be improved by using 'melanoma skin cancer', photographs of early melanoma in people with dark skin, and providing guidance on how to inspect hands and feet for suspicious moles. Copyright © 2010 John Wiley & Sons, Ltd.

Activating PIK3CA mutations coexist with BRAF or NRAS mutations in a limited fraction of melanomas.

PubMed

Manca, Antonella; Lissia, Amelia; Capone, Mariaelena; Ascierto, Paolo A; Botti, Gerardo; Caracò, Corrado; Stanganelli, Ignazio; Colombino, Maria; Sini, MariaCristina; Cossu, Antonio; Palmieri, Giuseppe

2015-01-28

Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma. Functional alterations are deeply involved in PI3K-AKT activation, with a minimal role reported for mutations in PIK3CA, the catalytic subunit of the PI3K gene. We here assessed the prevalence of the coexistence of BRAF/NRAS and PIK3CA mutations in a series of melanoma samples. A total of 245 tumor specimens (212 primary melanomas and 33 melanoma cell lines) was screened for mutations in BRAF, NRAS, and PIK3CA genes by automated direct sequencing. Overall, 110 (44.9%) samples carried mutations in BRAF, 26 (10.6%) in NRAS, and 24 (9.8%) in PIK3CA. All identified PIK3CA mutations have been reported to induce PI3K activation; those detected in cultured melanomas were investigated for their interference with the antiproliferative activity of the BRAF-mutant inhibitor vemurafenib. A reduced suppression in cell growth was observed in treated cells carrying both BRAF and PIK3CA mutations as compared with those presenting a mutated BRAF only. Among the analysed melanomas, 12/245 (4.9%) samples presented the coexistence of PIK3CA and BRAF/NRAS mutations. Our study further suggests that PIK3CA mutations account for a small fraction of PI3K pathway activation and have a limited impact in interfering with the BRAF/NRAS-driven growth in melanoma.

Sun Protection Practices and Sun Exposure among Children with a Parental History of Melanoma

PubMed Central

Glenn, Beth A.; Lin, Tiffany; Chang, L. Cindy; Okada, Ashley; Wong, Weng Kee; Glanz, Karen; Bastani, Roshan

2014-01-01

Background First-degree relatives of melanoma survivors have a substantially higher lifetime risk for melanoma than individuals with no family history. Exposure to ultraviolet radiation is the primary modifiable risk factor for the disease. Reducing UV exposure through sun protection may be particularly important for children with a parental history of melanoma. Nonetheless, limited prior research has investigated sun protection practices and sun exposure among these children. Methods The California Cancer Registry was used to identify melanoma survivors eligible to participate in a survey to assess their children's sun protection practices and sun exposure. The survey was administered by mail, telephone, or web to Latino and non-Latino white melanoma survivors with at least one child (0–17 years; N = 324). Results Sun exposure was high and the rate of sunburn was equivalent to or higher than estimates from average risk populations. Use of sun protection was suboptimal. Latino children were less likely to wear sunscreen and hats and more likely to wear sunglasses, although these differences disappeared in adjusted analyses. Increasing age of the child was associated with lower sun protection and higher risk for sunburn whereas higher objective risk for melanoma predicted improved sun protection and a higher risk for sunburns. Perception of high barriers to sun protection was the strongest modifiable correlate of sun protection. Conclusions Interventions to improve sun protection and reduce sun exposure and sunburns in high risk children are needed. Impact Intervening in high risk populations may help reduce the burden of melanoma in the U.S. PMID:25587110

Label-free high-throughput detection and quantification of circulating melanoma tumor cell clusters by linear-array-based photoacoustic tomography

NASA Astrophysics Data System (ADS)

Hai, Pengfei; Zhou, Yong; Zhang, Ruiying; Ma, Jun; Li, Yang; Shao, Jin-Yu; Wang, Lihong V.

2017-04-01

Circulating tumor cell (CTC) clusters, arising from multicellular groupings in a primary tumor, greatly elevate the metastatic potential of cancer compared with single CTCs. High-throughput detection and quantification of CTC clusters are important for understanding the tumor metastatic process and improving cancer therapy. Here, we applied a linear-array-based photoacoustic tomography (LA-PAT) system and improved the image reconstruction for label-free high-throughput CTC cluster detection and quantification in vivo. The feasibility was first demonstrated by imaging CTC cluster ex vivo. The relationship between the contrast-to-noise ratios (CNRs) and the number of cells in melanoma tumor cell clusters was investigated and verified. Melanoma CTC clusters with a minimum of four cells could be detected, and the number of cells could be computed from the CNR. Finally, we demonstrated imaging of injected melanoma CTC clusters in rats in vivo. Similarly, the number of cells in the melanoma CTC clusters could be quantified. The data showed that larger CTC clusters had faster clearance rates in the bloodstream, which agreed with the literature. The results demonstrated the capability of LA-PAT to detect and quantify melanoma CTC clusters in vivo and showed its potential for tumor metastasis study and cancer therapy.

Burden of skin cancer in Belgium and cost-effectiveness of primary prevention by reducing ultraviolet exposure.

PubMed

Pil, Lore; Hoorens, Isabelle; Vossaert, Katrien; Kruse, Vibeke; Tromme, Isabelle; Speybroeck, Niko; Brochez, Lieve; Annemans, Lieven

2016-12-01

Skin cancer (melanoma- and non-melanoma skin cancer) is one of the most rapidly increasing cancers worldwide. This study analysed the current and future economic burden of skin cancer in Belgium and the cost-effectiveness of primary prevention of skin cancer. A retrospective bottom-up cost-of-illness study was performed, together with a Markov model in order to analyse the cost-effectiveness and the budget impact analysis of primary prevention of skin cancer in Belgium. Total prevalence of skin cancer in Belgium was estimated to triple in the next 20years. The total economic burden of skin cancer in 2014 in Belgium was estimated at €106 million, with a cumulative cost of €3 billion in 2034. The majority of this total cost was due to melanoma (65%). Over a period of 50years, both a sensitisation campaign and a total ban on sunbed use would lead to a gain in quality-adjusted life-years and cost-savings. For every euro invested in the campaign, €3.6 would be saved on the long-term for the healthcare payer. Policy makers and clinicians should promote UV protection strategies, as they were estimated to be dominant strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

Aberrant intermediate filament and synaptophysin expression is a frequent event in malignant melanoma: an immunohistochemical study of 73 cases.

PubMed

Romano, Ryan C; Carter, Jodi M; Folpe, Andrew L

2015-08-01

Malignant melanomas are known to express vimentin, among other intermediate filaments. Though anomalous keratin expression by malignant melanoma has been reported, its frequency is not well-established and this phenomenon is not well-known. We have seen in consultation a number of malignant melanomas with anomalous expression of keratin, other intermediate filaments, or synaptophysin, and therefore studied a large group of primary and metastatic melanomas to determine the frequency of these events. About 73 cases of malignant melanoma (22 primaries and 51 metastases) from 71 patients (51 male, 20 female; mean 59 years, range 17-87 years) were retrieved from our archives. Prior diagnoses were confirmed by re-review of hematoxylin and eosin sections and relevant (e.g., S100 protein, HMB45, Melan-A, and tyrosinase) immunohistochemical studies. Available sections were immunostained for keratin (OSCAR and AE1/AE3 antibodies), desmin, neurofilament protein, glial fibrillary acidic protein, synaptophysin, and chromogranin A. Not all cases could be tested for all markers. Cases were predominantly epithelioid (48/73, 66%) or spindle cell/desmoplastic (25/73, 34%). S100 protein, Melan-A, HMB45, and tyrosinase were positive in 60/65 (92%), 34/64 (53%), 30/60 (50%), 25/48 (52%) of cases, respectively. All five S100-protein-negative cases expressed at least one of the other melanocytic markers: Melan-A (two of four, 50%), HMB45 (two of three, 67%), and tyrosinase (one of two, 50%). All cases expressed at least one melanocytic marker. Cases were positive for keratin (OSCAR, 17/61, 28%; AE1/AE3, 16/40, 40%), desmin (11/47, 24%), neurofilament protein (5/31, 16%), glial fibrillary acidic protein (3/32, 9%), and synaptophysin (10/34, 29%), typically only in a minority of cells. Chromogranin was negative (0/32, 0%). Altogether 9/73 cases (12%) showed expression of >1 intermediate filament. All S100-protein-negative melanomas showed anomalous intermediate filament expression (keratin--one case, desmin--three cases, neurofilament protein--one case). Anomalous intermediate filament or synaptophysin expression was more common in epithelioid (intermediate filament, 27/48, 56%; synaptophysin, 7/22, 32%) as compared with spindle cell/desmoplastic (intermediate filament, 8/25, 32%; synaptophysin, 3/12, 25%) melanomas. Overall, 48% (35/73) of cases showed anomalous expression of at least one intermediate filament. Anomalous expression of all intermediate filaments and synaptophysin was found in significant subsets of malignant melanoma, representing potentially serious diagnostic pitfalls. While the inclusion of consultation cases may inflate the frequency of these findings in this series, similar findings were also seen in institutional cases. Malignant melanoma showing anomalous intermediate filament and synaptophysin expression may easily be mistaken for carcinomas, rhabdomyosarcomas, and neuroendocrine tumors. Awareness of this phenomenon, careful histopathological evaluation, and an appropriate melanocytic immunohistochemical panel should facilitate the diagnosis of malignant melanoma with unusual immunophenotypes.

The Metastasis Suppressor NME1 Regulates Expression of Genes Linked to Metastasis and Patient Outcome in Melanoma and Breast Carcinoma

PubMed Central

MCCORKLE, JOSEPH R.; LEONARD, MARY K.; KRANER, SUSAN D.; BLALOCK, ERIC M.; DEQIN, MA; ZIMMER, STEPHEN G.; KAETZEL, DAVID M.

2015-01-01

NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip. Robust NME1 expression was achieved following infection with the Ad5-NME1 adenovirus in the human metastasis-derived cell lines WM1158 (melanoma) and WRO82 (follicular thyroid carcinoma), resulting in wide-ranging effects on gene expression in both settings. A substantial proportion of the NME1-regulated genes identified in the analyses were of clear potential relevance to metastasis, such as matrix metalloproteinase-1 (MMP1), angiopoeitin-2 (ANGPT2), SERPINB9 and colony stimulating factor receptor-2B (CSFR2B). Nine genes were identified (false discovery rate ≥0.1) that were regulated by NME1 in both the WM1158 and WRO82 cell lines, each possessing one of more such metastasis-relevant activities as stress fiber formation and focal adhesion (PPM1E, ZYX, PFN1), chemotaxis (CCR1) epithelial-mesenchymal signaling (WNT1), differentiation and morphogenesis (TBX4, ZFP36L2), and G protein modulation (GPR52 and PFN1). In addition, a number of the NME1-regulated genes were shown to be of prognostic value for distant disease-free survival and overall survival in melanoma and breast cancer. The combined expression of three NME1-regulated genes CSFR2B, MSF4A1 and SERPINB9 provided a strongly synergistic correlation with distant disease-free survival in the basal subtype of breast cancer (p<3.5e−5, hazard ratio=0.33). Our study demonstrates that analysis of NME1-dependent gene expression is a powerful approach for identifying potential modulators of metastatic potential in multiple cancer types, which in turn may represent useful therapeutic targets. The study also highlights NME1-dependent genes as potential prognostic/diagnostic indices, which are profoundly lacking at present in melanoma. PMID:25048347

The metastasis suppressor NME1 regulates expression of genes linked to metastasis and patient outcome in melanoma and breast carcinoma.

PubMed

McCorkle, Joseph R; Leonard, Mary K; Kraner, Susan D; Blalock, Eric M; Ma, Deqin; Zimmer, Stephen G; Kaetzel, David M

2014-01-01

NME1 is a well-documented metastasis suppressor gene, with suppressor activity demonstrated across a wide spectrum of human cancers including melanoma and carcinomas of the breast, stomach and thyroid. A primary aim of the current study was to identify profiles of genes whose expression is regulated by NME1 in cell lines of melanoma and thyroid carcinoma origin. Impact of NME1 was determined by forcing its expression transiently in cell lines using a novel Ad5-based adenoviral vector (Ad5-NME1), followed 48 h later by analysis of RNA expression profiles using the U133A microarray chip. Robust NME1 expression was achieved following infection with the Ad5-NME1 adenovirus in the human metastasis-derived cell lines WM1158 (melanoma) and WRO82 (follicular thyroid carcinoma), resulting in wide-ranging effects on gene expression in both settings. A substantial proportion of the NME1-regulated genes identified in the analyses were of clear potential relevance to metastasis, such as matrix metalloproteinase-1 (MMP1), angiopoietin-2 (ANGPT2), SERPINB9 and colony stimulating factor receptor-2B (CSFR2B). Nine genes were identified (false discovery rate <0.1) that were regulated by NME1 in both the WM1158 and WRO82 cell lines, each possessing one or more such metastasis-relevant activities as stress fiber formation and focal adhesion (PPM1E, ZYX, PFN1), chemotaxis (CCR1) epithelial-mesenchymal signaling (WNT6), differentiation and morphogenesis (TBX4, ZFP36L2), and G protein modulation (GPR52 and PFN1). In addition, a number of the NME1-regulated genes were shown to be of prognostic value for distant disease-free survival and overall survival in melanoma and breast cancer. The combined expression of three NME1-regulated genes CSFR2B, MSF4A1 and SERPINB9 provided a strongly synergistic correlation with distant disease-free survival in the basal subtype of breast cancer (p<3.5e(-5), hazard ratio=0.33). Our study demonstrates that analysis of NME1-dependent gene expression is a powerful approach for identifying potential modulators of metastatic potential in multiple cancer types, which in turn may represent useful therapeutic targets. The study also highlights NME1-dependent genes as potential prognostic/diagnostic indices, which are profoundly lacking at present in melanoma. Copyright© 2014, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Coffee consumption and the risk of malignant melanoma in the Norwegian Women and Cancer (NOWAC) Study.

PubMed

Lukic, Marko; Jareid, Mie; Weiderpass, Elisabete; Braaten, Tonje

2016-07-29

Coffee contains biologically-active substances that suppress carcinogenesis in vivo, and coffee consumption has been associated with a lower risk of malignant melanoma. We studied the impact of total coffee consumption and of different brewing methods on the incidence of malignant melanoma in a prospective cohort of Norwegian women. We had baseline information on total coffee consumption and consumption of filtered, instant, and boiled coffee from self-administered questionnaires for 104,080 women in the Norwegian Women and Cancer (NOWAC) Study. We also had follow-up information collected 6-8 years after baseline. Multiple imputation was used to deal with missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for malignant melanoma by consumption category of total, filtered, instant, and boiled coffee. During 1.7 million person-years of follow-up, 762 cases of malignant melanoma were diagnosed. Compared to light consumers of filtered coffee (≤1 cup/day), we found a statistically significant inverse association with low-moderate consumption (>1-3 cups/day, HR = 0.80; 95 % confidence interval [CI] 0.66-0.98) and high-moderate consumption of filtered coffee (>3-5 cups/day, HR = 0.77; 95 % CI 0.61-0.97) and melanoma risk (p trend = 0.02). We did not find a statistically significant association between total, instant, or boiled coffee consumption and the risk of malignant melanoma in any of the consumption categories. The data from the NOWAC Study indicate that a moderate intake of filtered coffee could reduce the risk of malignant melanoma.

Multiple primary cancers in Connecticut, 1935-82.

PubMed Central

Boice, J. D.; Curtis, R. E.; Kleinerman, R. A.; Flannery, J. T.; Fraumeni, J. F.

1986-01-01

Recently, the National Cancer Institute published a comprehensive monograph on multiple primary cancers in Connecticut and Denmark. This paper summarizes some of the observations made on the Connecticut population. Data compiled by the Connecticut Tumor Registry have extended our knowledge about the patterns of multiple primary cancers, especially among long-term survivors of cancer and among patients with relatively rare tumors about which little information currently exists. When compared with the general Connecticut population, cancer patients had a 31 percent (RR = 1.31) increased risk of developing a second cancer and a 23 percent (RR = 1.23) elevated risk of second cancer at a different site from the first. Common environmental exposures seemed responsible for the excess occurrence of many second cancers, particularly those related to cigarette smoking, alcohol consumption, or both. For example, persons with epithelial cancers of the lung, larynx, esophagus, buccal cavity, and pharynx were particularly prone to develop new cancers in the same or contiguous tissue throughout their lifetimes. Cancers of the colon, uterine corpus, breast, and ovary frequently occurred together, suggesting underlying hormonal or dietary influences. Only patients with prostate cancer were at significantly low risk for second cancer development; this might be an artifact of case finding, since advanced age at initial diagnosis was generally associated with an underascertainment of second cancers. Radiotherapy may have caused rectal and other cancer among patients with cancers of the female genital tract, and leukemia among patients with uterine corpus cancer. Chemotherapy with alkylating agents probably contributed to the excess of acute nonlymphocytic leukemia following multiple myeloma or cancers of the breast and ovary. Genetic susceptibility seemed to explain some tumor complexes, such as the multiple occurrences of cutaneous melanoma and the excess of bone cancer following retinoblastoma. Research into multiple cancer syndromes should enhance our understanding of carcinogenic factors and mechanisms and the development of strategies for cancer prevention and control. PMID:3541409

Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas

PubMed Central

Roller, Devin G.; Capaldo, Brian; Bekiranov, Stefan; Mackey, Aaron J.; Conaway, Mark R.; Petricoin, Emanuel F.; Gioeli, Daniel; Weber, Michael J.

2016-01-01

Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes (“back-seat drivers”) and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway. PMID:26673621

Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas.

PubMed

Roller, Devin G; Capaldo, Brian; Bekiranov, Stefan; Mackey, Aaron J; Conaway, Mark R; Petricoin, Emanuel F; Gioeli, Daniel; Weber, Michael J

2016-01-19

Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naïve BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes ("back-seat drivers") and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway.

[A case of leptomeningeal melanomatosis with acute paraplegia and multiple cranial nerve palsies].

PubMed

Hattori, Kasumi; Matsuda, Nozomu; Murakami, Takenobu; Ito, Eiichi; Ugawa, Yoshikazu

2017-12-27

A 62-year-old man with acute paraplegia was transferred to our hospital. He had flaccid paraplegia and multiple cranial nerve palsies, such as mydriasis of the left pupil, abduction palsy of the left eye, hoarseness and dysphagia, but no meningeal irritation signs. MRI of the spinal canal showed swellings of the conus medullaris and the cauda equine, and also contrast enhancement of the spinal meninges. The cerebrospinal fluid (CSF) showed pleocytosis and protein increment. The lymph node was swollen in his right axilla. The biopsy specimen from the right axillary lymph node revealed metastasis of malignant melanoma histologically. Careful check-up of his whole body found a malignant melanoma in the subungual region of the right ring finger. Repeated cytological examination revealed melanoma cells in the CSF, confirming the diagnosis of leptomeningeal melanomatosis. His consciousness was gradually deteriorated. His family members chose supportive care instead of chemotherapy or surgical therapy after full information about his conditions. Finally, he died 60 days after transfer to our hospital. This is a rare case of leptomenigeal melanomatosis presenting with acute paraplegia and multiple cranial nerve palsies. Careful follow-up and repeated studies are vital for the early diagnosis of leptomenigeal melanomatosis in spite of atypical clinical presentation.