Sample records for high-risk melanoma patients
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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.
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Association of Patient Risk Factors and Frequency of Nevus-Associated Cutaneous Melanomas.
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.
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Salerni, Gabriel; Carrera, Cristina; Lovatto, Louise; Puig-Butille, Joan Anton; Badenas, Celia; Plana, Estel; Puig, Susana; Malvehy, Josep
2011-01-01
Background Early detection of melanoma is the best way to improve prognosis. Digital follow up (DFU) programs of high-risk populations could be an efficient strategy for detecting early melanomas with low morbidity. Objective to report the added value of the use of the “two-step method” (digital total-body photography and digital dermoscopy) Methods Analysis of the surveillance of 618 high-risk melanoma patients included in our DFU-program from 1999 to 2008. Results A total of 11396 lesions were monitored (mean 18.44 per patient) during a median follow-up of 96 months (median 10 visits per patient). 1152 lesions, 1.86 per patient, were excised. Almost 70% (798) were lesions previously registered at least twice, while 356 (30%) were detected and removed in the same visit. During follow-up, 98 melanomas (8.5% of excised lesions) were diagnosed in 78 patients (12.6%). 53 melanomas were in situ (53.3%), while invasive (45) showed a Breslow index of less than 1 mm (median 0.5 mm) and none was ulcerated. Limitations Since there are no control groups we cannot convey if the combined use of total-body photography and digital dermoscopy is more beneficial than these techniques used separately. Conclusion DFU with Total-Body Photography and Dermoscopy in a selected high-risk population demonstrated the early detection of melanomas with a low rate of excisions. Long-term follow-up is required to allow the detection of slow growing melanomas. Based on our 10-year experience, melanomas can be diagnosed at any time, suggesting that in high-risk population, DFU should be maintained with time. PMID:21683472
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Routine Computer Tomography Imaging for the Detection of Recurrences in High-Risk Melanoma Patients.
Park, Tristen S; Phan, Giao Q; Yang, James C; Kammula, Udai; Hughes, Marybeth S; Trebska-McGowan, Kasia; Morton, Kathleen E; White, Donald E; Rosenberg, Steven A; Sherry, Richard M
2017-04-01
The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.
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Oliveria, Susan A; Heneghan, Maureen K; Halpern, Allan C; Hay, Jennifer L; Geller, Alan C
2012-05-01
To assess current self-reported communication and screening practices of dermatologists to their patients with melanoma about family members' risk of melanoma at the time of diagnosis and to understand the barriers that dermatologists encounter in communicating risk to patients. Descriptive survey study. Office-based practicing physicians in the United States. One thousand dermatologists. Melanoma risk communication practices. Of 974 eligible dermatologists, 406 completed the survey (response rate, 41.7%). Almost 85% of dermatologists reported that they often or always communicate risk to patients with melanoma about their first-degree relatives, and almost 80% reported that they often or always advise their patients with melanoma that their older children (18 years) may be at greater risk of skin cancer. However, less than 50% of dermatologists routinely offered to screen first-degree relatives who live nearby, while only 19.7% used medical record reminders to note communication of melanoma risk to family members. Most dermatologists reported no major barriers to melanoma risk communication. However, the presence of "any risk communication barrier" (time constraints, absence of guidelines, or lack of written material) was associated with reduced melanoma risk communication practices by dermatologists. The observed high rates of self-reported risk communication by dermatologists to patients with melanoma about their first-degree family members are encouraging. However, the reported low rates of actual screening of first-degree relatives warrant easy-to-administer office-based medical record reminders to facilitate and optimize screening of at-risk relatives.
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Adjuvant Sunitinib or Valproic Acid in High-Risk Patients With Uveal Melanoma
2017-10-25
Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Iris Melanoma; Stage I Intraocular Melanoma; Stage IIA Intraocular Melanoma; Stage IIB Intraocular Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIC Intraocular Melanoma
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Ferris, Laura K; Farberg, Aaron S; Middlebrook, Brooke; Johnson, Clare E; Lassen, Natalie; Oelschlager, Kristen M; Maetzold, Derek J; Cook, Robert W; Rigel, Darrell S; Gerami, Pedram
2017-05-01
A significant proportion of patients with American Joint Committee on Cancer (AJCC)-defined early-stage cutaneous melanoma have disease recurrence and die. A 31-gene expression profile (GEP) that accurately assesses metastatic risk associated with primary cutaneous melanomas has been described. We sought to compare accuracy of the GEP in combination with risk determined using the web-based AJCC Individualized Melanoma Patient Outcome Prediction Tool. GEP results from 205 stage I/II cutaneous melanomas with sufficient clinical data for prognostication using the AJCC tool were classified as low (class 1) or high (class 2) risk. Two 5-year overall survival cutoffs (AJCC 79% and 68%), reflecting survival for patients with stage IIA or IIB disease, respectively, were assigned for binary AJCC risk. Cox univariate analysis revealed significant risk classification of distant metastasis-free and overall survival (hazard ratio range 3.2-9.4, P < .001) for both tools. In all, 43 (21%) cases had discordant GEP and AJCC classification (using 79% cutoff). Eleven of 13 (85%) deaths in that group were predicted as high risk by GEP but low risk by AJCC. Specimens reflect tertiary care center referrals; more effective therapies have been approved for clinical use after accrual. The GEP provides valuable prognostic information and improves identification of high-risk melanomas when used together with the AJCC online prediction tool. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Lattanzi, Michael; Han, Joseph; Moran, Una; Utter, Kierstin; Tchack, Jeremy; Sabado, Rachel Lubong; Berman, Russell; Shapiro, Richard; Huang, Hsin-Hui; Osman, Iman; Bhardwaj, Nina; Pavlick, Anna C
2018-05-18
Cancer-testis antigen NY-ESO-1 is a highly immunogenic melanoma antigen which has been incorporated into adjuvant vaccine clinical trials. Three such early-phase trials were conducted at our center among patients with high-risk resected melanoma. We herein report on the pooled long-term survival outcomes of these patients in comparison to historical controls. All melanoma patients treated at NYU Langone Health under any of three prospective adjuvant NY-ESO-1 vaccine trials were retrospectively pooled into a single cohort. All such patients with stage III melanoma were subsequently compared to historical control patients identified via a prospective institutional database with protocol-driven follow-up. Survival times were calculated using the Kaplan-Meier method, and Cox proportional hazard models were employed to identify significant prognostic factors and control for confounding variables. A total of 91 patients were treated with an NY-ESO-1 vaccine for the treatment of high-risk resected melanoma. Of this group, 67 patients were stage III and were selected for comparative analysis with 123 historical control patients with resected stage III melanoma who received no adjuvant therapy. Among the pooled vaccine cohort (median follow-up 61 months), the estimated median recurrence-free survival was 45 months, while the median overall survival was not yet reached. In the control cohort of 123 patients (median follow-up 30 months), the estimated median recurrence-free and overall survival were 22 and 58 months, respectively. Within the retrospective stage III cohort, NY-ESO-1 vaccine was associated with decreased risk of recurrence (HR = 0.56, p < 0.01) and death (HR = 0.51, p = 0.01). Upon controlling for sub-stage, the adjuvant NY-ESO-1 clinical trial cohort continued to exhibit decreased risk of recurrence (HR = 0.45, p < 0.01) and death (HR = 0.40, p < 0.01). In this small retrospective cohort of resected stage III melanoma patients, adjuvant NY-ESO-1 vaccine immunotherapy was associated with longer recurrence-free and overall survival relative to historical controls. These data support the continued investigation of adjuvant NY-ESO-1 based immunotherapy regimens in melanoma.
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Goodson, Agnessa Gadeliya; Florell, Scott R.; Hyde, Mark; Bowen, Glen M.; Grossman, Douglas
2011-01-01
Background Our previous experience monitoring nevi in high risk patients by serial digital epiluminescence microscopy (DELM) photography achieved low biopsy rates, but was limited by melanomas presenting as new lesions or arising from nevi that had not been photographed. Objective To determine whether biopsy rates, efficiency of melanoma detection, and melanoma origin (de novo vs. nevus-derived) differed in a similar patient population monitored by total body (TB) photography. Methods 1076 patients (including 187 from prior cohort) underwent TB photography and were monitored using photographs obtained at the initial visit. Risk factors and median monitoring periods for these patients were comparable to patients previously monitored by DELM photography. Results 275 biopsies were performed in 467 patients on follow-up visits. Of 12 melanomas detected on follow-up, five were invasive; five presented as changing lesions and two as new lesions; nine arose de novo and the remainder was nevus-derived. Conclusions In our experience with both approaches, monitoring patients at risk for melanoma by TB (compared to DELM) photography was associated with lower biopsy rates and lower nevus to melanoma ratios, and facilitated detection of both new and changing lesions. In both cohorts, the majority of melanomas detected on follow-up arose de novo. PMID:20653722
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Serum microRNAs as biomarkers for recurrence in melanoma
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
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Taber, Jennifer M; Aspinwall, Lisa G
2015-10-01
A CDKN2A/p16 mutation confers 76 % lifetime risk of developing melanoma to US residents, and high-risk individuals are counseled to use sunscreen. Generally, for patients at population risk, gain framing more effectively promotes prevention behaviors; however, it is unknown whether loss frames might more effectively promote behavioral intentions and perceived control over disease risk among high-risk patients. Undergraduates (N = 146) underwent a simulated genetic counseling and test reporting session for hereditary melanoma. Participants watched a video of a genetic counselor providing information in which genetic risk of melanoma (Low: 15 %; High: 76 %) and framed recommendations to use sunscreen (Loss: Risk may increase by 15 % if don't use sunscreen; Gain: Risk may decrease by 15 % if use sunscreen) were manipulated. Controlling for baseline sunscreen use, high-risk participants given loss frames reported greater beliefs that sunscreen would reduce risk than high-risk participants given gain frames. Further, high-risk participants with fair skin tended to report greater intentions to use sunscreen when given loss frames versus gain frames. Perceived control over risk mediated the effect of message frame and disease risk on intentions to use sunscreen. When counseling patients with elevated cancer risk, genetic counselors may consider framing prevention behavioral recommendations in terms of potential losses.
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Communication about melanoma and risk reduction after melanoma diagnosis.
Rodríguez, Vivian M; Berwick, Marianne; Hay, Jennifer L
2017-12-01
Melanoma patients are advised to perform regular risk-reduction practices, including sun protection as well as skin self-examinations (SSEs) and physician-led examinations. Melanoma-specific communication regarding family risk and screening may promote such behaviors. To this end, associations between patients' melanoma-specific communication and risk reduction were examined. Melanoma patients (N = 169) drawn from a population-based cancer registry reported their current risk-reduction practices, perceived risk of future melanoma, and communication with physicians and relatives about melanoma risk and screening. Patients were, on average, 56 years old and 6.7 years' post diagnosis; 51% were male, 93% reported "fair/very fair" skin color, 75% completed at least some college, and 22% reported a family history of melanoma. Patients reported varying levels of regular (always/nearly always) sun protection: sunscreen use (79%), shade seeking (60%), hat use (54%), and long-sleeve shirt use (30%). Only 28% performed thorough SSE regularly, whereas 92% reported undergoing physician-led skin examinations within the past year. Participants who were female, younger, and had a higher perceived risk of future melanoma were more likely to report past communication. In adjusted analyses, communication remained uniquely associated with increased sunscreen use and SSE. Encouraging melanoma patients to have a more active role in discussions concerning melanoma risk and screening with relatives and physicians alike may be a useful strategy to promote 2 key risk-reduction practices post melanoma diagnosis and treatment. Future research is needed to identify additional strategies to improve comprehensive risk reduction in long-term melanoma patients. Copyright © 2016 John Wiley & Sons, Ltd.
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Nasser, Qasiem J.; Gombos, Dan S.; Williams, Michelle D.; Guadagnolo, B. Ashleigh; Morrison, William H.; Garden, Adam S.; Beadle, Beth M.; Canseco, Elvia; Esmaeli, Bita
2012-01-01
Purpose High-dose radiotherapy can cause contracture of the anophthalmic socket, but the incidence of this complication in patients with enucleation for uveal melanoma has not previously been reported. We reviewed the surgical management and outcomes in terms of successful prosthesis wear in patients with severe contracture of the anophthalmic socket treated with high-dose radiotherapy for high-risk uveal melanoma and estimated the relative risk of this complication. Methods The medical records of all consecutive patients enrolled in a prospective uveal-melanoma tissue-banking protocol at our institution who underwent enucleation between January 2003 and December 2010 were reviewed. Patients who underwent adjuvant radiotherapy of the enucleated socket were further studied. Results Of the 68 patients enrolled in the prospective tissue banking protocol, 12 had high-risk histologic features (e.g., extrascleral spread or vortex vein invasion) and were treated with 60 Gy of external-beam radiotherapy after enucleation. Five of these patients (41.7%) experienced severe socket contracture precluding prosthesis wear. The median time to onset of contracture following completion of radiotherapy was 20 months. Three patients underwent surgery, which entailed scar tissue release, oral mucous membrane grafting, and socket reconstruction; 2 patients declined surgery. All 3 patients who had surgery experienced significant improvement of socket contracture that enabled patients to wear a prosthesis again. Conclusion High-dose radiotherapy after enucleation in patients with uveal melanoma caused severe socket contracture and inability to wear a prosthesis in approximately 40% of patients. Surgical repair of the contracted socket using oral mucous membrane grafting can allow resumption of prosthesis wear. PMID:22581085
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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.
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Sun Exposure, Vitamin D Receptor Polymorphisms FokI and BsmI and Risk of Multiple Primary Melanoma
Mandelcorn-Monson, Rochelle; Marrett, Loraine; Kricker, Anne; Armstrong, Bruce K.; Orlow, Irene; Goumas, Chris; Paine, Susan; Rosso, Stefano; Thomas, Nancy; Millikan, Robert C.; Pole, Jason D.; Cotignola, Javier; Rosen, Cheryl; Kanetsky, Peter A.; Lee-Taylor, Julia; Begg, Colin B.; Berwick, Marianne
2011-01-01
Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one. We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed. Only the BsmI variant was associated with multiple primary melanoma (OR = 1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high. These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR. PMID:21612999
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Mayer, Jonathan E; Swetter, Susan M; Fu, Teresa; Geller, Alan C
2014-10-01
While most cancers have shown both decreased incidence and mortality over the past several decades, the incidence of melanoma has continued to grow, and mortality has only recently stabilized in the United States and in many other countries. Certain populations, such as men >60 years of age and lower socioeconomic status groups, face a greater burden from disease. For any given stage and across all ages, men have shown worse melanoma survival than women, and low socioeconomic status groups have increased levels of mortality. Novel risk factors can help identify populations at greatest risk for melanoma and can aid in targeted early detection. Risk assessment tools have been created to identify high-risk patients based on various factors, and these tools can reduce the number of patients needed to screen for melanoma detection. Diagnostic techniques, such as dermatoscopy and total body photography, and new technologies, such as multispectral imaging, may increase the accuracy and reliability of early melanoma detection. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.
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.
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Soura, E.; Eliades, P.; Shannon, K.; Stratigos, A.; Tsao, H.
2015-01-01
Malignant melanoma is considered the most lethal skin cancer if not detected and treated at its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (i.e. unilateral lineage, multi-generational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. Such patients have a high risk of developing multiple primary melanomas and internal organ malignancies especially pancreatic cancer; thus, a multidisciplinary approach is necessary in many cases. The value of dermoscopy examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. But, this must be performed with care and only by qualified individuals trained in cancer risk analysis. PMID:26892650
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GENETIC COUNSELLING IN MELANOMA
Badenas, Celia; Aguilera, Paula; Puig-Butillé, Joan A.; Carrera, Cristina; Malvehy, Josep; Puig, Susana
2012-01-01
Summary Genetic counselling may be offered to families with melanoma and to individuals with multiple melanomas to better understand the genetic susceptibility of the disease, the influence of environmental factors, the inheritance of the risk and behaviour that decreases the risk of dying from melanoma including specific dermatological follow-up such as total body photography and digital dermoscopy. Genetic testing may be offered to those individuals with more than a 10% chance of being a carrier of a mutation. This risk varies according to the incidence of melanoma in the country and sun behaviour. In countries with a low-medium incidence of melanoma, genetic testing should be offered to families with two cases of melanoma or an individual with two primary melanomas. In countries with a high incidence, families with three cases of melanoma, with two melanomas and one pancreatic adenocarcinoma, or patients with three primary melanomas may benefit from genetic testing. PMID:23046018
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Sun exposure, vitamin D receptor polymorphisms FokI and BsmI and risk of multiple primary melanoma.
Mandelcorn-Monson, Rochelle; Marrett, Loraine; Kricker, Anne; Armstrong, Bruce K; Orlow, Irene; Goumas, Chris; Paine, Susan; Rosso, Stefano; Thomas, Nancy; Millikan, Robert C; Pole, Jason D; Cotignola, Javier; Rosen, Cheryl; Kanetsky, Peter A; Lee-Taylor, Julia; Begg, Colin B; Berwick, Marianne
2011-12-01
Sunlight exposure increases risk of melanoma. Sunlight also potentiates cutaneous synthesis of vitamin D, which can inhibit melanoma cell growth and promote apoptosis. Vitamin D effects are mediated through the vitamin D receptor (VDR). We hypothesized that genetic variation in VDR affects the relationship of sun exposure to risk of a further melanoma in people who have already had one. We investigated the interaction between VDR polymorphisms and sun exposure in a population-based multinational study comparing 1138 patients with a multiple (second or subsequent) primary melanoma (cases) to 2151 patients with a first primary melanoma (controls); essentially a case-control study of melanoma in a population of melanoma survivors. Sun exposure was assessed using a questionnaire and interview, and was shown to be associated with multiple primary melanoma. VDR was genotyped at the FokI and BsmI loci and the main effects of variants at these loci and their interactions with sun exposure were analyzed. Only the BsmI variant was associated with multiple primary melanoma (OR=1.27, 95% CI 0.99-1.62 for the homozygous variant genotype). Joint effects analyses showed highest ORs in the high exposure, homozygous variant BsmI genotype category for each sun exposure variable. Stratified analyses showed somewhat higher ORs for the homozygous BsmI variant genotype in people with high sun exposure than with low sun exposure. P values for interaction, however, were high. These results suggest that risk of multiple primary melanoma is increased in people who have the BsmI variant of VDR. Copyright © 2011 Elsevier Ltd. All rights reserved.
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2018-06-18
Metastatic Non-Cutaneous Melanoma; Non-Cutaneous Melanoma; Recurrent Melanoma of the Skin; Recurrent Non-Cutaneous Melanoma; Stage III Cutaneous Melanoma AJCC v7; Stage III Mucosal Melanoma of the Head and Neck AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IVA Mucosal Melanoma of the Head and Neck AJCC v7; Stage IVB Mucosal Melanoma of the Head and Neck AJCC v7; Stage IVC Mucosal Melanoma of the Head and Neck AJCC v7
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High frequency of brain metastases after adjuvant therapy for high-risk melanoma.
Samlowski, Wolfram E; Moon, James; Witter, Merle; Atkins, Michael B; Kirkwood, John M; Othus, Megan; Ribas, Antoni; Sondak, Vernon K; Flaherty, Lawrence E
2017-11-01
The incidence of CNS progression in patients with high-risk regional melanoma (stages IIIAN2a-IIIC) is not well characterized. Data from the S0008 trial provided an opportunity to examine the role of CNS progression in treatment failure and survival. All patients were surgically staged. Following wide excision and full regional lymphadenectomy, patients were randomized to receive adjuvant biochemotherapy (BCT) or high-dose interferon alfa-2B (HDI). CNS progression was retrospectively identified from data forms. Survival was measured from date of CNS progression. A total of 402 eligible patients were included in the analysis (BCT: 199, HDI: 203). Median follow-up (if alive) was over 7 years (range: 1 month to 11 years). The site of initial progression was identifiable in 80% of relapsing patients. CNS progression was a component of systemic melanoma relapse in 59/402 patients (15% overall). In 34/402 patients (9%) CNS progression represented the initial site of treatment failure. CNS progression was a component of initial progression in 27% of all patients whose melanoma relapsed (59/221). The risk of CNS progression was highest within 3 years of randomization. The difference in CNS progression rates between treatment arms was not significant (BCT = 25, HDI = 34, P = 0.24). Lymph node macrometastases strongly associated with CNS progression (P = 0.001), while ulceration and head and neck primaries were not significant predictors. This retrospective analysis of the S0008 trial identified a high brain metastasis rate (15%) in regionally advanced melanoma patients. Further studies are needed to establish whether screening plus earlier treatment would improve survival following CNS progression. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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Escobedo, Loraine A; Crew, Ashley; Eginli, Ariana; Peng, David; Cousineau, Michael R; Cockburn, Myles
2017-05-01
Among 10,068 incident cases of invasive melanoma, we examined the effects of patient characteristics and access-to-care on the risk of advanced melanoma. Access-to-care was defined in terms of census tract-level sociodemographics, health insurance, cost of dermatological services and appointment wait-times, clinic density and travel distance. Public health insurance and education level were the strongest predictors of advanced melanomas but were modified by race/ethnicity and poverty: Hispanic whites and high-poverty neighborhoods were worse off than non-Hispanic whites and low-poverty neighborhoods. Targeting high-risk, underserved Hispanics and high-poverty neighborhoods (easily identified from existing data) for early melanoma detection may be a cost-efficient strategy to reduce melanoma mortality. Copyright © 2017 Elsevier Ltd. All rights reserved.
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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
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Adjuvant Treatment of Melanoma
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
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McLoone, J K; Watts, K J; Menzies, S W; Barlow-Stewart, K; Mann, G J; Kasparian, N A
2013-09-01
Providing ongoing clinical care that adequately addresses patients' medical, psychosocial and information needs is challenging, particularly for patient groups at increased risk of developing life-threatening disease such as malignant melanoma. This study examined a model of clinical care developed by the High Risk Clinic (HRC) of the Sydney Melanoma Diagnostic Centre in relation to patient satisfaction. Semi-structured telephone interviews were conducted and analyzed using the framework of Miles and Huberman, and themes were organized using the qualitative software package, QSR NVivo8. Twenty HRC patients participated in the study (nine men, 11 women; mean age 57.6 years, age range 34-74 years; response rate 91%). Satisfaction with clinical care at the HRC was high. Factors contributing to patient satisfaction included: rapid and regular access to physicians who were perceived by participants as experts, the development of confidence and trust in one's treating doctor, and a sense of being cared about and understood by one's healthcare team. Although one-third of the participants reported some inconveniences in attending the clinic, these were viewed as minor difficulties and not significant barriers to care. Formal psychological support was not sought or expected by participants, although many expressed long-standing melanoma-related fears and concerns. Accessible, expert medical attention, delivered in a patient-centered manner was integral to melanoma survivors' satisfaction with clinical management. Appropriate referrals to psychological support may further increase satisfaction with clinical care. Copyright © 2013 John Wiley & Sons, Ltd.
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Soriano, Virtudes; Malvehy, Josep; Berrocal, Alfonso; Martínez de Prado, Purificación; Quindós, María; Soria, Ainara; Márquez-Rodas, Iván; Palacio, Isabel; Cerezuela, Pablo; López-Vivanco, Guillermo; Alonso, Lorenzo; Samaniego, Elia; Ballesteros, Ana; Puértolas, Teresa; Díaz-Beveridge, Rodrigo; de la Cruz-Merino, Luis; López Castro, Rafael; López López, Rafael; Stevinson, Kendall; del Barrio, Patricia; Tornamira, Maria V.; Guillém, Vicente; Martín-Algarra, Salvador
2016-01-01
Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously. PMID:26958991
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Espinosa, Enrique; Soriano, Virtudes; Malvehy, Josep; Berrocal, Alfonso; Martínez de Prado, Purificación; Quindós, María; Soria, Ainara; Márquez-Rodas, Iván; Palacio, Isabel; Cerezuela, Pablo; López-Vivanco, Guillermo; Alonso, Lorenzo; Samaniego, Elia; Ballesteros, Ana; Puértolas, Teresa; Díaz-Beveridge, Rodrigo; de la Cruz-Merino, Luis; López Castro, Rafael; López López, Rafael; Stevinson, Kendall; Del Barrio, Patricia; Tornamira, Maria V; Guillém, Vicente; Martín-Algarra, Salvador
2016-06-01
Adjuvant interferon-α2b (IFN-α2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-α2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-α2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-α2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression-free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High-dose IFN-α2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-α2b treatment provided a benefit consistent with that described previously.
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Newton-Bishop, Julia A.; Beswick, Samantha; Randerson-Moor, Juliette; Chang, Yu-Mei; Affleck, Paul; Elliott, Faye; Chan, May; Leake, Susan; Karpavicius, Birute; Haynes, Sue; Kukalizch, Kairen; Whitaker, Linda; Jackson, Sharon; Gerry, Edwina; Nolan, Clarissa; Bertram, Chandra; Marsden, Jerry; Elder, David E.; Barrett, Jennifer H.; Bishop, D. Timothy
2009-01-01
Purpose A cohort study was carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. Methods A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years). Results In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio = 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had higher mean 25-hydroxyvitamin D3 levels than relapsers (49 v 46 nmol/L; P = .3; not statistically significant). In the cohort (prospective) study, higher 25-hydroxyvitamin D3 levels were associated with lower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-free survival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) for a 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-hydroxyvitamin D3 levels on RFS. Conclusion Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis, providing evidence that higher 25-hydroxyvitamin D3 levels, at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma. PMID:19770375
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Association of melanoma and natalizumab therapy in the Italian MS population: a second case report.
Laroni, A; Bedognetti, M; Uccelli, A; Capello, E; Mancardi, G L
2011-02-01
There is debate about a possible association between natalizumab treatment and higher risk of melanoma. Here we report a case of melanoma in a patient who developed melanoma after 77 infusions of natalizumab, without known risk factors. Pharmacovigilance programs of new drugs can help to monitor adverse events in patients at risk.
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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
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[Elective lymph node dissection in malignant melanoma--status of color Doppler findings].
Omlor, G; Dill-Müller, D; Gross, G; Kautz, G; Schüder, G; Zaun, H; Feifel, G
1996-01-01
Since there is still a controversial discussion about the ELND in melanoma patients, the purpose of this prospective study was to optimize the indication concerning ELND by ultrasound examinations. 144 patients with primary melanomas were checked every 3 months after excision. Echomorphologic pattern and intranodal vascularisation in the color-flow Doppler modus provide essential information for differential diagnosis. We found 47 patients (32.6%) with suspicious ultrasound lesions. 50% of these patients had no pathological clinical findings, the histological findings of excised lymph nodes were positive in all cases. It must be emphasized, however, that the group with lymph node metastases included 12 patients with low-risk-melanomas (2 x Tis, 10 x T1 < 1 mm tumor thickness). In comparison with a historical control group (141 patients), where ELND was performed routinely in high-risk-patients ( > T2), the incidence of ELND in our hospital decreased more than 50%; at the same time the percentage of detected lymph node metastases increased (twice).
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Sun protection and sunbathing practices among at-risk family members of patients with melanoma
2011-01-01
Background Despite the increased level of familial risk, research indicates that family members of patients with melanoma engage in relatively low levels of sun protection and high levels of sun exposure. The goal of this study was to evaluate a broad range of demographic, medical, psychological, knowledge, and social influence correlates of sun protection and sunbathing practices among first-degree relatives (FDRs) of melanoma patients and to determine if correlates of sun protection and sunbathing were unique. Methods We evaluated correlates of sun protection and sunbathing among FDRs of melanoma patients who were at increased disease risk due to low compliance with sun protection and skin surveillance behaviors. Participants (N = 545) completed a phone survey. Results FDRs who reported higher sun protection had a higher education level, lower benefits of sunbathing, greater sunscreen self-efficacy, greater concerns about photo-aging and greater sun protection norms. FDRs who reported higher sunbathing were younger, more likely to be female, endorsed fewer sunscreen barriers, perceived more benefits of sunbathing, had lower image norms for tanness, and endorsed higher sunbathing norms. Conclusion Interventions for family members at risk for melanoma might benefit from improving sun protection self-efficacy, reducing perceived sunbathing benefits, and targeting normative influences to sunbathe. PMID:21338483
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Thomas, Luc; Puig, Susana
2017-07-05
Early detection is a key strategy for reducing the mortality and economic burden associated with melanoma. Dermoscopy is a non-invasive and cost-effective tool for melanoma diagnosis, which has been shown to be a reliable and sensitive method for detecting early-stage skin cancer and reducing the number of unnecessary excisions. Patients at high risk of developing melanoma require long-term surveillance. Use of digital dermoscopy follow-up of these patients has led to improved outcomes. Combined follow-up programmes using total-body photography and digital dermoscopy have led to further improvements in early diagnosis and diagnostic accuracy. Dermoscopy is now widely used by dermatologists, but the public health impact of this tool is yet to be evaluated. Despite the clear advantages of dermoscopy and digital follow-up meth-ods, dermoscopy training and access to digital dermoscopy among dermatologists and general practitioners needs to be improved.
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Disparities in the Presentation and Management of Cutaneous Melanoma That Required Admission.
Al-Qurayshi, Zaid; Srivastav, Sudesh; Wang, Alun; Boh, Erin; Hamner, John; Hassan, Mohamed; Kandil, Emad
2018-06-18
In this study, we aimed to examine the association of demographic and socioeconomic factors with cutaneous melanoma that required admission. A cross-sectional study utilizing the Nationwide Inpatient Sample database, 2003-2009, was merged with County Health Rankings Data. A total of 2,765 discharge -records were included. Men were more likely to have melanoma in the head, neck, and trunk regions (p < 0.001), while extremities melanoma was more common in women (p < 0.001). Males had a higher risk of lymph node metastasis on presentation (OR 1.54, 95% CI [1.27-1.89]). Blacks and Hispanics were more likely to present with extremities melanoma. Patients with low annual income were more likely to be treated by low-volume surgeons and in hospitals located in high-risk communities (p < 0.05 each). Patients with Medicaid coverage were twice as likely to present with distant metastasis and were more likely to be managed by low-volume surgeons (p < 0.05 each). The presentation and outcomes of cutaneous melanoma have a distinct pattern of distribution based on patients' characteristics. © 2018 S. Karger AG, Basel.
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Favorable overall survival in stage III melanoma patients after adjuvant dendritic cell vaccination
Bol, Kalijn F; Aarntzen, Erik H J G; Hout, Florentien E M in 't; Schreibelt, Gerty; Creemers, Jeroen H A; Lesterhuis, W Joost; Gerritsen, Winald R; Grunhagen, Dirk J; Verhoef, Cornelis; Punt, Cornelis J A; Bonenkamp, Johannes J; de Wilt, Johannes H W; Figdor, Carl G; de Vries, I Jolanda M
2016-01-01
Melanoma patients with regional metastatic disease are at high risk for recurrence and metastatic disease, despite radical lymph node dissection (RLND). We investigated the immunologic response and clinical outcome to adjuvant dendritic cell (DC) vaccination in melanoma patients with regional metastatic disease who underwent RLND with curative intent. In this retrospective study, 78 melanoma patients with regional lymph node metastasis who underwent RLND received autologous DCs loaded with gp100 and tyrosinase and were analyzed for functional tumor-specific T cell responses in skin-test infiltrating lymphocytes. The study shows that adjuvant DC vaccination in melanoma patients with regional lymph node metastasis is safe and induced functional tumor-specific T cell responses in 71% of the patients. The presence of functional tumor-specific T cells was correlated with a better 2-year overall survival (OS) rate. OS was significantly higher after adjuvant DC vaccination compared to 209 matched controls who underwent RLND without adjuvant DC vaccination, 63.6 mo vs. 31.0 mo (p = 0.018; hazard ratio 0.59; 95%CI 0.42–0.84). Five-year survival rate increased from 38% to 53% (p < 0.01). In summary, in melanoma patients with regional metastatic disease, who are at high risk for recurrence and metastatic disease after RLND, adjuvant DC vaccination is well tolerated. It induced functional tumor-specific immune responses in the majority of patients and these were related to clinical outcome. OS was significantly higher compared to matched controls. A randomized clinical trial is needed to prospectively validate the efficacy of DC vaccination in the adjuvant setting. PMID:26942068
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Moreau, Joséphine; Pelletier, Fabien; Biichle, Sabeha; Mourey, Guillaume; Puyraveau, Marc; Badet, Nicolas; Caubet, Matthieu; Laresche, Claire; Garnache-Ottou, Francine; Saas, Philippe; Seilles, Estelle; Aubin, François
2017-10-01
We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 μL -1 ) than in patients with stage III (2041 μL -1 ) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut-off value (5311 μL -1 ) allowing the distinction between high-risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Eggermont, Alexander M M; Dummer, Reinhard
2017-11-01
The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us. Copyright © 2017 Elsevier Ltd. All rights reserved.
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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.
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High ALDH1 expression correlates with better prognosis in tumorigenic malignant melanoma.
Taylor, Laura A; Abraham, Ronnie M; Tahirovic, Emin; van Belle, Patricia; Li, Bin; Huang, Linfang; Elder, David E; Gimotty, Phyllis; Xu, Xiaowei
2017-05-01
Aldehyde dehydrogenase 1 (ALDH1) has been proposed as biomarker of stem cells for certain human cancers. ALDH1 expression has been correlated with poor patient outcomes in a variety of malignancies but better patient outcomes in others, and its prognostic significance in malignant melanoma is unclear. Thus, 68 melanoma patients with comprehensive clinical and pathologic follow-up data were used to construct a tissue microarray. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for ALDH1. Survival time was defined as the time between diagnosis and melanoma-specific death. Using univariate logistic regression, a low (<80 H-score) ALDH1 score showed 3.7-fold increase in risk for melanoma-specific death within 10 years when compared with high (>80) ALDH1 levels (P=0.017). Odds of MSD were lower by a factor of ~0.9 for each 10-point increase in H-Score. Median survival time was 44.1 months and 180.9 months for patients with low and high ALDH1 expression, respectively. Using multivariate analysis, ALDH1 H-score was found to be an independent prognostic factor. These findings suggest that ALDH1 expression in malignant melanoma has a favorable effect on patient survival. Further study is needed elucidate the function of this enzymatic protein in melanoma progression.
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[Melanoma in organ transplant patients].
Lévêque, L; Dalac, S; Dompmartin, A; Louvet, S; Euvrard, S; Catteau, B; Hazan, M; Schollhamer, M; Aubin, F; Dreno, B; Daguin, P; Chevrant-Breton, J; Frances, C; Bismuth, M J; Tanter, Y; Lambert, D
2000-02-01
The incidence of cutaneous melanoma has rapidly increased in the white population over the last decades. It has been estimated that the incidence doubles world-wide every 10 years. Different risk factors have been identified, including immunosuppression. The aim of our study-was to determine the relative risk of developing melanoma in the organ transplant population and the clinical and histological features of their melanomas. This retrospective study was conducted with the collaboration of 9 University Hospital Centers: Besançon, Brest, Caen, Dijon, Lille, Lyon, Nantes, Paris (Pitié-Salpétrière) and Rennes. A questionnaire was sent to the different departments of dermatology of these hospitals to obtain information on patients who had presented a melanoma after a transplantation between 1971 and 1997. During this period, there were 12,477 organ transplant recipients in the transplantation units of these 9 hospitals. Average follow-up for these patients was about 5 years and the average duration of immunosuppressive therapy was about 4.5 years. Among 12,477 organ transplant recipients, we found 17 cases of melanoma but no data could be obtain on one case: 14 occurred in renal transplant recipients and 3 in cardiac transplant recipients. Clinical and histological data were only available in 16 patients. The average time between transplantation and diagnosis of melanoma was 63 months, but it was 5 times shorter for 2 patients who had a past history of melanoma before transplantation. Two patients had a mucosal melanoma; for the cutaneous melanomas, 2 appeared on Dubreuilh melanosis, 2 were in situ melanomas, 7 were superficial spreading melanomas and 3 were nodular melanomas. The histological review of 11 cutaneous melanomas revealed a precursor nevus in 6 cases and a weak or no stroma reaction in 7/7 cases. Complete excision of the melanoma was performed in all patients except one with anorectal melanoma. Four patients died of visceral metastasis within a mean 15 months. The other 12 patients are still alive with a mean 3 year course since tumor treatment. We tried to determine the relative risk of developing melanoma in the renal transplant population (14 cases). The number of expected cases of melanoma was 5.54, giving a relative risk of 2.5. Only 4 studies have shown an increase in the incidence of melanoma in the renal transplant population: approximately 2 to 5-fold. In our study, the 2.5-fold increase in melanoma was estimated with an average 5 year follow-up and an average 5 year immunosuppressive therapy. This is probably an underestimation of risk because we were unable to make an exhaustive collection of cases of melanomas even though transplant recipients undergo more physical examinations than a reference population. The mean latency period from transplantation to melanoma diagnosis was 63 months, as in other studies. Histological examination showed that a precursor nevus is frequent with weak host cellular response to the tumor. The prognosis of these melanomas remains difficult to predict, but in our study, it would not appear to be as poor as expected. Discontinuation of immunosuppressive therapy would not appear to be necessary except in the presence of metastasis. Finally, our study demonstrates the importance of good patient follow-up, even after graft rejection due to the persistent risk of melanoma.
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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.
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Review of the role of sentinel node biopsy in cutaneous head and neck melanoma.
Roy, Jennifer M; Whitfield, Robert J; Gill, P Grantley
2016-05-01
Sentinel node biopsy (SNB) is recommended for selected melanoma patients in many parts of the world. This review examines the evidence surrounding the accuracy and prognostic value of SNB and completion neck dissection in head and neck melanoma. Sentinel nodes were identified in an average of 94.7% of head and neck cases compared with 95.3-100% in all melanoma cases. More false-negative sentinel nodes were found in head and neck cases. A positive sentinel node was associated with both lower disease-free survival (53.4 versus 83.2%) and overall survival (40 versus 84%). We conclude that SNB should be offered to all patients with intermediate and high-risk melanomas in the head and neck area. To date, evidence does not exist to demonstrate the safety of avoiding completion lymph node dissection in sentinel node-positive patients with head and neck melanoma. © 2015 Royal Australasian College of Surgeons.
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Association between choroidal pigmentation and posterior uveal melanoma in a white population
Harbour, J W; Brantley, M A; Hollingsworth, H; Gordon, M
2004-01-01
Background/aims: It is well known that light skin pigmentation is a risk factor for cutaneous melanoma. The aim of this study was to investigate the analogous association between choroidal pigmentation and posterior uveal melanoma. Methods: Cross sectional study of 65 consecutive patients diagnosed with posterior uveal melanoma (melanoma group) and 218 consecutive patients referred for general retinal evaluation (control group). All patients were white. A clinical grading system for estimating choroidal pigmentation was developed and histologically validated in seven patients. Results: Melanoma patients with light iris colour were significantly more likely to have darker choroidal pigmentation than controls (p = 0.005). Darker choroidal pigmentation was associated histologically with increased density of choroidal melanocytes (p = 0.005). Conclusions: Increased choroidal pigmentation, as a result of an increase in the density of pigmented choroidal melanocytes, is not protective but may actually be a risk factor for the development of posterior uveal melanoma in white patients. This finding may have implications for understanding the pathogenesis of uveal melanoma. PMID:14693770
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Gerami, Pedram; Cook, Robert W; Russell, Maria C; Wilkinson, Jeff; Amaria, Rodabe N; Gonzalez, Rene; Lyle, Stephen; Jackson, Gilchrist L; Greisinger, Anthony J; Johnson, Clare E; Oelschlager, Kristen M; Stone, John F; Maetzold, Derek J; Ferris, Laura K; Wayne, Jeffrey D; Cooper, Chelsea; Obregon, Roxana; Delman, Keith A; Lawson, David
2015-05-01
A gene expression profile (GEP) test able to accurately identify risk of metastasis for patients with cutaneous melanoma has been clinically validated. We aimed for assessment of the prognostic accuracy of GEP and sentinel lymph node biopsy (SLNB) tests, independently and in combination, in a multicenter cohort of 217 patients. Reverse transcription polymerase chain reaction (RT-PCR) was performed to assess the expression of 31 genes from primary melanoma tumors, and SLNB outcome was determined from clinical data. Prognostic accuracy of each test was determined using Kaplan-Meier and Cox regression analysis of disease-free, distant metastasis-free, and overall survivals. GEP outcome was a more significant and better predictor of each end point in univariate and multivariate regression analysis, compared with SLNB (P < .0001 for all). In combination with SLNB, GEP improved prognostication. For patients with a GEP high-risk outcome and a negative SLNB result, Kaplan-Meier 5-year disease-free, distant metastasis-free, and overall survivals were 35%, 49%, and 54%, respectively. Within the SLNB-negative cohort of patients, overall risk of metastatic events was higher (∼30%) than commonly found in the general population of patients with melanoma. In this study cohort, GEP was an objective tool that accurately predicted metastatic risk in SLNB-eligible patients. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Zalfa, Francesca; Panasiti, Vincenzo; Carotti, Simone; Zingariello, Maria; Perrone, Giuseppe; Sancillo, Laura; Pacini, Laura; Luciani, Flavie; Roberti, Vincenzo; D'Amico, Silvia; Coppola, Rosa; Abate, Simona Osella; Rana, Rosa Alba; De Luca, Anastasia; Fiers, Mark; Melocchi, Valentina; Bianchi, Fabrizio; Farace, Maria Giulia; Achsel, Tilmann; Marine, Jean-Christophe; Morini, Sergio; Bagni, Claudia
2017-01-01
The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival. Reduction of FMRP in metastatic melanoma cell lines impinges on cell migration, invasion and adhesion. Next-generation sequencing in human melanoma cells revealed that FMRP regulates a large number of mRNAs involved in relevant processes of melanoma progression. Our findings suggest an association between FMRP levels and the invasive phenotype in melanoma and might open new avenues towards the discovery of novel therapeutic targets. PMID:29144507
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Zalfa, Francesca; Panasiti, Vincenzo; Carotti, Simone; Zingariello, Maria; Perrone, Giuseppe; Sancillo, Laura; Pacini, Laura; Luciani, Flavie; Roberti, Vincenzo; D'Amico, Silvia; Coppola, Rosa; Abate, Simona Osella; Rana, Rosa Alba; De Luca, Anastasia; Fiers, Mark; Melocchi, Valentina; Bianchi, Fabrizio; Farace, Maria Giulia; Achsel, Tilmann; Marine, Jean-Christophe; Morini, Sergio; Bagni, Claudia
2017-11-16
The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival. Reduction of FMRP in metastatic melanoma cell lines impinges on cell migration, invasion and adhesion. Next-generation sequencing in human melanoma cells revealed that FMRP regulates a large number of mRNAs involved in relevant processes of melanoma progression. Our findings suggest an association between FMRP levels and the invasive phenotype in melanoma and might open new avenues towards the discovery of novel therapeutic targets.
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Walter, Jessica R; Xu, Shuai; Paller, Amy S; Choi, Jennifer N; Woodruff, Teresa K
2016-09-01
Melanoma is the most common cancer diagnosed for patients ages 25 to 29 years, the group with the highest birth rates in the United States. Oncofertility is a new field addressing the reproductive needs of patients with cancer facing fertility-threatening treatments. We sought to assess gender-specific fertility risk for Food and Drug Administration (FDA)-approved melanoma therapies with a new risk category system. We conducted a retrospective review of FDA, European Union, and Health Canada regulatory filings, along with previously published reports to grade fertility risk of systemic melanoma therapies. The proposed fertility risk category system is analogous to the FDA's A/B/C/D/X/N pregnancy-risk categories. For female patients, 58% of treatments represent a fertility risk (Category C and D), 33% have unknown risk (Category N), and 1 therapy (vemurafenib) did not show animal ovarian toxicity (Category B). For male patients, 33% represented a fertility risk (Category C and D), 50% of treatments had unknown risk (Category N), and 17% did not show animal testicular toxicity (Category B). Data on fertility risk for melanoma therapies approved after 2009 are limited to preclinical animal studies. Dermatologists have an opportunity to discuss fertility preservation, make appropriate referrals, and steward registries on reproductive outcomes for patients with melanoma. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Mocellin, Simone; Pasquali, Sandro; Rossi, Carlo R; Nitti, Donato
2010-04-07
Based on previous meta-analyses of randomized controlled trials (RCTs), the use of interferon alpha (IFN-alpha) in the adjuvant setting improves disease-free survival (DFS) in patients with high-risk cutaneous melanoma. However, RCTs have yielded conflicting data on the effect of IFN-alpha on overall survival (OS). We conducted a systematic review and meta-analysis to examine the effect of IFN-alpha on DFS and OS in patients with high-risk cutaneous melanoma. The systematic review was performed by searching MEDLINE, EMBASE, Cancerlit, Cochrane, ISI Web of Science, and ASCO databases. The meta-analysis was performed using time-to-event data from which hazard ratios (HRs) and 95% confidence intervals (CIs) of DFS and OS were estimated. Subgroup and meta-regression analyses to investigate the effect of dose and treatment duration were also performed. Statistical tests were two-sided. The meta-analysis included 14 RCTs, published between 1990 and 2008, and involved 8122 patients, of which 4362 patients were allocated to the IFN-alpha arm. IFN-alpha alone was compared with observation in 12 of the 14 trials, and 17 comparisons (IFN-alpha vs comparator) were generated in total. IFN-alpha treatment was associated with a statistically significant improvement in DFS in 10 of the 17 comparisons (HR for disease recurrence = 0.82, 95% CI = 0.77 to 0.87; P < .001) and improved OS in four of the 14 comparisons (HR for death = 0.89, 95% CI = 0.83 to 0.96; P = .002). No between-study heterogeneity in either DFS or OS was observed. No optimal IFN-alpha dose and/or treatment duration or a subset of patients more responsive to adjuvant therapy was identified using subgroup analysis and meta-regression. In patients with high-risk cutaneous melanoma, IFN-alpha adjuvant treatment showed statistically significant improvement in both DFS and OS.
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Nguyen, Brandon T; Kim, Ryan S; Bretana, Maria E; Kegley, Eric; Schefler, Amy C
2018-02-01
To evaluate the association between traditional clinical high-risk features of uveal melanoma patients and gene expression profile (GEP). This was a retrospective, single-center, case series of patients with uveal melanoma. Eighty-three patients met inclusion criteria for the study. Patients were examined for the following clinical risk factors: drusen/retinal pigment epithelium (RPE) changes, vascularity on B-scan, internal reflectivity on A-scan, subretinal fluid (SRF), orange pigment, apical tumor height/thickness, and largest basal dimensions (LBD). A novel point system was created to grade the high-risk clinical features of each tumor. Further analyses were performed to assess the degree of association between GEP and each individual risk factor, total clinical risk score, vascularity, internal reflectivity, American Joint Committee on Cancer (AJCC) tumor stage classification, apical tumor height/thickness, and LBD. Of the 83 total patients, 41 were classified as GEP class 1A, 17 as class 1B, and 25 as class 2. The presence of orange pigment, SRF, low internal reflectivity and vascularity on ultrasound, and apical tumor height/thickness ≥ 2 mm were not statistically significantly associated with GEP class. Lack of drusen/RPE changes demonstrated a trend toward statistical association with GEP class 2 compared to class 1A/1B. LBD and advancing AJCC stage was statistically associated with higher GEP class. In this cohort, AJCC stage classification and LBD were the only clinical features statistically associated with GEP class. Clinicians should use caution when inferring the growth potential of melanocytic lesions solely from traditional funduscopic and ultrasonographic risk factors without GEP data.
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Metastatic pathways in patients with cutaneous melanoma.
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.
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Risk Factors for Melanoma in Renal Transplant Recipients.
Ascha, Mona; Ascha, Mustafa S; Tanenbaum, Joseph; Bordeaux, Jeremy S
2017-11-01
Melanoma risk factors and incidence in renal transplant recipients can inform decision making for both patients and clinicians. To determine risk factors and characteristics of renal transplant recipients who develop melanoma. This cohort study of a large national data registry used a cohort of renal transplant recipients from the United States Renal Data System (USRDS) database from the years 2004 through 2012. Differences in baseline characteristics between those who did and did not develop melanoma were examined, and a survival analysis was performed. Patients with renal transplants who received a diagnosis of melanoma according to any inpatient or outpatient claim associated with a billing code for melanoma were included. A history of pretransplant melanoma, previous kidney transplantation, or transplantation after 2012 or before 2004 were exclusion criteria. The data analysis was conducted from 2015 to 2016. Receipt of a renal transplant. Incidence and risk factors for melanoma. Of 105 174 patients (64 151 [60.7%] male; mean [SD] age, 49.6 [15.3] years) who received kidney transplants between 2004 and 2012, 488 (0.4%) had a record of melanoma after transplantation. Significant risk factors for developing melanoma vs not developing melanoma included older age among recipients (mean [SD] age, 60.5 [10.2] vs 49.7 [15.3] years; P < .001) and donors (42.6 [15.0] vs 39.2 [15.1] years; P < .001), male sex (71.5% vs 60.7%; P < .001), recipient (96.1% vs 66.5%; P < .001) and donor (92.4% vs 82.9%; P < .001) white race, less than 4 HLA mismatches (44.9% vs 37.1%; P = .001), living donors (44.7% vs 33.7%; P < .001), and sirolimus (22.3% vs 13.2%; P < .001) and cyclosporine (4.9% vs 3.2%; P = .04) therapy. Risk factors significant on survival analysis included older recipient age (hazard ratio [HR] per year, 1.06; 95% CI, 1.05-1.06; P < .001), recipient male sex (HR, 1.53; 95% CI, 1.25-1.88; P < .001), recipient white race, living donors (HR, 1.35; 95% CI, 1.11-1.64; P = .002), and sirolimus (HR, 1.54; 95% CI, 1.22-1.94; P < .001) and cyclosporine (HR, 1.93; 95% CI, 1.24-2.99; P = .004) therapy. The age-standardized relative rate of melanoma in USRDS patients compared with Surveillance, Epidemiology, and End Results patients across all years was 4.9. A Kaplan-Meier estimate of the median time to melanoma among those patients who did develop melanoma was 1.45 years (95% CI, 1.31-1.70 years). Renal transplant recipients had greater risk of developing melanoma than the general population. We believe that the risk factors we identified can guide clinicians in providing adequate care for patients in this vulnerable group.
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Espinosa, Pablo; Pfeiffer, Ruth M; García-Casado, Zaida; Requena, Celia; Landi, Maria Teresa; Kumar, Rajiv; Nagore, Eduardo
2016-01-01
Melanoma survivors are at an increased risk of developing other malignancies, including keratinocyte skin cancer (KSC). While it is known that many risk factors for melanoma also impact risk of KSC in the general population, no previous study has investigated risk factors for KSC development in melanoma patients. We assessed associations of personal and clinical characteristics, including skin phenotype and variations in the melanocortin 1 receptor (MC1R) gene, with KSC risk in melanoma patients. We used prospective follow-up information on 1200 patients treated for melanoma at the Instituto Valenciano de Oncología, Spain, between 2000 and 2011. We computed hazard ratios and 95% confidence intervals (CIs) for the association of clinical, personal and genetic characteristics with risk of KSC, squamous cell carcinoma (SCC), or basal cell carcinoma (BCC) from Cox proportional hazard models. Five-year cumulative incidence based on competing risk models of SCC, BCC or KSC overall was computed using multivariate subdistribution hazard models. To assess predictive performance of the models, we computed areas under the receiver-operating characteristic curves (AUCs, discriminatory power) using cross-validation. Median follow-up was 57.2 months; a KSC was detected in 163 patients (13.6%). In multivariable Cox models, age, sex, sunburns, chronic sun exposure, past personal history of non-melanoma skin cancer or other non-cutaneous neoplasia, and the MC1R variants p.D294H and p.R163Q were significantly associated with KSC risk. A cumulative incidence model including age, sex, personal history of KSC, and of other non-cutaneous neoplasia had an AUC of 0.76 (95% CI: 0.71-0.80). When p.D294H and p.R163Q variants were added to the model, the AUC increased to 0.81 (95% CI: 0.77-0.84) (p-value for difference <0.0001). In addition to age, sex, skin characteristics, and sun exposure, p.R163Q and p.D294H MC1R variants significantly increased KSC risk among melanoma patients. Our findings may help identify patients who could benefit most from preventive measures. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients.
Huang, Sharon K; Hoon, Dave S B
2016-03-01
Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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Helgadottir, Hildur; Tuominen, Rainer; Olsson, Håkan; Hansson, Johan; Höiom, Veronica
2017-11-01
Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas. We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes. Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries. Familial MPM cases with germline CDKN2A mutations were youngest at the diagnosis of their second melanoma (median age 42 years) and had among the MPM cohorts the highest relative risks (RR) compared to controls of developing >2 melanomas (RR 238.4, 95% CI 74.8-759.9). CDKN2A mutated MPM cases and their first-degree relatives were the only cohorts with increased risks of nonskin cancers compared to controls (RR 3.6, 95% CI 1.9-147.1 and RR 3.2, 95% CI 1.9-5.6, respectively). In addition, CDKN2A mutated MPM cases had worse survival compared with both cases with familial (HR 3.0, 95% CI 1.3-8.1) and sporadic wild-type MPM (HR 2.63, 95% CI 1.3-5.4). Our study examined outcomes in subgroups of MPM patients, which affected the sample size of the study groups. This study demonstrates that CDKN2A mutation status and family history of melanoma significantly affects outcomes of MPM patients. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Personal history of non-melanoma skin cancer diagnosis and death from melanoma in women.
Chen, Steven T; Li, Xin; Han, Jiali
2018-04-15
Melanoma incidence is increasing. We evaluated risk of melanoma death after diagnosis of non-melanoma skin cancer (NMSC). We followed 77,288 female American nurses from the Nurses' Health Study from 1986 to 2012. We used Cox proportional hazards models to determine the hazard ratio (HR) of lethal and non-lethal melanoma diagnosis and melanoma death, according to personal NMSC history. Among melanoma cases, we examined the HR of melanoma death and the odds ratio (OR) of melanoma with a Breslow thickness ≥0.8 mm or Clark's levels of IV and V according to history of NMSC. We documented 930 melanoma cases without NMSC history and 615 melanoma cases with NMSC history over 1.8 million person-years. The multivariate-adjusted HR (95% confidence interval) of melanoma death associated with personal history of NMSC was 2.89 (1.85-4.50). Women with history of NMSC were more likely to develop non-lethal melanoma than lethal melanoma (HR (95% CI): 2.31 (2.05-2.60) vs. 1.74 (1.05-2.87)). Among melanoma cases, women with history of NMSC had a non-significant decreased risk of melanoma deaths (0.87 (0.55-1.37)), Breslow thickness ≥0.8 mm (0.85 (0.59-1.21)) and Clark's levels IV and V (0.81(0.52-1.24)). Women with NMSC history were less likely to be diagnosed with a lethal melanoma than a non-lethal melanoma, but overall rate of melanoma diagnosis was increased in both subtypes, leading to the increased risk of melanoma death. Our findings suggest the continued need for dermatologic screening for patients after NMSC diagnosis, given increased melanoma risk. Early detection among NMSC patients may decrease deaths from melanoma. © 2017 UICC.
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Personal attributions for melanoma risk in melanoma-affected patients and family members
Hay, Jennifer; DiBonaventura, Marco; Baser, Raymond; Press, Nancy; Shoveller, Jeanne; Bowen, Deborah
2010-01-01
Personal attributions for cancer risk involve factors that individuals believe contribute to their risk for developing cancer. Understanding personal risk attributions for melanoma may dictate gene-environment melanoma risk communication strategies. We examined attributions for melanoma risk in a population-based sample of melanoma survivors, first degree family members, and family members who are also parents (N=939). We conducted qualitative examination of open-ended risk attributions and logistic regression examining predictors (demographics, family member type, perceived risk) of the attributions reported (ultraviolet radiation [UVR] exposure, heredity/genetics, phenotype, personal melanoma history, miscellaneous). We found a predominance of risk attributions to UVR and heredity/genetics (80% and 45% of the sample, respectively). Those reporting higher education levels were more likely to endorse attributions to heredity/genetics, as well as to phenotype, than those of lower education levels. First-degree relatives and parent family members were more likely to endorse heredity/genetic attributions than melanoma survivors; melanoma survivors were more likely to endorse personal history of melanoma attributions compared to first-degree relatives and parent family members. These findings inform the development of risk communication interventions for melanoma families. PMID:20809355
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Bostom, Andrew G; Merhi, Basma; Walker, Joanna; Robinson-Bostom, Leslie
2016-01-01
Non-melanoma cutaneous carcinomas, or skin cancers, predominantly squamous cell carcinomas (SCCs), are the most common malignancies occurring in kidney transplant recipients (KTRs). Squamous cell carcinoma risk is dramatically elevated in KTRs, occurring at rates of up 45-250 times those reported in general populations. New non-melanoma skin cancers in KTRs with a prior non-melanoma skin cancer also develop at 3-times the rate reported in non-KTRs with the same clinical history. The unique aggressiveness of SCCs in KTRs increases patient morbidity, due to the high rate of new lesions requiring treatment, frequently surgical excision. Oral nicotinamide shows promise in the chemoprevention of the especially aggressive non-melanoma skin cancers which occur in KTRs. This benefit might be conferred via its inhibition of sirtuin enzymatic pathways. Nicotinamide’s concurrent hypophosphatemic effect may also partially ameliorate the disturbed calcium-phosphorus homeostasis in these patients-a putative risk factor for mortality, and graft failure. Conceivably, a phase 3 trial of nicotinamide for the prevention of non-melanoma skin cancers in KTRs, lasting at least 12-mo, could also incorporate imaging and laboratory measures which assess nicotinamide’s impact on subclinical cardiovascular and chronic kidney disease risk, and progression. PMID:28058215
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The prognostic value of serum S100B in patients with cutaneous melanoma: a meta-analysis.
Mocellin, Simone; Zavagno, Giorgio; Nitti, Donato
2008-11-15
S100B protein detected in the serum of patients with cutaneous melanoma has been long reported as a prognostic biomarker. However, no consensus exists on its implementation in the routine clinical setting. This study aimed to comprehensively and quantitatively summarize the evidence on the suitability of serum S100B to predict patients' survival. Twenty-two series enrolling 3393 patients with TNM stage I to IV cutaneous melanoma were reviewed. Standard meta-analysis methods were applied to evaluate the overall relationship between S100B serum levels and patients' survival (meta-risk). Serum S100B positivity was associated with significantly poorer survival (hazard ratio [HR] = 2.23, 95% CI: 1.92-2.58, p < 0.0001). Between-study heterogeneity was significant, which appeared to be related mainly to dissemination bias and the inclusion of patients with stage IV disease. Considering stage I to III melanoma (n = 1594), the meta-risk remained highly significant (HR = 2.28, 95% CI: 1.8-2.89; p < 0.0001) and studies' estimates were homogeneous. Subgroup analysis of series reporting multivariate survival analysis supported S100B as a prognostic factor independent of the TNM staging system. Our findings suggest that serum S100B detection has a clinically valuable independent prognostic value in patients with melanoma, with particular regard to stage I-III disease. Further investigation focusing on this subset of patients is justified and warranted before S100B can be implemented in the routine clinical management of melanoma. (c) 2008 Wiley-Liss, Inc.
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Serum amyloid A as a prognostic marker in melanoma identified by proteomic profiling.
Findeisen, Peter; Zapatka, Marc; Peccerella, Teresa; Matzk, Heike; Neumaier, Michael; Schadendorf, Dirk; Ugurel, Selma
2009-05-01
Currently known prognostic serum biomarkers of melanoma are powerful in metastatic disease, but weak in early-stage patients. This study was aimed to identify new prognostic biomarkers of melanoma by serum mass spectrometry (MS) proteomic profiling, and to validate candidates compared with established markers. Two independent sets of serum samples from 596 melanoma patients were investigated. The first set (stage I = 102; stage IV = 95) was analyzed by matrix assisted laser desorption and ionization time of flight (MALDI TOF) MS for biomarkers differentiating between stage I and IV. In the second set (stage I = 98; stage II = 91; stage III = 87; stage IV = 103), the serum concentrations of the candidate marker serum amyloid A (SAA) and the known biomarkers S100B, lactate dehydrogenase, and C reactive protein (CRP) were measured using immunoassays. MALDI TOF MS revealed a peak at m/z 11.680 differentiating between stage I and IV, which could be identified as SAA. High peak intensities at m/z 11.680 correlated with poor survival. In univariate analysis, SAA was a strong prognostic marker in stage I to III (P = .043) and stage IV (P = .000083) patients. Combination of SAA and CRP increased the prognostic impact to P = .011 in early-stage (I to III) patients. Multivariate analysis revealed sex, stage, tumor load, S100B, SAA, and CRP as independent prognostic factors, with an interaction between SAA and CRP. In stage I to III patients, SAA combined with CRP was superior to S100B in predicting patients' progression-free and overall survival. SAA combined with CRP might be used as prognostic serological biomarkers in early-stage melanoma patients, helping to discriminate low-risk patients from high-risk patients needing adjuvant treatment.
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Scheri, Randall P.; Pruitt, Scott K.; Herndon, James E.; Marcello, Jennifer; Tyler, Douglas S.; Abernethy, Amy P.
2013-01-01
Background While curable at early stages, few treatment options exist for advanced melanoma. Currently, no consensus exists regarding the optimal surveillance strategy for patients after resection. The objectives of this study were to identify patterns of metastatic recurrence, to determine the influence of metastatic site on survival, and to identify high-risk periods for recurrence. Methods A retrospective review of the Duke Melanoma Database from 1970 to 2004 was conducted that focused on patients who were initially diagnosed without metastatic disease. The time to first recurrence was computed from the date of diagnosis, and the associated hazard function was examined to determine the peak risk period of recurrence. Metastatic sites were coded by the American Joint Committee on Cancer (AJCC) system including local skin, distant skin and nodes (M1a), lung (M1b), and other distant (M1c). Results Of 11,615 patients initially diagnosed without metastatic disease, 4616 (40%) had at least one recurrence. Overall the risk of initial recurrence peaked at 12 months. The risk of initial recurrence at the local skin, distant skin, and nodes peaked at 8 months, and the risk at lung and other distant sites peaked at 24 months. Patients with a cutaneous or nodal recurrence had improved survival compared to other recurrence types. Conclusions The risk of developing recurrent melanoma peaked at one year, and the site of first recurrence had a significant impact on survival. Defining the timing and expected patterns of recurrence will be important in creating an optimized surveillance strategy for this patient population. PMID:23516415
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Malignant melanoma of the skin: long-term follow-up and time to first recurrence.
Hohnheiser, Annika M; Gefeller, Olaf; Göhl, Jonas; Schuler, Gerold; Hohenberger, Werner; Merkel, Susanne
2011-03-01
Surgical excision can cure most patients with malignant melanoma of the skin. However, the risk of recurrence remains for years. The aim of our study was to identify factors that influence time to recurrence and survival after the first recurrence with a special interest in late recurrences. Data from 2487 patients with malignant melanoma and primary treatment between 1978 and 1997 at the Department of Surgery or the Department of Dermatology, University Hospital Erlangen, Germany, were prospectively collected in the Melanoma Registry of the University Hospital Erlangen. After a median follow-up period of 13 years, overall survival, the time to first recurrence and survival after the first relapse were examined in univariate and multivariate analyses. Overall survival was found to be significantly worse in older patients, men, melanoma of the head or trunk, and melanoma with high pT and pN categories. In 523 patients, relapse from malignant melanoma was observed after a median of 24 months. Among patients with recurrences, young age and low pT and pN categories proved to be independent factors that prolonged the disease-free interval. Advanced age at the time of the recurrence diagnosis, male sex, high pN category, and distant metastases as the first manifestation of recurrence were associated with a poor prognosis after the first recurrence. Although thin lesions have a favorable prognosis, among a cohort with recurrences they showed a relatively high rate of late recurrences. These late recurrences have an extremely poor prognosis when they present with distant metastases.
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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.
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Olsen, Catherine M; Knight, Lani L; Green, Adèle C
2014-01-01
Following the introduction of highly active antiretroviral therapy (HAART) the risk of AIDS-defining cancers decreased but incidence of many non-AIDS-defining cancers has reportedly increased in those with HIV/AIDS. Whether melanoma risk has also changed in HIV/AIDS patients post-HAART is unknown and therefore we evaluated this in comparison with the risk before HAART. Systematic review and meta-analysis. We searched Medline, Embase and ISI science citation index databases to April 2013. All cohort studies of patients diagnosed with HIV/AIDS that permitted quantitative assessment of the association with melanoma were eligible. Detailed quality assessment of eligible studies was conducted, focussing particularly on adjustment for ethnicity, a priori considered essential for an unbiased assessment of melanoma risk. Data were pooled using a random effects model. From 288 articles, we identified 21 that met the inclusion criteria, 13 presenting data for the post-HAART era and 8 for the pre-HAART era. Post-HAART the pooled relative risk (pRR) for the association between HIV/AIDS and melanoma was 1.26 (95% CI, 0.97-1.64) and 1.50 (95% CI 1.12-2.01) among studies that accounted for ethnicity, with evidence of significant heterogeneity (P = 0.004, I2 = 55.5). Pre-HAART pRRs were 1.26 (95% CI 1.11-1.43; P het = 0.82) and 1.28 (95% CI 1.10-1.49) among studies adjusted for ethnicity. People with HIV/AIDS remain at a significantly increased risk of developing melanoma in the post-HAART era. White skinned people with HIV/AIDS should be screened regularly and counselled against excessive sun exposure.
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Olsen, Catherine M.; Knight, Lani L.; Green, Adèle C.
2014-01-01
Objective Following the introduction of highly active antiretroviral therapy (HAART) the risk of AIDS-defining cancers decreased but incidence of many non-AIDS-defining cancers has reportedly increased in those with HIV/AIDS. Whether melanoma risk has also changed in HIV/AIDS patients post-HAART is unknown and therefore we evaluated this in comparison with the risk before HAART. Design Systematic review and meta-analysis. Methods We searched Medline, Embase and ISI science citation index databases to April 2013. All cohort studies of patients diagnosed with HIV/AIDS that permitted quantitative assessment of the association with melanoma were eligible. Detailed quality assessment of eligible studies was conducted, focussing particularly on adjustment for ethnicity, a priori considered essential for an unbiased assessment of melanoma risk. Data were pooled using a random effects model. Results From 288 articles, we identified 21 that met the inclusion criteria, 13 presenting data for the post-HAART era and 8 for the pre-HAART era. Post-HAART the pooled relative risk (pRR) for the association between HIV/AIDS and melanoma was 1.26 (95% CI, 0.97–1.64) and 1.50 (95% CI 1.12–2.01) among studies that accounted for ethnicity, with evidence of significant heterogeneity (P = 0.004, I2 = 55.5). Pre-HAART pRRs were 1.26 (95% CI 1.11–1.43; Phet = 0.82) and 1.28 (95% CI 1.10–1.49) among studies adjusted for ethnicity. Conclusions People with HIV/AIDS remain at a significantly increased risk of developing melanoma in the post-HAART era. White skinned people with HIV/AIDS should be screened regularly and counselled against excessive sun exposure. PMID:24740329
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Perceptions of tanning risk among melanoma patients with a history of indoor tanning.
Nergard-Martin, Jennifer; Caldwell, Chauncey; Barr, Morgan; Dellavalle, Robert P; Solomon, James A
2018-01-01
A new US Food and Drug Administration (FDA) regulation classified tanning beds as class II, requiring indoor tanning facilities to inform users of the risk of skin cancer in efforts to reverse the growing trend in indoor tanning. However, little is known from the patient's perspective on whether knowledge of the risk of skin cancer development is a deterrent to indoor tanning. There also is conflicting literature regarding the relationship among frequency of indoor tanning, age at onset of melanoma diagnosis, and characteristics of diagnosis in melanoma patients with a history of indoor tanning. An international survey was conducted in patients 18 years and older who self-reported being diagnosed with melanoma after indoor tanning. The purpose of this study was to investigate the patients' perspective on indoor-tanning behaviors as associated with the severity of their melanomas and the time frame in which they were diagnosed as well as their perceived views on the safety of indoor tanning and the frequency in which they continue to tan indoors.
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Radiation Therapy Field Extent for Adjuvant Treatment of Axillary Metastases From Malignant Melanoma
DOE Office of Scientific and Technical Information (OSTI.GOV)
Beadle, Beth M.; Guadagnolo, B. Ashleigh; Ballo, Matthew T.
2009-04-01
Purpose: To compare treatment-related outcomes and toxicity for patients with axillary lymph node metastases from malignant melanoma treated with postoperative radiation therapy (RT) to either the axilla only or both the axilla and supraclavicular fossa (extended field [EF]). Methods and Materials: The medical records of 200 consecutive patients treated with postoperative RT for axillary lymph node metastases from malignant melanoma were retrospectively reviewed. All patients received postoperative hypofractionated RT for high-risk features; 95 patients (48%) received RT to the axilla only and 105 patients (52%) to the EF. Results: At a median follow-up of 59 months, 111 patients (56%) hadmore » sustained relapse, and 99 patients (50%) had died. The 5-year overall survival, disease-free survival, and distant metastasis-free survival rates were 51%, 43%, and 46%, respectively. The 5-year axillary control rate was 88%. There was no difference in axillary control rates on the basis of the treated field (89% for axilla only vs. 86% for EF; p = 0.4). Forty-seven patients (24%) developed treatment-related complications. On both univariate and multivariate analyses, only treatment with EF irradiation was significantly associated with increased treatment-related complications. Conclusions: Adjuvant hypofractionated RT to the axilla only for metastatic malignant melanoma with high-risk features is an effective method to control axillary disease. Limiting the radiation field to the axilla only produced equivalent axillary control rates to EF and resulted in lower treatment-related complication rates.« less
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Wang, Jie; Shen, Yigen; Wang, Jiaoni; Xue, Yangjing; Liao, Lianming; Thapa, Saroj; Ji, Kangting
2017-07-11
Data on the association between using PDE5 inhibitors and malignant melanoma are conflicting. To estimate the relation of using PDE5 inhibitors with risk of malignant melanoma, Medline (Ovid) and Embase (Ovid) databases were searched up to February 2017, and a random effects model was used to calculate the summary risk estimates. Five observational studies were included. Five studies reports encompassed a total of 15,979 melanoma cases occurring among 1, 188,414 participants. The pooled multivariable-adjusted RR of melanoma in patients with using PDE5 inhibitors was 1.12 (95% CI: 1.03-1.21, I2 = 0.48). Findings from this systematic review support that PDE5 inhibitor use is associated with increased risk of melanoma in ED patients, the result remains inclusive and warrants further study in the future.
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Rossi, Carlo Riccardo; Mocellin, Simone; Campana, Luca Giovanni; Borgognoni, Lorenzo; Sestini, Serena; Giudice, Giuseppe; Caracò, Corrado; Cordova, Adriana; Solari, Nicola; Piazzalunga, Dario; Carcoforo, Paolo; Quaglino, Pietro; Caliendo, Virginia; Ribero, Simone
2018-01-01
Approximately 20% of melanoma patients harbor metastases in non-sentinel nodes (NSNs) after a positive sentinel node biopsy (SNB), and recent evidence questions the therapeutic benefit of completion lymph node dissection (CLND). We built a nomogram for prediction of NSN status in melanoma patients with positive SNB. Data on anthropometric and clinicopathological features of patients with cutaneous melanoma who underwent CLND after a positive SNB were collected from nine Italian centers. Multivariate logistic regression was utilized to identify predictors of NSN status in a training set, while model efficiency was validated in a validation set. Data were available for 1220 patients treated from 2000 through 2016. In the training set (n = 810), the risk of NSN involvement was higher when (1) the primary melanoma is thicker or (2) sited in the trunk/head and neck; (3) fewer nodes are excised and (4) more nodes are involved; and (5) the lymph node metastasis is larger or (6) is deeply located. The model showed high discrimination (area under the receiver operating characteristic curve 0.74, 95% confidence interval [CI] 0.70-0.79) and calibration (Brier score 0.16, 95% CI 0.15-0.17) performance in the validation set (n = 410). The nomogram including these six clinicopathological variables performed significantly better than five other previously published models in terms of both discrimination and calibration. Our nomogram could be useful for follow-up personalization in clinical practice, and for patient risk stratification while conducting clinical trials or analyzing their results.
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[The role of endogenous and exogenous factors in the etiology of skin melanoma].
Zaridze, D G; Mukeriia, A F; Basieva, T Kh; Shlenskaia, I N; Bukin, Iu V
1992-01-01
The results of case-control study of skin melanoma carried out in Moscow are presented. They point to considerable influence of endogenous factors on the relative risk of melanoma. The risk of melanoma is increased by such factors as light color of the skin, presence of freckles and moles. Exposure to UV-radiation raised the risk of melanoma, however, after relevant adjustment for the said factors relative risk was reduced. Consumption of greens and high blood levels of alpha-tocopherol significantly decreased the risk of melanoma. Female users of oral contraceptives had significantly lower risk of skin melanoma.
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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.
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Sunburn, suntan and the risk of cutaneous malignant melanoma--The Western Canada Melanoma Study.
Elwood, J. M.; Gallagher, R. P.; Davison, J.; Hill, G. B.
1985-01-01
A comparison of interview data on 595 patients with newly incident cutaneous melanoma, excluding lentigo maligna melanoma and acral lentiginous melanoma, with data from comparison subjects drawn from the general population, showed that melanoma risk increased in association with the frequency and severity of past episodes of sunburn, and also that melanoma risk was higher in subjects who usually had a relatively mild degree of suntan compared to those with moderate or deep suntan in both winter and summer. The associations with sunburn and with suntan were independent. Melanoma risk is also increased in association with a tendency to burn easily and tan poorly and with pigmentation characteristics of light hair and skin colour, and history freckles; the associations with sunburn and suntan are no longer significant when these other factors are taken into account. This shows that pigmentation characteristics, and the usual skin reaction to sun, are more closely associated with melanoma risk than are sunburn and suntan histories. PMID:3978032
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Occupational exposure to electromagnetic fields and sex-differential risk of uveal melanoma.
Behrens, Thomas; Lynge, Elsebeth; Cree, Ian; Sabroe, Svend; Lutz, Jean-Michel; Afonso, Noemia; Eriksson, Mikael; Guénel, Pascal; Merletti, Franco; Morales-Suarez-Varela, Maria; Stengrevics, Aivars; Févotte, Joëlle; Llopis-González, Agustin; Gorini, Giuseppe; Sharkova, Galina; Hardell, Lennart; Ahrens, Wolfgang
2010-11-01
The association between occupational exposure to electromagnetic fields (EMF) and the risk of uveal melanoma was investigated in a case-control study in nine European countries. Incident cases of uveal melanoma and population as well as hospital controls were included and frequency matched by country, 5-year birth cohort and sex. Subjects were asked whether they had worked close to high-voltage electrical transmission installations, computer screens and various electrical machines, or in complex electrical environments. Measurements of two Scandinavian job-exposure matrices were applied to estimate lifelong cumulative EMF exposure. Unconditional logistic regression analyses, stratified by sex and eye colour were calculated, adjusting for several potential confounders. 293 patients with uveal melanoma and 3198 control subjects were interviewed. Women exposed to electrical transmission installations showed elevated risks (OR 5.81, 95% CI 1.72 to 19.66). Positive associations with exposure to control rooms were seen among men and women, but most risk increases were restricted to subjects with dark iris colour. Application of published EMF measurements revealed stronger risk increases among women compared to men. Again, elevated risks were restricted to subjects with dark eye colour. Although based on a low prevalence of exposure to potential occupational sources of EMF, our data indicate that exposed dark-eyed women may be at particular risk for uveal melanoma.
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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.
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Toro, Jorge R.; Blake, Patrick W.; Björkholm, Magnus; Kristinsson, Sigurdur Y.; Wang, Zhuoqiao; Landgren, Ola
2009-01-01
We investigated whether a previous diagnosis of non-melanoma skin cancer among chronic lymphocytic leukemia patients is a predictor of poor outcome. Using the Swedish Cancer Registry, we conducted a population-based study to evaluate the survival patterns among chronic lymphocytic leukemia patients with and without non-melanoma skin cancer. Cox proportional hazards regression models were used and Kaplan-Meier curves were constructed. Of a total of 12,041 chronic lymphocytic leukemia cases identified, 236 cases, including 111 squamous cell cancer, had a prior history of non-melanoma skin cancer. Chronic lymphocytic leukemia patients with a prior history of non-melanoma skin cancer had a 1.29-fold (95% CI 1.10–1.52; p=0.0024) increased risk of dying; and those with a history of squamous cell cancer had a further elevated 1.86-fold (95% CI 1.46–2.36; p<0.0001) risk of dying. Kaplan-Meier plots showed that patients with a history of non-melanoma skin cancer, particularly those with squamous cell cancer, had significantly poorer survival than chronic lymphocytic leukemia patients without non-melanoma skin cancer (p<0.0001; log-rank test). Non-melanoma skin cancer may be a novel clinical predictor of worse chronic lymphocytic leukemia outcome. PMID:19794092
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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.
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Visual screening for malignant melanoma: a cost-effectiveness analysis.
Losina, Elena; Walensky, Rochelle P; Geller, Alan; Beddingfield, Frederick C; Wolf, Lindsey L; Gilchrest, Barbara A; Freedberg, Kenneth A
2007-01-01
To evaluate the cost-effectiveness of various melanoma screening strategies proposed in the United States. We developed a computer simulation Markov model to evaluate alternative melanoma screening strategies. Hypothetical cohort of the general population and siblings of patients with melanoma. Intervention We considered the following 4 strategies: background screening only, and screening 1 time, every 2 years, and annually, all beginning at age 50 years. Prevalence, incidence, and mortality data were taken from the Surveillance, Epidemiology, and End Results Program. Sibling risk, recurrence rates, and treatment costs were taken from the literature. Outcomes included life expectancy, quality-adjusted life expectancy, and lifetime costs. Cost-effectiveness ratios were in dollars per quality-adjusted life year (US dollars/QALY) gained. In the general population, screening 1 time, every 2 years, and annually saved 1.6, 4.4, and 5.2 QALYs per 1000 persons screened, with incremental cost-effectiveness ratios of US dollars 10,100/QALY, US dollars 80,700/QALY, and US dollars 586,800/QALY, respectively. In siblings of patients with melanoma (relative risk, 2.24 compared with the general population), 1-time, every-2-years, and annual screenings saved 3.6, 9.8, and 11.4 QALYs per 1000 persons screened, with incremental cost-effectiveness ratios of US dollars 4000/QALY, US dollars 35,500/QALY, and US dollars 257,800/QALY, respectively. In higher risk siblings of patients with melanoma (relative risk, 5.56), screening was more cost-effective. Results were most sensitive to screening cost, melanoma progression rate, and specificity of visual screening. One-time melanoma screening of the general population older than 50 years is very cost-effective compared with other cancer screening programs in the United States. Screening every 2 years in siblings of patients with melanoma is also cost-effective.
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Severe sunburn and subsequent risk of primary cutaneous malignant melanoma in scotland.
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
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Trinh, Van Anh; Zobniw, Chrystia; Hwu, Wen-Jen
2017-08-01
Patients with resected stage II or III melanoma are at high risk of recurrence, with 5-year mortality rate of 40-60%. Adjuvant interferon-alfa has demonstrated a small RFS and OS benefit versus observation in this patient population. However, the adjuvant treatment landscape is evolving rapidly. Areas covered: This review aims to summarize the safety and efficacy profiles of adjuvant IFNα/PEG-IFNα, revisit the controversy surrounding its application, and reappraise its position in the rapidly changing treatment landscape of resected melanoma. A literature search using PubMed database was undertaken using search words melanoma, interferon-alfa, pegylated interferon-alfa, adjuvant therapy. Expert opinion: Currently, there is no international consensus regarding the optimal dosing schedule for adjuvant IFNα, but HD IFNα-2b remains the most widely used regimen. The AEs of HD IFNα-2b are substantial; however, toxicity management experience amassed over the past 2 decades has significantly improved safety. Many exciting studies are ongoing to examine the roles of immune checkpoint inhibitors and BRAF-targeted therapies in the adjuvant setting and will further delineate the role of adjuvant IFNα.
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Smit, Kyra N; van Poppelen, Natasha M; Vaarwater, Jolanda; Verdijk, Robert; van Marion, Ronald; Kalirai, Helen; Coupland, Sarah E; Thornton, Sophie; Farquhar, Neil; Dubbink, Hendrikus-Jan; Paridaens, Dion; de Klein, Annelies; Kiliç, Emine
2018-05-01
Uveal melanoma is a highly aggressive cancer of the eye, in which nearly 50% of the patients die from metastasis. It is the most common type of primary eye cancer in adults. Chromosome and mutation status have been shown to correlate with the disease-free survival. Loss of chromosome 3 and inactivating mutations in BAP1, which is located on chromosome 3, are strongly associated with 'high-risk' tumors that metastasize early. Other genes often involved in uveal melanoma are SF3B1 and EIF1AX, which are found to be mutated in intermediate- and low-risk tumors, respectively. To obtain genetic information of all genes in one test, we developed a targeted sequencing method that can detect mutations in uveal melanoma genes and chromosomal anomalies in chromosome 1, 3, and 8. With as little as 10 ng DNA, we obtained enough coverage on all genes to detect mutations, such as substitutions, deletions, and insertions. These results were validated with Sanger sequencing in 28 samples. In >90% of the cases, the BAP1 mutation status corresponded to the BAP1 immunohistochemistry. The results obtained in the Ion Torrent single-nucleotide polymorphism assay were confirmed with several other techniques, such as fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and Illumina SNP array. By validating our assay in 27 formalin-fixed paraffin-embedded and 43 fresh uveal melanomas, we show that mutations and chromosome status can reliably be obtained using targeted next-generation sequencing. Implementing this technique as a diagnostic pathology application for uveal melanoma will allow prediction of the patients' metastatic risk and potentially assess eligibility for new therapies.
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Ethnicity and Cutaneous Melanoma in the City of Sao Paulo, Brazil: A Case-Control Study
Luiz, Olinda C.; Gianini, Reinaldo José; Gonçalves, Fernanda T.; Francisco, Guilherme; Festa-Neto, Cyro; Sanches, José Antonio; Gattas, Gilka J. F.; Chammas, Roger; Eluf-Neto, José
2012-01-01
Background Over the last century the incidence of cutaneous melanoma has increased worldwide, a trend that has also been observed in Brazil. The identified risk factors for melanoma include the pattern of sun exposure, family history, and certain phenotypic features. In addition, the incidence of melanoma might be influenced by ethnicity. Like many countries, Brazil has high immigration rates and consequently a heterogenous population. However, Brazil is unique among such countries in that the ethnic heterogeneity of its population is primarily attributable to admixture. This study aimed to evaluate the contribution of European ethnicity to the risk of cutaneous melanoma in Brazil. Methodology/Principal Findings We carried out a hospital-based case-control study in the metropolitan area of Sao Paulo, Brazil. We evaluated 424 hospitalized patients (202 melanoma patients and 222 control patients) regarding phenotypic features, sun exposure, and number of grandparents born in Europe. Through multivariate logistic regression analysis, we found the following variables to be independently associated with melanoma: grandparents born in Europe—Spain (OR = 3.01, 95% CI: 1.03–8.77), Italy (OR = 3.47, 95% CI: 1.41–8.57), a Germanic/Slavic country (OR = 3.06, 95% CI: 1.05–8.93), or ≥2 European countries (OR = 2.82, 95% CI: 1.06–7.47); eye color—light brown (OR = 1.99, 95% CI: 1.14–3.84) and green/blue (OR = 4.62; 95% CI 2.22–9.58); pigmented lesion removal (OR = 3.78; 95% CI: 2.21–6.49); no lifetime sunscreen use (OR = 3.08; 95% CI: 1.03–9.22); and lifetime severe sunburn (OR = 1.81; 95% CI: 1.03–3.19). Conclusions Our results indicate that European ancestry is a risk factor for cutaneous melanoma. Such risk appears to be related not only to skin type, eye color, and tanning capacity but also to others specific characteristics of European populations introduced in the New World by European immigrants. PMID:22558444
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Using a family systems approach to investigate cancer risk communication within melanoma families.
Harris, Julie N; Hay, Jennifer; Kuniyuki, Alan; Asgari, Maryam M; Press, Nancy; Bowen, Deborah J
2010-10-01
The family provides an important communication nexus for information and support exchange about family cancer history, and adoption of family-wide cancer risk reduction strategies. The goals of this study were to (1) use the family systems theory to identify characteristics of this sample of families at increased risk of developing melanoma and (2) to relate familial characteristics to the frequency and style of familial risk communication. Participants were first-degree relatives (n=313) of melanoma patients, recruited into a family web-based intervention study. We used multivariable logistic regression models to analyze the association between family functioning and family communication. Most participants were female (60%), with an average age of 51 years. Fifty percent of participants reported that they spoke to their relatives about melanoma risk and people were more likely to speak to their female family members. Familial adaptation, cohesion, coping, and health beliefs were strongly associated with an open style of risk communication within families. None were associated with a blocked style of risk communication. Only cohesion and adaptation were associated with the amount of risk communication that occurred within families. Overall, individuals who came from families that were more highly cohesive, adaptable, and shared strong beliefs about melanoma risk were more likely to communicate openly about melanoma. The fact that this association was not consistent across blocked communication and communication frequency highlights the multifaceted nature of this process. Future research should focus on the interplay between different facets of communication. Copyright © 2010 John Wiley & Sons, Ltd.
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CEACAM1: Expression and Role in Melanocyte Transformation
Turcu, Gabriela; Ion, Daniela Adriana; Brînzea, Alice; Cioplea, Mirela Daniela; Jilaveanu, Lucia Beatrice
2016-01-01
Metastases represent the main cause of death in melanoma patients. Despite the current optimized targeted therapy or immune checkpoint inhibitors the treatment of metastatic melanoma is unsatisfactory. Because of the poor prognosis of advanced melanoma there is an urgent need to identify new biomarkers to differentiate melanoma cells from normal melanocytes, to stratify patients according to their risk, and to identify subgroups of patients that require close follow-up or more aggressive therapy. Furthermore, melanoma progression has been associated with the dysregulation of cell adhesion molecules. We have reviewed the literature and have discussed the important role of the expression of the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) in the development of melanoma. Thus, novel insights into CEACAM1 may lead to promising strategies in melanoma treatment, in monitoring melanoma patients, in assessing the response to immunotherapy, and in completing the standard immunohistochemical panel used in melanoma examination. PMID:27642217
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Rychetnik, Lucie; McCaffery, Kirsten; Morton, Rachael L; Thompson, John F; Menzies, Scott W; Irwig, Les
2013-04-01
There is limited evidence on the relative effectiveness of different follow-up schedules for patients with AJCC stage I or II melanoma, but less frequent follow-up than is currently recommended has been proposed. To describe melanoma clinicians' perspectives on the functions of follow-up, factors that influence follow-up intervals, and important considerations for extending intervals. Qualitative interviews with 16 clinicians (surgical oncologists, dermatologists, melanoma unit physicians) who conduct follow-up at two of Australia's largest specialist centers. Follow-up is conducted for early detection of recurrences or new primary melanomas, to manage patient anxiety, support patient self-care, and as part of shared care. Recommended intervals are based on guidelines but account for each patient's clinical risk profile, level of anxiety, patient education requirements, capacity to engage in skin self-examination, and how the clinician prefers to manage any suspicious lesions. To revise guidelines and implement change it is important to understand the rationale underpinning existing practice. Extended follow-up intervals for early stage melanoma are more likely to be adopted after the first year when patients are less anxious and sufficiently prepared to conduct self-examination. Clinicians may retain existing schedules for highly anxious patients or those unable to examine themselves. Copyright © 2012 Wiley Periodicals, Inc.
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2017-10-16
Cervical Carcinoma; Esophageal Carcinoma; Mucosal Melanoma; Mucosal Melanoma of the Head and Neck; Oral Cavity Mucosal Melanoma; Recurrent Melanoma; Stage II Vulvar Cancer AJCC v7; Stage III Vulvar Cancer AJCC v7; Stage IIIA Vulvar Cancer AJCC v7; Stage IIIB Vulvar Cancer AJCC v7; Stage IIIC Vulvar Cancer AJCC v7; Stage IV Oral Cavity Cancer AJCC v6 and v7; Stage IV Vulvar Cancer AJCC v7; Stage IVA Oral Cavity Cancer AJCC v6 and v7; Stage IVB Oral Cavity Cancer AJCC v6 and v7; Stage IVC Oral Cavity Cancer AJCC v6 and v7; Vaginal Carcinoma
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Franco, Renato; Cantile, Monica; Scala, Stefania; Catalano, Elisabetta; Cerrone, Margherita; Scognamiglio, Giosuè; Pinto, Antonio; Chiofalo, Maria Grazia; Caracò, Corrado; Anniciello, Anna Maria; Abbruzzese, Alberto; Caraglia, Michele; Botti, Gerardo
2010-03-15
Sentinel lymph node (SLN) biopsy is an important independent prognostic factor for invasive cutaneuos melanoma, although its role is strongly debated. In clinical practice SLN leads to complete lymph node dissection of basin draining melanoma site. However only 7-30% of positive sentinel node patients present additional non SLN metastasis. Melanoma cells diffusion through SLN and extranodal spreading depends upon biological features, such as cell chemokine receptors and adhesion molecules. CXCR4 has been proposed in melanoma patients as prognostic marker. Therefore we have analyzed both histopathological parameters and CXCR4 expression in melanoma infiltrate of SLN, in order to evaluate its potential prognostic role. Micrometastases were detected in 23 cases (48.93%); metastases >2 mm in 23 cases (48.93%) and isolated metastatic cells in one case (2.01%). High CXCR4 expression was observed in 21 nodal metastases. Node metastases in complete dissection were associated to >10% relative tumor area (RTA) in all lymph nodes (p = 0.006). Extranodal invasion (p = 0.006) and >2 mm centripetal metastasis thickness (p = 0.01), while shorter Disease Free Survival (DFS) was significantly associated to high CXCR4 expression (p = 0.02). Forty-seven positive lymph node metastases were collected and analysed for both histopathological parameters and CXCR4 expression. More than 10% RTA in SLN, extranodal invasion and centripetal metastasis thickness all predict additional lymph node metastases in melanoma site draining basins. Moreover, high CXCR4 expression is correlated to shorter DFS and could be used as a prognostic marker in order to stratify melanoma patients at higher progression risk.
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Willingness to pay for a cure of low-risk melanoma patients in Germany.
Augustin, Matthias; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; Wilden, Sophia; Kähler, Katharina C
2018-01-01
Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.
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Willingness to pay for a cure of low-risk melanoma patients in Germany
Augustin, Matthias; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; Wilden, Sophia
2018-01-01
Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception. PMID:29795621
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miR-137 inhibits glutamine catabolism and growth of malignant melanoma by targeting glutaminase.
Luan, Wenkang; Zhou, Zhou; Zhu, Yan; Xia, Yun; Wang, Jinlong; Xu, Bin
2018-01-01
Glutamine catabolism is considered to be an important metabolic pathway for cancer cells. Glutaminase (GLS) is the important rate-limiting enzyme of glutamine catabolism. miR-137 functions as a tumor suppressor in many human malignant tumors. However, the role and molecular mechanism of miR-137 and GLS in malignant melanoma has not been reported. In this study, we showed that miR-137 was decreased in melanoma tissue, and the low miR-137 level and high GLS expression are independent risk factor in melanoma. miR-137 suppressed the proliferation and glutamine catabolism of melanoma cells. GLS is crucial for glutamine catabolism and growth of malignant melanoma. We also demonstrated that miR-137 acts as a tumor suppressor in melanoma by targeting GLS. This result elucidates a new mechanism for miR-137 in melanoma development and provides a survival indicator and potential therapeutic target for melanoma patients. Copyright © 2017 Elsevier Inc. All rights reserved.
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Xeroderma pigmentosum genes and melanoma risk.
Paszkowska-Szczur, K; Scott, R J; Serrano-Fernandez, P; Mirecka, A; Gapska, P; Górski, B; Cybulski, C; Maleszka, R; Sulikowski, M; Nagay, L; Lubinski, J; Dębniak, T
2013-09-01
Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility. Copyright © 2013 UICC.
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Berzina, Anna; Azarjana, Kristine; Cema, Ingrida; Pjanova, Dace; Rivosh, Alexander
2011-01-01
OBJECTIVE. To describe the prognostic factors and epidemiological characteristics of cutaneous and mucosal head and neck melanoma and to identify the variables associated with mortality from this disease. MATERIAL AND METHODS. Patients treated for head and neck melanoma in the Oncology Centre of Latvia, Riga during a 10-year period were identified. Records from 124 cases were analyzed in a descriptive, retrospective study. For each patient, information regarding age, sex, tumor anatomic site, as well as ulceration, histological tumor subtypes, Breslow thickness and Clark invasion level was viewed. Disease specific survival rates were calculated. The frequencies of all study variables and their 95% confidence intervals were determined. Kaplan-Meier survival curves were produced to illustrate the survival differences for each variable. RESULTS. The patients' mean age was 67.36 years. The study included 81 females (65.32%) and 43 males (34.67%). The prevalent anatomical site for cutaneous head and neck melanoma was the cheek - 49% (n=55) and the intraocular site for mucosal melanoma (61.5%). A high percentage of thick cutaneous melanoma was detected. In 53 cases (47.3%) out of 112 cutaneous melanoma the tumor ulceration was found. Nodular melanoma subtype was predominating (38%). The incidence of cutaneous melanoma has increased unequally whereas mucosal melanoma of the head and neck is an uncommon cancer and the incidence rates in Latvia during a ten year period are decreasing. CONCLUSION. Female sex, advanced age, facial skin, tumor thickness, nodular subtype and ulceration carried a relevant risk of poor prognosis.
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Helfand, M; Mahon, S M; Eden, K B; Frame, P S; Orleans, C T
2001-04-01
Malignant melanoma is often lethal, and its incidence in the United States has increased rapidly over the past 2 decades. Nonmelanoma skin cancer is seldom lethal, but, if advanced, can cause severe disfigurement and morbidity. Early detection and treatment of melanoma might reduce mortality, while early detection and treatment of nonmelanoma skin cancer might prevent major disfigurement and to a lesser extent prevent mortality. Current recommendations from professional societies regarding screening for skin cancer vary. To examine published data on the effectiveness of routine screening for skin cancer by a primary care provider, as part of an assessment for the U.S. Preventive Services Task Force. We searched the MEDLINE database for papers published between 1994 and June 1999, using search terms for screening, physical examination, morbidity, and skin neoplasms. For information on accuracy of screening tests, we used the search terms sensitivity and specificity. We identified the most important studies from before 1994 from the Guide to Clinical Preventive Services, second edition, and from high-quality reviews. We used reference lists and expert recommendations to locate additional articles. Two reviewers independently reviewed a subset of 500 abstracts. Once consistency was established, the remainder were reviewed by one reviewer. We included studies if they contained data on yield of screening, screening tests, risk factors, risk assessment, effectiveness of early detection, or cost effectiveness. We abstracted the following descriptive information from full-text published studies of screening and recorded it in an electronic database: type of screening study, study design, setting, population, patient recruitment, screening test description, examiner, advertising targeted at high-risk groups or not targeted, reported risk factors of participants, and procedure for referrals. We also abstracted the yield of screening data including probabilities and numbers of referrals, types of suspected skin cancers, biopsies, confirmed skin cancers, and stages and thickness of skin cancers. For studies that reported test performance, we recorded the definition of a suspicious lesion, the "gold-standard" determination of disease, and the number of true positive, false positive, true negative, and false negative test results. When possible, positive predictive values, likelihood ratios, sensitivity, and specificity were recorded. No randomized or case-control studies have been done that demonstrate that routine screening for melanoma by primary care providers reduces morbidity or mortality. Basal cell carcinoma and squamous cell carcinoma are very common, but detection and treatment in the absence of formal screening are almost always curative. No controlled studies have shown that formal screening programs will improve this already high cure rate. While the efficacy of screening has not been established, the screening procedures themselves are noninvasive, and the follow-up test, skin biopsy, has low morbidity. Five studies from mass screening programs reported the accuracy of skin examination as a screening test. One of these, a prospective study, tracked patients with negative results to determine the number of patients with false-negative results. In this study, the sensitivity of screening for skin cancer was 94% and specificity was 98%. Several recent case-control studies confirm earlier evidence that risk of melanoma rises with the presence of atypical moles and/or many common moles. One well-done prospective study demonstrated that risk assessment by limited physical exam identified a relatively small (<10%) group of primary care patients for more thorough evaluation. The quality of the evidence addressing the accuracy of routine screening by primary care providers for early detection of melanoma or nonmelanoma skin cancer ranged from poor to fair. We found no studies that assessed the effectiveness of periodic skin examination by a clinician in reducing melanoma mortality. Both self-assessment of risk factors or clinician examination can classify a small proportion of patients as at highest risk for melanoma. Skin cancer screening, perhaps using a risk-assessment technique to identify high-risk patients who are seeing a physician for other reasons, merits additional study as a strategy to address the excess burden of disease in older adults.
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Individual risk of cutaneous melanoma in New Zealand: developing a clinical prediction aid.
Sneyd, Mary Jane; Cameron, Claire; Cox, Brian
2014-05-22
New Zealand and Australia have the highest melanoma incidence rates worldwide. In New Zealand, both the incidence and thickness have been increasing. Clinical decisions require accurate risk prediction but a simple list of genetic, phenotypic and behavioural risk factors is inadequate to estimate individual risk as the risk factors for melanoma have complex interactions. In order to offer tailored clinical management strategies, we developed a New Zealand prediction model to estimate individual 5-year absolute risk of melanoma. A population-based case-control study (368 cases and 270 controls) of melanoma risk factors provided estimates of relative risks for fair-skinned New Zealanders aged 20-79 years. Model selection techniques and multivariate logistic regression were used to determine the important predictors. The relative risks for predictors were combined with baseline melanoma incidence rates and non-melanoma mortality rates to calculate individual probabilities of developing melanoma within 5 years. For women, the best model included skin colour, number of moles > =5 mm on the right arm, having a 1st degree relative with large moles, and a personal history of non-melanoma skin cancer (NMSC). The model correctly classified 68% of participants; the C-statistic was 0.74. For men, the best model included age, place of occupation up to age 18 years, number of moles > =5 mm on the right arm, birthplace, and a history of NMSC. The model correctly classified 67% of cases; the C-statistic was 0.71. We have developed the first New Zealand risk prediction model that calculates individual absolute 5-year risk of melanoma. This model will aid physicians to identify individuals at high risk, allowing them to individually target surveillance and other management strategies, and thereby reduce the high melanoma burden in New Zealand.
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Pasquali, S; Sommariva, A; Spillane, A J; Bilimoria, K Y; Rossi, C R
2017-03-01
In an attempt to ensure high standards of cancer care, there is increasing interest in determining and monitoring the quality of interventions in surgical oncology. In recent years, this has been particularly the case for melanoma surgery. The vast majority of patients with melanoma undergo surgery. Usually, this is with combinations of wide excision, sentinel lymph node biopsy and lymphadenectomy. The indications for these procedures evolved during a time when no effective systemic adjuvant therapy was available, and whilst the rationale has been sound, the justification for differences in extent and thoroughness has generally been supported by inadequate or low-level evidence. This has led to a substantial variation among melanoma centres or even among surgeons within a centre in how these procedures are done. With recent rapid progress in the efficacy of systemic treatments that are impacting on overall survival, the prospect of long-term survival in these previously high risk patients means that more than ever long-term locoregional control of melanoma is imperative. Furthermore, the understanding of effects of systemic therapy on locoregional disease will only be interpretable if surgeons use standardized, high quality techniques. This article focuses on standardization and evolution of quality indicators for melanoma surgery and how these might have a positive impact on patient care. Copyright © 2016 Elsevier Ltd, BASO ~ the Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
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Tumor location predicts survival in cutaneous head and neck melanoma.
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.
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Outcomes of mucosal melanoma of the head and neck.
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.
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Tanning bed exposure increases the risk of malignant melanoma.
Ting, William; Schultz, Kara; Cac, Natalie N; Peterson, Michael; Walling, Hobart W
2007-12-01
Epidemiologic studies have associated tanning bed exposure and cutaneous melanoma. The relationship between the extent of tanning bed exposure and the risk of melanoma has not been elucidated in detail. Surveys assessing the extent of tanning bed exposure and the history of skin cancer, including malignant melanoma, were collected from academic dermatology clinic patients (n = 1518). Of these, 551 (36.3%) completed all components of the survey. The available medical records, including pathology reports (n = 501; 33%), were reviewed to confirm cases of skin cancer. Data on potential confounding factors, including indoor vs. outdoor occupation and leisure activities, Fitzpatrick skin type, history of blistering sunburn, use of sunscreen and sun protective clothing, history of phototherapy, and level of education, were assessed and compared. Of the patients surveyed, 487 (32.1%) reported tanning bed exposure. Women aged 45 years or younger accounted for about 60% of all tanning bed users. Seventy-nine cases of malignant melanoma were reported, 22 in women aged 45 years or younger. In the entire cohort, the "ever-use" of tanning beds was found to be a significant risk factor for the development of melanoma [P < 0.05; odds ratio (OR), 1.64; 95% confidence interval (95% CI), 1.01-2.67]. The risk was greater in women aged 45 years or younger (P < 0.05; OR, 3.22; 95% CI, 1.01-11.46). Patients with a history of melanoma were significantly more likely to report tanning bed sessions exceeding 20 min (P < 0.01; OR, 3.18; 95% CI, 1.48-6.82); this association was even stronger for women aged 45 years or younger (OR, 4.12; 95% CI, 1.41-12.02). The study was subject to recall bias, included only patients at a midwestern academic practice, and had a relatively low response rate. Exposure to tanning beds increases the risk of malignant melanoma, especially in women aged 45 years or younger. These findings reinforce the hazards of tanning bed exposure.
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Schouwenburg, Maartje G; Jochems, Anouk; Leeneman, Brenda; Franken, Margreet G; van den Eertwegh, Alfons J M; Haanen, John B A G; van Zeijl, Michiel C T; Aarts, Maureen J; van Akkooi, Alexander C J; van den Berkmortel, Franchette W P J; Blokx, Willeke A M; de Groot, Jan Willem B; Hospers, Geke A P; Kapiteijn, Ellen; Koornstra, Rutger H; Kruit, Wim H; Louwman, Marieke W J; Piersma, Djura; van Rijn, Rozemarijn S; Suijkerbuijk, Karijn P M; Ten Tije, Albert J; Vreugdenhil, Gerard; Wouters, Michel W J M; van der Hoeven, Jacobus J M
2018-08-01
The aim of this population-based study was to identify the factors associated with clinical outcomes in vemurafenib-treated patients and to evaluate outcomes across subgroups of patients with different risk profiles. Data were retrieved from the Dutch Melanoma Treatment Registry. Time to next treatment (TTNT) and overall survival (OS) of all metastatic melanoma patients who received vemurafenib between 2012 and 2015 were assessed using Kaplan-Meier estimates. A risk score was developed on the basis of all prognostic factors associated with TTNT and OS derived from multivariable Cox regression analyses. Patients were stratified according to the presence of prognostic risk factors by counting the number of factors, ranging from 0 to 6. A total of 626 patients received vemurafenib with a median follow-up of 35.8 months. The median TTNT and OS were 4.7 months [95% confidence intervals (CI): 4.4-5.1] and 7.3 months (95% CI: 6.6-8.0). The strongest prognostic factors were serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance score, number of organ sites involved and brain metastases. Patients with a favourable risk profile (no risk factors) had a median TTNT and OS of 7.1 (95% CI: 5.8-8.5) and 15.4 months (95% CI: 10.0-20.9). The median OS more than halved for patients with greater than or equal to 2 risk factors compared with patients with no risk factors. The clinical outcomes of vemurafenib in metastatic melanoma patients with a favourable risk profile are comparable with the results of the trials. Combining prognostic factors into a risk score could be valuable to stratify patients into favourable and poor-prognosis groups.
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Semkova, Kristina; Lott, Jason P; Lazova, Rossitza
2014-09-01
Although recent advances in genetics have revealed distinct mutational profiles and molecular signaling pathways associated with Spitzoid malignant melanoma (SMM), less is known about the clinicopathologic characteristics and behavior of SMM compared with conventional melanoma. We sought to determine the clinicopathologic characteristics and mortality risk associated with SMM and conventional malignant melanoma. We conducted a retrospective study of 30 patients with SMM and 30 patients with conventional melanoma. The two groups were matched by age, gender, and depth of tumor invasion. Additional patient- and tumor-level characteristics were compared between groups and regression modeling was used to assess relative mortality risk. Unadjusted analyses of SMM and conventional malignant melanoma revealed no significant differences in clinical impression, anatomic location, mitotic rate, and presence of ulceration. Sentinel lymph node biopsy, completion lymphadenectomy, and visceral metastases did not differ between groups. Cox proportional hazards regression showed no differences in mortality between Spitzoid and conventional melanoma. Small sample size, short follow-up duration, and residual confounding may limit the accuracy and generalizability of our results. SMM and conventional malignant melanoma differ in some clinicopathologic features. We did not find a statistically significant difference in mortality between the two. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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Biology of advanced uveal melanoma and next steps for clinical therapeutics.
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.
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Sun Protection Practices and Sun Exposure among Children with a Parental History of Melanoma
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
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Herms, Florian; Kramkimel, Nora; Regnier-Rosencher, Elodie; Carlotti, Agnès; Chanal, Johan; Boitier, Françoise; Aractingi, Selim; Dupin, Nicolas; Avril, Marie-Françoise
2016-10-01
Cutaneous squamous cell carcinoma (cSCC) is a frequent side-effect of vemurafenib treatment. The main aim of this study was to identify the clinical risk factors associated with the development of cSCC in melanoma patients treated with vemurafenib. We carried out a retrospective study, including 63 consecutive melanoma patients treated with vemurafenib for BRAF-mutant metastatic melanoma in an oncodermatological department. Clinical and follow-up data were collected and analysed, and a comparison of the subgroups who did and did not develop cSCC was performed. A total of 42.9% of patients (n=27) treated with vemurafenib developed one or more cSCC. Patients with cSCC were significantly older (P=0.01). Clear eyes were also associated with a higher risk of developing cSCC (odds ratio=3.50; 95% confidence interval: 1.08-12.43). Three patients developed cSCC more than 1 year after the initiation of treatment (12, 16 and 18 months, respectively). Clinicians should be vigilant in older patients undergoing vemurafenib therapy as well as patients with clear eyes as they seem to be at increased risk of developing cSCC, even late after the initiation of treatment.
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Corrias, Maria Valeria; Levreri, Isabella; Scaruffi, Paola; Raffaghello, Lizzia; Carlini, Barbara; Bocca, Paola; Prigione, Ignazia; Stigliani, Sara; Amoroso, Loredana; Ferrone, Soldano; Pistoia, Vito
2012-01-01
The high molecular weight melanoma-associated antigen (HMW-MAA) and the cytoplasmic melanoma-associated antigen (cyt-MAA/LGALS3BP) are expressed in melanoma. Their serum levels are increased in melanoma patients and correlate with clinical outcome. We investigated whether these molecules can serve as prognostic markers for neuroblastoma (NB) patients. Expression of cyt-MAA and HMW-MAA was evaluated by flow cytometry in NB cell lines, patients’ neuroblasts (FI-NB), and short-term cultures of these latter cells (cNB). LGALS3BP gene expression was evaluated by RT–qPCR on FI-NB, cNB, and primary tumor specimens. Soluble HMW-MAA and cyt-MAA were tested by ELISA. Cyt-MAA and HMW-MAA were expressed in NB cell lines, cNB, and FI-NB samples. LGALS3BP gene expression was higher in primary tumors and cNB than in FI-NB samples. Soluble cyt-MAA, but not HMW-MAA, was detected in NB cell lines and cNBs supernatants. NB patients’ serum levels of both antigens were higher than those of the healthy children. High cyt-MAA serum levels at diagnosis associated with higher incidence of relapse, independently from other known risk factors. In conclusion, both HMW-MAA and cyt-MAA antigens, and LGALS3BP gene, were expressed by NB cell lines and patients’ neuroblasts, and both antigens’ serum levels were increased in NB patients. Elevated serum levels of cyt-MAA at diagnosis correlated with relapse, supporting that cyt-MAA may serve as early serological biomarker to individuate patients at higher risk of relapse that may require a more careful follow-up, after being validated in a larger cohort of patients at different time-points during follow-up. Given its immunogenicity, cyt-MAA may also be a potential target for NB immunotherapy. PMID:21660451
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McCourt, C; Coleman, H G; Murray, L J; Cantwell, M M; Dolan, O; Powe, D G; Cardwell, C R
2014-04-01
Beta-blockers have potential antiangiogenic and antimigratory activity. Studies have demonstrated a survival benefit in patients with malignant melanoma treated with beta-blockers. To investigate the association between postdiagnostic beta-blocker usage and risk of melanoma-specific mortality in a population-based cohort of patients with malignant melanoma. Patients with incident malignant melanoma diagnosed between 1998 and 2010 were identified within the U.K. Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with malignant melanoma with a melanoma-specific death (cases) recorded by the Office of National Statistics were matched on year of diagnosis, age and sex to four malignant melanoma controls (who lived at least as long after diagnosis as their matched case). A nested case-control approach was used to investigate the association between postdiagnostic beta-blocker usage and melanoma-specific death and all-cause mortality. Conditional logistic regression was applied to generate odds ratios (ORs) and 95% confidence intervals (CIs) for beta-blocker use determined from general practitioner prescribing. Beta-blocker medications were prescribed after malignant melanoma diagnosis to 20·2% of 242 patients who died from malignant melanoma (cases) and 20·3% of 886 matched controls. Consequently, there was no association between beta-blocker use postdiagnosis and cancer-specific death (OR 0·99, 95% CI 0·68-1·42), which did not markedly alter after adjustment for confounders including stage (OR 0·87, 95% CI 0·56-1·34). No significant associations were detected for individual beta-blocker types, by defined daily doses of use or for all-cause mortality. Contrary to some previous studies, beta-blocker use after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in this U.K. population-based study. © 2014 British Association of Dermatologists.
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Robinson, June K.; Wayne, Jeffrey D.; Martini, Mary C.; Hultgren, Brittney A.; Mallett, Kimberly A.; Turrisi, Rob
2017-01-01
IMPORTANCE More than 1 million patients with melanoma in the United States are at risk to develop a second primary melanoma. Early detection of melanoma improves survival. Patients with melanoma may be able to self-manage care with their skin-check partners (“partners”) and alert the physician when a concerning lesion is identified, thus providing an important adjunct to yearly skin examinations by a physician. OBJECTIVE To evaluate the effect of a structured skin self-examination (SSE) intervention for patients with melanoma and their partners (“dyads”) on SSE performance and the detection of new melanomas by the dyad or the physician. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial with 24-month follow-up assessments. Patients with stage 0 to IIB melanoma and their skin-check partners participated from June 6, 2011, to April 24, 2015. INTERVENTIONS Dyads of patients and their partners were randomly assigned to receive the skills training intervention or customary care (control group). MAIN OUTCOMES AND MEASURES The main outcome was frequency of SSE performance. The secondary outcome was detection of a new or recurrent melanoma by the dyad or physician. The tertiary outcome was the number of unscheduled physician appointments for concerning lesions. RESULTS The study cohort comprised 494 participants. The patient population was 51.2% (253 of 494) female and had a mean (SD) age of 55 (10) years. Patients in the intervention arms had significantly increased SSEs with their partners at 4, 12, and 24 months (P < .001 for all) compared with the control group (mean differences, 1.57 [95% CI, 1.29–1.85], 0.72 [95% CI, 0.39–1.06], and 0.94 [95% CI, 0.58–1.30], respectively). Patients in the intervention arms identified new melanomas more than those in the control group ( χ12=28.77, P < .01 [n = 51 melanomas in situ] and χ12=6.43, P < .05 [n = 18 invasive melanomas]) and did not increase physician visits. CONCLUSIONS AND RELEVANCE Patients with melanoma and their partners reliably performed SSE after participating in a structured skills training program lasting approximately 30 minutes, with reinforcement every 4 months by the study dermatologist. Accurate SSE by those at risk to develop melanoma may enhance early detection and relieve some of the burden on health services to provide continuing follow-up to a growing population of eligible patients. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01432860 PMID:27367303
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Ma, Xu; He, Zhijuan; Li, Ling; Yang, Daping; Liu, Guofeng
2017-09-29
Recent advancements in cancer biology have identified a large number of lncRNAs that are dysregulated expression in the development and tumorigenesis of cancers, highlighting the importance of lncRNAs as a key player for human cancers. However, the prognostic value of lncRNAs still remains unclear and needs to be further investigated. In the present study, we aim to assess the prognostic value of lncRNAs in cutaneous melanoma by integrated lncRNA expression profiles from TCGA database and matched clinical information from a large cohort of patients with cutaneous melanoma. We finally identified a set of six lncRNAs that are significantly associated with survival of patients with cutaneous melanoma. A linear combination of six lncRNAs ( LINC01260, HCP5, PIGBOS1, RP11-247L20.4, CTA-292E10.6 and CTB-113P19.5 ) was constructed as a six-lncRNA signature which classified patients of training cohort into the high-risk group and low-risk group with significantly different survival time. The prognostic value of the six-lncRNA signature was validated in both the validation cohort and entire TCGA cohort. Moreover, the six-lncRNA signature is independent of known clinic-pathological factors by multivariate Cox regression analysis and demonstrated good performance for predicting three- and five-year overall survival by time-dependent receiver operating characteristic (ROC) analysis. Our study provides novel insights into the molecular heterogeneity of cutaneous melanoma and also shows potentially important implications of lncRNAs for prognosis and therapy for cutaneous melanoma.
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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.
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The natural history of thin melanoma and the utility of sentinel lymph node biopsy.
Durham, Alison B; Schwartz, Jennifer L; Lowe, Lori; Zhao, Lili; Johnson, Andrew G; Harms, Kelly L; Bichakjian, Christopher K; Orsini, Amy P; McLean, Scott A; Bradford, Carol R; Cohen, Mark S; Johnson, Timothy M; Sabel, Michael S; Wong, Sandra L
2017-12-01
Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm 2 , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm 2 , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone. © 2017 Wiley Periodicals, Inc.
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Predictors of false negative sentinel lymph node biopsy in trunk and extremity melanoma.
Sinnamon, Andrew J; Neuwirth, Madalyn G; Bartlett, Edmund K; Zaheer, Salman; Etherington, Mark S; Xu, Xiaowei; Elder, David E; Czerniecki, Brian J; Fraker, Douglas L; Karakousis, Giorgos C
2017-12-01
Nodal recurrence following negative sentinel lymph node biopsy (SLNB) for melanoma is known as false-negative (FN) SLNB. Risk factors for FN SLNB among patients with trunk and extremity melanoma have not been well-defined. After retrospective review, SLNB procedures were classified FN, true positive (TP; positive SLNB), or true negative (TN; negative SLNB without recurrence). Factors associated with high false negative rate (FNR) and low negative predictive value (NPV) were identified by comparing FNs to TPs and TNs, respectively. Survival was evaluated using Kaplan-Meier methods. Of 1728 patients, 234 were TP and 37 were FN for overall FNR of 14% and NPV of 97.5%. Age ≥65 years was independently associated with high FNR (FNR 20% in this group). Breslow thickness >1 mm and ulceration were independently associated with low NPV. Among patients with ulcerated tumors >4 mm, NPV was 88%. Median time to recurrence for FNs was 13 months. Among patients with primary melanomas ≤2 mm in depth, overall and distant disease-free survival were significantly shorter with FN SLNB than TP SLNB. Older age is associated with increased FNR; patients with thick, ulcerated lesions should be considered for increased nodal surveillance after negative SLNB given low NPV in this group. © 2017 Wiley Periodicals, Inc.
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Association of Vitamin A and Carotenoid Intake with Melanoma Risk in a Large Prospective Cohort
Asgari, Maryam M.; Brasky, Theodore M.; White, Emily
2012-01-01
Laboratory data suggest that intake of vitamin A and carotenoids, may have chemopreventive benefits against melanoma, but epidemiologic studies examining the association have yielded conflicting results. We examined whether dietary and supplemental vitamin A and carotenoid intake was associated with melanoma risk among 69,635 men and women who were participants of the Vitamins and Lifestyle (VITAL) cohort study in Western Washington. After an average of 5.84 years of follow-up, 566 incident melanomas were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risk of melanoma associated with dietary, supplement and total vitamin A and carotenoid intake after adjusting for melanoma risk factors. Baseline use of individual retinol supplements was associated with a significant reduction in melanoma risk (HR: 0.60, 95% CI: 0.41–0.89). High-dose (>1200 ug/day) supplemental retinol was also associated with reduced melanoma risk (HR: 0.74, 95% CI: 0.55–1.00), as compared to non-users. The reduction in melanoma risk was stronger in sun-exposed anatomic sites. There was no association of melanoma risk with dietary or total intake of vitamin A or carotenoids. Retinol supplementation may have a preventative role in melanoma among women. PMID:22377763
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Nagore, E; Hueso, L; Botella-Estrada, R; Alfaro-Rubio, A; Serna, I; Guallar, Jp; González, I; Ribes, I; Guillen, C
2010-01-01
Malignant melanoma risk factors have been studied in different geographical area populations. However, no study has focused on risk factors which are more frequently associated to the over 60's age group. A case-control study was performed that included 160 patients age > or = 60 years diagnosed of cutaneous melanoma and 318 controls matched for age and sex. Both groups were assessed, by personal interview and physical examination, for different phenotype characteristics (hair and eye color, phototype), the presence of other cutaneous lesions (solar lentigines, actinic keratoses and nevi), degree and type of solar exposure and personal and family past history of cutaneous or non-cutaneous cancer. Differences were evaluated by contingency tables and univariate and multivariate logistic regression. Of 17 factors, those risk factors with a strong effect on the development of melanoma in the elderly were: fair eyes, severe sunburns, years of occupational sun exposure, smoking, > 50 melanocytic nevi and personal history of NMSC and other non-cutaneous neoplasias. Tobacco smoking is an independent risk factor for cutaneous melanoma in the elderly. Intense (both acute and chronic) sun exposure and constitutional features, such as tumor susceptibility (NMSC, non-cutaneous neoplasias, and multiple nevi) are also associated with melanoma risk. All these factors should help to better design educational campaigns in older people.
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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.
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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.
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Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland.
Steffen, Jan; Varon, Raymonda; Mosor, Maria; Maneva, Galina; Maurer, Martin; Stumm, Markus; Nowakowska, Dorota; Rubach, Maryna; Kosakowska, Ewa; Ruka, Włodzimierz; Nowecki, Zbigniew; Rutkowski, Piotr; Demkow, Tomasz; Sadowska, Małgorzata; Bidziński, Mariusz; Gawrychowski, Krzysztof; Sperling, Karl
2004-08-10
It has been suggested based on familial data that Nijmegen breakage syndrome (NBS) heterozygotes have an increased risk of malignant tumors. We found 15 carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of the NBS1 gene among 1,289 consecutive patients from Central Poland with various cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from this region. Most of the 657del5 mutation carriers were found among patients with melanoma (4/105), non-Hodgkin lymphoma (2/42) and breast cancer (4/224) and of the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3 others the R215W molecular variant. The frequencies of 657del5 mutation carriers among patients with melanoma and non-Hodgkin lymphoma and of R215W carriers in patients with colorectal cancer were significantly higher than in controls (p < 0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and R215W mutations in all cancer patients were also significantly higher than in controls (p < 0.05). Two carriers of the 657del5 mutation had second primary tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers (14/77) were twice more frequent than in population controls. Three carriers of this mutation (2 probands with melanoma) reported melanoma in relatives. These results suggest strongly that NBS1 heterozygosity may be associated with elevated risk of some cancers. Larger studies are needed to evaluate the impact of the high frequency of germline NBS1 mutations on the cancer burden in the Slav populations. Copyright 2004 Wiley-Liss, Inc.
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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.
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Total Body Photography as an Aid to Skin Self-examination: A Patient's Perspective.
Secker, Lisanne J; Bergman, Wilma; Kukutsch, Nicole A
2016-02-01
Skin self-examination can help patients who are at high risk for developing melanoma to become more involved in their own surveillance and treatment. This study examined the use of total body photography as an aid to skin self-examination from the patients' perspective. A total of 179 individuals at high risk for developing melanoma who had undergone total body photography (60.5% response rate) completed a self-reported questionnaire assessing the frequency of skin self-examination, perceived usefulness of total body photography, and a variety of potential demographic, clinical and psychological factors. Only approximately half of the participants indicated skin self-examination as useful and 78.9% preferred clinical skin examination by a specialist. Finding total body photography useful was associated with having received instructions on how to perform skin self-examination, the use of a (hand)mirror, and confidence to detect changing moles. These findings allow us to develop strategies to further improve patients' self-screening behaviours.
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Transected thin melanoma: Implications for sentinel lymph node staging.
Herbert, Garth; Karakousis, Giorgos C; Bartlett, Edmund K; Zaheer, Salman; Graham, Danielle; Czerniecki, Brian J; Fraker, Douglas L; Ariyan, Charlotte; Coit, Daniel G; Brady, Mary S
2018-03-01
Indications for sentinel lymph node (SLN) biopsy in patients with thin melanoma (≤1 mm thick) are controversial. We asked whether deep margin (DM) positivity at initial biopsy of thin melanoma is associated with SLN positivity. Cases were identified using prospectively maintained databases at two melanoma centers. Patients who had undergone SLN biopsy for melanoma ≤1 mm were included. DM status was assessed for association with SLN metastasis in univariate and multivariate analyses. 1413 cases were identified, but only 1129 with known DM status were included. 39% of patients had a positive DM on original biopsy. DM-positive and DM-negative patients did not differ significantly in primary thickness, ulceration, or mitotic activity. DM-positive and DM-negative patients had similar incidence of SLN metastasis (5.7% vs 3.5%; P = 0.07). Positive DM was not associated with SLN metastasis on univariate analysis (OR 1.69, 95% CI: 0.95-3.00, P = 0.07) or on multivariate analysis adjusted for Breslow depth, Clark level, mitotic rate, and ulceration (OR = 1.59, 95% CI: 0.89-2.85; P = 0.12). For patients with thin melanoma, a positive DM on initial biopsy is not associated with risk of SLN metastasis, so DM positivity should not be considered an indication for SLN staging in an otherwise low-risk patient. © 2017 Wiley Periodicals, Inc.
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Rat, Cédric; Quereux, Gaelle; Grimault, Charlotte; Fernandez, Jérémy; Poiraud, Mickael; Gaultier, Aurélie; Chaslerie, Anicet; Pivette, Jacques; Khammari, Amir; Dreno, Brigitte; Nguyen, Jean-Michel
2016-01-01
Objective The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. Design This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. Setting Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. Patients Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. Main outcome measures Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. Results A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61–0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60–0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55–0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17–0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77–0.98]; p < 0.028). Conclusion This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. Key Points Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities.• Despite the involvement of general practitioners, the implementation of targeted melanoma screening did not avoid inclusion inequalities.• Men, older patients, patients suffering from chronic diseases, and low-income patients were less likely to benefit from screening.• The display of a conventional or an alarmist poster in the waiting room did not statistically reduce these inclusion inequalities. PMID:27467203
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Intraocular (Eye) Melanoma—Patient Version
Intraocular (uveal) melanoma is a rare cancer that forms in the eye. It usually has no early signs or symptoms. As with melanoma of the skin, risk factors include having fair skin and light-colored eyes. Start here to find information on intraocular melanoma treatment.
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The increase in melanoma: are dietary furocoumarins responsible?
Sayre, Robert M; Dowdy, John C
2008-01-01
According to most cancer registries the incidence of cutaneous melanoma (CM) has been increasing for several decades. Unlike other skin cancers, CM does not clearly correlate with exposure to ultraviolet radiation. The strongest etiological evidence for CM in man is genetic predisposition, evidenced by very high risks in primary relatives of melanoma patients, and photochemotherapy with 8-methoxy psoralen in combination with ultraviolet-A radiation (PUVA) to treat psoriasis and vitiligo. Retrospective studies of PUVA patients show significantly increased incidence of CM. Psoralens, and other furocoumarins, are phototoxic and photocarcinogenic, intercalate DNA and photochemically induce mutations. Furocoumarins are botanical phytoalexins found to varying extents in a variety of vegetables and fruits, notably citrus fruits. The levels of furocoumarins present in our diets, while normally well below that causing evident acute phototoxicity, do cause pharmacologically relevant drug interactions. For the past approximately 50 years CM has increased at similar rates as the increased availability and consumption of citrus products. Recently in a large study of nurses, only orange juice drinking, indicative of dietary preference for citrus, was positively associated with significantly increased risk of developing CM. We hypothesize that the increases in cutaneous melanoma incidence may be in part related to concomitant increases in dietary photocarcinogenic furocoumarins.
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Strategies for early melanoma detection: approaches to the patient with nevi
Goodson, Agnessa G.; Grossman, Douglas
2009-01-01
Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. Although there are no non-invasive techniques for definitive diagnosis of melanoma, and the “gold standard” remains biopsy with histologic examination, a variety of modalities may facilitate early melanoma diagnosis and the detection of new and changing nevi. This article reviews general clinical principles of early melanoma detection, and various modalities that are currently available or on the horizon, providing the clinician with an up-to-date understanding of management strategies for their patients with numerous or atypical nevi. Learning objectives At the conclusion of this learning activity, participants should: 1) understand the clinical importance of early melanoma detection; 2) appreciate the challenges of early melanoma diagnosis and which patients are at highest risk; 3) know general principles of early melanoma detection; 4) be familiar with current and emerging modalities that may facilitate early melanoma diagnosis and the detection of new and changing nevi; 5) know the advantages and limitations of each modality; and 6) be able to practice a combined approach to the patient with numerous or clinically atypical nevi. PMID:19389517
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Tumour mutation status and melanoma recurrence following a negative sentinel lymph node biopsy.
Adler, Nikki R; Wolfe, Rory; McArthur, Grant A; Kelly, John W; Haydon, Andrew; McLean, Catriona A; Mar, Victoria J
2018-05-14
A proportion of patients develop recurrence following a tumour-negative sentinel lymph node biopsy (SLNB). This study aimed to explore whether melanoma patients with BRAF or NRAS mutant tumours have an increased risk of developing disease recurrence following a negative SLNB compared to patients with wild-type tumours. Prospective cohort study of melanoma patients at three tertiary referral centres in Melbourne, who underwent SLNB. Clinical, pathological and molecular characteristics and recurrence data were prospectively recorded. Multivariate Cox proportional hazards regression models estimated the adjusted hazard ratio (aHR) and corresponding 95% confidence interval (CI) for the association between mutation status and development of recurrence following a negative-SLNB. Overall, 344/477 (72.1%) patients had a negative SLNB. Of these, 54 (15.7%) developed subsequent recurrence. The risk of disease recurrence following a negative SLNB was increased for patients with either a BRAF or NRAS mutant tumour compared to wild-type tumours (aHR 1.92, 95% CI: 1.02-3.60, p = 0.04). Melanoma patients with BRAF or NRAS mutant tumours had an increased risk compared to patients with BRAF/NRAS wild-type tumours of developing disease recurrence following a tumour-negative SLNB. The findings also confirm the importance of continued surveillance to monitor for disease recurrence among SLNB-negative patients.
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2018-06-13
Clinical Stage III Cutaneous Melanoma AJCC v8; Pathologic Stage III Cutaneous Melanoma AJCC v8; Pathologic Stage IIIA Cutaneous Melanoma AJCC v8; Pathologic Stage IIIB Cutaneous Melanoma AJCC v8; Pathologic Stage IIIC Cutaneous Melanoma AJCC v8; Pathologic Stage IIID Cutaneous Melanoma AJCC v8
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Day, C L; Mihm, M C; Lew, R A; 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; Sober, A J
1982-01-01
Fourteen variables were tested for their ability to predict visceral or bony metastases in 177 patients with clinical Stage I melanoma of intermediate thickness (1.51 - 3.39 mm). A Cox multivariate analysis yielded a combination of four variables that best predicted bony or visceral metastases for these patients: 1) mitoses greater than 6/min 2 (p = 0.0007), 2) location other than the forearm of leg) p = 0.009, 3) ulceration width greater than 3 mm (p = 0.04), 4) microscopic satellites (p = 0.05). The overall prognostic model chi square was 32.40 with 4 degrees of freedom (p less than 10 (-5). Combinations of the above variables were used to separate these patients into at least two risk groups. The high risk patients had at least a 35% or greater chance of developing visceral metastases within five years, while the low risk group had greater than an 85% chance of being disease free at five years. Criteria for the high risk group were as follows: 1) mitoses greater than 6/mm 2 in at least one area of the tumor, irrespective of primary tumor location, or 2) a melanoma located at some site other than the forearm or leg and histologic evidence in the primary tumor of either ulceration greater than 3 mm wide or microscopic satellites. The low risk group was defined as follows: 1) mitoses less than or equal to 6/mm 2 and a location on the leg or forearm, or 2) mitoses less than or equal to 6/mm 2 and the absence in histologic sections of the primary tumor of both microscopic satellites and ulceration greater then 3 mm wide. The number of patients in this series who did not undergo elective regional node dissection (N = 47) was probably too small to detect any benefit from this procedure. Based on survival rates from this and other studies, it is estimated that approximately 1500 patients with clinical Stage I melanoma of intermediate thickness in each arm of a randomized clinical trial would be needed to detect an increase in survival rates from elective regional node dissection. PMID:7055382
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Stagni, Camilla; Zamuner, Carolina; Elefanti, Lisa; Zanin, Tiziana; Bianco, Paola Del; Sommariva, Antonio; Fabozzi, Alessio; Pigozzo, Jacopo; Mocellin, Simone; Montesco, Maria Cristina; Chiarion-Sileni, Vanna; De Nicolo, Arcangela; Menin, Chiara
2018-06-01
Metastatic melanoma is characterized by complex genomic alterations, including a high rate of mutations in driver genes and widespread deletions and amplifications encompassing various chromosome regions. Among them, chromosome 7 is frequently gained in BRAF -mutant melanoma, inducing a mutant allele-specific imbalance. Although BRAF amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if BRAF copy-number variation and BRAF mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess BRAF copy number and mutant allele frequency in pretreatment melanoma samples from 46 patients who received MAPK inhibitor-based therapy, and we analyzed the association with progression-free survival. We found that 65% patients displayed BRAF gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced BRAF -mutant/wild-type allele ratio, whereas 14% and 23% patients had low and high BRAF mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid BRAF status versus those with BRAF gains [HR, 2.86; 95% confidence interval (CI), 1.29-6.35; P = 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95% CI, 1.33-15.53; P = 0.016). Our data suggest that quantitative analysis of the BRAF gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors. Mol Cancer Ther; 17(6); 1332-40. ©2018 AACR . ©2018 American Association for Cancer Research.
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Ives, Natalie J; Suciu, Stefan; Eggermont, Alexander M M; Kirkwood, John; Lorigan, Paul; Markovic, Svetomir N; Garbe, Claus; Wheatley, Keith
2017-09-01
Many randomised trials assessing interferon-α (IFN-α) as adjuvant therapy for high-risk malignant melanoma have been undertaken. To better assess the role of IFN-α, an individual patient data (IPD) meta-analysis of these trials was undertaken. IPD was sought from all randomised trials of adjuvant IFN-α versus no IFN-α for high-risk melanoma. Primary outcomes were event-free survival (EFS) and overall survival (OS). Standard methods for quantitative IPD meta-analysis were used. Subgroup analyses by dose, duration of treatment and various patient and disease-specific parameters were performed. Fifteen trials were included in the analysis (eleven with IPD). EFS was significantly improved with IFN-α (hazard ratio [HR] = 0.86, CI 0.81-0.91; P < 0.00001), as was OS (HR = 0.90, CI 0.85-0.97; P = 0.003). The absolute differences in EFS at 5 and 10 years were 3.5% and 2.7%, and for OS were 3.0% and 2.8% respectively in favour of IFN-α. There was no evidence that the benefit of IFN-α differed depending on dose or duration of treatment, or by age, gender, site of primary tumour, disease stage, Breslow thickness, or presence of clinical nodes. Only for ulceration was there evidence of an interaction (test for heterogeneity: P = 0.04 for EFS; P = 0.002 for OS); only patients with ulcerated tumours appeared to obtain benefit from IFN-α. This meta-analysis provides clear evidence that adjuvant IFN-α significantly reduces the risk of relapse and improves survival and shows no benefit for higher doses compared to lower doses. The increased benefit in patients with ulcerated tumours, and lack of benefit in patients without ulceration, needs further investigation. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Vemurafenib: in unresectable or metastatic melanoma.
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.
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Erim, Yesim; Scheel, Jennifer; Breidenstein, Anja; Metz, Claudia Hd; Lohmann, Dietmar; Friederich, Hans-Christoph; Tagay, Sefik
2016-07-07
Uveal melanoma patients with a poor prognosis can be detected through genetic analysis of the tumor, which has a very high sensitivity. A large number of patients with uveal melanoma decide to receive information about their individual risk and therefore routine prognostic genetic testing is being carried out on a growing number of patients. It is obvious that a positive prediction for recidivism in the future will emotionally burden the respective patients, but research on the psychosocial impact of this innovative method is lacking. The aim of the current study is therefore to investigate the psychosocial impact (psychological distress and quality of life) of prognostic genetic testing in patients with uveal melanoma. This study is a non-randomized controlled prospective clinical observational trial. Subjects are patients with uveal melanoma, in whom genetic testing is possible. Patients who consent to genetic testing are allocated to the intervention group and patients who refuse genetic testing form the observational group. Both groups receive cancer therapy and psycho-oncological intervention when needed. The psychosocial impact of prognostic testing is investigated with the following variables: resilience, social support, fear of tumor progression, depression, general distress, cancer-specific and general health-related quality of life, attitude towards genetic testing, estimation of the perceived risk of metastasis, utilization and satisfaction with psycho-oncological crisis intervention, and sociodemographic data. Data are assessed preoperatively (at initial admission in the clinic) and postoperatively (at discharge from hospital after surgery, 6-12 weeks, 6 and 12 months after initial admission). Genetic test results are communicated 6-12 weeks after initial admission to the clinic. We created optimal conditions for investigation of the psychosocial impact of prognostic genetic testing. This study will provide information on the course of disease and psychosocial outcomes after prognostic genetic testing. We expect that empirical data from our study will give a scientific basis for medico-ethical considerations.
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Li, Shan; Liu, Yanqiong; Zeng, Zhiyu; Peng, Qiliu; Li, Ruolin; Xie, Li; Qin, Xue; Zhao, Jinmin
2013-08-01
Results of the association between non-steroidal anti-inflammatory drugs (NSAIDs) and melanoma risk have been inconsistent. We performed a meta-analysis of relevant studies to investigate the hypothesis of an association between NSAID use and melanoma risk. Systematic searches of the PubMed and several other databases up to 23 March 2013 were retrieved. All epidemiologic studies regarding NSAIDs and melanoma risk were included. Fixed- or random-effects meta-analytical models were used to calculate relative risk (RR) and corresponding 95 % confidence intervals (CIs). Sensitivity analyses, Galbraith plots, and subgroup analyses were also performed. Six case-control studies including 93,432 melanoma cases and 401,251 controls, six cohort studies consisting of 563,380 subjects, and one randomized controlled trial encompassing 39,876 participants were included in this analysis. Compared to non-use, ever use of any NSAIDs was not statistically significantly associated with melanoma risk based on the random-effects models (RR = 0.97, 95 % CI = 0.90-10.4, p = 0.401). No differences were found in the effects on melanoma risk of aspirin, non-aspirin NSAIDs, and cyclooxygenase-2 inhibitor use overall and stratified by gender. However, a slight reduction in the risk of melanoma by taking aspirin was observed in case-control studies (RR = 0.88, 95 % CI = 0.80-0.96, p = 0.004). Findings from this pooled analysis do not support the hypothesis that NSAID use provides potential benefits in preventing melanoma. More and larger randomized trials, including adequate numbers of patients, are required to further evaluate the relationship between NSAID use and melanoma.
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Immunotherapy of patients with metastatic melanoma.
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.
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Communication by Mothers with Breast Cancer or Melanoma with Their Children
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
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Communication by mothers with breast cancer or melanoma with their children.
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.
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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.
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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.
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Vitamin D status and risk for malignant cutaneous melanoma: recent advances
Ombra, Maria N.; Doneddu, Valentina; Sini, Maria C.; Colombino, Maria; Rozzo, Carla; Stanganelli, Ignazio; Tanda, Francesco; Cossu, Antonio; Palmieri, Giuseppe
2017-01-01
Cutaneous malignant melanoma, whose incidence is increasing steadily worldwide, is the result of complex interactions between individual genetic factors and environmental risk factors. Ultraviolet radiation represents the most important environmental risk factor for the development of skin cancers, including melanoma. Sun exposure and early sunburn during childhood are the principal causes of cutaneous melanoma insurgence in adults, with double the risk relative to a nonexposed population. Consequently, ultraviolet protection has long been recognized as an important measure to prevent such a malignancy. Biological and epidemiological data suggest that vitamin D status could affect the risk of cancer and play a role in cancer prevention by exerting antiproliferative effects. Solar radiations are critical for vitamin D synthesis in humans; however, uncontrolled and intensive sun exposure is dangerous to skin health and may contribute toward the development of cutaneous malignant melanoma. An optimum balance between sun protection and exposure is thus advocated. Additional research is required to confirm the preventive role of vitamin D in melanoma incidence or a positive influence on patient outcome. PMID:28125434
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The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length
Bishop, D. Timothy; Taylor, John C.; Hayward, Nicholas K.; Brossard, Myriam; Cust, Anne E.; Dunning, Alison M.; Lee, Jeffrey E.; Moses, Eric K.; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Elder, David E.; Friedman, Eitan; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Harland, Mark; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Martin, Nicholas G.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Radford-Smith, Graham L.; Randerson-Moor, Juliette; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; MacGregor, Stuart; Pooley, Karen A.; Ward, Sarah V.; Mann, Graham J.; Amos, Christopher I.; Pharoah, Paul D. P.; Demenais, Florence; Law, Matthew H.; Newton Bishop, Julia A.; Barrett, Jennifer H.
2014-01-01
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk. PMID:25231748
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Uveal melanoma in relation to ultraviolet light exposure and host factors.
Holly, E A; Aston, D A; Char, D H; Kristiansen, J J; Ahn, D K
1990-09-15
We conducted a case-control interview study among 1277 subjects (407 patients, 870 controls selected by using random digit dial) in 11 western United States to determine whether uveal melanoma and cutaneous melanoma shared common risk factors. After adjustment for other factors, the risk of uveal melanoma was increased for those with green, gray, or hazel eyes [relative risk (RR) = 2.5, P less than 0.001] or blue eyes (RR = 2.2, P less than 0.001) when compared to brown. A tendency to sunburn after 0.5 h midday summer sun exposure increased risk for uveal melanoma (burn with tanning RR = 1.5, P = 0.02; burn with little tanning RR = 1.8, P less than 0.001; burn with no tanning RR = 1.7, P = 0.002); as did exposure to UV or black lights (RR = 3.7, P = 0.003); and welding burn, sunburn of the eye, or snow blindness (RR = 7.2, P less than 0.001). An association with uveal melanoma was also noted with an increasing number of large nevi (P = 0.04 for trend), although the individual risk estimates were not remarkable. These data suggest that host factors and exposure to UV light are risk factors for uveal melanoma.
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Gibney, Geoffrey T.; Kudchadkar, Ragini R.; DeConti, Ronald C.; Thebeau, Melissa S.; Czupryn, Maria P.; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J.; Fisher, Kate J.; Horak, Christine E.; Inzunza, H. David; Yu, Bin; Martinez, Alberto J.; Younos, Ibrahim; Weber, Jeffrey S.
2015-01-01
Purpose The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Results Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4+/CD4+, CD25+Treg/CD4+, and tetramer specific CD8+ T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25+Treg/CD4+ populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Conclusions Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. PMID:25524312
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Gibney, Geoffrey T; Kudchadkar, Ragini R; DeConti, Ronald C; Thebeau, Melissa S; Czupryn, Maria P; Tetteh, Leticia; Eysmans, Cabell; Richards, Allison; Schell, Michael J; Fisher, Kate J; Horak, Christine E; Inzunza, H David; Yu, Bin; Martinez, Alberto J; Younos, Ibrahim; Weber, Jeffrey S
2015-02-15
The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. ©2014 American Association for Cancer Research.
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Smoking and cutaneous melanoma: findings from The QSkin Sun and Health cohort study.
Dusingize, Jean Claude; Olsen, Catherine M; Pandeya, Nirmala; Thompson, Bridie S; Webb, Penelope M; Green, Adèle C; Neale, Rachel E; Whiteman, David C
2018-05-22
Previous studies suggest that smokers have lower risks of cutaneous melanoma than non-smokers, but data from population-based prospective studies are scarce. We investigated associations between smoking and melanoma in a cohort study purpose-designed to investigate skin cancer outcomes. Participants with no prior history of melanoma (n=38,697) completed a risk factor survey at baseline (2011). Patients were followed through linkage to the cancer registry. We estimated hazard ratios and 95% confidence intervals for associations between smoking (including intensity, duration, time since quitting) and melanoma using multivariate Cox proportional hazards regression, accounting for death as a competing event. During a mean follow-up of 3.5 years, invasive melanomas developed in 247 participants. Compared with never smokers, former smokers (but not current smokers) had lower risks of invasive melanoma (HR: 0.76; 95%CI 0.57-1.01). Among former smokers, risks were lower with greater quantity of cigarettes smoked (HR: 0.75; 95%CI 0.56-0.98 per 10 cigarettes/day). No association was observed with duration of smoking while longer time since quitting was associated with a relative risk of melanoma that was not significantly different from the null (HR: 1.18; 95%CI: 0.91-1.51, for every 10 years since quitting). We observed complex associations between smoking and melanoma, with some suggestion that former smokers had lower risks than never or current smokers. The apparent inverse association among former smokers may be due to residual confounding, although surveillance bias or biological effects cannot be excluded entirely. Smoking does not increase the risk of cutaneous melanoma. Copyright ©2018, American Association for Cancer Research.
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Intraocular (Uveal) Melanoma Symptoms, Tests, Prognosis, and Stages (PDQ®)—Patient Version
Intraocular melanoma is a rare cancer that forms from cells that make melanin in the eye. It is the most common eye cancer in adults and may not cause early signs or symptoms. Find out risk factors, tests to diagnose, prognosis, and staging for intraocular melanoma.
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Kassianos, A P; Emery, J D; Murchie, P; Walter, F M
2015-06-01
Smartphone health applications ('apps') are widely available but experts remain cautious about their utility and safety. We reviewed currently available apps for the detection of melanoma (July 2014), aimed at general community, patient and generalist clinician users. A proforma was used to extract and assess each app that met the inclusion criteria, and we undertook content analysis to evaluate their content and the evidence applied in their development. Thirty-nine apps were identified with the majority available only for Apple users. Over half (n = 22) provided information or education about melanoma, ultraviolet radiation exposure prevention advice, and skin self-examination strategies, mainly using the ABCDE (A, Asymmetry; B, Border; C, Colour; D, Diameter; E, Evolving) method. Half (n = 19) helped users take and store images of their skin lesions either for review by a dermatologist or for self-monitoring to identify change, an important predictor of melanoma; a similar number (n = 18) used reminders to help users monitor their skin lesions. A few (n = 9) offered expert review of images. Four apps provided a risk assessment to patients about the probability that a lesion was malignant or benign, and one app calculated users' future risk of melanoma. None of the apps appeared to have been validated for diagnostic accuracy or utility using established research methods. Smartphone apps for detecting melanoma by nonspecialist users have a range of functions including information, education, classification, risk assessment and monitoring change. Despite their potential usefulness, and while clinicians may choose to use apps that provide information to educate their patients, apps for melanoma detection require further validation of their utility and safety. © 2015 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.
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Balch, Charles M.; Murad, Tariq M.; Soong, Seng-Jaw; Ingalls, Anna Lee; Halpern, Norman B.; Maddox, William A.
1978-01-01
A multifactorial analysis was used to identify the dominant prognostic variables affecting survival from a computerized data base of 339 melanoma patients treated at this institution during the past 17 years. Five of the 13 parameters examined simultaneously were found to independently influence five year survival rates: 1) pathological stage (I vs II, p = 0.0014), 2) lesion ulceration (present vs absent, p = 0.006), 3) surgical treatment (wide excision vs wide excision plus lymphadenectomy, p = 0.024), 4) melanoma thickness (p = 0.032), and 5) location (upper extremity vs lower extremity vs trunk vs head and neck, p = 0.038). Additional factors considered that had either indirect or no influence on survival rates were clinical stage of disease, age, sex, level of invasion, pigmentation, lymphocyte infiltration, growth pattern, and regression. Most of these latter variables derived their prognostic value from correlation with melanoma thickness, except sex which correlated with location (extremity lesions were more frequent on females, trunk lesions on males). This statistical analysis enabled us to derive a mathematical equation for predicting an individual patient's probability of five year survival. Three categories of risk were delineated by measuring tumor thickness (Breslow microstaging) in Stage I patients: 1) thin melanomas (<0.76 mm) were associated with localized disease and a 100% cure rate: 2) intermediate thickness melanomas (0.76-4.00 mm) had an increasing risk (up to 80%) of harboring regional and/or distant metastases and 3) thick melanomas (≥4.00 mm) had a 80% risk of occult distant metastases at the time of initial presentation. The level of invasion (Clark's microstaging) correlated with survival, but was less predictive than measuring tumor thickness. Within each of Clark's Level II, III and IV groups, there were gradations of thickness with statistically different survival rates. Both microstaging methods (Breslow and Clark) were less predictive factors in patients with lymph node or distant metastases. Clinical trials evaluating alternative surgical treatments or adjunctive therapy modalities for melanoma patients should incorporate these parameters into their assessment, especially in Stage I (localized) disease where tumor thickness and the anatomical site of the primary melanoma are dominant prognostic factors. PMID:736651
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The European approach to in-transit melanoma lesions.
Hoekstra, H J
2008-05-01
The biological behavior of melanoma is unpredictable. Three to five per cent of melanoma patients will develop in-transit lesions and the median time to recurrence ranges between 13-16 months. At the time of recurrence the risk of occult nodal metastasis, with clinically negative regional lymph nodes, is as high as 50%. The risk of in-transit lesions depends on the tumor biology and not on the surgical approach to the regional lymph nodes. The high incidence of in-transit lesions at the lower limb may be caused by the gravity and delayed lymphatic drainage. The treatment of limited disease is local excision, laser ablation, cryosurgery, while multiple in-transit lesions or bulky disease located in a limb can be successfully treated with regional chemotherapy, a therapeutic isolated limb perfusion or infusion with melphalan or a combination of melphalan and tumor necrosis factor (TNF) alpha. If local regional treatment or systemic dacarbazine based systemic treatment fails, novel systemic treatment strategies with vaccines, antibodies and gene therapy are currently investigated.
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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
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Seidenari, Stefania; Benati, Elisa; Ponti, Giovanni; Borsari, Stefania; Ferrari, Chiara; Albertini, Giuseppe; Altomare, Gianfranco; Arcangeli, Fabio; Aste, Nicola; Bernengo, Maria Grazia; Bongiorno, Maria Rita; Borroni, Giovanni; Calvieri, Stefano; Chimenti, Sergio; Cusano, Francesco; Fracchiolla, Claudio; Gaddoni, Giuseppe; Girolomoni, Giampiero; Guarneri, Biagio; Lanzoni, Anna; Lombardi, Mara; Lotti, Torello; Mariotti, Antonio; Marsili, Franco; Micali, Giuseppe; Parodi, Aurora; Peris, Ketty; Peserico, Andrea; Quaglino, Pietro; Santini, Marcello; Schiavon, Sergio; Tonino, Camillo; Trevisan, Giusto; Tribuzi, Paola; Valentini, Paolo; Vena, Gino A; Virgili, Annarosa
2012-01-01
Although no study has definitively shown that unfocused screening of skin cancer is effective, many campaigns have been organized with the aim of increasing awareness on melanoma risk factors. The objective of this study was to analyse the results of the Skin Cancer Screening Day in Italy during the period 2005-2007, to determine the priorities for melanoma control plans in a Mediterranean country. A total of 5002 patients were screened by dermatologists in 31 cities. Individuals who considered themselves to have many naevi and those with a family history of melanoma showed a higher number of common and atypical naevi. Ten melanomas, 20 basal cell carcinomas and two squamous cell carcinomas were histopathologically confirmed. Our observations provide the following suggestions for melanoma prevention strategies: (a) an unfocused campaign is suitable to inform the public about the importance of self-examination of the skin, but is not useful to identify a larger number of melanomas; and (b) melanoma screening campaigns should focus on a selected population, which meets rigorous risk criteria to maintain higher cost-effectiveness. The financial support to effective melanoma screening programmes could be increased, especially in southern populations where lower levels of self-surveillance and socioeconomic conditions represent risk factors for late identification of melanoma.
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Valpione, Sara; Pasquali, Sandro; Campana, Luca Giovanni; Piccin, Luisa; Mocellin, Simone; Pigozzo, Jacopo; Chiarion-Sileni, Vanna
2018-04-11
Ipilimumab is a licensed immunotherapy for metastatic melanoma patients and, in the US, as adjuvant treatment for high risk melanoma radically resected. The use of ipilimumab is associated with a typical but unpredictable pattern of side effects. The purpose of this study was to identify clinical features and blood biomarkers capable of predicting ipilimumab related toxicity. We performed a prospective study aimed at analyzing potential clinical and biological markers associated with immune-related toxicity in patients treated with ipilimumab (3 mg/kg, q3w). We enrolled 140 consecutive melanoma patients treated with ipilimumab for metastatic disease. The following prospectively collected data were utilized: patient characteristics, previous therapies, level of circulating biomarkers associated with tumour burden or immune-inflammation status (lactic dehydrogenase, C-reactive protein, β2-microglobulin, vascular endothelial growth factor, interleukin-2, interleukin-6, S-100, alkaline phosphatase, transaminases) and blood cells subsets (leukocyte and lymphocyte subpopulations). Logistic regression was used for multivariate analysis of data. Out of 140 patients, 36 (26%) experienced a severe adverse event, 33 (24%) discontinued treatment for severe toxicity. Among the immune-profile biomarkers analyzed, only interleukin-6 was associated with the risk of toxicity. Female patients had a further increase of immune-related adverse events. Low baseline interleukin-6 serum levels (OR = 2.84, 95% CI 1.34-6.03, P = 0.007) and sex female (OR = 1.5, 95% CI 1.06-2.16 P = 0.022) and were significant and independent risk factors for immune related adverse events. Baseline IL6 serum levels and female sex were significantly and independently associated with higher risk of severe toxicity and could be exploited in clinical practice to personalize toxicity surveillance in patients treated with ipilimumab.
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Addison's disease as a presentation of metastatic malignant melanoma.
Srinivasan, B; Patel, M; Ethunandan, M; Ilankovan, V
2016-01-01
Melanoma accounts for 5% of all skin cancers. The risk of metastasis is related to the thickness of the tumour, and can affect local, regional and distant sites. Adrenal metastasis from melanoma of the head and neck is uncommon and often asymptomatic. Addison's disease as a presentation of metastatic melanoma is extremely rare and we are unaware of previous reports in the world literature. We report a case of a patient with metastatic melanoma presenting with signs and symptoms of Addison's disease.
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A Large Cohort Study of Nonsteroidal Anti-inflammatory Drug Use and Melanoma Incidence
Maruti, Sonia S.; White, Emily
2008-01-01
Results of laboratory studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may have chemopreventive activity and therapeutic efficacy against melanoma. However, few published epidemiological studies have examined the association between NSAID use and melanoma risk. We examined whether NSAID use was associated with melanoma risk among 63 809 men and women in the Vitamins and Lifestyle (VITAL) cohort study. Participants self-reported NSAID use (low-dose aspirin, regular or extra-strength aspirin, and nonaspirin NSAIDs) during the previous 10 years and data related to their melanoma risk factors on a baseline questionnaire. After linkage of the VITAL database to the NCI Surveillance, Epidemiology, and End Results cancer registry, 349 patients with incident melanoma were identified through December 31, 2005. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma by NSAID use as categorized by overall use, duration of use, and dose (expressed as average number of days of use during the past 10 years). All statistical tests were two-sided. After adjusting for melanoma risk factors and indications for NSAID use, no association between NSAID use and melanoma risk was found. When use of at least 4 d/wk was compared with nonuse, no melanoma risk reduction was detected for any NSAID dose (HR = 1.12, 95% CI = 0.84 to 1.48), for any NSAID excluding low-dose aspirin (HR = 1.03, 95% CI = 0.74 to 1.43), for regular- or extra-strength aspirin (HR = 1.10, 95% CI = 0.76 to 1.58), or for nonaspirin NSAIDs (HR = 1.22, 95% CI = 0.75 to 1.99). Moreover, NSAID use was not associated with tumor invasion (Pinteraction = .38), tumor thickness (Ptrend = .98), or risk of metastasis (HR = 1.09, 95% CI = 0.32 to 3.62). NSAIDs do not appear to be good candidates for the chemoprevention of melanoma. PMID:18577752
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Tanning beds: A call to action for further educational and legislative efforts.
Farley, Clara; Alimi, Yewande; Espinosa, Lauren R; Perez, Sebastian; Knechtle, William; Hestley, Andrea; Carlson, Grant W; Russell, Maria C; Delman, Keith A; Rizzo, Monica
2015-08-01
Melanoma is steadily increasing over the past decade. Recent studies confirmed a link between tanning bed use and melanoma. We sought to determine the prevalence and frequency of tanning bed among young patients with melanoma. We retrospectively analyzed tanning bed use among young melanoma patients compared to controls selected from the hospital medical records. A telephone survey investigated family history of melanoma or skin cancer, hair color, eye color, skin type, tanning bed use, and patient awareness of dangers of tanning bed use. A total of 601 melanoma cases were identified; 265 (44%) completed the telephone survey as did 195 (31%) controls. Of these 460 subjects, 260 were female. Females were 3.0 times more likely to have used a tanning bed. Melanoma patients had natural light color hair, blue-green eyes, and 2.0 times more likely to use a tanning bed than controls. Among the tanning bed users, 90% were aware of danger of tanning bed. Our study found that tanning beds were more likely to be used by young women, the majority of whom are aware of the associated risks. Eliminating the use of tanning beds should be considered to decrease the incidence of melanoma. © 2015 Wiley Periodicals, Inc.
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The Epidemiology, Prevention, and Detection of Melanoma
Riker, Adam I.; Zea, Nicolas; Trinh, Tan
2010-01-01
We are seeing a record number of newly diagnosed skin cancers worldwide, with the incidence of melanoma increasing at a faster rate than almost all other cancers. As clinicians, we will have, by far, the greatest impact on reducing this incidence through better methods of early detection of melanoma and proven prevention methods and techniques. The medical community must enhance its efforts to increase its training of new health care personnel who are capable of diagnosing and treating this record number of patients with skin cancer. We must also try to increase the access to our limited number of dermatologists and provide novel ways of patient education such as through skin self-examinations, total body photography, and improved education for our children. By providing easier access to skin examinations, we will increase our chances of detecting melanoma in its earliest and most curable form. The dangers of indoor tanning beds and salons must be transparent to those that use them, focusing on expanding the oversight of such facilities by our local and federal governmental agencies while establishing legislation in several states to further limit their use to our youth, who are especially at high risk for developing melanoma in the future. This review will focus on the epidemiology, prevention, and detection of melanoma. PMID:21603359
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Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.
Eggermont, Alexander M M; Blank, Christian U; Mandala, Mario; Long, Georgina V; Atkinson, Victoria; Dalle, Stéphane; Haydon, Andrew; Lichinitser, Mikhail; Khattak, Adnan; Carlino, Matteo S; Sandhu, Shahneen; Larkin, James; Puig, Susana; Ascierto, Paolo A; Rutkowski, Piotr; Schadendorf, Dirk; Koornstra, Rutger; Hernandez-Aya, Leonel; Maio, Michele; van den Eertwegh, Alfonsus J M; Grob, Jean-Jacques; Gutzmer, Ralf; Jamal, Rahima; Lorigan, Paul; Ibrahim, Nageatte; Marreaud, Sandrine; van Akkooi, Alexander C J; Suciu, Stefan; Robert, Caroline
2018-05-10
The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma. Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated. At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group. As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; ClinicalTrials.gov number, NCT02362594 ; EudraCT number, 2014-004944-37 .).
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The role of BRAF V600 mutation in melanoma
2012-01-01
BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors. PMID:22554099
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Use of Tanning Beds and Incidence of Skin Cancer
Zhang, Mingfeng; Qureshi, Abrar A.; Geller, Alan C.; Frazier, Lindsay; Hunter, David J.; Han, Jiali
2012-01-01
Purpose We sought to evaluate the risk effect of tanning bed use on skin cancers among teenage and young adults. We also expected to determine whether a dose-response relationship was evident. Patients and Methods We observed 73,494 female nurses for 20 years (from 1989 to 2009) in a large and well-characterized cohort in the United States and investigated whether frequency of tanning bed use during high school/college and at ages 25 to 35 years were associated with a risk of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. We used Cox proportional hazards models and carefully adjusted for host risk factors, ultraviolet index of residence, and sun exposure behaviors at a young age. Results During follow-up, 5,506 nurses were diagnosed with BCC, 403 with SCC, and 349 with melanoma. The multivariable-adjusted hazard ratio (HR) of skin cancer for an incremental increase in use of tanning beds of four times per year during both periods was 1.15 (95% CI, 1.11 to 1.19; P < .001) for BCC, 1.15 (95% CI, 1.01 to 1.31; P = .03) for SCC, and 1.11 (95% CI, 0.97 to 1.27; P = .13) for melanoma. Compared with tanning bed use at ages 25 to 35 years, we found a significantly higher risk of BCC for use during high school/college (multivariable-adjusted HR for use more than six times per year compared with no use was 1.73 during high school/college v 1.28 at ages 25 to 35 years; P for heterogeneity < .001). Conclusion Our data provide evidence for a dose-response relationship between tanning bed use and the risk of skin cancers, especially BCC, and the association is stronger for patients with a younger age at exposure. PMID:22370316
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Tanning bed use and melanoma: Establishing risk and improving prevention interventions.
Le Clair, Marie Z; Cockburn, Myles G
2016-06-01
Exposure to ultraviolet radiation (UVR) from indoor tanning devices is thought to cause melanoma and other negative health consequences. Despite these findings, the practice of indoor tanning in the United States remains prevalent. In this paper we aim to present a clear discussion of the relationship between indoor tanning and melanoma risk, and to identify potential strategies for effective melanoma prevention by addressing indoor tanning device use. We reviewed relevant literature on the risks of indoor tanning, current indoor tanning legislation, and trends in indoor tanning and melanoma incidence. Study was conducted at the University of Southern California, Los Angeles, CA between the years of 2014 and 2015. Our findings reaffirm the relationship between indoor tanning and melanoma risk, and suggest a widespread public misunderstanding of the negative effects of indoor tanning. This review argues for an aggressive initiative to reduce indoor tanning in the United States, to design prevention efforts tailored towards specific high risk groups, and the need to better inform the public of the risks of indoor tanning.
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Palmieri, Giuseppe; Satriano, Sabrina MR; Budroni, Mario; Cossu, Antonio; Tanda, Francesco; Canzanella, Sergio; Caracò, Corrado; Simeone, Ester; Daponte, Antonio; Mozzillo, Nicola; Comella, Giuseppe; Castello, Giuseppe; Ascierto, Paolo A
2006-01-01
Background Detection of circulating malignant cells (CMCs) through a reverse transcriptase-polymerase chain reaction (RT-PCR) assay seems to be a demonstration of systemic disease. We here evaluated the prognostic role of RT-PCR assays in serially-taken peripheral blood samples from patients with malignant melanoma (MM). Methods One hundred forty-nine melanoma patients with disease stage ranging from I to III were consecutively collected in 1997. A multi-marker RT-PCR assay was used on peripheral blood samples obtained at time of diagnosis and every 6 months during the first two years of follow-up (total: 5 samples). Univariate and multivariate analyses were performed after 83 months of median follow-up. Results Detection of at least one circulating mRNA marker was considered a signal of the presence of CMC (referred to as PCR-positive assay). A significant correlation was found between the rate of recurrences and the increasing number of PCR-positive assays (P = 0.007). Presence of CMC in a high number (≥2) of analysed blood samples was significantly correlated with a poor clinical outcome (disease-free survival: P = 0.019; overall survival: P = 0.034). Multivariate analysis revealed that presence of a PCR-positive status does play a role as independent prognostic factors for overall survival in melanoma patients, adding precision to the predictive power of the disease stage. Conclusion Our findings indicated that serial RT-PCR assay may identify a high risk subset of melanoma patients with occult cancer cells constantly detected in blood circulation. Prolonged presence of CMCs seems to act as a surrogate marker of disease progression or a sign of more aggressive disease. PMID:17107608
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Palmieri, Giuseppe; Satriano, Sabrina M R; Budroni, Mario; Cossu, Antonio; Tanda, Francesco; Canzanella, Sergio; Caracò, Corrado; Simeone, Ester; Daponte, Antonio; Mozzillo, Nicola; Comella, Giuseppe; Castello, Giuseppe; Ascierto, Paolo A
2006-11-15
Detection of circulating malignant cells (CMCs) through a reverse transcriptase-polymerase chain reaction (RT-PCR) assay seems to be a demonstration of systemic disease. We here evaluated the prognostic role of RT-PCR assays in serially-taken peripheral blood samples from patients with malignant melanoma (MM). One hundred forty-nine melanoma patients with disease stage ranging from I to III were consecutively collected in 1997. A multi-marker RT-PCR assay was used on peripheral blood samples obtained at time of diagnosis and every 6 months during the first two years of follow-up (total: 5 samples). Univariate and multivariate analyses were performed after 83 months of median follow-up. Detection of at least one circulating mRNA marker was considered a signal of the presence of CMC (referred to as PCR-positive assay). A significant correlation was found between the rate of recurrences and the increasing number of PCR-positive assays (P = 0.007). Presence of CMC in a high number (> or =2) of analysed blood samples was significantly correlated with a poor clinical outcome (disease-free survival: P = 0.019; overall survival: P = 0.034). Multivariate analysis revealed that presence of a PCR-positive status does play a role as independent prognostic factors for overall survival in melanoma patients, adding precision to the predictive power of the disease stage. Our findings indicated that serial RT-PCR assay may identify a high risk subset of melanoma patients with occult cancer cells constantly detected in blood circulation. Prolonged presence of CMCs seems to act as a surrogate marker of disease progression or a sign of more aggressive disease.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Pinkham, Mark B., E-mail: mark.pinkham@health.qld.gov.au; University of Queensland, Brisbane; Foote, Matthew C.
Purpose: To describe the anatomic distribution of regionally recurrent disease in patients with stage III melanoma in the axilla after curative-intent surgery with and without adjuvant radiation therapy. Methods and Materials: A single-institution, retrospective analysis of a prospective database of 277 patients undergoing curative-intent treatment for stage III melanoma in the axilla between 1992 and 2012 was completed. For patients who received radiation therapy and those who did not, patterns of regional recurrence were analyzed, and univariate analyses were performed to assess for potential factors associated with location of recurrence. Results: There were 121 patients who received adjuvant radiation therapymore » because their clinicopathologic features conferred a greater risk of regional recurrence. There were 156 patients who received no radiation therapy. The overall axillary control rate was 87%. There were 37 patients with regional recurrence; 17 patients had received adjuvant radiation therapy (14%), and 20 patients (13%) had not. The likelihood of in-field nodal recurrence was significantly less in the adjuvant radiation therapy group (P=.01) and significantly greater in sites adjacent to the axilla (P=.02). Patients with high-risk clinicopathologic features who did not receive adjuvant radiation therapy also tended to experience in-field failure rather than adjacent-field failure. Conclusions: Patients who received adjuvant radiation therapy were more likely to experience recurrence in the adjacent-field regions rather than in the in-field regions. This may not simply reflect higher-risk pathology. Using this data, it may be possible to improve outcomes by reducing the number of adjacent-field recurrences after adjuvant radiation therapy.« less
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Sabel, Michael S; Rice, John D; Griffith, Kent A; Lowe, Lori; Wong, Sandra L; Chang, Alfred E; Johnson, Timothy M; Taylor, Jeremy M G
2012-01-01
To identify melanoma patients at sufficiently low risk of nodal metastases who could avoid sentinel lymph node biopsy (SLNB), several statistical models have been proposed based upon patient/tumor characteristics, including logistic regression, classification trees, random forests, and support vector machines. We sought to validate recently published models meant to predict sentinel node status. We queried our comprehensive, prospectively collected melanoma database for consecutive melanoma patients undergoing SLNB. Prediction values were estimated based upon four published models, calculating the same reported metrics: negative predictive value (NPV), rate of negative predictions (RNP), and false-negative rate (FNR). Logistic regression performed comparably with our data when considering NPV (89.4 versus 93.6%); however, the model's specificity was not high enough to significantly reduce the rate of biopsies (SLN reduction rate of 2.9%). When applied to our data, the classification tree produced NPV and reduction in biopsy rates that were lower (87.7 versus 94.1 and 29.8 versus 14.3, respectively). Two published models could not be applied to our data due to model complexity and the use of proprietary software. Published models meant to reduce the SLNB rate among patients with melanoma either underperformed when applied to our larger dataset, or could not be validated. Differences in selection criteria and histopathologic interpretation likely resulted in underperformance. Statistical predictive models must be developed in a clinically applicable manner to allow for both validation and ultimately clinical utility.
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Sabel, Michael S.; Rice, John D.; Griffith, Kent A.; Lowe, Lori; Wong, Sandra L.; Chang, Alfred E.; Johnson, Timothy M.; Taylor, Jeremy M.G.
2013-01-01
Introduction To identify melanoma patients at sufficiently low risk of nodal metastases who could avoid SLN biopsy (SLNB). Several statistical models have been proposed based upon patient/tumor characteristics, including logistic regression, classification trees, random forests and support vector machines. We sought to validate recently published models meant to predict sentinel node status. Methods We queried our comprehensive, prospectively-collected melanoma database for consecutive melanoma patients undergoing SLNB. Prediction values were estimated based upon 4 published models, calculating the same reported metrics: negative predictive value (NPV), rate of negative predictions (RNP), and false negative rate (FNR). Results Logistic regression performed comparably with our data when considering NPV (89.4% vs. 93.6%); however the model’s specificity was not high enough to significantly reduce the rate of biopsies (SLN reduction rate of 2.9%). When applied to our data, the classification tree produced NPV and reduction in biopsies rates that were lower 87.7% vs. 94.1% and 29.8% vs. 14.3%, respectively. Two published models could not be applied to our data due to model complexity and the use of proprietary software. Conclusions Published models meant to reduce the SLNB rate among patients with melanoma either underperformed when applied to our larger dataset, or could not be validated. Differences in selection criteria and histopathologic interpretation likely resulted in underperformance. Development of statistical predictive models must be created in a clinically applicable manner to allow for both validation and ultimately clinical utility. PMID:21822550
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Update on primary head and neck mucosal melanoma
López, Fernando; Rodrigo, Juan P.; Cardesa, Antonio; Triantafyllou, Asterios; Devaney, Kenneth O.; Mendenhall, William M.; Haigentz, Missak; Strojan, Primož; Pellitteri, Phillip K.; Bradford, Carol R.; Shaha, Ashok R.; Hunt, Jennifer L.; de Bree, Remco; Takes, Robert P.; Rinaldo, Alessandra; Ferlito, Alfio
2016-01-01
Primary mucosal melanomas (PMMs) of the head and neck are uncommon malignancies that arise mainly in the nasal cavity and paranasal sinuses, followed by the oral cavity. The mainstay of treatment is radical surgical resection followed by adjuvant radiotherapy in selected patients with high-risk features. Multimodality therapy has not been well studied and is not standardized. Adjuvant radiotherapy seems to improve locoregional control but does not improve overall survival (OS). Elective neck dissection is advocated in patients with oral PMM. Systemic therapy should be considered only for patients with metastatic or unresectable locoregional disease. Despite improvements in the field of surgery, radiotherapy, and systemic therapy, patients with PMM still face a very unfavorable prognosis (5-year disease-free survival [DFS] <20%) with high rates of locoregional recurrence and distant metastasis. The present review aims to summarize the current state of knowledge on the molecular biology, pathological diagnosis, and management of this disease. PMID:25242350
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Association between Lithium Use and Melanoma Risk and Mortality: A Population-Based Study.
Asgari, Maryam M; Chien, Andy J; Tsai, Ai Lin; Fireman, Bruce; Quesenberry, Charles P
2017-10-01
Laboratory studies show that lithium, an activator of the Wnt/ß-catenin signaling pathway, slows melanoma progression, but to our knowledge no published epidemiologic studies have explored this association. We conducted a retrospective cohort study of adult white Kaiser Permanente Northern California members (n = 2,213,848) from 1997-2012 to examine the association between lithium use and melanoma risk. Lithium exposure (n = 11,317) was assessed from pharmacy databases, serum lithium levels were obtained from electronic laboratory databases, and incident cutaneous melanomas (n = 14,056) were identified from an established cancer registry. In addition to examining melanoma incidence, melanoma hazard ratios and 95% confidence intervals for lithium exposure were estimated using Cox proportional hazards models, adjusted for potential confounders. Melanoma incidence per 100,000 person-years among lithium-exposed individuals was 67.4, compared with 92.5 in unexposed individuals (P = 0.027). Lithium-exposed individuals had a 32% lower risk of melanoma (hazard ratio = 0.68, 95% confidence interval = 0.51-0.90) in unadjusted analysis, but the estimate was attenuated and nonsignificant in adjusted analysis (adjusted hazard ratio = 0.77, 95% confidence interval = 0.58-1.02). No lithium-exposed individuals presented with thick (>4 mm) or advanced-stage melanoma at diagnosis. Among melanoma patients, lithium-exposed individuals were less likely to suffer melanoma-associated mortality (rate = 4.68/1,000 person-years) compared with the unexposed (rate = 7.21/1,000 person-years). Our findings suggest that lithium may reduce melanoma risk and associated mortality. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Rosenberg, Steven A.; Zhai, Yifan; Yang, James C.; Schwartzentruber, Douglas J.; Hwu, Patrick; Marincola, Francesco M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Seipp, Claudia A.; Einhorn, Jan H.; Roberts, Bruce; White, Donald E.
2008-01-01
Background: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. Methods: In phase I studies, 54 patients received escalating doses (between 107 and 1011 plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed. Results: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients. Conclusions: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens. PMID:9862627
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Melanoma: a global perspective.
Ossio, Raul; Roldán-Marín, Rodrigo; Martínez-Said, Héctor; Adams, David J; Robles-Espinoza, Carla Daniela
2017-07-01
Most of our current knowledge of melanoma is derived from the study of patients from populations of European descent, for whom public health, sun protection initiatives and screening measures have appreciably decreased disease mortality. Notably, some melanoma subtypes that most commonly develop in other populations are not associated with exposure to ultraviolet (UV) light, suggesting a different disease aetiology. Further study of these subtypes is necessary to understand their risk factors and genomic architecture, and to tailor therapies and public health campaigns to benefit patients of all ethnic groups.
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MOYANO, MARÍA SERENO; GUTIÉRREZ-GUTIÉRREZ, GERARDO; RODRÍGUEZ-ESTEBAN, ISABEL; CRESPO, GEMMA SÁNCHEZ; CASADO, ENRIQUE
2010-01-01
We present the case of a patient with a solitary left frontoparietal brain metastasis of melanoma previously treated with surgery. Three months later, the patient was admitted to the emergency room in a confusional state with meningeal signs. A cerebrospinal fluid (CSF) test and magnetic resonance imaging findings suggested a subarachnoid haemorrhage (SAH) and/or meningeal carcinomatosis. The results of a cytological examination of the CSF showed neoplastic epithelial cells consistent with metastatic melanoma cells. Resection of metastatic posterior fossa lesions is often cited as a risk factor for leptomeningeal dissemination, however, when the resection is limited to the anterior fossa, this complication is relatively rare. In contrast, SAH may be a complication of leptomeningeal dissemination and responsible for acute meningeal syndrome. Treatment with high doses of corticoids did not show any improvement, and intrathecal chemotherapy was not possible due to the patient's poor functional status. She succumbed 1 week after admission. PMID:22870120
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Hyperspectral imaging for melanoma screening
NASA Astrophysics Data System (ADS)
Martin, Justin; Krueger, James; Gareau, Daniel
2014-03-01
The 5-year survival rate for patients diagnosed with Melanoma, a deadly form of skin cancer, in its latest stages is about 15%, compared to over 90% for early detection and treatment. We present an imaging system and algorithm that can be used to automatically generate a melanoma risk score to aid clinicians in the early identification of this form of skin cancer. Our system images the patient's skin at a series of different wavelengths and then analyzes several key dermoscopic features to generate this risk score. We have found that shorter wavelengths of light are sensitive to information in the superficial areas of the skin while longer wavelengths can be used to gather information at greater depths. This accompanying diagnostic computer algorithm has demonstrated much higher sensitivity and specificity than the currently commercialized system in preliminary trials and has the potential to improve the early detection of melanoma.
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Dandekar, Monisha; Lowe, Lori; Fullen, Douglas R; Johnson, Timothy M; Sabel, Michael S; Wong, Sandra L; Patel, Rajiv M
2014-10-01
Sentinel lymph node (SLN) status currently represents the single most important prognostic factor in clinically localized melanoma and is widely used in patients with melanoma at significant risk for nodal micrometastasis. Although several studies have looked at the rates and implications of inaccuracies in the histopathologic diagnosis of melanocytic lesions, accuracy in the histologic interpretation of the SLN in melanoma has not been addressed. The goal of this study was to determine the rates of discordance in the histopathologic evaluation of the SLN and the potential clinical impact on patients referred to a comprehensive melanoma center. A prospectively collected database was queried for melanoma patients who had SLN biopsies performed at outside institutions before referral to the University of Michigan Multidisciplinary Melanoma Program between 2006 and 2009. These cases were reviewed and clinical follow-up obtained. After internal review of the SLN material, 13 (8 %) of 167 cases had major discrepancies in diagnosis that impacted patient management and prognosis. The disease of five patients was subsequently downstaged and the disease of eight patients was upstaged after internal review of the SLNs and reversal in diagnoses. There appears to be a small yet significant rate of discordance in diagnosis of the SLN for melanoma after expert histopathologic review. The implications of this discordance and revision of diagnosis is substantial. Expert histopathologic review of the SLN warrants consideration to provide the most accurate prognostic information and optimal patient care.
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Damude, S; Wevers, K P; Murali, R; Kruijff, S; Hoekstra, H J; Bastiaannet, E
2017-09-01
Completion lymph node dissection (CLND) in sentinel node (SN)-positive melanoma patients is accompanied with morbidity, while about 80% yield no additional metastases in non-sentinel nodes (NSNs). A prediction tool for NSN involvement could be of assistance in patient selection for CLND. This study investigated which parameters predict NSN-positivity, and whether the biomarker S-100B improves the accuracy of a prediction model. Recorded clinicopathologic factors were tested for their association with NSN-positivity in 110 SN-positive patients who underwent CLND. A prediction model was developed with multivariable logistic regression, incorporating all predictive factors. Five models were compared for their predictive power by calculating the Area Under the Curve (AUC). A weighted risk score, 'S-100B Non-Sentinel Node Risk Score' (SN-SNORS), was derived for the model with the highest AUC. Besides, a nomogram was developed as visual representation. NSN-positivity was present in 24 (21.8%) patients. Sex, ulceration, number of harvested SNs, number of positive SNs, and S-100B value were independently associated with NSN-positivity. The AUC for the model including all these factors was 0.78 (95%CI 0.69-0.88). SN-SNORS was the sum of scores for the five parameters. Scores of ≤9.5, 10-11.5, and ≥12 were associated with low (0%), intermediate (21.0%) and high (43.2%) risk of NSN involvement. A prediction tool based on five parameters, including the biomarker S-100B, showed accurate risk stratification for NSN-involvement in SN-positive melanoma patients. If validated in future studies, this tool could help to identify patients with low risk for NSN-involvement. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
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Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype.
Nielsen, Kari; Harbst, Katja; Måsbäck, Anna; Jönsson, Göran; Borg, Ake; Olsson, Håkan; Ingvar, Christian
2010-08-01
Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.
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Ribero, S; Longo, C; Dika, E; Fortes, C; Pasquali, S; Nagore, E; Glass, D; Robert, C; Eggermont, A M; Testori, A; Quaglino, P; Nathan, P; Argenziano, G; Puig, S; Bataille, V
2017-01-01
Management of melanoma during pregnancy can be extremely challenging. The reported incidence of melanoma in pregnancy ranges from 2.8 to 5.0 per 100 000 pregnancies. There are no guidelines for the management of melanoma during pregnancy. The survey was designed to investigate the opinions of melanoma physicians on decision making in relation to pregnancy and melanoma. A clinical scenario-based survey on management of pregnancy in melanoma was distributed all over Europe via the membership of the EORTC and other European melanoma societies. A total of 290 questionnaires were returned with a larger participation from southern Europe. A large heterogeneity was found for the answers given in the different clinical scenarios with 50% of the answers showing discordance, especially regarding sentinel lymph node biopsy during pregnancy. Discordant answers were also found for the counselling of women about a potential delay in getting pregnant after a high-risk melanoma (35% for a 2 year wait minimum vs. 57% no waiting needed), while for thin melanomas, as expected, there was more concordance with 70% of the physicians recommending no delay. Fifteen per cent of physicians recommended an abortion in stage II melanoma during the third month of pregnancy. Twenty per cent of the responders advised against hormonal replacement therapy in melanoma patients. The management of melanoma during pregnancy varies widely in Europe. At present, there is a lack of consensus in Europe, which may lead to very important decisions in women with melanoma, and guidelines are needed. © 2016 European Academy of Dermatology and Venereology.
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Sutton, Selina K.; Koach, Jessica; Tan, Owen; Liu, Bing; Carter, Daniel R.; Wilmott, James S.; Yosufi, Benafsha; Haydu, Lauren E.; Mann, Graham J.; Thompson, John F.; Long, Georgina V.; Liu, Tao; McArthur, Grant; Zhang, Xu Dong; Scolyer, Richard A.; Cheung, Belamy B.; Marshall, Glenn M.
2014-01-01
High basal or induced expression of the tripartite motif protein, TRIM16, leads to reduce cell growth and migration of neuroblastoma and skin squamous cell carcinoma cells. However, the role of TRIM16 in melanoma is currently unknown. TRIM16 protein levels were markedly reduced in human melanoma cell lines, compared with normal human epidermal melanocytes due to both DNA methylation and reduced protein stability. TRIM16 knockdown strongly increased cell migration in normal human epidermal melanocytes, while TRIM16 overexpression reduced cell migration and proliferation of melanoma cells in an interferon beta 1 (IFNβ1)-dependent manner. Chromatin immunoprecipitation assays revealed TRIM16 directly bound the IFNβ1 gene promoter. Low level TRIM16 expression in 91 melanoma patient samples, strongly correlated with lymph node metastasis, and, predicted poor patient prognosis in a separate cohort of 170 melanoma patients with lymph node metastasis. The BRAF inhibitor, vemurafenib, increased TRIM16 protein levels in melanoma cells in vitro, and induced growth arrest in BRAF-mutant melanoma cells in a TRIM16-dependent manner. High levels of TRIM16 in melanoma tissues from patients treated with Vemurafenib correlated with clinical response. Our data, for the first time, demonstrates TRIM16 is a marker of cell migration and metastasis, and a novel treatment target in melanoma. PMID:25333256
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Wu, Yelena P.; Aspinwall, Lisa G.; Conn, Bridgid M.; Stump, Tammy; Grahmann, Bridget; Leachman, Sancy A.
2016-01-01
Background and Objectives To examine the effectiveness of behavioral interventions for melanoma prevention targeted to individuals at elevated risk due to personal and/or family history. Methods Through literature searches in 5 search databases (through July 2014), 20 articles describing 14 unique interventions focused on melanoma prevention among individuals at elevated risk for the disease were identified. Interventions targeting only patients undergoing active treatment for melanoma were excluded. Results The average study quality was moderate. The majority of interventions (6 out of 9, 66% of studies) led to improvements in one or more photoprotective behaviors, particularly for improvements in use of protective clothing (3 out of 5, 60% of studies), and frequency and/or thoroughness of skin self-examinations (9 out of 12, 75%). Fewer interventions (5 out of 14, 36%) targeted uptake of total body skin examinations (60% led to improvements). Also, fewer interventions targeted all three preventive behaviors (5 out of 14, 36%). Conclusions Findings suggest future interventions should aim to improve adherence across multiple preventive behaviors, over a longer time period (past 8 months post-intervention), and target high-risk children. Studies should include adequate sample sizes to investigate moderators and mediators of intervention effectiveness. Interventions may be strengthened by new techniques, such as incorporating family members (e.g., to improve thoroughness of skin self-examinations) and eHealth technology. PMID:27090434
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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.
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Hübner, Joachim; Waldmann, Annika; Eisemann, Nora; Noftz, Maria; Geller, Alan C; Weinstock, Martin A; Volkmer, Beate; Greinert, Rüdiger; Breitbart, Eckhard W; Katalinic, Alexander
2017-07-07
Early detection is considered to improve the prognosis of cutaneous melanoma. The value of population-based screening for melanoma, however, is still controversial. The aim of this study was to evaluate the predictive power of established risk factors in the setting of a population-based screening and to provide empirical evidence for potential risk stratifications. We reanalyzed data (including age, sex, risk factors, and screening results) of 354 635 participants in the Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany project conducted in the German state of Schleswig-Holstein (2003-2004). In multivariable analysis, atypical nevi [odds ratio (OR): 17.4; 95% confidence interval (CI): 14.4-20.1], personal history of melanoma (OR: 5.3; 95% CI: 3.6-7.6), and multiple (≥40) common nevi (OR: 1.3; 95% CI: 1.1-1.6) were associated with an increased risk of melanoma detection. Family history and congenital nevi were not significantly associated with melanoma detection in the Skin Cancer Research to provide Evidence for Effectiveness of Screening in Northern Germany population. The effects of several risk-adapted screening strategies were evaluated. Hypothesizing a screening of individuals aged more than or equal to 35 years, irrespective of risk factors (age approach), the number needed to screen is 559 (95% CI: 514-612), whereas a screening of adults (aged ≥20) with at least one risk factor (risk approach) leads to an number needed to screen of 178 (95% CI: 163-196). Converted into one screen-detected melanoma, the number of missed melanomas is 0.15 (95% CI: 0.12-0.18) with the age approach and 0.22 (95% CI: 0.19-0.26) with the risk approach. The results indicate that focusing on individuals at high risk for melanoma may improve the cost-effectiveness and the benefit-to-harm balance of melanoma screening programs.
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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
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Gamble, Ryan G; Asdigian, Nancy L; Aalborg, Jenny; Gonzalez, Victoria; Box, Neil F; Huff, Laura S; Barón, Anna E; Morelli, Joseph G; Mokrohisky, Stefan T; Crane, Lori A; Dellavalle, Robert P
2012-10-01
Ultraviolet (UV) photography has been used to motivate sun safety in behavioral interventions. The relationship between sun damage shown in UV photographs and melanoma risk has not been systematically investigated. To examine the relationship between severity of sun damage in UV photographs and phenotypic melanoma risk factors in children. UV, standard visible and cross-polarized photographs were recorded for 585 children. Computer software quantified sun damage. Full-body nevus counts, skin color by colorimetry, facial freckling, hair and eye color were collected in skin examinations. Demographic data were collected in telephone interviews of parents. Among 12-year-old children, sun damage shown in UV photographs correlated with phenotypic melanoma risk factors. Sun damage was greatest for children who were non-Hispanic white and those who had red hair, blue eyes, increased facial freckling, light skin and greater number of nevi (all P values < .001). Results were similar for standard visible and cross-polarized photographs. Freckling was the strongest predictor of sun damage in visible and UV photographs. All other phenotypic melanoma risk factors were also predictors for the UV photographs. Differences in software algorithms used to score the photographs could produce different results. UV photographs portray more sun damage in children with higher risk for melanoma based on phenotype. Therefore sun protection interventions targeting those with greater sun damage on UV photographs will target those at higher melanoma risk. This study establishes reference ranges dermatologists can use to assess sun damage in their pediatric patients. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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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
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Epigenetic regulation of REG1A and chemosensitivity of cutaneous melanoma
Sato, Yusuke; Marzese, Diego M; Ohta, Katsuya; Huang, Sharon K; Sim, Myung Shin; Chong, Kelly; Hoon, Dave SB
2013-01-01
Regenerating gene 1A (REG1A) plays an important role in tissue regeneration and in cell proliferation in epithelium origin tumors; however, its role in melanoma has not been explored in details. The objective of this study was to identify whether REG1A is expressed in cutaneous melanoma and if REG1A expression status can predict prognosis in cutaneous melanoma patients with metastasis. We also determined whether epigenetic regulation of the promoter region regulates REG1A expression. AJCC stage III cutaneous melanoma specimens with clinically well annotated stage III lymph node melanoma metastasis tissue microarray were assessed by IHC. MALDI-TOF-mass spectrometry and HM450K array were used to identify REG1A promoter region CpG site methylation. Chemotherapeutic agent response by melanoma cells as related to REG1A protein expression was assessed. Post-surgery melanoma patients followed by adjuvant chemotherapy with high REG1A expression had a significantly better prognosis (disease-specific survival) compared with patients with low REG1A expression (log rank test; p = 0.0013). The demethylating reagent 5-Aza-2′-deoxycytidine activated REG1A promoter region resulting in enhanced REG1A mRNA and protein expression in melanoma cell lines. Promoter region CpG methylation was shown to regulate REG1A expression in melanoma cells. Moreover, melanoma lines with high REG1A mRNA expression were more susceptible to Dacarbazine and Cisplatin, as compared with those with low REG1A mRNA expression. In conclusion, REG1A expression status may be useful as a biomarker in melanoma patients for sensitivity to these chemotherapeutic agents. The epigenetic regulation of the REG1A promoter region may offer a potential therapeutic approach to improve chemotherapy for metastatic melanoma patients. PMID:23903855
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High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.
Masaki, Taro; Wang, Yun; DiGiovanna, John J; Khan, Sikandar G; Raffeld, Mark; Beltaifa, Senda; Hornyak, Thomas J; Darling, Thomas N; Lee, Chyi-Chia R; Kraemer, Kenneth H
2014-05-01
We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population. © 2014 Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
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Associations between environmental factors and incidence of cutaneous melanoma. Review
2012-01-01
Background Cutaneous melanoma is one of the most serious skin cancers. It is caused by neural crest-derived melanocytes - pigmented cells normally present in the epidermis and, sometimes, in the dermis. Methods We performed a review of current knowledge on the risk factors of cutaneous melanoma. Relevant studies were identified using the PubMed, Science Direct, Medline, Scopus, Scholar Google and ISI Web of Knowledge databases. Results Melanoma incurs a considerable public health burden owing to the worldwide dramatic rise in incidence since the mid-1960s. Ultraviolet radiation exposure is the predominant environmental risk factor. The role of geographical (latitude) and individual factors such as skin type, life style, vitamin D levels and antioxidant protection, sunburn, and exposure to other environmental factors possibly contributing to melanoma risk (such as cosmetics including sunscreen, photosensitising drugs, and exogenous hormones) are reviewed in this article. Recently, both rare high risk susceptibility genes and common polymorphic genes contributing to melanoma risk have been identified. Conclusions Cutaneous melanoma is a complex cancer with heterogeneous aetiology that continues to increase in incidence. Introduction of new biomarkers may help to elucidate the mechanism of pathogenesis and individual susceptibility to the disease, and make both prevention and treatment more effective. PMID:22759494
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Causes of infertility as predictors of subsequent cancer risk.
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.
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Mierzwa-Dobranowska, Marzena; Romanowska-Dixon, Bozena
2012-01-01
This study will show a comparison of two groups of patients with uveal melanoma; one group with multiple primary cancer, and a second group with no identifiable second cancer, in terms of education and occupation. Study concerns 240 patients, who were isolated from patients being treated with uveal melanoma at the Department of Ophthalmology and Ocular Oncology Jagiellonian University Medical College in the period from 1998 to 2007. On the basis of medical history and medical records 97 patients were diagnosed with the one or more independent primary cancers. These patients were subjected to comparative analysis with a group of 143 patients with uveal melanoma as a control group. Analyzing the impact of education on the recognition of multiple primary cancer, there were significantly more frequent diagnoses of second primary cancers among patients with secondary and higher education than among those who had primary and vocational education. Among the obtained data on patients in the study group, the largest occupational group (according to the ISCO-88 (COM)) constituted "professionals". In the control group prevailed "craft and related trades workers". The results suggest the great importance of knowledge about risk factors for the development of cancer among patients with uveal melanoma and the ensuing more scrupulous search for succesive primary neoplasm and indicate the neccesity of organizing broad prophylactic actions. uveal melanoma, multiple primary cancer.
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van den Brom, Rob R H; van der Geest, Kornelis S M; Brouwer, Elisabeth; Hospers, Geke A P; Boots, Annemieke M H
2018-06-01
The biological behavior of melanoma is unfavorable in the elderly when compared to young subjects. We hypothesized that differences in T-cell responses might underlie the distinct behavior of melanoma in young and old melanoma patients. Therefore, we investigated the circulating T-cell compartment of 34 patients with metastatic melanoma and 42 controls, which were classified as either young or old. Absolute numbers of CD4+ T cells were decreased in young and old melanoma patients when compared to the age-matched control groups. Percentages of naive and memory CD4+ T cells were not different when comparing old melanoma patients to age-matched controls. Percentages of memory CD4+ T cells tended to be increased in young melanoma patients compared to young controls. Proportions of naive CD4+ T cells were lower in young patients than in age-matched controls, and actually comparable to those in old patients and controls. This was accompanied with increased percentages of memory CD4+ T cells expressing HLA-DR, Ki-67, and PD-1 in young melanoma patients in comparison to the age-matched controls, but not in old patients. Proportions of CD45RA-FOXP3 high memory regulatory T cells were increased in young and old melanoma patients when compared to their age-matched controls, whereas those of CD45RA+FOXP3 low naive regulatory T cells were similar. We observed no clear modulation of the circulating CD8+ T-cell repertoire in melanoma patients. In conclusion, we show that CD4+ T cells of young melanoma patients show signs of activation, whereas these signs are less clear in CD4+ T cells of old patients.
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Characteristic features of cutaneous melanoma in a dermatology referral centre in Tehran, Iran.
Kamyab, Kambiz; Kazemi, Sheyda; Azimi, Pourya; Azizpour, Arghavan; Ghandi, Narges; Pirooz, Elham; Noormohammadpour, Pedram; Mirshams-Shahshahani, Mostafa; Daneshpazhooh, Maryam
2017-11-01
The characteristics of cutaneous melanoma in the Middle-Eastern countries is poorly described. Therefore we conducted this study to determine the characteristics of melanoma in Iran. A retrospective, cross sectional study of melanoma patients seen at a tertiary referral centre, Iran, from May 2004 to October 2014. Clinical data included age and gender of the patients at the time of diagnosis, tumour location and tumour size. Histological characteristics included Breslow thickness, Clark level and subtype of tumour. A total of 450 cases of melanoma with a male/female ratio of 1.1:1 were reviewed. The mean age of patients was 57.5 years. The most frequent histological subtypes were acral lentiginous melanoma (30%) and lentigo maligna melanoma (29%). In 215 cases (49%) the tumour was located on the extremities. The second most common site was the face. Tumour invasion was mainly at Clark level III and IV. The mean Breslow thickness was 2.8 mm; 143 (38%) melanomas had a Breslow thickness less than 1 mm (T1) and 86 (23%) were more than 4 mm (T4). This study indicates that clinical and histological features of melanoma in Iranians (who are mainly of skin phototypes 3-4) are different from those observed in Western countries. Further cohort studies are required to evaluate the role of ethnic and environmental risk factors for melanoma in different populations. © 2017 The Australasian College of Dermatologists.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Kamat, Paresh P.; Gupta, Sanjay; Ensor, Joe E.
The purpose of this study was to assess the role of hepatic arterial embolization (HAE) and chemoembolization (HACE) in patients with large-volume liver metastases. Patients with metastatic neuroendocrine tumors, melanomas, or gastrointestinal stromal tumors (GISTs) with >75% liver involvement who underwent HAE or HACE were included in the study. Radiologic response, progression-free survival (PFS), overall survival (OS), and postprocedure complications were assessed. Sixty patients underwent 123 treatment sessions. Of the 48 patients for whom follow-up imaging was available, partial response was seen in 12 (25%) patients, minimal response in 6 (12%), stable disease in 22 (46%), and progressive disease inmore » 8 (17%). Median OS and PFS were 9.3 and 4.9 months, respectively. Treatment resulted in radiologic response or disease stabilization in 82% and symptomatic response in 65% of patients with neuroendocrine tumors. Patients with neuroendocrine tumors had higher response rates (44% vs. 27% and 0%; p = 0.31) and longer PFS (9.2 vs. 2.0 and 2.3 months; p < 0.0001) and OS (17.9 vs. 2.4 and 2.3 months; p < 0.0001) compared to patients with melanomas and GISTs. Major complications occurred in 21 patients after 23 (19%) of the 123 sessions. Nine of the 12 patients who developed major complications resulting in death had additional risk factors-carcinoid heart disease, sepsis, rapidly worsening performance status, or anasarca. In conclusion, in patients with neuroendocrine tumors with >75% liver involvement, HAE/HACE resulted in symptom palliation and radiologic response or disease stabilization in the majority of patients. Patients with hepatic metastases from melanomas and GISTs, however, did not show any appreciable benefit from this procedure. Patients with massive liver tumor burden, who have additional risk factors, should not be subjected to HAE/HACE because of the high risk of procedure-related mortality.« less
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Conic, Ruzica Z; Cabrera, Claudia I; Khorana, Alok A; Gastman, Brian R
2018-01-01
The ideal timing for melanoma treatment, predominantly surgery, remains undetermined. Patient concern for receiving immediate treatment often exceeds surgeon or hospital availability, requiring establishment of a safe window for melanoma surgery. To assess the impact of time to definitive melanoma surgery on overall survival. Patients with stage I to III cutaneous melanoma and with available time to definitive surgery and overall survival were identified by using the National Cancer Database (N = 153,218). The t test and chi-square test were used to compare variables. Cox regression was used for multivariate analysis. In a multivariate analysis of patients in all stages who were treated between 90 and 119 days after biopsy (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.18) and more than 119 days (HR, 1.12; 95% CI, 1.02-1.22) had a higher risk for mortality compared with those treated within 30 days of biopsy. In a subgroup analysis of stage I, higher mortality risk was found in patients treated within 30 to 59 days (HR, 1.05; 95% CI, 1.01-1.1), 60 to 89 days (HR, 1.16; 95% CI, 1.07-1.25), 90 to 119 days (HR, 1.29; 95% CI, 1.12-1.48), and more than 119 days after biopsy (HR, 1.41; 95% CI, 1.21-1.65). Surgical timing did not affect survival in stages II and III. Melanoma-specific survival was not available. Expeditious treatment of stage I melanoma is associated with improved outcomes. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Roberts, Daniel J; Hornung, Carlton A; Polk, Hiram C
2009-07-01
The purpose of this report is to put the dueling factors of risk and prevention for melanoma in perspective for the thoughtful pediatric specialist to facilitate preteen preventive health counseling. We examined the rate of malignant melanoma among Kentucky residents and compared this rate with indicators of tanning bed prevalence in a large metropolitan area and sunscreen sales from a major distributor. We obtained malignant melanoma annual incidence data from the Kentucky Cancer Registry, which recorded Kentucky population incidence rates over the years 1995 to 2004. The rates reflected 2 malignant melanoma classifications: pre-invasive cancer only, or both invasive and noninvasive cancers combined. The age-adjusted incidence rate per hundred thousand for combined invasive and pre-invasive malignant melanoma swelled from 21.9 in 1995 to 31.3 in 2004. The respective invasive-only malignant melanoma incidence rates increased less dramatically, from 17.3 to 20.7, during this same 10-year time period. Since 1983, the number of separate tanning bed businesses increased from 1 in 1983 to 119 by the mid-1990s, and then declined to about 74 separate businesses by 2003. Sunscreen sales data is uneven between states and is currently inconclusive. Although current data cannot draw a precise link between melanoma and the use of tanning beds, the associated risk is implicit, as the ultraviolet A (UVA) and ultraviolet B (UVB) radiation in tanning bed usage is a well-established melanoma risk factor. In advising patients, the pediatric specialist should consider that melanoma rates are poised as a balance of some known risk factors and a few potential preventive factors.
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Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P
2018-02-01
Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.
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Lawson, David H.; Lee, Sandra; Zhao, Fengmin; Tarhini, Ahmad A.; Margolin, Kim A.; Ernstoff, Marc S.; Atkins, Michael B.; Cohen, Gary I.; Whiteside, Theresa L.; Butterfield, Lisa H.; Kirkwood, John M.
2015-01-01
Purpose We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. Patients and Methods Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2–positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2–negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. Results A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF–treated patients with resected visceral metastases. When survival in HLA-A2–positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. Conclusion Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation. PMID:26351350
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Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma.
Shi, Jianxin; Zhou, Weiyin; Zhu, Bin; Hyland, Paula L; Bennett, Hunter; Xiao, Yanzi; Zhang, Xijun; Burke, Laura S; Song, Lei; Hsu, Chih Hao; Yan, Chunhua; Chen, Qingrong; Meerzaman, Daoud; Dagnall, Casey L; Burdette, Laurie; Hicks, Belynda; Freedman, Neal D; Chanock, Stephen J; Yeager, Meredith; Tucker, Margaret A; Goldstein, Alisa M; Yang, Xiaohong R
2016-12-01
Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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Rare germline copy number variations and disease susceptibility in familial melanoma
Shi, Jianxin; Zhou, Weiyin; Zhu, Bin; Hyland, Paula L; Bennett, Hunter; Xiao, Yanzi; Zhang, Xijun; Burke, Laura S; Song, Lei; Hsu, Chih Hao; Yan, Chunhua; Chen, Qingrong; Meerzaman, Daoud; Dagnall, Casey L; Burdette, Laurie; Hicks, Belynda; Freedman, Neal D; Chanock, Stephen J; Yeager, Meredith; Tucker, Margaret A; Goldstein, Alisa M; Yang, Xiaohong R
2016-01-01
Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and SNP arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g. PARP1, CDKN2A) or co-segregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare co-segregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma. PMID:27476724
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Nonpigmented Metastatic Melanoma in a Two-Year-Old Girl: A Serious Diagnostic Dilemma
Diniz, Gulden; Tosun Yildirim, Hulya; Yamaci, Selcen
2015-01-01
Although rare, malignant melanoma may occur in children. Childhood melanomas account for only 0.3–3% of all melanomas. In particular the presence of congenital melanocytic nevi is associated with an increased risk of development of melanoma. We herein report a case of malignant melanoma that developed on a giant congenital melanocytic nevus and made a metastasis to the subcutaneous tissue of neck in a two-year-old girl. The patient was hospitalized for differential diagnosis and treatment of cervical mass with a suspicion of hematological malignancy, because the malignant transformation of congenital nevus was not noticed before. In this case, we found out a nonpigmented malignant tumor of pleomorphic cells after the microscopic examination of subcutaneous lesion. Nonpigmented metastatic melanoma was diagnosed by several immunohistochemical and flow cytometric studies. She was offered palliative chemotherapy; however, her parents did not accept treatment. The patient died within 9 months of diagnosis. We emphasized here that the possibility of malignant melanoma in the differential diagnosis of childhood tumors should be kept in mind. PMID:25763285
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Toyama, Shingo; Department of Heavy Particle Therapy and Radiation Oncology, Faculty of Medicine, Saga University, Saga; Tsuji, Hiroshi, E-mail: h_tsuji@nirs.go.jp
2013-06-01
Purpose: To determine the long-term results of carbon ion radiation therapy (C-ion RT) in patients with choroidal melanoma, and to assess the usefulness of CT-based 2-port irradiation in reducing the risk of neovascular glaucoma (NVG). Methods and Materials: Between January 2001 and February 2012, a total of 116 patients with locally advanced or unfavorably located choroidal melanoma received CT-based C-ion RT. Of these patients, 114 were followed up for more than 6 months and their data analyzed. The numbers of T3 and T2 patients (International Union Against Cancer [UICC], 5th edition) were 106 and 8, respectively. The total dose ofmore » C-ion RT varied from 60 to 85 GyE, with each dose given in 5 fractions. Since October 2005, 2-port therapy (51 patients) has been used in an attempt to reduce the risk of NVG. A dose-volume histogram analysis was also performed in 106 patients. Results: The median follow-up was 4.6 years (range, 0.5-10.6 years). The 5-year overall survival, cause-specific survival, local control, distant metastasis-free survival, and eye retention rates were 80.4% (95% confidence interval 89.0%-71.8%), 82.2% (90.6%-73.8%), 92.8% (98.5%-87.1%), 72.1% (81.9%-62.3%), and 92.8% (98.1%-87.5%), respectively. The overall 5-year NVG incidence rate was 35.9% (25.9%-45.9%) and that of 1-port group and 2-port group were 41.6% (29.3%-54.0%) and 13.9% (3.2%-24.6%) with statistically significant difference (P<.001). The dose-volume histogram analysis showed that the average irradiated volume of the iris-ciliary body was significantly lower in the non-NVG group than in the NVG group at all dose levels, and significantly lower in the 2-port group than in the 1-port group at high dose levels. Conclusions: The long-term results of C-ion RT for choroidal melanoma are satisfactory. CT-based 2-port C-ion RT can be used to reduce the high-dose irradiated volume of the iris-ciliary body and the resulting risk of NVG.« less
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Chung, Grace Y; Brown, Gina; Gibson, Desmond
2015-10-01
Melanoma incidence is increasing among Hispanics/Latinos in California. This community-based project reached out to a rural Hispanic/Latino community in North San Diego County to provide melanoma prevention and screening education. At a local community health fair, bilingual volunteer lay health workers led 10- to 15-minute-long information sessions on melanoma disease, risk factors, and skin self-examination techniques. Pearson chi-square analyses of participants' (N = 34) responses to pre- and postintervention evaluation surveys indicate significant increases in knowledge, risk awareness, and self-efficacy for self-screening. The results revealed that Hispanics/Latinos in a low socioeconomic stratum might be at moderate to high risk for developing melanoma. Their low annual income, low level of education, occupational sun-exposure, and lack of access to health care are likely factors that deter at-risk Hispanics/Latinos from seeking health care. © 2015 Society for Public Health Education.
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Bay, Christiane; Kejs, Anne Mette Tranberg; Storm, Hans H; Engholm, Gerda
2015-02-01
The incidence of melanoma of the skin has risen in Denmark in recent decades, the increase being steeper from 2004. It is unclear whether this represents a true rise in incidence or whether it is caused by an increased awareness of the condition. To assess whether the increase was characterised by early-stage melanomas and a higher proportion of melanomas with superficial spreading morphology, we studied all skin melanoma patients registered in the Danish Cancer Register 1989-2011 (n=27,010) and followed up for death through 2013. Trends in age-standardised incidence by sex, subsite and morphology, relative survival, TNM stage distribution and stage-specific relative survival from 2004 were analysed. The incidence of melanoma more than doubled over 23 years. A steeper increase from 2004 was driven mainly by superficial spreading tumours, but the proportion of nodular melanomas in patients 50 years of age and over also increased significantly. The largest increase occurred for stage I tumours and for tumours on the trunk. From 1989-1993 to 2009-2011 the 5-year relative survival increased at 12% and 6% points for male and female patients, respectively. Greater awareness, and thus lower stage at diagnosis (mediated by a large skin cancer prevention campaign from 2007), might explain part of the increase, but the increase in nodular melanoma also points to a genuine increase in the risk of melanoma. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Clinical Perspective of 3D Total Body Photography for Early Detection and Screening of Melanoma.
Rayner, Jenna E; Laino, Antonia M; Nufer, Kaitlin L; Adams, Laura; Raphael, Anthony P; Menzies, Scott W; Soyer, H Peter
2018-01-01
Melanoma incidence continues to increase across many populations globally and there is significant mortality associated with advanced disease. However, if detected early, patients have a very promising prognosis. The methods that have been utilized for early detection include clinician and patient skin examinations, dermoscopy (static and sequential imaging), and total body photography via 2D imaging. Total body photography has recently witnessed an evolution from 2D imaging with the ability to now create a 3D representation of the patient linked with dermoscopy images of individual lesions. 3D total body photography is a particularly beneficial screening tool for patients at high risk due to their personal or family history or those with multiple dysplastic naevi-the latter can make monitoring especially difficult without the assistance of technology. In this perspective, we discuss clinical examples utilizing 3D total body photography, associated advantages and limitations, and future directions of the technology. The optimal system for melanoma screening should improve diagnostic accuracy, be time and cost efficient, and accessible to patients across all demographic and socioeconomic groups. 3D total body photography has the potential to address these criteria and, most importantly, optimize crucial early detection.
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Effects of fertility drugs on cancers other than breast and gynecologic malignancies.
Brinton, Louise A; Moghissi, Kamran S; Scoccia, Bert; Lamb, Emmet J; Trabert, Britton; Niwa, Shelley; Ruggieri, David; Westhoff, Carolyn L
2015-10-01
To examine the relationship of ovulation-stimulating drugs to risk of cancers other than breast and gynecologic malignancies. Retrospective cohort study, with additional follow-up since initial report. Reproductive endocrinology practices. Among a cohort of 12,193 women evaluated for infertility between 1965 and 1988, a total of 9,892 women (81.1% of the eligible population) were followed through 2010, via passive and active (questionnaire) approaches. None. Hazard ratios (HRs) and 95% confidence intervals (CIs) for various fertility treatment parameters for select cancers. During 30.0 median years of follow-up (285,332 person-years), 91 colorectal cancers, 84 lung cancers, 55 thyroid cancers, and 70 melanomas were diagnosed among study subjects. Clomiphene citrate (CC), used by 38.1% of patients, was not associated with colorectal or lung cancer risks, but was related significantly to melanoma (HR = 1.95; 95% CI: 1.18-3.22), and non-significantly to thyroid cancer risks (HR = 1.57; 95% CI: 0.89-2.75). The highest melanoma risks were seen among those with the lowest drug exposure levels, but thyroid cancer risk was greatest among the heavily exposed patients (HR = 1.96; 95% CI: 0.92-4.17 for those receiving >2,250 mg). Clomiphene citrate-associated risks for thyroid cancer were somewhat higher among nulligravid, compared with gravid, women, but did not differ according to distinct causes of infertility. Gonadotropins, used by only 9.7% of subjects, were not related to risk of any of the assessed cancers. Our results provide support for continued monitoring of both melanoma and thyroid cancer risk among patients receiving fertility drugs. Published by Elsevier Inc.
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Chwirot, B W; Chwirot, S; Sypniewska, N; Michniewicz, Z; Redzinski, J; Kurzawski, G; Ruka, W
2001-12-01
Multicenter study of the diagnostic parameters was conducted by three groups in Poland to determine if in situ fluorescence detection of human cutaneous melanoma based on digital imaging of spectrally resolved autofluorescence can be used as a tool for a preliminary selection of patients at increased risk of the disease. Fluorescence examinations were performed for 7228 pigmented lesions in 4079 subjects. Histopathologic examinations showed 56 cases of melanoma. A sensitivity of fluorescence detection of melanoma was 82.7% in agreement with 82.5% found in earlier work. Using as a reference only the results of histopathologic examinations obtained for 568 cases we found a specificity of 59.9% and a positive predictive value of 17.5% (melanomas versus all pigmented lesions) or 24% (melanomas versus common and dysplastic naevi). The specificity and positive predictive value found in this work are significantly lower than reported earlier but still comparable with those reported for typical screening programs. In conclusion, the fluorescence method of in situ detection of melanoma can be used in screening large populations of patients for a selection of patients who should be examined by specialists.
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Qureshi, Abrar A; Laden, Francine; Colditz, Graham A; Hunter, David J
2008-03-10
Occurrences of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) have been associated with varying geography. Our goal was to evaluate differences in risk of these skin cancers according to residence at varying UV indices at 3 time points. Prospective 1984-2002 study of 84 836 female nurses who lived in different UV index regions of the United States at birth and at 15 or 30 years of age. The outcome measure was diagnosis of melanoma, SCC, or BCC. During the 18-year study, 420 cases of melanoma, 863 cases of SCC, and 8215 cases of BCC occurred. At 30 years of age, age-adjusted risks for SCC were 1.47 (95% confidence interval [CI], 1.22-1.76) and 1.90 (95% CI, 1.51-2.36) for women residing in states with a UV index of 6 (medium) and 7 or more (high), respectively. Although elevated, the age-adjusted risk of BCC at 30 years of age associated with residence in these states was substantially less. Although the risk of melanoma was not elevated for women living in these states at 30 years of age, it was significantly elevated among women living in states with UV indices of 6 at birth and at 15 years of age. There was no material change in risk estimates with multivariate adjustment. For women who reported living in states with UV indices of 7 or more at all 3 time points, the multivariate risk of SCC was highest. The risk of SCC is independently affected by residence in locations with medium and high UV indices; the gradient of risk is weaker for BCC; and the risk of melanoma does not change significantly across this gradient.
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Shimizu, Akira; Kaira, Kyoichi; Yasuda, Masahito; Asao, Takayuki; Ishikawa, Osamu
2016-02-01
Class III β-tubulin (TUBB3) has been recognized as being associated with resistance to taxane-based regimens in several cancers. However, little is known about the clinicopathological significance of TUBB3 expression in patients with cutaneous malignant melanoma. The aim of this study was to examine the prognostic significance of TUBB3 expression in cutaneous malignant melanoma. A total of 106 patients with surgically resected cutaneous malignant melanoma were assessed. Tumour sections were immunohistochemically stained for TUBB3, Ki-67 and microvessel density with CD34. TUBB3 was highly expressed in 80% (85/106) of patients. No statistically significant relationship was observed between the high expression of TUBB3 and any variables. On univariate analysis, ulceration, disease stage, TUBB3 and CD34 revealed a significant relationship with overall survival and progression-free survival. Multivariate analysis confirmed that a low TUBB3 expression was an independent prognostic factor for poor prognosis of cutaneous malignant melanoma. The decreased expression of TUBB3 could be a significant marker for predicting unfavourable prognosis in patients with cutaneous malignant melanoma.
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Increased Cancer Risks in Myotonic Dystrophy
Win, Aung Ko; Perattur, Promilla G.; Pulido, Jose S.; Pulido, Christine M.; Lindor, Noralane M.
2012-01-01
Objective To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested in several studies but the risks of cancers have not been quantified. Patients and Methods A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method. Results A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval [CI], 1.80-12.93; P=.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; P<.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; P=.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; P=.05). The estimated cumulative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma. Conclusion Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers. PMID:22237010
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Bracalente, Candelaria; Rinflerch, Adriana R.; Ibañez, Irene L.; García, Francisco M.; Volonteri, Victoria; Galimberti, Gastón N.; Klamt, Fabio; Durán, Hebe
2018-01-01
Melanoma is an aggressive cancer with highly metastatic ability. We propose cofilin-1, a key protein in the regulation of actin dynamics and migration, as a prognostic marker. We determined cofilin-1 levels in a retrospective cohort of patients with melanomas and benign lesions of melanocytes (nevi) by immunohistochemistry. Higher cofilin-1 levels were found in malignant melanoma (MM) with Breslow Index (BI)>2 vs MM with BI<2, melanoma in situ (MIS) and nevi and also in MM with metastasis vs MM without detected metastasis. Kaplan-Meier survival curves were performed, clustering patients according to either the type of melanocytic lesions or cofilin-1 level. Survival curves demonstrated worse prognosis of patients with high vs low cofilin-1 levels. TCGA database analysis of melanoma also showed low survival in patients with upregulated cofilin-1 mRNA vs patients without alteration in CFL1 mRNA expression. As cofilin-1 has a dual function depending on its intracellular localization, we evaluated nuclear and cytoplasmic levels of cofilin-1 in melanoma and nevi samples by immunofluorescence. MM with high Breslow index and metastatic cells not only presented cytoplasmic cofilin-1, but also showed this protein at the nucleus. An increase in nuclear/cytoplasmic cofilin-1 mean fluorescence ratio was observed in MM with BI>2 vs MM with BI<2, MIS and nevi. In conclusion, an association of cofilin-1 levels with malignant features and an inverse correlation with survival were demonstrated. Moreover, this study suggests that not only the higher levels of cofilin-1, but also its nuclear localization can be proposed as marker of worse outcome of patients with melanoma. PMID:29844875
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Bracalente, Candelaria; Rinflerch, Adriana R; Ibañez, Irene L; García, Francisco M; Volonteri, Victoria; Galimberti, Gastón N; Klamt, Fabio; Durán, Hebe
2018-05-08
Melanoma is an aggressive cancer with highly metastatic ability. We propose cofilin-1, a key protein in the regulation of actin dynamics and migration, as a prognostic marker. We determined cofilin-1 levels in a retrospective cohort of patients with melanomas and benign lesions of melanocytes (nevi) by immunohistochemistry. Higher cofilin-1 levels were found in malignant melanoma (MM) with Breslow Index (BI)>2 vs MM with BI<2, melanoma in situ (MIS) and nevi and also in MM with metastasis vs MM without detected metastasis. Kaplan-Meier survival curves were performed, clustering patients according to either the type of melanocytic lesions or cofilin-1 level. Survival curves demonstrated worse prognosis of patients with high vs low cofilin-1 levels. TCGA database analysis of melanoma also showed low survival in patients with upregulated cofilin-1 mRNA vs patients without alteration in CFL1 mRNA expression. As cofilin-1 has a dual function depending on its intracellular localization, we evaluated nuclear and cytoplasmic levels of cofilin-1 in melanoma and nevi samples by immunofluorescence. MM with high Breslow index and metastatic cells not only presented cytoplasmic cofilin-1, but also showed this protein at the nucleus. An increase in nuclear/cytoplasmic cofilin-1 mean fluorescence ratio was observed in MM with BI>2 vs MM with BI<2, MIS and nevi. In conclusion, an association of cofilin-1 levels with malignant features and an inverse correlation with survival were demonstrated. Moreover, this study suggests that not only the higher levels of cofilin-1, but also its nuclear localization can be proposed as marker of worse outcome of patients with melanoma.
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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.
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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.
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Vickery, Erin L; Seidler, Elizabeth M; Jones, Todd E; Veledar, Emir; Chen, Suephy C
2014-11-01
There is an increasing demand for a limited number of pigmented lesion clinic (PLC) visits at dermatology centers. To determine the proportion of visits to PLCs that are more frequent ("additional screening") than the recommended ("standard") follow-up schedule and to determine if certain patient characteristics correlate with the demand for these visits. A retrospective medical chart review of all PLC visits at an academic dermatology center from October 2010 to January 2012. A total of 609 patients associated with 1756 visits were identified. Of these, 25 patients associated with 26 visits were excluded owing to lack of melanoma diagnosis or risk factors, leaving 584 patients and 1730 visits. Diagnoses of these patients included in situ and invasive melanoma, dysplastic nevi, Spitz nevi, atypical nevus syndrome, family history of melanoma only, and other risk factors. The mean (SD) age was 48 (16) years, and 235 (40.2%) of the patients were male. The proportion of additional screening visits compared with standard visits. Standard visits were defined as occurring at the following frequencies: annually for mildly dysplastic nevi, Spitz nevi, or solely family history of melanoma; biannually for the first year, then annually thereafter for moderately dysplastic nevi or atypical nevus syndrome; biannually for up to 3 years, then annually thereafter for severely dysplastic nevi or melanomas in situ; every 3 months for 2 years, biannually for the following 2 years, then annually thereafter for invasive melanoma. A total of 1400 visits (80.9%) were standard, 257 (14.9%) were for additional screening, and 73 (4.2%) were "problem focused." Thirty percent of patients had at least 1 additional screening visit. The distribution of diagnoses among standard vs additional screening visits differed significantly, with "family history only" and "other risk factors" taking up a larger percentage of standard visits (15.1%) than the percentage of additional screening visits (8.9%), and all other diagnoses being better represented among additional screening visits (P = .04). No particular patient characteristic described those who sought additional screening visits. A substantial proportion of additional screening PLC visits exist and are desired by all patients with pigmented lesions. We propose alternative clinic models, such as diagnosis-specific, adjunctive fee-for-additional-service, and teledermatology clinics to meet patient needs while creating resources to expand PLC visits.
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Cutaneous melanoma in situ: translational evidence from a large population-based study.
Mocellin, Simone; Nitti, Donato
2011-01-01
Cutaneous melanoma in situ (CMIS) is a nosologic entity surrounded by health concerns and unsolved debates. We aimed to shed some light on CMIS by means of a large population-based study. Patients with histologic diagnosis of CMIS were identified from the Surveillance Epidemiology End Results (SEER) database. The records of 93,863 cases of CMIS were available for analysis. CMIS incidence has been steadily increasing over the past 3 decades at a rate higher than any other in situ or invasive tumor, including invasive skin melanoma (annual percentage change [APC]: 9.5% versus 3.6%, respectively). Despite its noninvasive nature, CMIS is treated with excision margins wider than 1 cm in more than one third of cases. CMIS is associated with an increased risk of invasive melanoma (standardized incidence ratio [SIR]: 8.08; 95% confidence interval [CI]: 7.66-8.57), with an estimated 3:5 invasive/in situ ratio; surprisingly, it is also associated with a reduced risk of gastrointestinal (SIR: 0.78, CI: 0.72-0.84) and lung (SIR: 0.65, CI: 0.59-0.71) cancers. Relative survival analysis shows that persons with CMIS have a life expectancy equal to that of the general population. CMIS is increasingly diagnosed and is often overtreated, although it does not affect the life expectancy of its carriers. Patients with CMIS have an increased risk of developing invasive melanoma (which warrants their enrollment in screening programs) but also a reduced risk of some epithelial cancers, which raises the intriguing hypothesis that genetic/environmental risk factors for some tumors may oppose the pathogenesis of others.
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Mucosal melanomas in the racially diverse population of California.
Altieri, Lisa; Wong, Michael K; Peng, David H; Cockburn, Myles
2017-02-01
Mucosal melanomas are rare, poorly understood neoplasms without a consensus standard of care. We sought to define mucosal melanoma tumor characteristics and the racial/ethnic attributes of patients with mucosal melanomas. We analyzed 130,920 cutaneous melanomas and 1919 mucosal melanomas recorded in the population-based California Cancer Registry from 1988 to 2013. Although only 1% of melanomas occurring in nonHispanic whites were mucosal, other racial/ethnic groups had a higher proportion of mucosal melanomas (15% for Asian/Pacific Islanders, 9% for nonHispanic blacks, and 4% for Hispanics). Anorectal mucosal melanomas were most common in female Asian/Pacific Islanders, whereas genitourinary mucosal melanomas were highest in nonHispanic whites, and head and neck tumors were most common among Hispanics. Stage at presentation was not uniform among racial/ethnic groups, with Asian/Pacific Islanders having the highest rates of metastasis. The lack of a standardized staging system for mucosal melanomas confounds classification and knowledge regarding metastasis. Small sample size limits comparative analysis across race, stage, site, and depth. Mucosal melanomas differ by race/ethnicity with regard to anatomic site, stage, and depth. Because early detection offers the best chance of increased survival, greater awareness will aid clinicians who care for patients at risk for these aggressive tumors. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Kvaskoff, Marina; Siskind, Victor; Green, Adèle C
2012-02-01
To investigate risk factors for lentigo maligna melanoma (LMM) compared with superficial spreading melanoma (SSM). Population-based case-control study in Queensland, Australia. General community. Population-based sample of 49 patients with LMM and 141 with SSM (in situ or invasive) aged 14 to 86 years at diagnosis in 1979 and 1980 and 232 control subjects. Response rates were 97.1% in cases and 91.8% in controls. Risks of both subtypes in relation to phenotypic and environmental factors, estimated by multinomial logistic regression. The number of solar lentigines was the strongest determinant for LMM (odds ratio [OR], 15.93; P < .001 for trend) and significantly weaker for SSM (4.61; P < .001 for trend; P = .04 for homogeneity). Skin cancer history was significantly associated with LMM (OR, 2.84) but not with SSM (1.33; P = .07 for homogeneity). In contrast, the number of nevi was the strongest determinant for SSM (OR, 23.22; P < .001 for trend) while significantly weaker for LMM (3.60; P = .02 for trend; P < .001 for homogeneity). Multiple lifetime sunburns almost tripled the risk for SSM, whereas no association was detected with LMM (P = .04 for homogeneity). Shared risk factors for both subtypes were the number of solar keratoses (P < .001 for trend for both) and sun-sensitive complexion (ie, light eye/hair colors, sunburn propensity, and freckling) (2-fold to 5-fold increased risks). A propensity to lentigines is a stronger predictor of LMM, whereas high nevus propensity is a stronger predictor of SSM. Skin cancer history appears to determine LMM risk only, whereas the number of lifetime sunburns determines SSM only. Prevention strategies could be tailored differently given these distinctive points of difference.
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Evaluation of the National Skin Cancer Campaign: a Swiss experience of Euromelanoma.
Lieberherr, Sven; Seyed Jafari, S Morteza; Cazzaniga, Simone; Bianchi, Enrica; Schlagenhauff, Bettina; Tscharner, Gion; Hafner, Jürg; Mainetti, Carlo; Lapointe, Anne-Karine; Hunger, Robert E
2017-10-24
Skin cancer is a burden to healthcare and patients worldwide. The incidence of skin cancer has been rising during recent decades and this trend is expected to continue in the future. Numerous risk factors have been identified and prevention strategies developed. The Euromelanoma campaign is a pan-European skin cancer prevention programme, targeted to both primary and secondary prevention of malignant melanoma. The current study aimed to evaluate the results of the Swiss skin cancer screening day 2016. A questionnaire was used to obtain data on characteristics and suspected skin cancers of all participants. Follow-up of patients with suspicious lesions was performed 3 to 6 months later. During the campaign, 2795 people were screened. Of the screened individuals, 157 participants (58% female, 42% male; mean age 58.8 years) underwent further evaluations; 6 cutaneous malignant melanomas, 21 basal cell carcinomas and 2 squamous cell carcinomas were detected. Detection rates were 0.21% for cutaneous melanoma, 0.75% for basal cell carcinoma and 0.07% for squamous cell carcinoma. Our study provides an up-to-date evaluation of the Swiss Euromelanoma campaign 2016. The results are mostly in line with data from other European studies. Considering the morbidity, mortality and financial and social impact of skin cancer, the capacity to raise awareness of risk factors, skin cancer prevention methods and educating high-risk and at-risk individuals, we may assume that a National Screening Day has a crucial impact on the public health system.
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Peralta, Rosario; Sabban, Emilia Cohen; Friedman, Paula; Marcucci, Carolina; Bollea Garlatti, Luis A; Galimberti, Gastón; Cabo, Horacio
2017-01-01
Albino patients are at great risk for developing cutaneous neoplasms, including melanomas. In this paper we describe the dermatoscopic findings of nevi in two patients with oculocutaneous albinism type Ia (OCA-Ia) highlighting that they manifest a vascular pattern similar to that described for amelanotic melanoma. We propose managing these patients with dermoscopy, using the comparative approach, digital follow up (DFU), and reflectance confocal microscopy as a complementary tool for difficult cases.
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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.
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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
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High expression of FOXP3 in primary melanoma is associated with tumour progression.
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.
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Evidence for the Role of Blue Light in the Development of Uveal Melanoma
Logan, Patrick; Bernabeu, Miguel; Ferreira, Alberto; Burnier, Miguel N.
2015-01-01
Uveal melanoma is the most common malignancy of the adult eye. Although it is a relatively infrequent tumor, clinical prognosis is often poor owing to a high incidence of aggressive metastatic disease, for which there are limited treatment options. Little is known about the etiology of this condition, although several risk factors have been identified. Unlike cutaneous melanoma, however, ultraviolet radiation does not figure prominently among these risk factors. In this review, we focus on an associated form of visible electromagnetic radiation, high-energy short-wave (blue) light, a causative agent in various forms of age-related retina damage, as a previously overlooked risk factor in uveal melanoma development and progression. Finally, we discuss the impact of these data on contemporary ocular therapy, particularly the debate surrounding the filtering capabilities of intraocular lenses used to replace dysfunctional crystalline lenses during cataract surgery. PMID:26075084
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Marabondo, Stephen; Kaufman, Howard L
2017-12-01
In 1998, high-dose interleukin-2 (IL-2) was the first immunotherapy approved for the treatment of metastatic melanoma based on durable objective responses documented in a subset of patients but widespread utilization was limited by significant toxicity. Advances in targeted therapy and the emergence of T cell checkpoint inhibitors, which can generally be given in the ambulatory setting, have further limited consideration of IL-2 for melanoma patients and the role of IL-2 in the current landscape of melanoma treatment is uncertain. Areas covered: In this review, we will describe advances in clinical diagnostic and management strategies that have improved the therapeutic window for IL-2 therapy in patients with melanoma. Further, we will describe the potential for using IL-2 in patients whose disease has progressed after other interventions or as part of combination immunotherapy approaches that are now in clinical development. We will also review the common toxicities of IL-2 therapy and their current management will be discussed. Expert opinion: High-dose IL-2 remains an important option for patients with melanoma and has an improved therapeutic window in the contemporary era. The reasons why IL-2 is not utilized more frequently and measures for enhancing its use will be detailed.
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Shields, Jerry A; Shields, Carol L
2015-02-01
To review the management of ciliary body and choroidal melanoma (posterior uveal melanoma [PUM]) over the last century with an emphasis on changing concepts. Retrospective review. Review of personal experience over 40 years and pertinent literature on management of PUM. Diagnosis and therapy for PUM. Patient survival. In the early 1900s, most patients presented with a large symptomatic melanoma that necessitated enucleation, and the systemic prognosis was poor. In the 1970s, controversy erupted regarding the role of enucleation for PUM. Some authorities advocated prompt enucleation, and others proposed that enucleation promoted metastasis, known as the "Zimmerman hypothesis." Others recommended observation, withholding treatment until tumor growth was documented. During the 1970s, there was a trend toward eye-saving procedures, including laser photocoagulation, surgical removal of tumor, and techniques of radiotherapy. Despite local treatment success, systemic prognosis remained guarded with approximately 40% mortality overall. However, there was convincing evidence that smaller tumors offered a significantly better prognosis. Currently, there is a movement toward earlier identification and treatment of small melanomas using clinical factors predictive of malignant potential, in keeping with similar philosophy regarding other cancers. Further understanding of melanoma cytogenetics and molecular pathways have helped to recognize patients at risk for metastasis. At-risk patients are offered systemic therapeutic trials to prevent metastasis. We anticipate that the future management of PUM will focus on detection of clinical and imaging clues for earliest diagnosis, prompt local tumor treatment, and systemic targeted therapies for microscopic metastasis or prevention of metastasis. Personalized evaluation of patient-specific melanoma molecular pathway signature could allow for therapeutic intervention at a site specific to the pathway abnormality that leads to the development of melanoma. Management of PUM has made major strides over the past century from the days of enucleation for massive, fatal tumor to early detection of smallest tumors with a more favorable prognosis. Current and future targeted specific tumor pathway interruption using systemic agents could improve survival. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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Associations of MC1R Genotype and Patient Phenotypes with BRAF and NRAS Mutations in Melanoma.
Thomas, Nancy E; Edmiston, Sharon N; Kanetsky, Peter A; Busam, Klaus J; Kricker, Anne; Armstrong, Bruce K; Cust, Anne E; Anton-Culver, Hoda; Gruber, Stephen B; Luo, Li; Orlow, Irene; Reiner, Anne S; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Sacchetto, Lidia; Dwyer, Terence; Parrish, Eloise A; Hao, Honglin; Gibbs, David C; Frank, Jill S; Ollila, David W; Begg, Colin B; Berwick, Marianne; Conway, Kathleen
2017-12-01
Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF + were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS + with older age relative to the wild type (BRAF - /NRAS - ) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (P interaction < 0.05) but inversely associated with BRAF V600K (P trend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS + , and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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A challenging case of ocular melanoma.
Costache, Mariana; Dumitru, Adrian Vasile; Pătraşcu, Oana Maria; Popa-Cherecheanu, Daniela Alina; Bădilă, Patricia; Miu, Jeni Cătălina; Procop, Alexandru; Popa, Manuela; Tampa, Mircea Ştefan; Sajin, Maria; Simionescu, Olga; Cîrstoiu, Monica Mihaela
2015-01-01
Ocular melanoma is a rare malignancy found in clinical practice. In this paper, we present a case of highly aggressive ocular melanoma, which was surgically removed at the Department of Ophthalmology and diagnosed at the Department of Pathology, Emergency University Hospital, Bucharest, Romania, using conventional histopathological techniques. Uveal melanoma, a subset of ocular melanoma, has a distinct behavior in comparison to cutaneous melanoma and has a widely divergent prognosis. Approximately half of patients with ocular melanoma will develop metastatic disease, predominantly with hepatic, pulmonary or cerebral location, over a 10 to 15 years period. No systemic therapy was associated with an evident clinical outcome for patients with advanced disease and overall survival rate remains poor.
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A technetium-labeled monoclonal antibody for imaging metastatic melanoma
DOE Office of Scientific and Technical Information (OSTI.GOV)
Frytak, S.; Creagan, E.T.; Brown, M.L.
1991-04-01
Twenty patients with histologically proven metastatic melanoma were scanned with a 99mtechnetium ({sup 99}mTc)-labeled melanoma antibody to determine the detection rate of known malignant lesions and to evaluate the antibody's ability to discover occult metastases. Isotope localization in different organs was as follows: liver 100%, bone 100%, subcutaneous lesions 80%, lymph nodes 54%, and lung 33%. Four unsuspected bone lesions and 16 occult subcutaneous lesions were found. False positive lesions were noted in two instances--one benign thyroid adenoma, and one arthritic bone lesion. One patient developed an atypical serum sickness reaction with a rash and arthralgias that responded rapidly tomore » treatment. The {sup 99}mTc antimelanoma antibody is a safe and effective method to detect metastatic melanoma. It has potential use for screening newly diagnosed melanomas that carry an increased risk of recurrence.« less
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PRIMARY ACQUIRED MELANOSIS OF THE CONJUNCTIVA: EXPERIENCE WITH 311 EYES
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
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Choi, Seohee Deanne; D'Souza, Mario I; Menzies, Scott W; Weninger, Wolfgang
2018-05-23
Patients on biologic therapy are thought to be at increased risk of developing non-melanoma skin cancers and melanomas. It is unknown whether biologic therapy alters the natural history of melanocytic naevi. Therefore, a prospective observational study was conducted to determine whether psoriasis patients on biologic therapy develop changes in naevi. Clinical and dermoscopic assessment of all melanocytic naevi was performed in 45 psoriasis patients on biologic therapy versus a control cohort of 43 subjects, using sequential digital dermoscopic imaging and total body photography. The mean follow-up period was 1.5 years. The study and control patients had comparable age, gender, previous and family history of non-melanoma skin cancers and melanomas, as well as previous sun exposure and total number of naevi. The number of naevi with major dermoscopic changes was 3% in the study and 1.9% in the control group, with an adjusted incidence rate ratio of 1.45 (95% confidence interval 0.90-2.33; P = 0.125). The rate of minor changes was 15.9% in the study group versus 19.4% in the control (adjusted incidence rate ratio 0.77, 95% confidence interval 0.57-1.08; P = 0.14). There were six new dysplastic naevi in 4/45 biologic patients and four in 4/43 controls; however, the difference was not significant (relative risk 0.96, 95% confidence interval -0.12 to 0.12; P = 0.95). There were no melanomas in either group. Over a mean follow-up period of 1.5 years there was no evidence of significantly different changes in naevi or development of new dysplastic naevi in psoriasis patients on biologic treatment compared to controls. © 2018 The Australasian College of Dermatologists.
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Biochemotherapy in patients with advanced head and neck mucosal melanoma.
Bartell, Holly L; Bedikian, Agop Y; Papadopoulos, Nicholas E; Dett, Tina K; Ballo, Matthew T; Myers, Jeffrey N; Hwu, Patrick; Kim, Kevin B
2008-12-01
No systemic therapy regimen has been recognized as effective for metastatic mucosal melanoma of the head and neck. We retrospectively analyzed the effectiveness of biochemotherapy in patients with advanced head and neck mucosal melanoma. We evaluated the medical records of 15 patients at our institution who had received various biochemotherapy regimens for advanced head and neck mucosal melanoma. After a median follow-up duration of 13 months, 3 patients (20%) had partial response, and 4 patients (27%) had complete response. The median time to disease progression for all 15 patients was 10 months. The median overall survival duration for all patients was 22 months. Although this was a small study, our results, especially the high complete response and overall response rates, indicate that biochemotherapy for advanced head and neck mucosal melanoma should be considered as a systemic treatment option for patients with this aggressive malignancy.
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Update on PEG-interferon α-2b as adjuvant therapy in melanoma.
Di Trolio, Rossella; Simeone, Ester; Di Lorenzo, Giuseppe; Grimaldi, Antonio Maria; Romano, Anna; Ayala, Fabrizio; Caracò, Corrado; Mozzillo, Nicola; Ascierto, Paolo A
2012-09-01
Based on the results of European Organization for Research and Treatment of Cancer (EORTC) 18991 trial, the US Food and Drug Administration (FDA) approved PEG-interferon α-2b (PEG-IFN) (Sylatron) as adjuvant therapy for high-risk melanoma. The EORTC 18991 trial was an open-label study of resectable stage III melanoma with 1,256 patients who were randomized to observation-alone or to treatment with PEG-IFN for up to 5 years. The median recurrence-free survival of the treatment groups was significantly longer, while overall survival, a secondary endpoint, was not significantly different between the two groups. This review, after a short summary of interferon α-2b trials, critically analyzes the EORTC18991 trial, as well as the subgroup results and future perspectives for this stage of disease.
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Ascierto, Paolo A; Napolitano, Maria; Celentano, Egidio; Simeone, Ester; Gentilcore, Giusy; Daponte, Antonio; Capone, Mariaelena; Caracò, Corrado; Calemma, Rosa; Beneduce, Gerardo; Cerrone, Margherita; De Rosa, Vincenzo; Palmieri, Giuseppe; Castello, Giuseppe; Kirkwood, John M; Marincola, Francesco M; Mozzillo, Nicola
2010-08-16
High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen. Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b. Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.
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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.
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Local tumour control and eye preservation after gamma-knife radiosurgery of choroidal melanomas.
Wackernagel, Werner; Holl, Etienne; Tarmann, Lisa; Mayer, Christoph; Avian, Alexander; Schneider, Mona; Kapp, Karin S; Langmann, Gerald
2014-02-01
To report on local tumour control and eye preservation after gamma knife radiosurgery (GK-RS) to treat choroidal melanomas. A total of 189 patients with choroidal melanoma were treated with GK-RS, with treatment doses between 25 and 80 Grays. The main outcome measures of our retrospective analysis were local tumour control, time to recurrence, eye retention rate and the reason for and time to secondary enucleation. Patient-associated, tumour-associated and treatment-associated parameters were evaluated as potential risk factors. Local tumour control was achieved in 94.4% of patients. The estimated tumour control rates were 97.6% at 1 year, 94.2% at 5 years and 92.4% at 10 years after treatment. Recurrence was observed between 3.1 months and 60.7 months post-treatment (median: 13.5 months). Advanced tumour stage (Tumour, Node, Metastasis (TNM) 3-4) was the most important risk factor for recurrence (Fine-Gray model; subhazard ratio, SHR: 3.3; p=0.079). The treatment dose was not related to tumour recurrence. The eye preservation rate was 81.6% at 5 years after treatment, remaining stable thereafter. Twenty-five eyes (14.1%) had to be enucleated at between 17 days and 68.0 months (median: 13.9 months) after GK-RS, and advanced tumour stage (Cox model; p=0.005), treatment dose (p=0.048), pretreatment visual acuity (p=0.016), and retinal detachment (p=0.027) were risk factors for requiring enucleation. GK-RS achieved a high tumour control rate, comparable to linear accelerator-based radiotherapy. Advanced TNM stage was a predictive risk factor for tumour recurrence and for secondary enucleation after GK-RS. Lower treatment doses were unrelated to tumour recurrence, although they were associated with an improved eye retention rate.
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Sun exposure and protection behaviors among long-term melanoma survivors and non-cancer controls
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
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Orbital amelanotic melanoma in xeroderma pigmentosum: A rare association
Amitava, Abadan K; Mehdi, Ghazala; Sharma, Rajeev; Alam, Mohammad S
2008-01-01
Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder of DNA repair in which the body′s normal ability to repair damage caused by ultraviolet light is deficient. This leads to a 1000-fold increased risk of cutaneous and ocular neoplasms. Ocular neoplasms occurring in XP in order of frequency are squamous cell carcinoma, basal cell carcinoma and melanoma. Malignant melanomas occur at an early age in patients with XP. We report a case of XP with massive orbital melanoma in an eight-year-old boy which is unique due to its amelanotic presentation confirmed histopathologically. PMID:18711275
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Ponti, Giovanni; Manfredini, Marco; Greco, Stefano; Pellacani, Giovanni; Depenni, Roberta; Tomasi, Aldo; Maccaferri, Monia; Cascinu, Stefano
2017-12-01
The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management. Between 1991 and 2015, 63 mutated melanoma patients were treated and monitored during their diagnostic and therapeutic management at a single institution. BRAF-mutated melanoma patients were the most common, representing 70% of the study population, while NRAS- and C-KIT-mutated melanoma represented 19% and 11% respectively. BRAF-mutated melanomas were mostly located at sites of intermittent sun exposure, and were associated with higher Breslow thickness and an increased number of mitosis. NRAS mutated melanoma were mainly observed in chronic sun-damaged areas and had a negative prognostic value, with shorter time to progression and a high incidence of central nervous system involvement. C-KIT mutated melanoma were located at acral and mucosal sites. Overall survival observed in the three groups of patients revealed wide differences. BRAF, NRAS and C-KIT melanomas constitute distinct clinico-pathological entities. BRAF-mutated melanoma benefit from both anti-BRAF and anti-MEK targeted therapies while triple-negative melanomas could benefit from novel anti-CTLA-4 and anti-PD-L1 immunotherapeutic approaches. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Yano, Seiichi; Ashida, Kenji; Nagata, Hiromi; Ohe, Kenji; Wada, Naoko; Takeichi, Yukina; Hanada, Yuki; Ibayashi, Yuta; Wang, Lixiang; Sakamoto, Shohei; Sakamoto, Ryuichi; Uchi, Hiroshi; Shiratsuchi, Motoaki; Furue, Masutaka; Nomura, Masatoshi; Ogawa, Yoshihiro
2018-06-08
Nivolumab, an anti-programmed cell death-1 monoclonal antibody, has improved the survival of patients with malignant melanoma. Despite its efficacy, nivolumab inconsistently induces thyroid dysfunction as an immune-related adverse event (irAE). This study aimed to evaluate nivolumab-induced thyroid dysfunction to determine the risks and mechanisms of thyroid irAEs. After excluding 10 patients, data of 24 patients with malignant melanoma (aged 17-85 years; 54% female) were retrospectively analyzed. Thyroid irAEs were observed in seven patients (29%). Three patients had hypothyroidism after preceding transient thyrotoxicosis, and the other four patients had hypothyroidism without thyrotoxicosis. Levothyroxine-Na replacement was required in three patients. Antithyroid antibody (ATA) titer was elevated in one of four assessable patients. The average (±SD) time to onset of thyroid irAE was 33.6 (±21.9) weeks. The administration period of nivolumab was longer in patients with thyroid irAEs than in those without thyroid irAEs (P < 0.01). There were no significant differences between patients with and without thyroid irAEs regarding age, sex, tumor stage, response to nivolumab therapy, baseline thyroid function, antithyroid peroxidase antibody (anti-TPO Ab) and antithyroglobulin antibody (anti-Tg Ab). Thyroid dysfunction was a common irAE of nivolumab in malignant melanoma. Neither anti-TPO Ab nor anti-Tg Ab was associated with the risk for nivolumab-induced thyroid dysfunction. A conventional ATA-independent mechanism might be involved in thyroid irAEs. Further studies are required to clarify the mechanism and identify the predictive factors of thyroid irAEs.
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Cutaneous Melanoma In Situ: Translational Evidence from a Large Population-Based Study
Nitti, Donato
2011-01-01
Background. Cutaneous melanoma in situ (CMIS) is a nosologic entity surrounded by health concerns and unsolved debates. We aimed to shed some light on CMIS by means of a large population-based study. Methods. Patients with histologic diagnosis of CMIS were identified from the Surveillance Epidemiology End Results (SEER) database. Results. The records of 93,863 cases of CMIS were available for analysis. CMIS incidence has been steadily increasing over the past 3 decades at a rate higher than any other in situ or invasive tumor, including invasive skin melanoma (annual percentage change [APC]: 9.5% versus 3.6%, respectively). Despite its noninvasive nature, CMIS is treated with excision margins wider than 1 cm in more than one third of cases. CMIS is associated with an increased risk of invasive melanoma (standardized incidence ratio [SIR]: 8.08; 95% confidence interval [CI]: 7.66–8.57), with an estimated 3:5 invasive/in situ ratio; surprisingly, it is also associated with a reduced risk of gastrointestinal (SIR: 0.78, CI: 0.72–0.84) and lung (SIR: 0.65, CI: 0.59–0.71) cancers. Relative survival analysis shows that persons with CMIS have a life expectancy equal to that of the general population. Conclusions. CMIS is increasingly diagnosed and is often overtreated, although it does not affect the life expectancy of its carriers. Patients with CMIS have an increased risk of developing invasive melanoma (which warrants their enrollment in screening programs) but also a reduced risk of some epithelial cancers, which raises the intriguing hypothesis that genetic/environmental risk factors for some tumors may oppose the pathogenesis of others. PMID:21632457
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Hultgren, Brittney A; Turrisi, Rob; Mallett, Kimberly A; Ackerman, Sarah; Robinson, June K
2016-02-01
Melanoma has a high survival rate if it is detected early. Training patients with early-stage melanoma who are at risk of developing new melanomas to perform skin self-examination (SSE) may improve survival. To examine for whom the intervention works best in a sample composed of dyads of patients with melanoma and skin-check partners who received an SSE intervention vs customary care. For 494 patients with stage 0 to IIB melanoma (mean age, 55 years; 253 [51.2%] females) and their skin-check partners (mean age, 55 years; 280 [56.7%] females), a randomized clinical trial was conducted in ambulatory care dermatologic offices from June 6, 2011, to April 14, 2014. Follow-up assessments were performed at 12 months. Analysis was performed between March 23 and June 25, 2015. Dyads of 494 patients and their partners were randomly assigned to receive the intervention (395 patients) or customary care (control) (99 patients). The main outcome was patient SSE self-efficacy. Partner motivation to assist with SSE and relationship quality (eg, agreeability, activities with partner, and happiness) were assessed for moderation of the influence of the intervention's effect on SSE self-efficacy. Relationship quality, defined by activities with the partner (β = -0.892, SE = 0.432, t = -2.066; P = .001) and happiness (β = -4.586, SE = 2.044, t = -2.24; P = .001), significantly moderated the intervention effects on patients' SSE self-efficacy. In contrast, patient-partner agreeability (β = -0.262, SE = 0.148, t = -1.773; P = .09) and partner motivation (β = -0.328, SE = 1.024, t = -0.320; P = .10) did not significantly moderate the intervention effects on patients' SSE self-efficacy. Differences between the conditions were highest when activities performed with the partner were below average (mean difference, 6.652; P = .001) and when happiness was below average (mean difference, 7.000; P = .001). Although everyone receiving the intervention experienced some benefit, the findings indicate the greatest increases in self-efficacy were observed for those with below-average activities performed with the partner and happiness. The training of patients with melanoma and their partners in early-detection SSE benefited some more than others. Pairs who have low relationship quality, as determined by activities performed with the partner and happiness, may have received the greatest benefits from the training intervention because they were given an activity to perform together. clinicaltrials.gov Identifier: NCT01432860.
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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
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Burns, William R.; Zhao, Yangbing; Frankel, Timothy L.; Hinrichs, Christian S.; Zheng, Zhili; Xu, Hui; Feldman, Steven A.; Ferrone, Soldano; Rosenberg, Steven A.; Morgan, Richard A.
2011-01-01
Immunotherapy, particularly the adoptive cell transfer (ACT) of tumor infiltrating lymphocytes (TIL), is a very promising therapy for metastatic melanoma. Some patients unable to receive TIL have been successfully treated with autologous peripheral blood lymphocytes (PBL), genetically modified to express HLA class I antigen restricted, melanoma antigen-reactive T-cell receptors; however, substantial numbers of patients remain ineligible due to the lack of expression of the restricting HLA class I allele. We sought to overcome this limitation by designing a non-MHC-restricted, chimeric antigen receptor (CAR) targeting the high molecular weight-melanoma associated antigen (HMW-MAA), which is highly expressed on over 90% of human melanomas but has a restricted distribution in normal tissues. HMW-MAA-specific CARs containing an antigen recognition domain based on variations of the HMW-MAA-specific monoclonal antibody (mAb) 225.28S and a T-cell activation domain based on combinations of CD28, 4-1BB, and CD3ζ activation motifs were constructed within a retroviral vector to allow stable gene transfer into cells and their progeny. Following optimization of the HMW-MAA-specific CAR for expression and function in human PBL, these gene-modified T cells secreted cytokines, were cytolytic, and proliferated in response to HMW-MAA expressing cell lines. Furthermore, the receptor functioned in both CD4+ and CD8+ cells, was non-MHC-restricted, and reacted against explanted human melanomas. To evaluate this HMW-MAA-specific CAR in patients with metastatic melanoma, we developed a clinical-grade retroviral packaging line. This may represent a novel means to treat the majority of patients with advanced melanoma, most notably those unable to receive current ACT therapies. PMID:20395199
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Locoregional spread of cutaneous melanoma: sonography findings.
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.
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Germline BAP1 mutations predispose to malignant mesothelioma
Testa, Joseph R.; Cheung, Mitchell; Pei, Jianming; Below, Jennifer E.; Tan, Yinfei; Sementino, Eleonora; Cox, Nancy J.; Dogan, A. Umran; Pass, Harvey I.; Trusa, Sandra; Hesdorffer, Mary; Nasu, Masaki; Powers, Amy; Rivera, Zeyana; Comertpay, Sabahattin; Tanji, Mika; Gaudino, Giovanni; Yang, Haining; Carbone, Michele
2011-01-01
Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma1, and because mesothelioma clustering is observed in some families1, we searched for genetic predisposing factors. We discovered germline mutations in BAP1 (BRCA1-associated protein 1) in two families with a high incidence of mesothelioma. Somatic alterations affecting BAP1 were observed in familial mesotheliomas, indicating biallelic inactivation. Besides mesothelioma, some BAP1 mutation carriers developed uveal melanoma. Germline BAP1 mutations were also found in two of 26 sporadic mesotheliomas: both patients with mutant BAP1 were previously diagnosed with uveal melanoma. Truncating mutations and aberrant BAP1 expression were common in sporadic mesotheliomas without germline mutations. These results reveal a BAP1-related cancer syndrome characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved, and that mesothelioma predominates upon asbestos exposure. These findings will help identify individuals at high risk of mesothelioma who could be targeted for early intervention. PMID:21874000
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de Souza, Camila Ferreira; Xander, Patrícia; Monteiro, Ana Carolina; Silva, Amanda Gonçalves dos Santos; da Silva, Débora Castanheira Pereira; Mai, Sabine; Bernardo, Viviane; Lopes, José Daniel; Jasiulionis, Miriam Galvonas
2012-01-01
Background Metastatic melanoma is a highly aggressive skin cancer and currently resistant to systemic therapy. Melanomas may involve genetic, epigenetic and metabolic abnormalities. Evidence is emerging that epigenetic changes might play a significant role in tumor cell plasticity and metastatic phenotype of melanoma cells. Principal findings In this study, we developed a systematic approach to identify genes implicated in melanoma progression. To do this, we used the Affymetrix GeneChip Arrays to screen 34,000 mouse transcripts in melan-a melanocytes, 4C pre-malignant melanocytes, 4C11− non-metastatic and 4C11+ metastatic melanoma cell lines. The genome-wide association studies revealed pathways commonly over-represented in the transition from immortalized to pre-malignant stage, and under-represented in the transition from non-metastatic to metastatic stage. Additionally, the treatment of cells with 10 µM 5-aza-2′-deoxycytidine (5AzaCdR) for 48 hours allowed us to identify genes differentially re-expressed at specific stages of melan-a malignant transformation. Treatment of human primary melanocytes with the demethylating agent 5AzaCdR in combination to the histone deacetylase inhibitor Trichostatin A (TSA) revealed changes on melanocyte morphology and gene expression which could be an indicator of epigenetic flexibility in normal melanocytes. Moreover, changes on gene expression recognized by affecting the melanocyte biology (NDRG2 and VDR), phenotype of metastatic melanoma cells (HSPB1 and SERPINE1) and response to cancer therapy (CTCF, NSD1 and SRC) were found when Mel-2 and/or Mel-3-derived patient metastases were exposed to 5AzaCdR plus TSA treatment. Hierarchical clustering and network analyses in a panel of five patient-derived metastatic melanoma cells showed gene interactions that have never been described in melanomas. Significance Despite the heterogeneity observed in melanomas, this study demonstrates the utility of our murine melanoma progression model to identify molecular markers commonly perturbed in metastasis. Additionally, the novel gene expression signature identified here may be useful in the future into a model more closely related to translational research. PMID:22984562
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Thomas, Nancy E.; Busam, Klaus J.; From, Lynn; Kricker, Anne; Armstrong, Bruce K.; Anton-Culver, Hoda; Gruber, Stephen B.; Gallagher, Richard P.; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A.; Groben, Pamela A.; Hao, Honglin; Orlow, Irene; Reiner, Anne S.; Luo, Li; Paine, Susan; Ollila, David W.; Wilcox, Homer; Begg, Colin B.; Berwick, Marianne
2013-01-01
Purpose Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. Patients and Methods On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. Results Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. Conclusion At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions. PMID:24127443
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Study of the histopathological types of cutaneous melanoma in Palmas-TO from 2001 to 2011.
Costa, Nilo Fernandes da; Fernandes, Nurimar Conceição; Borges, Myrlena Regina Machado Mescouto
2015-01-01
Cutaneous melanoma (CM) is considered serious for causing frequent metastasis, presenting high mortality, resistance to available therapies and incidences in laboring activity. To study the histopathological types of cutaneous melanoma in Palmas-TO from 2001 to 2011, according to risk factors, location of lesions, Clark levels and Breslow thickness. A descriptive, retrospective and quantitative research in reports of the Serviços de Anatomia Patológica in Palmas (SAPP) and Registro de Câncer de Base Populacional de Palmas (RCBPP). The years of highest incidences were: 2004 (8 cases/17.8%), 2008 and 2011 (7 cases each/15.6%) and 2010 (6 cases/13.3%). Among the 45 cases studied, there were predominance in patients between 41 and 60 years old, women, caucasians, farmers, located in trunk, in situ type, superficial extensive and metastatic cutaneous, Clark levels I (20%) and IV (17.7%), Breslow thickness ≤1 mm (35.5%) and 2.01 to 4 mm (24.4%). The most common histopathological types were: cutaneous melanoma in situ, superficial extensive and metastatic, followed by nodular cutaneous melanoma, and finally, by other forms. In this study, Clark levels and Breslow thickness pointed to greater importance of thin melanomas and sun exposure without appropriate protection in farmers.
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Diagnostic inaccuracy of smartphone applications for melanoma detection.
Wolf, Joel A; Moreau, Jacqueline F; Akilov, Oleg; Patton, Timothy; English, Joseph C; Ho, Jonhan; Ferris, Laura K
2013-04-01
To measure the performance of smartphone applications that evaluate photographs of skin lesions and provide the user with feedback about the likelihood of malignancy. Case-control diagnostic accuracy study. Academic dermatology department. PARTICIPANTS AND MATERIALS: Digital clinical images of pigmented cutaneous lesions (60 melanoma and 128 benign control lesions) with a histologic diagnosis rendered by a board-certified dermatopathologist, obtained before biopsy from patients undergoing lesion removal as a part of routine care. Sensitivity, specificity, and positive and negative predictive values of 4 smartphone applications designed to aid nonclinician users in determining whether their skin lesion is benign or malignant. Sensitivity of the 4 tested applications ranged from 6.8% to 98.1%; specificity, 30.4% to 93.7%; positive predictive value, 33.3% to 42.1%; and negative predictive value, 65.4% to 97.0%. The highest sensitivity for melanoma diagnosis was observed for an application that sends the image directly to a board-certified dermatologist for analysis; the lowest, for applications that use automated algorithms to analyze images. The performance of smartphone applications in assessing melanoma risk is highly variable, and 3 of 4 smartphone applications incorrectly classified 30% or more of melanomas as unconcerning. Reliance on these applications, which are not subject to regulatory oversight, in lieu of medical consultation can delay the diagnosis of melanoma and harm users.
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New Safety Margins for Melanoma Surgery: Nice Possibility for Drinking of "Just That Cup of Coffee"?
Tchernev, Georgi; Chokoeva, Anastasiya Atanasova
2017-06-15
The American Joint Committee on Cancer (AJCC's) skin melanoma surgical treatment recommendations from 2011 are characterised by a prima facie "freedom of choice" regarding how extensive should be the excisions for melanomas with tumour thickness up to 2 mm and melanoma in situ. It is unclear why the recommended surgical security margins vary between 0.5 and 1 cm for melanoma in situ, whereas for melanomas with a tumour thickness of up to 1.99 mm, the range of variation is also between 1 and 2 cm, without specifying when the surgical field should be broader and, narrower, accordingly. This "uncertainty or lack of intent" of the guilders often leads to the same surgical approach to melanomas at different stages, or to a different approach in cases of melanomas at the same stage, in contrast. Therefore, this should be defined as wrong, logically. We present 3 patients with cutaneous melanomas, treated with similar fields of surgical security. Current issues, generated within the framework of melanoma's surgery guided by the recommendations of the AJCC are also discussed. A new surgical approach in patients with melanoma is recommended, discussed for the first time in world literature. We hypothesize that the introduction of a certain recommendations for a 2 cm surgical field in all directions during the initial excision, combined with the parallel performance of a sentinel lymph node biopsy, will lead in fact to several important advantages: 1) avoiding of the secondary excision in at least 70% - 90% of the patients (depending on the tumor thickness), 2) minimizing the risk of lymphatic effusion change and misinterpretation of the sentinel lymph node biopsy's results in patients with secondary excision; 3) optimization of the surgical team's work; 4) minimizing the possibility of unprepared/uninformed personnel to take part in decisions for treating a specific disease such as skin melanoma, 4) facilitating the appropriate patients' group selection at the appropriate stage when involving them in different studies, leading to equal leveling of the initial positions. Whether the proposed approach will be subjected to a detailed discussion of AJCC's expert's remains currently unclear.
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Cortellini, Alessio; Parisi, Alessandro; Fargnoli, Maria Concetta; Cannita, Katia; Irelli, Azzurra; Porzio, Giampiero; Martinazzo, Claudio; Ficorella, Corrado
2018-01-01
Patients with autoimmune diseases were not evaluated in clinical trials with immune checkpoint inhibitors (ICIs), since a history of immune disorders, such as Guillain-Barré syndrome (GBS) and psoriasis, is one of the major risk factors for the development of immune-related adverse events (irAEs). This risk cannot be defined; therefore, physicians are called to manage these patients in clinical practice. We report the case of a 62-year-old male patient affected by metastatic melanoma, with a history of GBS and psoriasis, and treated with sequential ipilimumab, pembrolizumab, and nivolumab, without significant toxicities. This case report supports that although a history of immune disorders is one of the major risk factors for development of irAEs, in some patients, it could be possible to safely administer sequential treatments with ICIs. A proper decision should be made, considering therapeutic options, disease-related risks, and those related to a recurrence of preexisting autoimmune disorders.
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The utility of ultrasound in patients with melanoma.
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.
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Use of tanning beds and incidence of skin cancer.
Zhang, Mingfeng; Qureshi, Abrar A; Geller, Alan C; Frazier, Lindsay; Hunter, David J; Han, Jiali
2012-05-10
We sought to evaluate the risk effect of tanning bed use on skin cancers among teenage and young adults. We also expected to determine whether a dose-response relationship was evident. We observed 73,494 female nurses for 20 years (from 1989 to 2009) in a large and well-characterized cohort in the United States and investigated whether frequency of tanning bed use during high school/college and at ages 25 to 35 years were associated with a risk of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. We used Cox proportional hazards models and carefully adjusted for host risk factors, ultraviolet index of residence, and sun exposure behaviors at a young age. During follow-up, 5,506 nurses were diagnosed with BCC, 403 with SCC, and 349 with melanoma. The multivariable-adjusted hazard ratio (HR) of skin cancer for an incremental increase in use of tanning beds of four times per year during both periods was 1.15 (95% CI, 1.11 to 1.19; P < .001) for BCC, 1.15 (95% CI, 1.01 to 1.31; P = .03) for SCC, and 1.11 (95% CI, 0.97 to 1.27; P = .13) for melanoma. Compared with tanning bed use at ages 25 to 35 years, we found a significantly higher risk of BCC for use during high school/college (multivariable-adjusted HR for use more than six times per year compared with no use was 1.73 during high school/college v 1.28 at ages 25 to 35 years; P for heterogeneity < .001). Our data provide evidence for a dose-response relationship between tanning bed use and the risk of skin cancers, especially BCC, and the association is stronger for patients with a younger age at exposure.
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Li-Fraumeni syndrome presenting as mucosal melanoma: Case report and treatment considerations.
Klein, Jonah D; Kupferman, Michael E
2017-02-01
Li-Fraumeni syndrome (LFS) is a familial cancer predisposition associated with a germline mutation in TP53. Patients with LFS are at risk of developing malignancies and require comprehensive screening. We describe an index case of LFS presenting with mucosal melanoma. A 21-year-old woman presented with a left maxillary mucosal lesion and a left neck mass. Biopsies revealed metastatic mucosal melanoma, which is a pathology previously unreported in LFS families. Genetic testing revealed LFS, with a germline TP53 mutation, and pedigree analysis identified 9 first-degree and second-degree relatives with hematologic malignancies. The patient underwent a maxillectomy and left neck dissection, followed by adjuvant radiotherapy. At 30-month follow-up, there was no evidence of local, regional, or distant failure, nor did she develop a second primary tumor. This represents the first reported case of LFS associated with mucosal melanoma. Treatment considerations, specifically the risks of adjuvant therapy in LFS, are discussed. © 2016 Wiley Periodicals, Inc. Head Neck 39: E20-E22, 2017. © 2016 Wiley Periodicals, Inc.
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CYR61 suppresses growth of human malignant melanoma.
Chen, Jun; Liu, Yang; Sun, Qilin; Wang, Beiqing; Li, Ningli; Chen, Xiangdong
2016-11-01
Cysteine-rich protein 61 (CCN1/CYR61) is an important marker of proliferation and metastasis in malignant melanoma, making it a potential target for melanoma treatment. In this study, we compared the expression of CRY61 in Chinese patients with malignant melanoma with its expression in patients with other skin tumors or with no skin pathological conditions. We examined the effects of anti-human CYR61 monoclonal antibody on proliferation and evaluated the changes in CYR61 expression and cell proliferation in response to treatment with either epirubicin or interferon (IFN)-α. CYR61 was expressed at lower levels in patients with malignant melanoma than in patients with other skin tumors or with no pathology. Following the treatment of B16 cells with epirubicin and IFN-α, CYR61 levels increased, cell growth was inhibited, and proliferating cell nuclear antigen expression decreased. Thus, CYR61 could become a therapeutic target for malignant melanoma patients with high CYR61 expression.
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Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases.
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.
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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.
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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.
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GNAQ mutation in a patient with metastatic mucosal melanoma.
Kim, Chung-Young; Kim, Dae Won; Kim, Kevin; Curry, Jonathan; Torres-Cabala, Carlos; Patel, Sapna
2014-07-16
Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma.
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GNAQ mutation in a patient with metastatic mucosal melanoma
2014-01-01
Background Mucosal melanomas represent about 1% of all melanoma cases and classically have a worse prognosis than cutaneous melanomas. Due to the rarity of mucosal melanomas, only limited clinical studies with metastatic mucosal melanoma are available. Mucosal melanomas most commonly contain mutations in the gene CKIT, and treatments have been investigated using targeted therapy for this gene. Mutations in mucosal melanoma are less common than in cutaneous or uveal melanomas and occur in descending order of frequency as: CKIT (20%), NRAS (5%) or BRAF (3%). Mutations in G-alpha proteins, which are associated with activation of the mitogen-activated protein kinase pathway, have not been reported in mucosal melanomas. These G-alpha protein mutations occur in the genes GNAQ and GNA11 and are seen at a high frequency in uveal melanomas, those melanomas that begin in the eye. Case presentation A 59-year old Caucasian male was diagnosed with a mucosal melanoma after evaluation for what was thought to be a hemorrhoid. Molecular analysis of the tumor revealed a GNAQ mutation. Ophthalmologic exam did not disclose a uveal melanoma. Conclusion Here we report, to our knowledge, the first known case of GNAQ mutation in a patient with metastatic mucosal melanoma. PMID:25030020
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Fortes, Cristina; Mastroeni, Simona; Segatto M, Marjorie; Hohmann, Clarissa; Miligi, Lucia; Bakos, Lucio; Bonamigo, Renan
2016-04-01
The objective of the study was to examine the association between occupational exposure to pesticides and cutaneous melanoma, controlling for all possible confounders. A pooled analysis of two case-control studies was conducted in two different geographic areas (Italy and Brazil). Detailed pesticides exposure histories were obtained. Ever use of any pesticide was associated with a high risk of cutaneous melanoma (odds ratio 2.58; 95% confidence interval 1.18-5.65) in particular exposure to herbicides (glyphosate) and fungicides (mancozeb, maneb), after controlling for confounding factors. When subjects were exposed to both pesticides and occupational sun exposure, the risk increased even more (odds ratio 4.68; 95% confidence interval 1.29-17.0). The study suggests an augmented risk of cutaneous melanoma among subjects with exposure to pesticides, in particular among those exposed to occupational sun exposure.
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Ocular melanoma: an overview of the current status
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
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Koh, H K; Sinks, T H; Geller, A C; Miller, D R; Lew, R A
1993-01-01
Although the precise etiology of melanoma remains unknown, much data link sunlight to melanoma. The imperfect evidence associating sun exposure (particularly UVB radiation) with melanoma emerges from human data, obviating problems inherent in extrapolation from animal and other models. However, the mechanism by which sunlight might possibly initiate or promote melanoma remains obscure. Some clarification should emerge from the potential isolation of genes that carry susceptibility to melanoma in families prone to the disease; such work could serve as a basis to distinguish genetic and environmental influences in melanoma [167]. Continued studies of faulty DNA repair in XP patients may elucidate the steps in mutagenesis and carcinogenesis. Future case-control studies must address the limits on the accuracy of recall and the limits on statistical methods to separate the cluster of phenotypic risk needed in determining biologically effective dose. Animal and in vitro studies must contribute more insight. Further research in the South American opossum models appears promising [72]. Although ozone depletion has been documented, there has been little definitive evidence of subsequent increase of UVB at the Earth's surface. Nevertheless, the threat posed by ozone depletion deserves continued environmental action and public education. The role of precursor lesions, particularly dysplastic nevi/atypical moles, must be clarified with future research. The distribution of melanoma among various work forces suggests that occupational risk factors may play an important role in the etiology of this disease [168-170]. The consistent reports of excess melanoma among accountants, clerical workers, professional workers, and teachers deserve further study. Furthermore, evidence of excesses in printing and press, petrochemical, and the telecommunications industries require follow-up. Carefully planned studies that account for nonoccupational risk factors are recommended. Research over the last four decades has brought much information about melanoma etiology. More work is needed to learn the precise cause and ultimately to prevent avoidable mortality from malignant melanoma.
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Fujisawa, Yasuhiro; Otsuka, Fujio
2012-10-01
The benefit of a sentinel lymph node (SLN) biopsy and adjuvant therapy for patients with thick (>4 mm) melanoma has not been well studied in the Asian population. We examined the benefit of an SLN biopsy and adjuvant therapy on prognosis in Japanese patients with thick melanoma. A review of the melanoma database collected from 26 institutions in Japan identified 291 patients with thick melanoma between 2005 and 2010. Univariate and multivariate analyses were performed to evaluate the factors predictive of the overall survival (OS) and the disease-free survival (DFS). Of the 242 patients with thick melanoma who underwent an SLN biopsy, the results for 96 (40%) were positive. On multivariate analysis, increased Breslow thickness (relative risk, 1.11; 95% confidence interval, 1.05-1.17; P=0.0002) and SLN metastasis (2.14; 1.04-4.43; P=0.040) were associated with a poor OS. Increased Breslow thickness (1.11; 1.04-1.18; P =0.0018), ulceration (3.11; 1.25-7.72; P=0.014), satellitosis (3.89; 1.62-9.31; P=0.0023), and SLN metastasis (2.24; 1.16-4.36; P=0.017) were associated with DFS. Adjuvant chemotherapy had no impact on either OS or DFS. Adjuvant use of a monthly dermal injection of interferon-β (IFN-β) was associated with a improvement in both OS (0.34; 0.17-0.67; P=0.0022) and DFS (0.42; 0.20-0.86; P=0.018). An SLN biopsy provided useful prognostic information and the adjuvant use of IFN-β improved both OS and DFS in Japanese patients with thick melanoma. These results were consistent with those of previous studies carried out on a white population. Therefore, we suggest that an SLN biopsy and adjuvant IFN should be considered for patients with thick melanoma irrespective of the Breslow thickness or ethnicity.
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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.
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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
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Lian, Bin; Si, Lu; Cui, Chuanliang; Chi, Zhihong; Sheng, Xinan; Mao, Lili; Li, Siming; Kong, Yan; Tang, Bixia; Guo, Jun
2013-08-15
Mucosal melanoma is rare and associated with extremely poor prognosis. However, standard adjuvant therapy for mucosal melanoma has not been established. We conducted a randomized phase II clinical trial in patients with resected mucosal melanoma to compare the efficacy and safety of high-dose IFN-α2b (HDI) and temozolomide-based chemotherapy as adjuvant therapy. Patients with mucosal melanoma in stage II/III after surgery were randomized into three groups: observation group (group A, surgery alone), HDI group (group B, treated with 15 × 10(6) U/m(2)/d IFN-α2b, followed by 9 × 10(6) U IFN-α2b), and temozolomide (200 mg/m(2)/d) plus cisplatin (75 mg/m(2)) group (group C). The endpoints were relapse-free survival (RFS), overall survival (OS), and toxicities. One hundred and eighty-nine patients were enrolled and finally analyzed. With a median follow-up of 26.8 months, the median RFS was 5.4, 9.4, and 20.8 months for group A, B, and C, respectively. Estimated median OS for group A, B, and C was 21.2, 40.4, and 48.7 months, respectively. Patients treated with temozolomide plus cisplatin showed significant improvements in RFS (P < 0.001) and OS (P < 0.01) than those treated with either HDI or surgery alone. Toxicities were generally mild to moderate. Both temozolomide-based chemotherapy and HDI are effective and safe as adjuvant therapies for resected mucosal melanoma as compared with observation alone. However, HDI tends to be less effective than temozolomide-based chemotherapy for patients with resected mucosal melanoma in respect to RFS. The temozolomide plus cisplatin regimen might be a better choice for patients with resected mucosal melanoma. ©2013 AACR.
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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
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Caracò, Corrado; Celentano, Egidio; Lastoria, Secondo; Botti, Gerardo; Ascierto, Paolo Antonio; Mozzillo, Nicola
2004-03-01
Management of patients with cutaneous melanoma in the absence of lymph node metastases is still controversial. The experience at the National Cancer Institute in Naples was analyzed to evaluate 3-year disease-free survival and overall survival for all patients who underwent sentinel lymph node biopsy (SLB) with Breslow thickness greater than 4 mm. Data from 359 sentinel biopsies performed in the past 5 years were reviewed to determine the effect of the treatment on disease-free survival and overall survival after stratifying patients for node status, tumor ulceration, and Breslow thickness. Statistical analysis showed a better 3-year survival for sentinel node-negative patients than for sentinel node-positive cases (88.4% and 72.9%, respectively; P <.05). Tumor ulceration retained its prognostic significance despite lymph node status, indicating a higher risk for development of distant metastases. Survival curves associated with thicker melanomas did not show significant differences between negative- and positive-SLB patients. SLB provides accurate staging of nodal status in melanoma patients who have no clinical evidence of metastases. Longer follow-up and final results from ongoing trials are necessary to definitively clarify the role of this procedure.
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Lack of Radiation Maculopathy After Palladium-103 Plaque Radiotherapy for Iris Melanoma
DOE Office of Scientific and Technical Information (OSTI.GOV)
Yousef, Yacoub A.; Finger, Paul T., E-mail: pfinger@eyecancer.com
2012-07-15
Purpose: To report on the risk of radiation maculopathy for iris and iridociliary melanomas treated by {sup 103}Pd plaque radiotherapy. Methods and Materials: This is a retrospective clinical case series of 30 eyes in 30 patients with melanomas limited to the iris or invading the ciliary body. The main outcome measures included demographic information, laterality, tumor size, location, visual acuity, radiation dose, local control, retinal evaluation, and duration of follow-up. Results: Thirty patients were followed for a median 36 months (range, 12-90 months). Sixteen of 30 tumors (53%) were pure iris melanomas, and 14 (47%) were primary iris melanomas extendingmore » into the ciliary body. Radiation dosimetry showed that the median tumor apex dose was 85 Gy (range, 75-100 Gy), lens dose 43.5 Gy (range, 17.8-60 Gy), fovea dose 1.8 Gy (range, 1.3-5 Gy), and central optic disc dose 1.7 Gy (range, 1.3-4.7 Gy). Cataracts developed in 20 of the 28 phakic eyes (71.4%). No patient in this series developed radiation maculopathy or radiation optic neuropathy. Last best-corrected visual acuity was {>=}20/25 in 28 patients (93%) at a median 36 months' follow-up. Conclusion: Though visual acuities were transiently affected by radiation cataract, no radiation maculopathy or optic neuropathy has been noted after {sup 103}Pd treatment of iris and iridociliary melanomas.« less
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Lymphatic vessel density and VEGF-C expression as independent predictors of melanoma metastases.
Špirić, Zorica; Eri, Živka; Erić, Mirela
2017-11-01
In many patients, the clinical behaviour of cutaneous melanoma is very difficult to predict by traditional histologic and clinical parameters. This study aimed to examine the role of quantitative parameters of tumour lymphangiogenesis and vascular endothelial growth factor (VEGF)-C in predicting metastatic risk in patients with cutaneous melanoma. One hundred melanoma specimens were stained with lymphatic-specific antibody D2-40 and with anti-VEGF-C antibody. Quantitative parameters of lymphangiogenesis-lymphatic vessel density (LVD) and lymphatic vessel area (LVA)-were determined by computer-assisted morphometric analysis. Moderate or strong staining was assessed as a positive expression of VEGF-C in tumour cells. Univariate analysis revealed that intratumoural LVD, peritumoural LVD, VEGF-C expression in tumour cells, melanoma thickness, Clark level, ulceration, gender and histologic type were significant predictors of lymph node metastasis (p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.005, p = 0.005, p = 0.011 and p = 0.027, respectively). No significant association of intratumoural and peritumoural LVA with metastases was found. In multivariate analysis, independent predictors of metastatic risks were melanoma thickness [odds ratio OR = 1.655, 95% confidence interval (CI) 1.102-2.484, p = 0.015], intratumoural LVD (OR = 1.086, 95% CI 1.027-1.148, p = 0.004), peritumoural LVD (OR = 1.050, 95% CI 1.008-1.094, p = 0.020) and a positive VEGF-C expression in tumour cells (OR = 20.337, 95% CI 2.579-160.350, p = 0.004). This study identified intratumoural and peritumoural LVD and the VEGF-C expression in tumour cells as more significant predictors of metastatic risk than melanoma thickness, ulceration and other clinical-pathological parameters. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
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BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma.
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.
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Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program.
González-Cao, M; Arance, A; Piulats, J M; Marquez-Rodas, I; Manzano, J L; Berrocal, A; Crespo, G; Rodriguez, D; Perez-Ruiz, E; Berciano, M; Soria, A; Castano, A G; Espinosa, E; Montagut, C; Alonso, L; Puertolas, T; Aguado, C; Royo, M A; Blanco, R; Rodríguez, J F; Muñoz, E; Mut, P; Barron, F; Martin-Algarra, S
2017-06-01
The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.
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Krammer, Ramona; Heinzerling, Lucie
2014-01-01
Background New melanoma therapies, like e.g. ipilimumab, improve survival. However, only a small subset of patients benefits while 60% encounter side effects. Furthermore, these marginal benefits come at a very high price of €110’000 per treatment. This study examines attitudes towards melanoma therapy options of physicians, healthy individuals and patients, their willingness to pay and preference of quality versus length of life. Methods Based on findings from a focus group questionnaires were developed and pretested. After obtaining ethical approval and informed consent surveys were conducted in a total of 90 participants (n = 30 for each group). Statistical analyses were conducted using R. Findings Attitudes vastly differed between healthy participants, physicians and melanoma patients. Whereas melanoma patients show a high willingness to endure side effects despite very small survival gains (down to 1 extra week) or even only hope with no survival benefit, healthy controls are more critical, while physicians are the most therapy adverse. Consequently, if given €100’000 and the free decision what to spend the money on the willingness to pay for therapy was much higher in the patient group (68%) compared to 28% of healthy controls and only 43% of the physicians, respectively. When lowering the amount of cash that could be received instead of ipilimumab to €50’000 or €10’000 to test price sensitivity 69% (+1%) and 76% (+8%) of melanoma patients, respectively, preferred ipilimumab over cash. When judging on societal spending even melanoma patients opted for spending on ipilimumab in only 21%. Conclusion The judgment about the benefits of new treatment options largely differs between groups, physicians being the most critical against therapy. Price elasticity was low. PMID:25369124
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Cao, M González; Auge, J M; Molina, R; Martí, R; Carrera, C; Castel, T; Vilella, R; Conill, C; Sánchez, M; Malvehy, J; Puig, S
2007-01-01
Serum levels of melanoma markers may have a role in monitoring disease evolution in metastatic melanoma. Serial measurements of melanoma inhibiting activity protein (MIA), lactate dehydrogenase (LDH), S-100 and beta2-microglubulin were obtained from 42 metastatic melanoma patients during their biochemotherapy treatment. High pre-treatment serum levels of S-100, LDH, MIA and P2-microglobulin were detected in 50%, 57%, 50% and 24% of the patients, respectively. Only S-100 had prognostic significance for both disease-free (p=0.011) and overall survival (p=0.021). In patients who responded to treatment, S-100 levels decreased significantly from pre-treatment to the time of response (p = 0.050). When patients progressed, levels of MIA and P2-microglobulin increased significantly (p =0.028 and p =0.030, respectively). Correlation with disease evolution was found for S-100, MIA and P2-microglobulin levels. Despite the small sample size of the study, S-100 was a significant prognostic marker for overall survival and disease-free survival.
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Low Rates of Dermatologic Care and Skin Cancer Screening Among Inflammatory Bowel Disease Patients.
Anderson, Alyce; Ferris, Laura K; Click, Benjamin; Ramos-Rivers, Claudia; Koutroubakis, Ioannis E; Hashash, Jana G; Dunn, Michael; Barrie, Arthur; Schwartz, Marc; Regueiro, Miguel; Binion, David G
2018-04-30
Dermatologic manifestations of inflammatory bowel disease (IBD) are common, and certain IBD medications increase the risk of skin cancer. To define the rates of care and factors associated with dermatologic utilization with a focus on skin cancer screening. We utilized a prospective, natural history IBD research registry to evaluate all outpatient healthcare encounters from 2010 to 2016. Gastrointestinal, dermatologic and primary care visits per individual were identified. We calculated the proportion of patients obtaining care, categorized primary indications for dermatologic visits, determined the incidence of melanoma and non-melanoma skin cancers, and used logistic regression to determine factors associated with dermatology utilization. Of the 2127 IBD patients included, 452 (21.3%) utilized dermatology over the study period, and 55 (2.6%) had a total body skin examination at least once. The 452 patients incurred 1633 dermatology clinic visits, 278 dermatologic procedures, and 1108 dermatology telephone encounters. The most frequent indication was contact dermatitis or dermatitis. Factors associated with dermatology use were family history of skin cancer, employment, systemic steroids, longer disease duration, emergency room use, and the number of IBD-related clinic visits. Between 8.3 and 11% of IBD patients recommended for skin cancer screening visited dermatology each year, and the resulting incidence of non-melanoma skin cancer was 35.4/10,000 [95% CI 23.3-51.5] and melanoma was 6.56/10,000 [95% CI 2.1-15.3]. Less than one in ten IBD patients obtain dermatologic care. Given the increased risk of skin cancers among IBD patients, an emphasis on education, prevention, and screening merits attention.
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Associations of Statins and Diabetes with Diagnosis of Ulcerated Cutaneous Melanoma.
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.
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[Multiple post-chemotherapy plantar nevi].
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.
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Liu, Frank Xiaoqing; Witt, Edward A; Ebbinghaus, Scot; DiBonaventura Beyer, Grace; Basurto, Enrique; Joseph, Richard W
2017-10-25
Understanding the perceptions of patients and oncology nurses about the relative importance of benefits and risks associated with newer treatments of advanced melanoma can help to inform clinical decision-making. The aims of this study were to quantify and compare the views of patients and oncology nurses regarding the importance of attributes of treatments of advanced melanoma. A discrete choice experiment (DCE) was conducted in US-based oncology nurses and patients diagnosed with advanced melanoma. Patients and nurses were enlisted through online panels. In a series of scenarios, respondents had to choose between 2 hypothetical treatments, each with 7 attributes: mode of administration (MoA), dosing schedule (DS), median duration of therapy (DoT), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and grade 3 or 4 adverse events (AEs). Hierarchical Bayesian logistic regression models were used to estimate preference weights. A total of 200 patients with advanced melanoma and 150 oncology nurses participated. The relative importance estimates of attributes by patients and nurses, respectively, were as follows: OS, 33% and 28%; AEs, 29% and 26%; ORR, 25% and 27%; PFS, 12% and 15%; DS, 2% and 3%; DoT, 0% and 0%; and MoA, 0% and 0%. Both patients and oncology nurses valued OS, ORR, and AEs as the most important treatment attributes for advanced melanoma, followed by PFS, whereas DS, DoT, and MoA were given less value in their treatment decisions. Oncology nurses and patients have similar views on important treatment considerations for advanced melanoma, which can help build trust in shared decision-making.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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Song, Fengju; Chen, Steven T; Li, Xin; Han, Jiali
2018-05-01
Previous studies have found an increased risk for invasive cutaneous melanoma (CM) among those with a history of keratinocyte carcinoma (KC). The aim of this study was to evaluate the risk of CM death after KC. The study was based on the Health Professionals Follow-up Study. A Cox proportional hazards model was used to examine the hazard ratio (HR) of death due to CM associated with personal history of KC among the entire study population (primary analysis) and among participants with invasive CM (secondary analysis), respectively. We documented a total of 908 participants with invasive CM over a total of 0.7 million person-years of follow-up. Among all participants, the risk for development of either lethal or nonlethal invasive CM increased for those with a history of KC. The risk for death due to melanoma based on KC history was not significantly increased, with an HR of 1.53 (95% confidence interval, 0.95-2.46). In the case-only analysis, those with a history of KC had a significantly lower risk for death due to melanoma than those with no such history (HR, 0.60; 95% confidence interval, 0.35-0.94). Because the population covered by the Health Professionals Follow-up Study consists exclusively of male health professionals, the results of this study may not be extended to the entire population. Personal history of KC is associated with a decreased risk for melanoma-specific death among male patients with invasive CM. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Tang, Jean Y.; Fu, Teresa; LeBlanc, Erin; Manson, JoAnn E.; Feldman, David; Linos, Eleni; Vitolins, Mara Z.; Zeitouni, Nathalie C.; Larson, Joseph; Stefanick, Marcia L.
2011-01-01
Purpose In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial. Methods Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication. Results Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; Pinteraction = .038), which was not observed in women without history of NMSC. Conclusion Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation. PMID:21709199
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Salerno, Elise P.; Bedognetti, Davide; Mauldin, Ileana S.; Deacon, Donna H.; Shea, Sofia M.; Obeid, Joseph M.; Coukos, George; Gajewski, Thomas F.; Marincola, Francesco M.; Slingluff, Craig L.
2016-01-01
ABSTRACT We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction. PMID:28123876
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lindeloef, B.E.; Eklund, G.
1986-12-01
During the years 1949 to 1975, 14,237 patients received therapeutic doses of grenz rays for the treatment of benign skin disorders such as chronic eczema, psoriasis, and warts. The records of 14,140 of these patients (99.3%) formed the basis for an epidemiologic study of the incidence of skin malignancies in this population. Information about the patients, diagnoses, doses, and sites of treatment was obtained from separate records. The follow-up time was 15 years on the average. We searched the Swedish Cancer Registry, Stockholm, for records reporting the incidence of malignant skin tumors in the study population (incidences of basal cellmore » carcinoma are not registered). The expected number of malignancies was calculated on the basis of age- and sex-standardized incidence data from the Swedish Cancer Registry. In 58 patients, a malignant skin tumor was diagnosed more than five years after grenz-ray therapy had first been administered. Nineteen patients had malignant melanomas, and 39 patients had other malignant skin tumors. The expected number of melanomas was 17.8, and that of other malignant skin tumors was 26.9. None of the patients with melanomas, and only eight of the patients with other malignant skin tumors, had received grenz-ray therapy at the site of the tumor. Six of these eight patients had also been exposed to other known carcinogens. Four hundred eighty-one patients had received an accumulated high dose of grenz rays (greater than or equal to 10 000 rad (greater than or equal to 100 Gy)) on one and the same area. No malignancies were found on those areas. Although we cannot exclude grenz-ray therapy as a risk factor in the development of nonmelanoma skin malignancies, this risk, if any, is small, if recommendations for therapy are followed.« less
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Karachaliou, Niki; Gonzalez-Cao, Maria; Crespo, Guillermo; Drozdowskyj, Ana; Aldeguer, Erika; Gimenez-Capitan, Ana; Teixido, Cristina; Molina-Vila, Miguel Angel; Viteri, Santiago; De Los Llanos Gil, Maria; Algarra, Salvador Martin; Perez-Ruiz, Elisabeth; Marquez-Rodas, Ivan; Rodriguez-Abreu, Delvys; Blanco, Remedios; Puertolas, Teresa; Royo, Maria Angeles; Rosell, Rafael
2018-01-01
Background: Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated. Results: A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression. Conclusions: IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1. PMID:29383037
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Soldevila, Berta; Alonso, Núria; Martínez-Arconada, Maria J; Granada, Maria L; Boada, Aram; Vallejos, Virginia; Fraile, Manuel; Fernández-Sanmartín, Marco A; Pujol-Borrell, Ricardo; Puig-Domingo, Manel; Sanmartí, Anna; Martínez-Cáceres, Eva M
2013-04-01
One of the side effects of interferon-alpha therapy is interferon-induced thyroiditis (IIT). The role of lymphocyte subpopulations in IIT melanoma patients remains to be defined. Our objective was to assess different peripheral blood lymphocyte subpopulations, mainly regulatory T cells (Tregs), in melanoma patients who developed IIT. From 30 melanoma patients receiving high-dose interferon (HDI)-alpha 2b (IFN-α2b) treatment, those who developed IIT (IIT patients) were selected and compared with patients who did not develop IIT (Co-MM) and healthy controls (Co-H). Peripheral blood mononuclear cells were obtained before treatment (BT), mid-treatment (MT), end of treatment (ET), 24 weeks post-treatment and at appearance of IIT (TT). Nine patients developed IIT (30%): four Hashimoto's thyroiditis and five destructive thyroiditis. An increase in Tregs was observed in both melanoma groups during HDI treatment. A decrease in CD3(+) , NKT lymphocyte subpopulations and Bcl2 expression on B cells was also observed in both groups. However, no changes were observed in the percentage of CD4(+) , CD8(+) , CD3(+) γδ(+) , CD19(+) , transitional B cells (CD24(high) CD38(high) CD19(+) CD27(-) ), natural killer (NK), invariant NKT (iNKT) lymphocytes and Th1/Th2 balance when BT was compared with ET. At TT, IIT patients had a higher Tregs percentage than Co-MM (P = 0·012) and Co-H (P = 0·004), a higher iNKT percentage than Co-MM (P = 0·011), a higher transitional B cells percentage than Co-H (P = 0·015), a lower CD3(+) percentage than Co-H (P = 0·001) and a lower Bcl2 expression on B cells than Co-H (P < 0·001). Our results point to the immunomodulatory effects of IFN-α on different lymphocyte subpopulations and a possible role of Tregs in melanoma patients who developed IIT. © 2012 Blackwell Publishing Ltd.
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Campillo, José Antonio; López-Hernández, Ruth; Martínez-Banaclocha, Helios; Bolarín, José Miguel; Gimeno, Lourdes; Mrowiec, Anna; López, Manuela; Las Heras, Beatriz; Minguela, Alfredo; Moya-Quiles, Maria Rosa; Legáz, Isabel; Frías-Iniesta, José Francisco; García-Alonso, Ana María; Álvarez-López, María Rocío; Martínez-Escribano, Jorge Antonio; Muro, Manuel
2015-01-01
A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA(*)009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA(*)009 and HLA-B(*)51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA(*)009 nor the combination MICA(*)009/HLA-B(*)51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis.
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Cho, Hyunje G; Ransohoff, Katherine J; Yang, Lingyao; Hedlin, Haley; Assimes, Themistocles; Han, Jiali; Stefanick, Marcia; Tang, Jean Y; Sarin, Kavita Y
2018-07-01
Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma. Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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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.
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Russo, Irene; Caroppo, Francesca; Alaibac, Mauro
2015-01-01
A tremendous amount of information was published over the past decades in relation to the role of vitamins in various neoplastic diseases. In particular, several studies showed an inverse relationship between selected vitamins intake and cancer risk. In this review we will focus on the role played by vitamins in melanoma with particular regard to vitamin A, D, K, E and C. Given that vitamin supplementation is easy, convenient, and readily accepted by patients, in the future the use of vitamins in chemoprevention and therapy of melanoma could be encouraged if supported by pre-clinical and clinical evidence. PMID:26213971
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Diagnosis of metastatic melanoma by fine-needle biopsy: analysis of 2,204 cases.
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.
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Melanoma Biomolecules: Independently Identified but Functionally Intertwined
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
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Jiang, Guan; Li, Rong-Hua; Sun, Chao; Liu, Yan-Qun; Zheng, Jun-Nian
2014-01-01
Malignant melanoma is the most aggressive and deadly form of skin cancer. Dacarbazine (DTIC) has been the approved first-line treatment for metastatic melanoma in routine clinical practice. However, response rates with single-agent DTIC are low. The objective of this study was to compare the efficacy and safety of DTIC with or without placebo and DTIC-based combination therapies in patients with advanced metastatic melanoma. We searched from electronic databases such as The Cochrane Library, MEDLINE, EBSCO, EMBASE, Ovid, CNKI, and CBMDisc from 2003 to 2013. The primary outcome measures were overall response and 1-year survival, and the secondary outcome measurements were adverse events. Nine randomized controlled trials (RCTs) involving 2,481 patients were included in the meta-analysis. DTIC-based combination therapies was superior to DTIC alone in overall response (combined risk ratio [RR] = 1.60, 95% confidence interval [CI]: 1.27-2.01) and 1-year survival (combined RR = 1.26, 95% CI: 1.14-1.39). Patients with DTIC-based combination therapies had higher incidence of adverse events including nausea (combined RR = 1.23, 95% CI: 1.10-1.36), vomiting (combined RR = 1.73, 95% CI: 1.41-2.12) and neutropenia (combined RR = 1.75, 95% CI: 1.42-2.16) compared to the group for DTIC alone. These data suggested that DTIC-based combination therapies could moderately improve the overall response and the 1-year survival but increased the incidence of adverse events. Further large-scale, high-quality, placebo-controlled, double-blind trials are needed to confirm this conclusion.
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Payne, Roxanne; Glenn, Lyn; Hoen, Helena; Richards, Beverley; Smith, John W; Lufkin, Robert; Crocenzi, Todd S; Urba, Walter J; Curti, Brendan D
2014-01-01
High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected. A retrospective analysis of the outcomes of 500 patients with metastatic renal cell carcinoma (RCC) (n = 186) or melanoma (n = 314) treated with high-dose IL-2 between 1997 and 2012 at Providence Cancer Center was performed. IL-2 was administered at a dose of 600,000 international units per kg by IV bolus every 8 hours for up to 14 doses. A second cycle was administered 16 days after the first and patients with tumor regression could receive additional cycles. Survival and anti-tumor response were analyzed by diagnosis, severity of toxicity, number of IL-2 cycles and subsequent therapy. The objective response rate in melanoma was 28% (complete 12% and partial 16%), and in RCC was 24% (complete 7% and partial 17%). The 1-, 2- and 3-year survivals were 59%, 41% and 31%, for melanoma and 75%, 56% and 44%, for RCC, respectively. The proportion of patients with complete or partial response in both melanoma and RCC was higher in patients who a) required higher phenylephrine doses to treat hypotension (p < 0.003), b) developed acidosis (bicarbonate < 19 mmol (p < 0.01)), or c) thrombocytopenia (<50, 50-100, >100,000 platelets; p < 0.025). The proportion achieving a complete or partial response was greater in patients with melanoma who received 5 or more compared with 4 or fewer IL-2 cycles (p < 0.0001). The incidence of death from IL-2 was less than 1% and was not higher in patients who required phenylephrine. High-dose IL-2 can be administered safely; severe toxicity including hypotension is reversible and can be managed in a community hospital. The tumor response and survival reported here are superior to the published literature and support treating patients to their individualized maximum tolerated dose. IL-2 should remain part of the treatment paradigm in selected patients with melanoma and RCC.
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Estimating the cost of skin cancer detection by dermatology providers in a large health care system.
Matsumoto, Martha; Secrest, Aaron; Anderson, Alyce; Saul, Melissa I; Ho, Jonhan; Kirkwood, John M; Ferris, Laura K
2018-04-01
Data on the cost and efficiency of skin cancer detection through total body skin examination are scarce. To determine the number needed to screen (NNS) and biopsy (NNB) and cost per skin cancer diagnosed in a large dermatology practice in patients undergoing total body skin examination. This is a retrospective observational study. During 2011-2015, a total of 20,270 patients underwent 33,647 visits for total body skin examination; 9956 lesion biopsies were performed yielding 2763 skin cancers, including 155 melanomas. The NNS to detect 1 skin cancer was 12.2 (95% confidence interval [CI] 11.7-12.6) and 1 melanoma was 215 (95% CI 185-252). The NNB to detect 1 skin cancer was 3.0 (95% CI 2.9-3.1) and 1 melanoma was 27.8 (95% CI 23.3-33.3). In a multivariable model for NNS, age and personal history of melanoma were significant factors. Age switched from a protective factor to a risk factor at 51 years of age. The estimated cost per melanoma detected was $32,594 (95% CI $27,326-$37,475). Data are from a single health care system and based on physician coding. Melanoma detection through total body skin examination is most efficient in patients ≥50 years of age and those with a personal history of melanoma. Our findings will be helpful in modeling the cost effectiveness of melanoma screening by dermatologists. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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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.
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Treatment of uveal melanoma: where are we now?
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
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Rare nodular malignant melanoma of the heel in the Caribbean: A case report.
Warner, Wayne A; Sookdeo, Vandana Devika; Umakanthan, Srikanth; Sarran, Kevin; Pran, Lemuel; Fortuné, Maurice; Greaves, Wesley; Narinesingh, Sharda; Harnanan, Dave; Maharaj, Ravi
2017-01-01
Malignant melanoma of the heel is a rare melanoma subtype with incidence rates that reflect the complex relationship between sun exposure at certain geographic locations, individual melanin levels and overall melanoma risk. It is oftentimes characterized by poor prognosis because of delays in presentation resulting in longitudinal tumor invasion, lymph node involvement and metastasis. A 59-year-old woman was admitted to the Eric Williams Medical Sciences Complex, Trinidad and Tobago with a 5mm pruritic lesion on her left heel. At presentation, the lesion was asymmetric with border irregularities, color heterogeneity, with dynamics in elevation and overall size. She was subsequently diagnosed with malignant melanoma with left inguinal lymphadenopathy. A single stage wide local excision (WLE) of the left heel lesion with a split-thickness skin graft (STSG) and a left inguinal lymphadenectomy were performed. Dacarbazine (Bayer) was administered post operatively. Globally, the incidence of malignant melanoma is rapidly increasing, particularly, in countries like Trinidad and Tobago with a significant population of non-fair skinned individuals. There is need for strategic initiatives to increase patient adherence in these populations. The rarity of malignant heel melanomas heightens the need for increased patient awareness and greater clinical surveillance to ensure early diagnosis and treatment. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Conjunctival amelanotic malignant melanoma arising in primary acquired melanosis sine pigmento.
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.
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High-risk sun-tanning behaviour: a quantitative study in Denmark, 2008-2011.
Hansen, M R; Bentzen, J
2014-09-01
The incidences of melanoma and non-melanoma skin cancer have increased markedly over the past 30 years. The main risk factor is ultraviolet radiation from the sun and from sunbeds. The Danish Sun Safety campaign was launched in 2007 to curb this development by reducing the exposure of adolescents and young children. In this study, the characteristics of high-risk sun-tanning behaviour were assessed and the effect of the campaign was determined. Cross-sectional study. Data from annual Internet surveys were compiled in 2008-2011 of 18, 685 15-64-year-old Danes. A tanning index based on sunbed use and intentional tanning in and outside Denmark was the outcome measure in a linear regression model, which included age, gender, skin type, education, income and survey year as exposure variables. High-risk tanning behaviour was associated with female gender, younger age, shorter education, skin type 3 or 4, higher income, smaller household and living in larger cities. The tanning index, where 100 represent high-risk behaviour, increased by 13.45 points for women as compared with men, dropped by 1.35 points for each 5-year increase in age, rose by 20.72 points for skin type 4 as compared with type 1 and increased by 10.33 points with an income >€105, 409 as compared with <€26, 352. High-risk behaviour decreased during the study period, especially among women and younger people. High-risk sun-tanning behaviour is linked to certain personal and social characteristics. After initiation of the Danish Sun Safety Campaign in 2007, this high-risk behaviour decreased, especially in the groups initially targeted by the campaign. The campaign may thus reduce the future incidence of melanoma and non-melanoma skin cancer. Copyright © 2014 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
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Dudley, Mark E.; Wunderlich, John R.; Yang, James C.; Sherry, Richard M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Royal, Richard E.; Kammula, Udai; White, Don E.; Mavroukakis, Sharon A.; Rogers, Linda J.; Gracia, Gerald J.; Jones, Stephanie A.; Mangiameli, David P.; Pelletier, Michelle M.; Gea-Banacloche, Juan; Robinson, Michael R.; Berman, David M.; Filie, Armando C.; Abati, Andrea; Rosenberg, Steven A.
2006-01-01
Purpose We investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. Patients and Methods Thirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL)-2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m2). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. Results Eighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 ± 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. Conclusion Lymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma. PMID:15800326
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Delgado, S; Rodriguez Reyes, A; Mora Rios, L; Dueñas-González, A; Taja-Chayeb, L; Moragrega Adame, E
2018-01-01
To describe the ultrasound, histopathological and genetic characteristics of uveal melanoma in a Mexican-Mestizo population. A total of 39 enucleated eyes with a histopathological diagnosis of uveal melanoma were assessed by describing the clinical findings, and ultrasound, histopathological and genetic features. A high correlation was observed between tumour height measurement using ultrasound and histopathology. In our cases, tumour size and reflectivity were higher compared with those reported in the literature. The preliminary data on the molecular assessment of the tumours show the presence of an unreported polymorphism (T>C IVS5+34) and one sample with GNAQ mutation (A>C CAA>CCA Gln 209 Pro). Ultrasound is a reliable method to identify the size of the tumour. Furthermore, knowledge of the molecular mechanisms promises new perspectives for the development of new targeted therapeutics. Fortunately this leads to progress in the treatment of patients with metastatic disease or prevents it in those at high risk. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.
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Sun-protective behaviors in populations at high risk for skin cancer
Diao, Diana Y; Lee, Tim K
2014-01-01
Over 3 million new cases of skin cancer are diagnosed in the US annually. Melanoma, a subtype of skin cancer that can be fatal if the disease is not detected and treated at an early stage, is the most common cancer for those aged 25–29 years and the second most common cancer in adolescents and young adults aged 15–29 years. The primary carcinogen for the genesis of skin cancers is ultraviolet light from solar radiation and tanning beds. In spite of massive health campaigns to raise public awareness on ultraviolet radiation, sun-protective practices still fall behind. A plausible explanation is the lack of behavioral change in the populations at risk; in this review article, we examine sun-protective behavior in the four high-risk skin cancer groups: skin cancer survivors, individuals with a family history of melanoma, individuals with physical characteristics associated with skin cancer risk, and organ transplantation patients. Findings in the literature demonstrate that increased knowledge and awareness does not consequently translate into behavioral changes in practice. Behavior can differ as a result of different attitudes and beliefs, depending on the population at risk. Thus, intervention should be tailored to the population targeted. A multidisciplinary health team providing consultation and education is required to influence these much needed changes. PMID:24379732
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NASA Astrophysics Data System (ADS)
He, Yun; Wang, Lidai; Shi, Junhui; Yao, Junjie; Li, Lei; Zhang, Ruiying; Huang, Chih-Hsien; Zou, Jun; Wang, Lihong V.
2017-03-01
Metastasis is responsible for as many as 90% of cancer-related deaths, and the deadliest skin cancer, melanoma, has a high propensity for metastasis. Since hematogenous spread of circulating tumor cells (CTCs) is cancer's main route of metastasis, detecting and destroying CTCs can impede metastasis and improve patients' prognoses. Extensive studies employing exogenous agents to detect tumor-specific biomarkers and guide therapeutics to CTCs have achieved promising results, but biosafety remains a critical concern. Taking another approach, physical detection and destruction of CTCs is a safer way to evaluate and reduce metastasis risks. Melanoma cells strongly express melanosomes, providing a striking absorption contrast with the blood background in the red to near-infrared spectrum. Exploiting this intrinsic optical absorption contrast of circulating melanoma cells, we coupled dual-wavelength photoacoustic flow cytography with a nanosecond-pulsed laser killing mechanism that specifically targets melanoma CTCs. We have successfully achieved in vivo label-free imaging of rare single CTCs and CTC clusters in mice. Further, the photoacoustic signal from a CTC immediately hardware-triggers a lethal pinpoint laser irradiation that lyses it on the spot in a thermally confined manner. Our technology can facilitate early inhibition of metastasis by clearing circulating tumor cells from vasculature.
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Eriksson, Hanna; Lyth, Johan; Andersson, Therese M-L
2016-06-15
The survival in cutaneous malignant melanoma (CMM) is highly dependent on the stage of the disease. Stage III-IV CMM patients are at high risk of relapse with a heterogeneous outcome, but not all experience excess mortality due to their disease. This group is referred to as the cure proportion representing the proportion of patients who experience the same mortality rate as the general population. The aim of this study was to estimate the cure proportion of patients diagnosed with Stage III-IV CMM in Sweden. From the population-based Swedish Melanoma Register, we included 856 patients diagnosed with primary Stage III-IV CMM, 1990-2007, followed-up through 2013. We used flexible parametric cure models to estimate cure proportions and median survival times (MSTs) of uncured by sex, age, tumor site, ulceration status (in Stage III patients) and disease stage. The standardized (over sex, age and site) cure proportion was lower in Stage IV CMMs (0.15, 95% CI 0.09-0.22) than non-ulcerated Stage III CMMs (0.48, 95% CI 0.41-0.55) with a statistically significant difference of 0.33 (95% CI = 0.24-0.41). Ulcerated Stage III CMMs had a cure proportion of 0.27 (95% CI 0.21-0.32) with a statistically significant difference compared to non-ulcerated Stage III CMMs (difference 0.21; 95% CI = 0.13-0.30). The standardized MST of uncured was approximately 9-10 months longer for non-ulcerated versus ulcerated Stage III CMMs. We could demonstrate a significantly better outcome in patients diagnosed with non-ulcerated Stage III CMMs compared to ulcerated Stage III CMMs and Stage IV disease after adjusting for age, sex and tumor site. © 2016 UICC.
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The "SWOT" of BRAF inhibition in melanoma: RAF inhibitors, MEK inhibitors or both?
Nissan, Moriah H; Solit, David B
2011-12-01
Activating mutations in the BRAF gene are among the most prevalent kinase mutations in human cancer. BRAF mutations are most frequent in patients with melanoma where they occur in approximately 50% of patients with advanced disease. Remarkable clinical activity has recently been reported with highly selective RAF inhibitors in melanoma patients whose tumors harbor V600E BRAF mutations. The response rates of RAF inhibitors in patients with BRAF-mutant melanomas far exceed the activity level of any prior therapy studied in this disease. The results suggest that we have entered an era of personalized therapy for patients with metastatic melanoma in which treatment selection will be guided by BRAF mutational status. This review will discuss the strengths, weaknesses, opportunities and threats ("SWOT") of developing RAF and MEK selective inhibitors as anti-cancer therapies, recent insights into the mechanisms of intrinsic and acquired resistance to these agents, and current efforts to develop mechanism-based combination therapies.
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Hayes, Andrew J; Maynard, Lauren; Coombes, Gillian; Newton-Bishop, Julia; Timmons, Michael; Cook, Martin; Theaker, Jeffrey; Bliss, Judith M; Thomas, J Meirion
2016-02-01
The necessary margin of excision for cutaneous melanomas greater than 2 mm in thickness is controversial. At a median follow-up of 5 years, findings from our previously published randomised trial of narrow (1 cm) versus wide (3 cm) excision margins in patients with thick cutaneous melanomas showed that narrow margins were associated with an increased frequency of locoregional relapse, but no significant difference in overall survival was apparent. We now report a long-term survival analysis of that trial. We did a randomised, open-label multicentre trial in 59 hospitals--57 in the UK, one in Poland, and one in South Africa. Patients with one primary localised cutaneous melanoma greater than 2 mm in Breslow thickness on the trunk or limbs (excluding palms or soles) were randomly assigned (1:1) centrally to receive surgery with either a 1 cm or 3 cm excision margin following an initial surgery. The randomisation lists were generated with random permuted blocks and stratified by centre and extent of initial surgery. The endpoints of this analysis were overall survival and melanoma-specific survival. Analyses were done in the intention-to-treat population. This trial was not registered because it predated mandatory trial registration. Between Dec 16, 1992, and May 22, 2001, we randomly assigned 900 patients to surgery with either a 1 cm excision margin (n=453) or a 3 cm excision margin (n=447). At a median follow-up of 8·8 years (106 months [IQR 76-135], 494 patients had died, with 359 of these deaths attributed to melanoma. 194 deaths were attributed to melanoma in the 1 cm group compared with 165 in the 3 cm group (unadjusted hazard ratio [HR] 1·24 [95% CI 1·01-1·53]; p=0·041). Although a higher number of deaths overall occurred in the 1 cm group compared with the 3 cm group (253 vs 241), the difference was not significant (unadjusted HR 1·14 [95% CI 0·96-1·36]; p=0·14). Surgical complications were reported in 35 (8%) patients in the 1 cm excision margin group and 65 (15%) patients in the 3 cm group. Our findings suggest that a 1 cm excision margin is inadequate for cutaneous melanoma with Breslow thickness greater than 2 mm on the trunk and limbs. Current guidelines advise a 2 cm margin for melanomas greater than 2 mm in thickness but only a 1 cm margin for thinner melanomas. The adequacy of a 1 cm margin for thinner melanomas with poor prognostic features should be addressed in future randomised studies. Cancer Research UK, North Thames National Health Service Executive, Northern and Yorkshire National Health Service Executive, British United Provident Association Foundation, British Association of Plastic Surgeons, the Meirion Thomas Cancer Research Fund, and the National Institute for Health and Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust. Copyright © 2016 Hayes et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
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Recurrence and Survival Outcomes After Percutaneous Thermal Ablation of Oligometastatic Melanoma.
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.
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Harries, Mark; Mohr, Peter; Grange, Florent; Ehness, Rainer; Benjamin, Laure; Siakpere, Obukohwo; Barth, Janina; Stapelkamp, Ceilidh; Pfersch, Sylvie; McLeod, Lori; Wolowacz, Sorrel; Kaye, James A; Kontoudis, Ilias
2017-05-01
Real-world data on treatment patterns/outcomes in patients with advanced melanoma, while scarce, are useful for health technology assessments that govern patient access in many countries. We collected retrospective data on treatment patterns among patients in France, Germany and the UK with Stage IIIB/IIIC melanoma with macroscopic lymph node involvement, whose primary melanoma and regional lymph node metastases had been completely resected. Patients ≥18 years were diagnosed between 1 January 2009 and 31 December 2011. Data were obtained from patients' medical records and a patient survey. Forty-nine centres provided data on 558 patients: 53.6% had Stage IIIB disease; 58.2% were of working age (<65 years), 22.5% reported a change in employment status due to melanoma, 8% were on long-term sick leave; and 35.1% were deceased over the study period. Overall median distant metastases-free survival was 23.4 months and median disease-free survival was 13.3 months. Hospitalisation frequency increased during distant metastatic/terminal disease phases. Adjuvant therapy was received by 7.0% (14/199) of patients in France, 2.6% (5/195) in the UK, and 33.5% (55/164) in Germany. Low-dose interferon was used more frequently than other regimens. High-dose interferon was associated with discontinuation in 28.6% and dose delay/reduction in 33.3% of patients. Rapid disease progression combined with increased use of healthcare resources in later phases of disease result in a high burden-of-illness for patients and healthcare providers. The use of adjuvant interferon therapy varies considerably in this population in the countries studied, highlighting the need for improved treatments for melanoma. © 2017 John Wiley & Sons Ltd.
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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.
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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
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Identification, genetic testing, and management of hereditary melanoma.
Leachman, Sancy A; Lucero, Olivia M; Sampson, Jone E; Cassidy, Pamela; Bruno, William; Queirolo, Paola; Ghiorzo, Paola
2017-03-01
Several distinct melanoma syndromes have been defined, and genetic tests are available for the associated causative genes. Guidelines for melanoma genetic testing have been published as an informal "rule of twos and threes," but these guidelines apply to CDKN2A testing and are not intended for the more recently described non-CDKN2A melanoma syndromes. In order to develop an approach for the full spectrum of hereditary melanoma patients, we have separated melanoma syndromes into two types: "melanoma dominant" and "melanoma subordinate." Syndromes in which melanoma is a predominant cancer type are considered melanoma dominant, although other cancers, such as mesothelioma or pancreatic cancers, may also be observed. These syndromes are associated with defects in CDKN2A, CDK4, BAP1, MITF, and POT1. Melanoma-subordinate syndromes have an increased but lower risk of melanoma than that of other cancer(s) seen in the syndrome, such as breast and ovarian cancer or Cowden syndrome. Many of these melanoma-subordinate syndromes are associated with well-established predisposition genes (e.g., BRCA1/2, PTEN). It is likely that these predisposition genes are responsible for the increased susceptibility to melanoma as well but with lower penetrance than that observed for the dominant cancer(s) in those syndromes. In this review, we describe our extension of the "rule of twos and threes" for melanoma genetic testing. This algorithm incorporates an understanding of the spectrum of cancers and genes seen in association with melanoma to create a more comprehensive and tailored approach to genetic testing.
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GPNMB expression in uveal melanoma: a potential for targeted therapy.
Williams, Michelle D; Esmaeli, Bita; Soheili, Aydin; Simantov, Ronit; Gombos, Dan S; Bedikian, Agop Y; Hwu, Patrick
2010-06-01
Uveal melanoma is an aggressive disease without effective adjuvant therapy for metastases. Despite genomic differences between cutaneous and uveal melanomas, therapies based on shared biological factors could be effective against both tumor types. High expression of glycoprotein-NMB (GPNMB) in cutaneous melanomas led to the development of CDX-011 (glembatumumab vedotin), a fully human monoclonal antibody against the extracellular domain of GPNMB conjugated to the cytotoxic microtubule toxin monomethylauristatin E. Ongoing phase II trials suggest that CDX-011 has activity against advanced cutaneous melanomas. To determine the potential role of CDX-011 in uveal melanomas, we studied their GPNMB expression. Paraffin-embedded tissues from 22 uveal melanomas treated by enucleation from 2004-2007 at one institution were evaluated immunohistochemically for expression of GPNMB using biotinylated CDX-011 (unconjugated) antibody. Melanoma cells were evaluated for percentage and intensity of expression. Spectral imaging was used in one case with high melanin content. Clinical data were reviewed. Twelve women and 10 men with a median age of 58.7 years (range: 28-83 years) were included. Eighteen of 21 tumors evaluated immunohistochemically (85.7%) expressed GPNMB in 10-90% of tumor cells with variable intensity (5 tumors, 1+; 11, 2+; and 2, 3+). Eleven of 18 tumors (61.1%) expressed GPNMB in >or=50% of cells. Spectral imaging showed diffuse CDX-011 (unconjugated) reactivity in the remaining case. Uveal melanoma, like cutaneous melanoma, commonly expresses GPNMB. Ongoing clinical trials of CDX-011 should be extended to patients with metastatic uveal melanoma to determine potential efficacy in this subset of patients with melanoma.
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[The related factors of head and neck mocosal melanoma with lymph node metastasis].
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.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Hirasawa, Naoki; Tsuji, Hiroshi; Ishikawa, Hitoshi
2007-02-01
Purpose: To determine the risk factors for neovascular glaucoma (NVG) after carbon ion radiotherapy (C-ion RT) of choroidal melanoma. Methods and Materials: A total of 55 patients with choroidal melanoma were treated between 2001 and 2005 with C-ion RT based on computed tomography treatment planning. All patients had a tumor of large size or one located close to the optic disk. Univariate and multivariate analyses were performed to identify the risk factors of NVG for the following parameters; gender, age, dose-volumes of the iris-ciliary body and the wall of eyeball, and irradiation of the optic disk (ODI). Results: Neovascular glaucomamore » occurred in 23 patients and the 3-year cumulative NVG rate was 42.6 {+-} 6.8% (standard error), but enucleation from NVG was performed in only three eyes. Multivariate analysis revealed that the significant risk factors for NVG were V50{sub IC} (volume irradiated {>=}50 GyE to iris-ciliary body) (p = 0.002) and ODI (p = 0.036). The 3-year NVG rate for patients with V50{sub IC} {>=}0.127 mL and those with V50{sub IC} <0.127 mL were 71.4 {+-} 8.5% and 11.5 {+-} 6.3%, respectively. The corresponding rate for the patients with and without ODI were 62.9 {+-} 10.4% and 28.4 {+-} 8.0%, respectively. Conclusion: Dose-volume histogram analysis with computed tomography indicated that V50{sub IC} and ODI were independent risk factors for NVG. An irradiation system that can reduce the dose to both the anterior segment and the optic disk might be worth adopting to investigate whether or not incidence of NVG can be decreased with it.« less
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Management of Skin Cancer in the High-Risk Patient.
Behan, James W; Sutton, Adam; Wysong, Ashley
2016-12-01
Skin cancer is the most common of human cancers and outnumbers all other types of cancer combined in the USA by over threefold. The majority of non-melanoma skin cancers are easily treated with surgery or locally destructive techniques performed under local anesthesia in the cost-effective outpatient setting. However, there is a subset of "high-risk" cases that prove challenging in terms of morbidity, mortality, adjuvant treatment required, as well as overall cost to the health care system. In our opinion, the term "high risk" when applied to skin cancer can mean one of three things: a high-risk tumor with aggressive histologic and/or clinical features with an elevated risk for local recurrence or regional/distant metastasis, a high-risk patient with the ongoing development of multiple skin cancers, and a high-risk patient based on immunosuppression. We have recently proposed classifying NMSC as a chronic disease in a certain subset of patients. Although no consensus definition exists for a chronic disease in medicine, there are three components that are present in most definitions: duration of at least 1 year, need for ongoing medical care, and functional impairment and/or alteration of activities of daily living (ADLs) and quality of life (QOL). Immunosuppression can refer to exogenous (organ or stem cell transplant patients,) or endogenous (HIV, leukemia, lymphoma, genodermatoses with DNA mismatch repair problems or other immunosuppression) causes. These patients are at risk for high-risk tumors and/or the development of multiple tumors.
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Thomas, Nancy E; Busam, Klaus J; From, Lynn; Kricker, Anne; Armstrong, Bruce K; Anton-Culver, Hoda; Gruber, Stephen B; Gallagher, Richard P; Zanetti, Roberto; Rosso, Stefano; Dwyer, Terence; Venn, Alison; Kanetsky, Peter A; Groben, Pamela A; Hao, Honglin; Orlow, Irene; Reiner, Anne S; Luo, Li; Paine, Susan; Ollila, David W; Wilcox, Homer; Begg, Colin B; Berwick, Marianne
2013-11-20
Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.
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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.
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Barriers and Facilitators to Melanoma Prevention and Control Behaviors Among At-Risk Children.
Wu, Yelena P; Parsons, Bridget G; Mooney, Ryan; Aspinwall, Lisa G; Cloyes, Kristin; Hay, Jennifer L; Kohlmann, Wendy; Grossman, Douglas; Leachman, Sancy A
2018-04-06
Melanoma prevention is essential for children who are at elevated risk for the disease due to family history. However, children who carry a familial risk for the disease do not optimally adhere to recommended melanoma preventive behaviors. The current study sought to identify perceived barriers to and facilitators of children's engagement in melanoma preventive behaviors among children at elevated risk for melanoma due to family history of the disease (i.e., having a parent with a history of melanoma) from both parents' and childrens' perspectives. Qualitative methods were employed and consisted of separate focus group discussions with children (ages 8-17 years, n = 37) and their parents (n = 39). Focus group transcripts were coded using content analysis. Parents and children reported a number of barriers and facilitators, including on the individual (e.g., knowledge and awareness, preferences), social (e.g., peer influences, family modeling and communication), and contextual (e.g., healthcare provider communication) levels. The identified categories of barriers and facilitators both confirm and extend the literature documenting the reasons children who are at elevated risk for melanoma do not engage in melanoma prevention and control behaviors. Programs aiming to decrease melanoma risk among children of melanoma survivors could help families address their barriers to preventive behavior implementation and build on facilitators. Melanoma survivors and their children could benefit from support on their interactions with healthcare providers, schools, peers, and other caregivers about melanoma prevention.
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Robinson, June K; Gaber, Rikki; Hultgren, Brittney; Eilers, Steven; Blatt, Hanz; Stapleton, Jerod; Mallett, Kimberly; Turrisi, Rob; Duffecy, Jenna; Begale, Mark; Martini, Mary; Bilimoria, Karl; Wayne, Jeffrey
2014-01-13
Early detection of melanoma improves survival. Since many melanoma patients and their spouses seek the care of a physician after discovering their melanoma, an ongoing study will determine the efficacy of teaching at-risk melanoma patients and their skin check partner how to conduct skin self-examinations (SSEs). Internet-based health behavior interventions have proven efficacious in creating behavior change in patients to better prevent, detect, or cope with their health issues. The efficacy of electronic interactive SSE educational intervention provided on a tablet device has not previously been determined. The electronic interactive educational intervention was created to develop a scalable, effective intervention to enhance performance and accuracy of SSE among those at-risk to develop melanoma. The intervention in the office was conducted using one of the following three methods: (1) in-person through a facilitator, (2) with a paper workbook, or (3) with a tablet device used in the clinical office. Differences related to method of delivery were elucidated by having the melanoma patient and their skin check partner provide a self-report of their confidence in performing SSE and take a knowledge-based test immediately after receiving the intervention. The three interventions used 9 of the 26 behavioral change techniques defined by Abraham and Michie to promote planning of monthly SSE, encourage performing SSE, and reinforce self-efficacy by praising correct responses to knowledge-based decision making and offering helpful suggestions to improve performance. In creating the electronic interactive SSE educational intervention, the educational content was taken directly from both the scripted in-person presentation delivered with Microsoft PowerPoint by a trained facilitator and the paper workbook training arms of the study. Enrollment totaled 500 pairs (melanoma patient and their SSE partner) with randomization of 165 pairs to the in-person, 165 pairs to the workbook, and 70 pairs to electronic interactive SSE educational intervention. The demographic survey data showed no significant mean differences between groups in age, education, or income. The tablet usability survey given to the first 30 tablet pairs found that, overall, participants found the electronic interactive intervention easy to use and that the video of the doctor-patient-partner dialogue accompanying the dermatologist's examination was particularly helpful in understanding what they were asked to do for the study. The interactive group proved to be just as good as the workbook group in self-confidence of scoring moles, and just as good as both the workbook and the in-person intervention groups in self-confidence of monitoring their moles. While the in-person intervention performed significantly better on a skill-based quiz, the electronic interactive group performed significantly better than the workbook group. The electronic interactive and in-person interventions were more efficient (30 minutes), while the workbook took longer (45 minutes). This study suggests that an electronic interactive intervention can deliver skills training comparable to other training methods, and the experience can be accommodated during the customary outpatient office visit with the physician. Further testing of the electronic interactive intervention's role in the anxiety of the pair and pair-discovered melanomas upon self-screening will elucidate the impact of these tools on outcomes in at-risk patient populations. ClinicalTrials.gov NCT01013844; http://clinicaltrials.gov/show/NCT01013844 (Archived by WebCite at http://www.webcitation.org/6LvGGSTKK).
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Humanistic burden of disease for patients with advanced melanoma in Canada.
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.
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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
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Barak, Vivian; Frenkel, Shahar; Valyi-Nagy, Klara; Leach, Lu; Apushkin, Marsha A; Lin, Amy Y; Kalickman, Inna; Baumann, Nikola A; Pe'er, Jacob; Maniotis, Andrew J; Folberg, Robert
2007-10-01
To develop a method to screen for serum biomarkers of early hepatic metastasis from uveal melanoma. Cytokeratin 18 (TPS) was identified from gene expression profiles as protein generated by highly invasive uveal melanoma cells. Sera were collected from two groups of 15 SCID mice 2 weeks after injection of either tissue culture medium or MUM2B human metastatic uveal melanoma cells into the mouse liver. Serum TPS levels were assayed in 53 healthy human controls, 64 uveal melanoma patients who were disease free for at least 10 years, and 37 patients with metastatic uveal melanoma. After 2 weeks, small hepatic nodules (0.1-2.8 mm; mean, 0.80 mm) developed in 11 of 15 mice injected with MUM2B cells. Serum TPS levels in media-injected mice (84.7 U/L) were substantially lower than levels in MUM2B-injected mice (601 mug/L). TPS levels were significantly higher (P < 0.0001) in patients with metastatic uveal melanoma (139.63 +/- 22.20) than in healthy controls (54.23 +/- 0.01) or in patients free of disease (69.29 +/- 9.76). Significant differences were found between TPS levels before and after the development of hepatic metastases (P < 0.01), and serum TPS levels became elevated in four patients at least 6 months before the detection of hepatic metastases by abdominal ultrasonography. The direct-injection model of uveal melanoma in the mouse liver may be used to screen for potential serum biomarkers of metastatic uveal melanoma.
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Eriksson, H; Lyth, J; Månsson-Brahme, E; Frohm-Nilsson, M; Ingvar, C; Lindholm, C; Naredi, P; Stierner, U; Wagenius, G; Carstensen, J; Hansson, J
2013-08-01
A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden. We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010. The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55 years, patients with truncal tumours and during the first 5 years after diagnosis. Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Diagnosing malignant melanoma in ambulatory care: a systematic review of clinical prediction rules
Harrington, Emma; Clyne, Barbara; Wesseling, Nieneke; Sandhu, Harkiran; Armstrong, Laura; Bennett, Holly; Fahey, Tom
2017-01-01
Objectives Malignant melanoma has high morbidity and mortality rates. Early diagnosis improves prognosis. Clinical prediction rules (CPRs) can be used to stratify patients with symptoms of suspected malignant melanoma to improve early diagnosis. We conducted a systematic review of CPRs for melanoma diagnosis in ambulatory care. Design Systematic review. Data sources A comprehensive search of PubMed, EMBASE, PROSPERO, CINAHL, the Cochrane Library and SCOPUS was conducted in May 2015, using combinations of keywords and medical subject headings (MeSH) terms. Study selection and data extraction Studies deriving and validating, validating or assessing the impact of a CPR for predicting melanoma diagnosis in ambulatory care were included. Data extraction and methodological quality assessment were guided by the CHARMS checklist. Results From 16 334 studies reviewed, 51 were included, validating the performance of 24 unique CPRs. Three impact analysis studies were identified. Five studies were set in primary care. The most commonly evaluated CPRs were the ABCD, more than one or uneven distribution of Colour, or a large (greater than 6 mm) Diameter (ABCD) dermoscopy rule (at a cut-point of >4.75; 8 studies; pooled sensitivity 0.85, 95% CI 0.73 to 0.93, specificity 0.72, 95% CI 0.65 to 0.78) and the 7-point dermoscopy checklist (at a cut-point of ≥1 recommending ruling in melanoma; 11 studies; pooled sensitivity 0.77, 95% CI 0.61 to 0.88, specificity 0.80, 95% CI 0.59 to 0.92). The methodological quality of studies varied. Conclusions At their recommended cut-points, the ABCD dermoscopy rule is more useful for ruling out melanoma than the 7-point dermoscopy checklist. A focus on impact analysis will help translate melanoma risk prediction rules into useful tools for clinical practice. PMID:28264830
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Stark, Mitchell S.; Klein, Kerenaftali; Weide, Benjamin; Haydu, Lauren E.; Pflugfelder, Annette; Tang, Yue Hang; Palmer, Jane M.; Whiteman, David C.; Scolyer, Richard A.; Mann, Graham J.; Thompson, John F.; Long, Georgina V.; Barbour, Andrew P.; Soyer, H. Peter; Garbe, Claus; Herington, Adrian; Pollock, Pamela M.; Hayward, Nicholas K.
2015-01-01
The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are < 15%. Hence, melanoma detection in earlier stages (stages I–III) maximises the chances of patient survival. We measured the expression of a panel of 17 microRNAs (miRNAs) (MELmiR-17) in melanoma tissues (stage III; n = 76 and IV; n = 10) and serum samples (collected from controls with no melanoma, n = 130; and patients with melanoma (stages I/II, n = 86; III, n = 50; and IV, n = 119)) obtained from biobanks in Australia and Germany. In melanoma tissues, members of the ‘MELmiR-17’ panel were found to be predictors of stage, recurrence, and survival. Additionally, in a minimally-invasive blood test, a seven-miRNA panel (MELmiR-7) detected the presence of melanoma (relative to controls) with high sensitivity (93%) and specificity (≥ 82%) when ≥ 4 miRNAs were expressed. Moreover, the ‘MELmiR-7’ panel characterised overall survival of melanoma patients better than both serum LDH and S100B (delta log likelihood = 11, p < 0.001). This panel was found to be superior to currently used serological markers for melanoma progression, recurrence, and survival; and would be ideally suited to monitor tumour progression in patients diagnosed with early metastatic disease (stages IIIa–c/IV M1a–b) to detect relapse following surgical or adjuvant treatment. PMID:26288839
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Sentinel lymph node mapping in melanoma with technetium-99m dextran.
Neubauer, S; Mena, I; Iglesis, R; Schwartz, R; Acevedo, J C; Leon, A; Gomez, L
2001-06-01
The aim of this work is to evaluate the capability of Tc99m B Dextran as a lymphoscintigraphic agent in the detection of the sentinel node in skin lesions. Forty-one patients with melanomas (39) and Merkel cell tumors (2) had perilesional intradermal injection of Tc99m-Dextran 2 hours before surgery. Serial gamma camera images and a handheld gamma probe were used to direct sentinel node biopsy. In 39/41 patients, lymph channels and 52 sentinel nodes (one to three sentinel nodes/patient) could be visualized. In one patient, with a dorsal melanoma, no lymph channels or lymph nodes could be demonstrated on the images and only minimal radioactivity was found in the regional nodes with the probe. Another patient with a facial lesion failed to demonstrate lymph channels or nodes. No adverse reactions were observed. Tc99m-Dextran provided good definition of lymph channels and sentinel node localization, without the risks related to the use of potentially hazardous labeled materials of biological origin.
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Malignant melanoma misdiagnosed as diabetic foot ulcer: A case report.
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.
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Use of Oncept melanoma vaccine in 69 canine oral malignant melanomas in the UK.
Verganti, S; Berlato, D; Blackwood, L; Amores-Fuster, I; Polton, G A; Elders, R; Doyle, R; Taylor, A; Murphy, S
2017-01-01
Oral malignant melanomas carry a poor-to-guarded prognosis because of their local invasiveness and high metastatic propensity. The Oncept melanoma vaccine is licensed to treat dogs with stage II or III locally-controlled oral malignant melanoma and this retrospective study aimed to assess survival of affected dogs treated with the vaccine in the UK. Medical records of dogs with histopathologically-confirmed oral malignant melanoma that received the vaccine as part of their treatment were evaluated. Survival analyses for potential prognostic factors were performed. Sixty-nine dogs were included; 56 dogs, staged I to III, and with previous locoregional therapy, had a median survival time of 455 days (95% CI: 324 to 586 days). Based on Kaplan-Meier survival analysis with associated log-rank testing, no significant prognostic factors were identified for this population. Of the 13 patients with macroscopic disease treated with vaccine alone or in combination therapy, eight showed clinical response. Three patients with stage IV oral malignant melanoma survived 171, 178 and 288 days from diagnosis. Patients treated with the melanoma vaccine in our study had survival times similar to their counterparts receiving the vaccine in the USA. There were observed responses in patients with macroscopic disease and so the vaccine could be considered as palliative treatment in dogs with stage IV disease. © 2017 British Small Animal Veterinary Association.
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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.
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Malignant melanoma in World War II veterans.
Brown, J; Kopf, A W; Rigel, D S; Friedman, R J
1984-12-01
In a consecutive series of 1,067 patients entered into the data base of the Melanoma Cooperative Group at New York University School of Medicine between 1972 and 1980, 120 men were of draft age (18-31 years) during World War II (1941-1945). Questionnaires were sent to these 120 individuals; 89 responded. Simultaneously, a control (nonmelanoma) population of 65 men of similar age was queried. Each subject in both groups was asked whether he had served in the armed forces during World War II and, if so, what were his theaters of operation. Based on the response, 83% (74 of 89) of the melanoma group compared with 76% (49 of 65) of the control group had served in the armed forces during World War II; however, a significantly (p = 0.0002) greater percent of the melanoma patients (34%) served in the tropics than did the control subjects (6%). Further, overrepresented in the melanoma group that served in the tropics (compared with the melanoma group who served in the armed forces in nontropical theaters) were malignant melanomas that had their origin in nevocytic nevi. The findings suggest that Caucasian individuals heavily exposed to sunlight in the tropics for several years during early life may be at higher risk to the subsequent development of cutaneous malignant melanoma. In some individuals this may be a two-step phenomenon, in which the first step is the solar induction of nevocytic nevi and the second is malignant transformation within them.
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[Size-based classification of choroidal melanoma and its role in treatment decision-making].
Brovkina, A F; Stoyukhina, A S; Chesalin, I P
2016-01-01
To specify indications for brachytherapy (BT) in large choroidal melanoma (CM) so that tumor size and vital prognosis were considered. We retrospectively analyzed data from 161 CM patients who were treated with BT and followed-up at either the Ophthalmological Clinical Hospital or some other Moscow medical facility and also registered by the City Cancer Registry. Patient age at the time of starting the treatment lied within the range of 17 to 84 years and averaged 56.89±1.93 years. During the follow-up period (12-275 months, 95.65±8.4 months on average) hematogenous metastases were found in 23 (14.29%) patients. Liver involvement was diagnosed in 8 patients within the average of 23.13 months after treatment. Their average survival time was 11 months. A total of 142 patients were followed up for more than 36 months (104.87 months on average). Of them, 15 patients were diagnosed with metastatic CM within 37-167 months after BT (80.27 months on average). Despite metastatic disease they generally survived 2.8 time longer than the aforementioned patients (30.8 months). The cases were then divided into 3 groups according to J. Shields classification of CM. Small melanoma patients did not develop metastases within 99.96±12.47 months of follow-up. In medium melanomas, as many as 13.35% of cases were metastatic (with the average survival time of 20.66 months); in large melanomas - 19.51% (with the average survival time of 13.5 months). Treatment modality and follow-up periods being the same (7-8 years after BT), larger choroidal melanomas has been shown to be associated with higher risk of hematogenous metastases. For local treatment to be successive, the maximal diameter of the tumor should not exceed 10 mm. Every fifth patient of those with CM larger than 15 mm is likely to develop hematogenous metastases. The results obtained indicate the necessity of decreasing the size thresholds for choroidal melanomas, small and medium in the first place.
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Dermoscopy for melanoma detection in family practice
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
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Diagnostic Inaccuracy of Smart Phone Applications for Melanoma Detection
Wolf, Joel; Moreau, Jacqui; Akilov, Oleg; Patton, Timothy; English, Joseph C; Ho, Jon; Ferris, Laura Korb
2013-01-01
Objective To measure the performance of smart phone applications which evaluate photographs of skin lesions and provide the user feedback as to their likelihood of malignancy. Design Case-control diagnostic accuracy study Setting Academic dermatology department Participants Digital clinical images of pigmented cutaneous lesions (60 melanoma cases and 128 benign lesion controls), all with histologic diagnosis rendered by a board-certified dermatopathologist, obtained prior to biopsy in patients undergoing lesion removal as part of routine care. Main Outcome Measures Sensitivity, specificity, and positive and negative predictive values of four smart phone applications designed to aid non-clinician users in determining if their skin lesion is benign or malignant. Results Sensitivity of the four tested applications ranged from 6.8% to 98.1%. Specificity ranged from 30.4% to 93.7%. Positive predictive value ranged from 33.3% to 42.1%, and negative predictive value ranged from 65.4% to 97.0%. The highest sensitivity for melanoma diagnosis was observed for an application that sends the image directly to a board-certified dermatologist for analysis and the lowest sensitivity was observed for applications that use automated algorithms to analyze images. Conclusions The performance of smart phone applications in assessing melanoma risk is highly variable, and 3 out of 4 smart phone applications incorrectly classified 30% or more of melanomas as unconcerning. Reliance on these applications, which are not subject to regulatory oversight, in lieu of medical consultation, has the potential to delay the diagnosis of melanoma and to harm users. PMID:23325302
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Sentinel lymph node mapping in melanoma: the issue of false-negative findings.
Manca, Gianpiero; Rubello, Domenico; Romanini, Antonella; Boni, Giuseppe; Chiacchio, Serena; Tredici, Manuel; Mazzarri, Sara; Duce, Valerio; Colletti, Patrick M; Volterrani, Duccio; Mariani, Giuliano
2014-07-01
Management of cutaneous melanoma has changed after introduction in the clinical routine of sentinel lymph node biopsy (SLNB) for nodal staging. By defining the nodal basin status, SLNB provides a powerful prognostic information. Nevertheless, some debate still surrounds the accuracy of this procedure in terms of false-negative rate. Several large-scale studies have reported a relatively high false-negative rate (5.6%-21%), correctly defined as the proportion of false-negative results with respect to the total number of "actual" positive lymph nodes. In this review, we identified all the technical aspects that the nuclear medicine physician, the surgeon, and the pathologist should take into account to improve accuracy of the procedure and minimize the false-negative rate. In particular, SPECT/CT imaging detects more SLNs than those found by planar lymphoscintigraphy. Furthermore, the nuclear medicine community should reach a consensus on the radioactive counting rate threshold to better guide the surgeon in identifying the lymph nodes with the highest likelihood of housing metastases ("true biologic SLNs"). Analysis of the harvested SLNs by conventional techniques is also a further potential source for error. More accurate SLN analysis (eg, molecular analysis by reverse transcriptase-polymerase chain reaction) and more extensive SLN sampling identify more positive nodes, thus reducing the false-negative rate.The clinical factors identifying patients at higher-risk local recurrence after a negative SLNB include older age at diagnosis, deeper lesions, histological ulceration, and head-neck anatomic location of the primary lesion.The clinical impact of a false-negative SLNB on the prognosis of melanoma patients remains controversial, because the majority of studies have failed to demonstrate overall statistically significant disadvantage in melanoma-specific survival for false-negative SLNB patients compared with true-positive SLNB patients.When new more effective drugs will be available in the adjuvant setting for stage III melanoma patients, the implication of an accurate staging procedure for the sentinel lymph nodes will be crucial for both patients and clinicians. Standardization and accuracy of SLN identification, removal, and analysis are required.
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Jiang, Guan; Li, Rong-Hua; Sun, Chao; Liu, Yan-Qun; Zheng, Jun-Nian
2014-01-01
Background Malignant melanoma is the most aggressive and deadly form of skin cancer. Dacarbazine (DTIC) has been the approved first-line treatment for metastatic melanoma in routine clinical practice. However, response rates with single-agent DTIC are low. The objective of this study was to compare the efficacy and safety of DTIC with or without placebo and DTIC-based combination therapies in patients with advanced metastatic melanoma. Methods We searched from electronic databases such as The Cochrane Library, MEDLINE, EBSCO, EMBASE, Ovid, CNKI, and CBMDisc from 2003 to 2013. The primary outcome measures were overall response and 1-year survival, and the secondary outcome measurements were adverse events. Results Nine randomized controlled trials (RCTs) involving 2,481 patients were included in the meta-analysis. DTIC-based combination therapies was superior to DTIC alone in overall response (combined risk ratio [RR] = 1.60, 95% confidence interval [CI]: 1.27–2.01) and 1-year survival (combined RR = 1.26, 95% CI: 1.14–1.39). Patients with DTIC-based combination therapies had higher incidence of adverse events including nausea (combined RR = 1.23, 95% CI: 1.10–1.36), vomiting (combined RR = 1.73, 95% CI: 1.41–2.12) and neutropenia (combined RR = 1.75, 95% CI: 1.42–2.16) compared to the group for DTIC alone. Conclusion These data suggested that DTIC-based combination therapies could moderately improve the overall response and the 1-year survival but increased the incidence of adverse events. Further large-scale, high-quality, placebo-controlled, double-blind trials are needed to confirm this conclusion. PMID:25502446
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Unexpected pulmonary hypertensive crisis after surgery for ocular malignant melanoma.
Sato, Kaori; Saji, Tsutomu; Kaneko, Taku; Takahashi, Kei; Sugi, Kaoru
2014-11-24
To report a case of unexpected pulmonary hypertensive crisis caused by endothelin release from melanoma cells after surgery for choroidal melanoma. A 56-year-old man suddenly developed dyspnea after resection of choroidal melanoma. Worsening hypoxia required intensive treatment, including percutaneous cardiopulmonary support, after which a series of tests were immediately performed. The tentative diagnosis was idiopathic pulmonary arterial hypertension. Previous studies noted a significant association between melanoma and endothelin (ET)-1. We hypothesized that a substantial amount of ET-1 had been released from malignant melanoma cells during resection, thus triggering the pulmonary hypertensive crisis in our patient. The patient fully recovered after intensive treatment and administration of the endothelin receptor antagonist bosentan. The success of bosentan treatment, along with the extremely high level of ET-1 on pathologic analysis, confirmed our hypothesis regarding the increase in plasma ET-1 level. Copyright © 2014 Elsevier Inc. All rights reserved.
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High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients.
Logozzi, Mariantonia; De Milito, Angelo; Lugini, Luana; Borghi, Martina; Calabrò, Luana; Spada, Massimo; Perdicchio, Maurizio; Marino, Maria Lucia; Federici, Cristina; Iessi, Elisabetta; Brambilla, Daria; Venturi, Giulietta; Lozupone, Francesco; Santinami, Mario; Huber, Veronica; Maio, Michele; Rivoltini, Licia; Fais, Stefano
2009-01-01
Metastatic melanoma is an untreatable cancer lacking reliable and non-invasive markers of disease progression. Exosomes are small vesicles secreted by normal as well as tumor cells. Human tumor-derived exosomes are involved in malignant progression and we evaluated the presence of exosomes in plasma of melanoma patients as a potential tool for cancer screening and follow-up. We designed an in-house sandwich ELISA (Exotest) to capture and quantify exosomes in plasma based on expression of housekeeping proteins (CD63 and Rab-5b) and a tumor-associated marker (caveolin-1). Western blot and flow cytometry analysis of exosomes were used to confirm the Exotest-based findings. The Exotest allowed sensitive detection and quantification of exosomes purified from human tumor cell culture supernatants and plasma from SCID mice engrafted with human melanoma. Plasma levels of exosomes in melanoma-engrafted SCID mice correlated to tumor size. We evaluated the levels of plasma exosomes expressing CD63 and caveolin-1 in melanoma patients (n = 90) and healthy donors (n = 58). Consistently, plasma exosomes expressing CD63 (504+/-315) or caveolin-1 (619+/-310) were significantly increased in melanoma patients as compared to healthy donors (223+/-125 and 228+/-102, respectively). While the Exotest for CD63+ plasma exosomes had limited sensitivity (43%) the Exotest for detection of caveolin-1+ plasma exosomes showed a higher sensitivity (68%). Moreover, caveolin-1+ plasma exosomes were significantly increased with respect to CD63+ exosomes in the patients group. We describe a new non-invasive assay allowing detection and quantification of human exosomes in plasma of melanoma patients. Our results suggest that the Exotest for detection of plasma exosomes carrying tumor-associated antigens may represent a novel tool for clinical management of cancer patients.
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Ascertaining serum levels of trace elements in melanoma patients using PIXE and HR-ICPMS
NASA Astrophysics Data System (ADS)
Bernardes, S.; Tabacniks, M. H.; Santos, I. D. A. O.; Oliveira, A. F.; Shie, J. N.; Sarkis, J. E. S.; Oliveira, T.
2014-01-01
Melanoma is a serious and deadly form of skin cancer. However, patients' chances of survival and recovery are considerably increased when it is diagnosed and treated in its early stages. In this study, trace element concentrations in serum samples from patients with melanoma were measured using PIXE (Proton Induced X-ray Emission) and HR-ICPMS (High-Resolution Inductively Coupled Plasma Mass Spectrometry), with the purpose of correlating these concentrations with the disease. Blood samples from 30 melanoma patients and 116 healthy donors were collected at São Paulo Hospital (protocol CEP 1036/08 UNIFESP). Relevant clinical information on the patients has also been included in the statistical analysis. Analysis of the control group showed different P and Mg concentrations in individuals above and below 40 years of age. P, S, Ca, Cu and Zn concentrations in healthy individuals differed according to gender, highlighting the necessity to include age and gender variables in the case-control analysis. There were also differences in K, S, Ca and Se concentrations between the control and melanoma groups.
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Increased expression of sex determining region Y-box 11 (SOX11) in cutaneous malignant melanoma.
Jian, Jiao; Guoying, Wang; Jing, Zhao
2013-08-01
To observe sex determining region Y-box 11 (SOX11) gene expression in cutaneous malignant melanoma and its effect on tumour cell proliferation. Clinicopathological data and tissue samples from patients with cutaneous malignant melanoma, together with tissue samples from healthy volunteers (controls), were retrospectively reviewed. Protein levels of SOX11 and the antigen identified by monoclonal antibody Ki-67 (Ki-67) in skin lesions were analysed using immunohistochemistry. The correlation between protein levels and clinipathological parameters was investigated. Out of 40 patient samples, 25 (62.5%) were positive for SOX11 protein in malignant melanoma tissue. This was significantly higher than in 40 control tissue samples, in which no SOX11 protein was detected. Presence of SOX11 protein was positively related to the proliferation index of cutaneous malignant melanoma tumour cells. Presence of SOX11 protein in cutaneous malignant melanoma was related to tumour type, tumour location, lymph node metastasis and 5-year survival rate. Human cutaneous malignant melanoma tissues expressed high levels of SOX11 compared with healthy controls, suggesting that SOX11 may be a new prognostic marker for malignant melanoma.
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Perioperative BRAF inhibitors in locally advanced stage III melanoma.
Zippel, Douglas; Markel, Gal; Shapira-Frommer, Roni; Ben-Betzalel, Guy; Goitein, David; Ben-Ami, Eytan; Nissan, Aviram; Schachter, Jacob; Schneebaum, Schlomo
2017-12-01
Stage III malignant melanoma is a heterogeneous disease where those cases deemed marginally resectable or irresecatble are frequently incurable by surgery alone. Targeted therapy takes advantage of the high incidence of BRAF mutations in melanomas, most notably the V600E mutation. These agents have rarely been used in a neoadjuvant setting prior to surgery. Thirteen consecutive patients with confirmed BRAF V600E regionally advanced melanoma deemed marginally resectable or irrresectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The primary outcome measures were a successful resection and pathological response. Disease-free survival was a secondary outcome measure. Overall, 12/13 patients showed a marked clinical responsiveness to medical treatment, enabling a macroscopically successful resection in all cases. Four patients had a complete pathological response with no viable tumor evident in the resected specimens and eight patients showed evidence of minimally residual tumor with extensive tumoral necrosis and fibrosis. One patient progressed and died before surgery. At a median follow up of 20 months, 10 patients remain free of disease. Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival. © 2017 Wiley Periodicals, Inc.
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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.
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Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma.
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.
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DNA repair gene polymorphisms and risk of cutaneous melanoma: a systematic review and meta-analysis.
Mocellin, Simone; Verdi, Daunia; Nitti, Donato
2009-10-01
Polymorphisms of DNA repair-related genes might modulate cancer predisposition. We performed a systematic review and meta-analysis of the available evidence regarding the relationship between these polymorphisms and the risk of developing cutaneous melanoma. Relevant studies were searched using PubMed, Medline, Embase, Cancerlit, Cochrane and ISI Web of Knowledge databases. Data were gathered according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The model-free approach was adopted to perform the meta-analysis of the retrieved data. We identified 20 original reports that describe the relationship between melanoma risk and the single-nucleotide polymorphisms (SNPs) of 16 genes (cases = 4195). For seven SNPs considered in at least two studies, the findings were heterogeneous. Data were suitable for meta-analysis only in the case of the XPD/ERCC2 SNP rs13181 (cases = 2308, controls = 3698) and demonstrated that the variant C allele is associated with increased melanoma risk (odds ratio = 1.12, 95% confidence interval = 1.03-1.21, P = 0.01; population attributable risk = 9.6%). This is the first meta-analysis suggesting that XPD/ERCC2 might represent a low-penetrance melanoma susceptibility gene. Much work is still to be done before definitive conclusions can be drawn on the role of DNA repair alterations in melanomagenesis since for the other genes involved in this highly complex process, the available information is scarce or null.
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Bellerive, Claudine; Aziz, Hassan A; Bena, James; Wilkinson, Allan; Suh, John H; Plesec, Thomas; Singh, Arun D
2017-05-01
To evaluate the patterns, the risk factors, and the management of recurrence following brachytherapy in patients with posterior uveal melanoma, given that an understanding of the recurrence patterns can improve early recognition and management of local treatment failure in such patients. Retrospective cohort study. Setting: Multispecialty tertiary care center. A total of 375 eyes treated with episcleral brachytherapy for posterior uveal melanoma from January 2004 to December 2014. Exclusion criteria included inadequate follow-up (<1 year) and previous radiation therapy. Main Outcomes and Measures: Local control rate and time to recurrence were the primary endpoints. Kaplan-Meier estimation and Cox proportional hazards models were conducted to identify risk factors for recurrence. Twenty-one patients (5.6%) experienced recurrence (follow-up range 12-156 months; median 47 months). The median time to recurrence was 18 months (range 4-156 months). Five-year estimated local recurrence rate was 6.6%. The majority (90.5%) of the recurrences occurred within the first 5 years. The predominant site of recurrence was at the tumor margin (12 patients, 57.1%). Univariate analysis identified 3 statistically significant recurrence risk factors: advanced age, largest basal diameter, and the use of adjuvant transpupillary thermotherapy (TTT). Recurrent tumors were managed by repeat brachytherapy, TTT, or enucleation. Local recurrences following brachytherapy are uncommon 5 years after episcleral brachytherapy. Follow-up intervals can be adjusted to reflect time to recurrence. Most of the eyes with recurrent tumor can be salvaged by conservative methods. Copyright © 2017 Elsevier Inc. All rights reserved.
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Lucci, A; Citro, H W; Wilson, L
2001-05-15
The incidence of melanoma has increased in the past 10 years more rapidly than any other cancer. Exposure to intense solar radiation in youth significantly increases the lifetime risk of developing melanoma. We postulate that teenagers have little awareness of melanoma prevention or detection principles. The purpose of this study was to assess the knowledge of teenagers about melanoma and to identify which age groups are most receptive to altering their sun exposure behaviors. Two hundred and ten examinations testing general knowledge of sun exposure and melanoma were completed and returned by junior high and high school students ages 12 to 18 in Dallas and Houston, Texas. All students completing and returning the examination were provided with the correct answers to the test and a detailed explanation of each of the test items as part of an educational exercise. A second questionnaire was then administered to determine the effect of the educational exercise on future sun exposure practices. Students were divided into two age groups (12 to 15 and >or=16 years old) for comparison of scores on the knowledge examination and responses to behavioral items. Comparison of response rates between age groups was performed using chi(2) analysis. The return rate was 100%, with 109 students age 12-15 years, and 101 students >or=16 years. Seventy-six percent of all respondents sunbathed outdoors, and 18% had used a tanning bed in the past 6 months. Thirty-three percent of students admitted to at least three blistering sunburns in the past. The average score on the knowledge assessment examination was 65% correct for students >or=16 years old and 54% correct for those 12-15 years old. Students 12 to 15 years old were significantly more likely to indicate they planned to change future behaviors regarding performance of skin self-examinations and limiting sun exposure as compared to the older students. A significant number of teenagers have already enhanced their risk for future melanoma by suffering severe sunburns. Students younger than 16 years of age were significantly more likely to indicate they planned to change future behaviors after receiving information about melanoma. The data from this pilot study support education aimed at younger age groups to most effectively achieve risk reduction and prevent future melanomas. Copyright 2001 Academic Press.
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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.
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Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma.
Daud, Adil; Soon, Christopher; Dummer, Reinhard; Eggermont, Alexander M M; Hwu, Wen-Jen; Grob, Jean Jacques; Garbe, Claus; Hauschild, Axel
2012-08-01
Both native IFNα2b and pegylated IFNα2b (PegIFNα2b) are approved for the adjuvant treatment of high-risk melanoma. This review compares the toxicity profiles of high-dose IFNα2b (HDI) and PegIFNα2b, and provides recommendations on the management of common PegIFNα2b-related toxicities, based on available clinical data and published literature. The toxicity profile of PegIFNα2b at the approved dose (6 μg/kg/week for 8 weeks then 3 μg/kg/week for up to 5 years) is qualitatively similar to HDI in melanoma. The most common adverse events (AEs) are fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression. However, fatigue and flu-like symptoms appear less severe with PegIFNα2b, and toxicity seems to occur earlier, whereas with HDI toxicity may increase with time. Most AEs can be managed effectively by dose modification and aggressive symptom control. Dosing to tolerance using a three-step dose reduction schedule to maintain an ECOG performance status of 0 - 1 may enable patients experiencing toxicity to remain on treatment; this can be applied readily in clinical practice. PegIFNα2b is therefore a valuable alternative option for adjuvant treatment in melanoma, with a toxicity profile similar to that of HDI overall but a more convenient administration schedule.
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Rivera, Andrew; Nan, Hongmei; Li, Tricia; Qureshi, Abrar; Cho, Eunyoung
2016-01-01
Background Alcohol consumption is associated with increased risk of numerous cancers, but existing evidence for an association with melanoma is equivocal. No study has evaluated the association with different anatomic locations of melanoma. Methods We used data from three large prospective cohort studies to investigate whether alcohol intake was associated with risk of melanoma. Alcohol intake was assessed repeatedly by food-frequency questionnaires. A Cox proportional hazards model was used to calculate multivariate-adjusted hazard ratios (HRs). Results A total of 1,374 cases of invasive melanoma were documented during 3,855,706 person-years of follow-up. There was an association between higher alcohol intake and incidence of invasive melanoma (pooled multivariate HR 1.14; 95% confidence interval [CI]: 1.00–1.29] per drink/d, p trend = 0.04). Among alcoholic beverages, white wine consumption was associated with an increased risk of melanoma (pooled multivariate HR 1.13 [95% CI: 1.04–1.24] per drink/d, p trend <0.01) after adjusting for other alcoholic beverages. The association between alcohol consumption and melanoma risk was stronger for melanoma in relatively UV-spared sites (trunk) versus more UV-exposed sites (head, neck, or extremities). Compared to non-drinkers, the pooled multivariate-adjusted HRs for ≥20g/d of alcohol were 1.02 (95% CI: 0.64–1.62; P trend =0.25) for melanomas of the head, neck, and extremities and 1.73 (95% CI: 1.25–2.38; P trend =0.02) for melanomas of the trunk. Conclusions Alcohol intake was associated with a modest increase in the risk of melanoma, particularly in UV-protected sites. Impact These findings further support American Cancer Society Guidelines for Cancer Prevention to limit alcohol intake. PMID:27909090
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A Cohort Study of Vitamin D Intake and Melanoma Risk
Asgari, Maryam M.; Maruti, Sonia S.; Kushi, Lawrence H.; White, Emily
2009-01-01
Data suggest that vitamin D intake may have chemopreventive efficacy against melanoma, but there have been no published epidemiologic studies examining the association between vitamin D intake and melanoma risk in a large prospective cohort. We examined whether dietary and supplemental vitamin D intake was associated with melanoma risk among 68,611 men and women who were participants of the Vitamins and Lifestyle cohort study. Participants reported dietary vitamin D intake over the past year and 10-year use of multivitamin and individual vitamin D supplements on a baseline questionnaire. After follow-up through 2006, 455 incident melanomas were identified through linkage to the Surveillance, Epidemiology, and End Results cancer registry. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for vitamin D intake after adjustment for melanoma risk factors. Compared with the lowest quartile, we did not detect a risk reduction of melanoma in the highest quartiles of dietary vitamin D intake (RR = 1.31, CI = 0.94–1.82), 10-year average supplemental vitamin D intake (RR = 1.13, CI = 0.89–1.43), or combined dietary and supplemental intake (1.05, CI = 0.79–1.40). In this large prospective cohort, we did not find an association between vitamin D intake and melanoma risk. PMID:19194478
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Sun protection and skin self-examination in melanoma survivors.
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.
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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
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Nevi and lasers: Practical considerations.
Rogers, Tova; Krakowski, Andrew C; Marino, Maria L; Rossi, Anthony; Anderson, Richard R; Marghoob, Ashfaq A
2018-01-01
Lasers are increasingly used for elective ablation of melanocytic nevi (MN). However, the associated risks of treating MN with lasers are debated and not well studied. Theoretical risks include inadvertently treating a melanoma mistaken for a nevus, the inability to remove all nevus cells and the possibility for residual cells to undergo malignant transformation, and the difficulty in clinically monitoring the remnant nevus for melanoma progression. Additional concerns include the morphological suitability of a lesion for laser removal and managing patients' expectations about the variable cosmetic outcomes. These potential issues have prompted us to outline some practical suggestions for clinicians and patients to consider when determining the suitability of a nevus for laser ablation. The choice to perform laser removal of a nevus is personal, both from the perspective of the treating physician and that of the person being treated. While acknowledging some uncertainty, we believe that these suggestions can help mitigate risk and improve patient outcomes. Lasers Surg. Med. 50:7-9, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.
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Rosacea and risk of cancer in Denmark.
Egeberg, Alexander; Fowler, Joseph F; Gislason, Gunnar H; Thyssen, Jacob P
2017-04-01
Rosacea is a common facial skin disorder with an estimated prevalence of 5-10% among Caucasians. We compared cancer incidence in patients previously diagnosed with rosacea with that in the general population. Nationwide cohort study of the Danish population using individual-level linkage of administrative registers. All Danish citizens aged ≥18years were followed from January 1st 2008 to December 31st 2012. Patients with rosacea (the exposure) were compared with the general population, serving as control subjects. The outcome was a diagnosis of one of the following cancers: breast, ovarian, endometrial, cervical, kidney, malignant melanoma, non-melanoma skin cancer (NMSC), pancreatic, hepatic, thyroid, esophageal, and lung cancer. Baseline prevalence of cancers were assessed, incidence rates per 1000 person-years were calculated, and hazard ratios (HRs) adjusted for age, sex, socio-economic status, and healthcare consumption were estimated by Cox regression models. The study comprised a total of 49,475 patients with rosacea and 4,312,213 subjects from the general population. There was no increased risk of malignant melanoma, ovarian, endometrial, cervical, esophageal, kidney, pancreatic, or thyroid cancer. However the risk of hepatic cancer (HR 1.42; 95% confidence interval [CI] 1.06-1.90), NMSC (HR 95% CI 1.36; 1.26-1.47), and breast cancer (HR 1.25; 95% CI 1.15-1.36) was significantly increased, and the risk of incident lung cancer was significantly decreased (HR 0.78; 95% CI 0.69-0.89). We found an increased risk of NMSC, breast cancer, and hepatic cancer, and a reduced risk of lung cancer, among patients with rosacea. These results are in contrast to the limited published data on cancers in rosacea, and further studies are warranted to elucidate the potential relationship between rosacea and various cancers. The findings add to the overall clinical description of patients with rosacea. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Mehta, Gautam U; Malekzadeh, Parisa; Shelton, Thomas; White, Donald E; Butman, John A; Yang, James C; Kammula, Udai S; Goff, Stephanie L; Rosenberg, Steven A; Sherry, Richard M
2018-06-01
Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall survival were analyzed. Among 144 total patients, 15 patients with treated and 18 patients with untreated brain metastases were identified. Intracranial objective responses (OR) occurred in 28% patients with untreated brain metastases. The systemic OR rates for patients with M1c disease without identified brain disease, treated brain disease, and untreated brain disease, and were 49%, 33% and 33%, respectively, of which 59%, 20% and 16% were durable at last follow-up. The site of untreated brain disease was the most likely site of initial tumor progression (61%) in patients with untreated brain metastases. Overall, we found that ACT with TIL can eliminate small melanoma brain metastases. However, following TIL therapy these patients frequently progress in the brain at a site of untreated brain disease. Patients with treated or untreated brain disease are less likely to achieve durable systemic ORs following TIL therapy compared with M1c disease and no history of brain disease. Melanoma brain metastases likely require local therapy despite the systemic effect of ACT.
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Vitamin D receptor polymorphisms in patients with cutaneous melanoma.
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.
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Vitamin D receptor polymorphisms in patients with cutaneous melanoma
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
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Luo, Cong; Shen, Jiayu; Ying, Jieer; Fang, Xianhua; Wang, Xiaohong; Fu, Zhixuan; Liu, Peng
2017-01-01
Malignant melanoma is one kind of malignant disease which has high rates of mortality, metastasis, and poor prognosis. The therapeutic landscape is rapidly changing with the development of novel agents in recent decades, such as anti-PD-1 agents, anti-CTLA-4 agents, and BRAF inhibitors. However, since most of these novel agents are very expensive, not all patients can afford them. Apatinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2) and may also be effective on Ret, c-KIT, and c-src. Temozolomide (TMZ) is a second-generation alkylating agent and a cytotoxic drug for melanoma treatment. In this work, we reported a case of metastatic melanoma with an excellent response to apatinib/TMZ combination therapy with progression-free survival for more than one year. This patient showed high expression of CD117, VEGFR-3, and KIT mutation in exon 11, suggesting that apatinib may induce clinical response via inhibiting VEGFR and c-KIT. Apatinib/TMZ combination therapy could be a new option for the treatment of advanced melanoma with KIT mutation.
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Knapen, Lotte M; Koornstra, Rutger H T; Driessen, Johanna H M; van Vlijmen, Bas; Croes, Sander; Schalkwijk, Stein; Colbers, Angela; Gerritsen, Winald R; Burger, David M; de Vries, Frank; van Erp, Nielka P
2018-04-11
The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown. To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs. A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex. In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75). There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.
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Mitotic rate is associated with positive lymph nodes in patients with thin melanomas.
Wheless, Lee; Isom, Chelsea A; Hooks, Mary A; Kauffmann, Rondi M
2018-05-01
The American Joint Commission on Cancer will remove mitotic rate from its staging guidelines in 2018. Using a large nationally representative cohort, we examined the association between mitotic rate and lymph node positivity among thin melanomas. A total of 149,273 thin melanomas in the National Cancer Database were examined for their association of high-risk features of mitotic rate, ulceration, and Breslow depth with lymph node status. Among 17,204 patients with thin melanomas with data on Breslow depth, ulceration, and mitotic rate who underwent a lymph node biopsy, there was a strong linear relationship between odds of having a positive lymph node and mitotic rate (R 2 = 0.96, P < .0001, β = 3.31). The odds of having a positive node increased by 19% with each 1-point increase in mitotic rate (odds ratio, 1.19; 95% confidence interval, 1.17-1.21). Cases with negative nodes had a mean mitotic rate of 1.54 plus or minus 2.07 mitoses/mm 2 compared with 3.30 plus or minus 3.54 mitoses/mm 2 for those with positive nodes (P < .0001). The data collected do not allow for survival analyses. Mitotic rate was strongly associated with the odds of having a positive lymph node and should continue to be reported on pathology reports. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Effect of DETOX as an adjuvant for melanoma vaccine.
Schultz, N; Oratz, R; Chen, D; Zeleniuch-Jacquotte, A; Abeles, G; Bystryn, J C
1995-04-01
The identification of effective adjuvants is critical for tumor vaccine development. Towards this end, we examined whether the immunogenicity of a melanoma vaccine could be potentiated by DETOX, an adjuvant consisting of monophosphoryl lipid A (MPL) and purified mycobacterial cell-wall skeleton (CWS). Nineteen patients with resected stage III melanoma were immunized with a polyvalent melanoma antigen vaccine (40 micrograms) admixed with DETOX, q3 wks x 4. Seven patients received vaccine + low-dose DETOX (10 micrograms MPL + 100 micrograms CWS) and 12 received vaccine + high-dose DETOX (20 micrograms MPL + 200 micrograms CWS). A non-randomized control group of 35 patients was treated similarly with 40 micrograms vaccine + alum. One week after the fourth vaccine immunization, melanoma antibodies were increased over baseline in 7/7 (100%) patients treated with vaccine + low-dose DETOX, 8/12 (67%) patients treated with vaccine + high-dose DETOX, and in 4/19 (21%) of vaccine + alum patients. For the entire DETOX group, the antibody response rate was 15/19 (79%) compared 4/19 (21%) in the alum group (p < 0.001). In contrast, a strong delayed-type hypersensitivity (DTH) response (> or = 15 mm increase in DTH response over baseline) was induced in 50% of the entire DETOX group versus in 47% of the alum group. Median disease-free (DF) survival for the entire DETOX group was 17.8 months compared with 32.1 months in the alum group (p < 0.05). In conclusion, DETOX markedly potentiated antibody but had little effect on DTH responses to melanoma vaccine immunization. It did not appear to improve disease-free survival in comparison to alum in this non-randomized study.
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Monitoring for Extra-Intestinal Cancers in IBD.
Sifuentes, H; Kane, S
2015-11-01
Multiple studies have demonstrated an increased risk for extra-intestinal cancers in inflammatory bowel disease (IBD) patients, mainly from treatment modalities. Prominent cancers that are related to IBD treatment include the following: lymphoproliferative disorders associated with thiopurine use, hepatosplenic T cell lymphoma primarily in younger male patients on thiopurines and anti-tumor necrosis factor (TNF) agents, non-melanoma skin cancers in patients treated with thiopurines and anti-TNF agents, and melanomas in patients who are on monotherapy with anti-TNF agents. In addition, women with IBD may have higher rates of cervical dysplasia and cervical cancer. The focus of this review is to provide a comprehensive overview on extra-intestinal cancers in IBD patients and how to monitor for these malignancies.
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Pettersson, Helna; Knutsen, Håvar; Holmberg, Erik; Andréasson, Björn
2015-02-01
Several studies have reported an increased incidence of coexistent cancer in patients with myeloproliferative neoplasms (MPN), and myelosuppressive treatment has been speculated to be one of the causes. In this study, we have concentrated on malignancies diagnosed before the MPN diagnosis to eliminate the possible influence of MPN treatment. The patients were recruited from the Swedish and Norwegian cancer registries. One thousand seven hundred and 45 patients from the Swedish MPN Quality Registry and 468 patients from the Norwegian National Cancer Registry were included in this study covering a 3-yr period. The results show that primary concurrent cancer is higher among patients with MPN compared to the general population. When pooled together, the Swedish and the Norwegian cohort showed increased prevalence of all types of cancer in general compared with the general population, standard prevalence ratio (SPR) of 1.20 (95% CI 1.07-1.34). Significantly high SPRs were reached for skin malignant melanoma [1.89 (95% CI 1.33-2.62)], prostate cancer [1.39 (95% CI 1.11-1.71)], and hematologic cancer [1.49 (95% CI 1.00-2.12)]. In the polycythemia vera group, the risk of having prior malignant melanoma of the skin was significant, with an SPR of 2.20 (95% CI 1.17-3.77). For patients with essential thrombocythemia and primary myelofibrosis, no significant risks were found. Coexisting cancers have a high impact on the treatment strategies of MPN, as it narrows down the treatment options. Chronic inflammation, as a common denominator of MPN with other cancers, can catalyze each other's existence and progression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Nucleoli cytomorphology in cutaneous melanoma cells - a new prognostic approach to an old concept.
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.
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Noncutaneous malignant melanoma: a prognostic model from a retrospective multicenter study
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
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Gibney, Geoffrey T; Gauthier, Geneviève; Ayas, Charles; Galebach, Philip; Wu, Eric Q; Abhyankar, Sarang; Reyes, Carolina; Guérin, Annie; Yim, Yeun Mi
2015-08-01
Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0-1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan-Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5-10 mm vs. < 5 mm) and number of brain metastases (≥ 5 vs. < 2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. < 2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥ 2 extracranial disease sites, progressive extracranial disease, and ≥ 5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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In situ photoimmunotherapy: a tumour-directed treatment for melanoma.
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.
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Diet, plasma levels of beta-carotene and alpha-tocopherol, and risk of malignant melanoma.
Stryker, W S; Stampfer, M J; Stein, E A; Kaplan, L; Louis, T A; Sober, A; Willett, W C
1990-04-01
Dietary intake and the plasma levels of retinol, alpha-tocopherol, lycopene, alpha-carotene, and beta-carotene for 204 cases with malignant melanoma were compared with those of 248 controls. Cases and controls were patients 18 years of age or older making their first visit to a dermatology subspecialty clinic for pigmented lesions from July 1, 1982 to September 1, 1985. Intakes of nutrients were estimated using a semiquantitative food frequency questionnaire. No significant associations with malignant melanoma were observed for higher plasma levels of lycopene, retinol, or alpha-carotene in logistic regression analyses after controlling for age, sex, plasma lipids, and known constitutional risk factors (hair color and ability to tan). In similar models, the odds ratio comparing the highest with the lowest quintile was 0.9 (95% confidence interval (CI) 0.5-1.5) for plasma beta-carotene, 0.7 (95% CI 0.5-1.3) for plasma alpha-tocopherol, 0.7 (95% CI 0.4-1.2) for carotene intake, and 0.7 (95% CI 0.4-1.3) for total vitamin E intake. A trend toward reduced risk of melanoma was observed for increasing intake of iron (not including supplements); this was related to the more frequent consumption of baked goods, such as cake, among controls. Alcohol consumption was positively associated with risk of melanoma (chi for trend = 2.1, p = 0.03); the odds ratio for consumption of over 10 g/day compared with persons with no alcohol intake was 1.8 (95% CI 1.0-3.3).
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Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma
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
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Fear of new or recurrent melanoma after treatment for localised melanoma.
Bell, Katy J L; Mehta, Yachna; Turner, Robin M; Morton, Rachael L; Dieng, Mbathio; Saw, Robyn; Guitera, Pascale; McCaffery, Kirsten; Low, Donald; Low, Cynthia; Jenkins, Marisa; Irwig, Les; Webster, Angela C
2017-11-01
To estimate the amount of fear of new or recurrent melanoma among people treated for localised melanoma in an Australian specialist centre. We randomly selected 400 potential participants from all those treated for localised melanoma at the Melanoma Institute Australia during 2014 (n = 902). They were asked to complete an adapted version of the Fear of Cancer Recurrence Inventory (FCRI). We calculated summary statistics for demographics, clinical variables and total FCRI and subscale scores. Two hundred fifteen people (54%) completed the FCRI questionnaire. The overall mean severity subscale score was 15.0 (95% CI 14.0-16.1). A high proportion of participants had scores above a proposed threshold to screen for clinical fear of cancer recurrence (77% and 63% of participants with and without new or recurrent melanoma had severity subscale scores ≥13). Most participants also had scores above a threshold found to have high specificity for clinical fear of cancer recurrence (65% and 48% of participants with and without new or recurrent melanoma had severity subscale scores ≥16). The severity subscale appeared to discriminate well between groups with differing levels of risk of new or recurrent melanoma. There is a substantial amount of fear of new or recurrent melanoma among this population, despite most having a very good prognosis. Copyright © 2017 John Wiley & Sons, Ltd.
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A multilingual assessment of melanoma information quality on the Internet.
Bari, Lilla; Kemeny, Lajos; Bari, Ferenc
2014-06-01
This study aims to assess and compare melanoma information quality in Hungarian, Czech, and German languages on the Internet. We used country-specific Google search engines to retrieve the first 25 uniform resource locators (URLs) by searching the word "melanoma" in the given language. Using the automated toolbar of Health On the Net Foundation (HON), we assessed each Web site for HON certification based on the Health On the Net Foundation Code of Conduct (HONcode). Information quality was determined using a 35-point checklist created by Bichakjian et al. (J Clin Oncol 20:134-141, 2002), with the NCCN melanoma guideline as control. After excluding duplicate and link-only pages, a total of 24 Hungarian, 18 Czech, and 21 German melanoma Web sites were evaluated and rated. The amount of HON certified Web sites was the highest among the German Web pages (19%). One of the retrieved Hungarian and none of the Czech Web sites were HON certified. We found the highest number of Web sites containing comprehensive, correct melanoma information in German language, followed by Czech and Hungarian pages. Although the majority of the Web sites lacked data about incidence, risk factors, prevention, treatment, work-up, and follow-up, at least one comprehensive, high-quality Web site was found in each language. Several Web sites contained incorrect information in each language. While a small amount of comprehensive, quality melanoma-related Web sites was found, most of the retrieved Web content lacked basic disease information, such as risk factors, prevention, and treatment. A significant number of Web sites contained malinformation. In case of melanoma, primary and secondary preventions are of especially high importance; therefore, the improvement of disease information quality available on the Internet is necessary.
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Wu, Xiao-Cheng; Eide, Melody J; King, Jessica; Saraiya, Mona; Huang, Youjie; Wiggins, Charles; Barnholtz-Sloan, Jill S; Martin, Nicolle; Cokkinides, Vilma; Miller, Jacqueline; Patel, Pragna; Ekwueme, Donatus U; Kim, Julian
2011-11-01
Most melanoma studies use data from the National Cancer Institute Surveillance, Epidemiology, and End Results Program or individual cancer registries. Small numbers of melanoma cases have limited in-depth analyses for all racial and ethnic groups. We sought to describe racial and ethnic variations in melanoma incidence and survival. Incidence for invasive melanoma and 5-year melanoma-specific survival were calculated for whites, blacks, American Indians/Alaskan Natives, Asians/Pacific Islanders (API), and Hispanics using data from 38 population-based cancer registries. Incidence rates of melanoma were significantly higher for females than males among whites and Hispanics under 50 years of age and APIs under 40 years of age. White and black patients were older (median age: 59-63 years) compared with Hispanics, American Indians/Alaskan Natives, and API (median age: 52-56 years). The most common histologic type was acral lentiginous melanoma among blacks and superficial spreading melanoma among all other racial and ethnic groups. Hispanics had the highest incidence rate of acral lentiginous melanoma, significantly higher than whites and API. Nonwhites were more likely to have advanced and thicker melanomas at diagnosis and lower melanoma-specific survival compared with whites. Over 50% of melanoma cases did not have specified histology. The numbers of nonwhite patients were still relatively small despite broad population coverage (67% of United States). Racial and ethnic differences in age at melanoma diagnosis, anatomic sites, and histologic types suggest variations in etiologic pathways. The high percentages of advanced and thicker melanomas among nonwhites highlight the need to improve melanoma awareness for all race and ethnicity in the United States. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
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Ulmer, Anja; Dietz, Klaus; Werner-Klein, Melanie; Häfner, Hans-Martin; Schulz, Claudia; Renner, Philipp; Weber, Florian; Breuninger, Helmut; Röcken, Martin; Garbe, Claus; Fierlbeck, Gerhard; Klein, Christoph A
2018-03-01
Complete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes. We quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 10 6 lymph node cells, i.e. the disseminated cancer cell density (DCCD). We uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCD NSN = DCCD SN c /10 1 - c (c = 0.69; 95% confidence interval [CI]: 0.62-0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCD SN (p = 0.02; HR 1.34, 95% CI: 1.05-1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07-2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCD SN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs. The assessment of DCCD SN renders CLND for staging purposes unnecessary. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Jacinto, Frances A; Fisher, George H; Espana, Edgar M; Leyngold, Ilya M; Margo, Curtis E
2016-10-01
We report a patient with previous in situ melanoma of the forehead skin who was referred for treatment of a bulbar conjunctival melanoma and a separate superficially invasive melanoma of the eyelid skin, and we offer a review of the biological and clinical implications of patients who have multiple primary melanomas. This article offers a clinicopathological correlation with a review of the relevant literature. An 80-year-old white man was referred for evaluation of a suspicious conjunctival tumor and a lower-eyelid lesion. Excisional biopsies revealed that both were primary melanomas arising within in situ disease. Over the span of 25 years, the patient had three separate foci of in situ melanoma, two of which spawned invasive melanoma. Separate melanomas arising from the bulbar conjunctiva and eyelid skin have rarely been reported. Multiple primary melanomas of the skin, however, are not uncommon. Based on studies of persons with multiple cutaneous melanomas, the prognosis is best predicted by the tumor with the greatest depth of invasion. Patients with multiple melanomas should be examined for dysplastic nevi, additional cutaneous melanomas, and screened periodically for future lesions. Ongoing studies enrolling patients with multiple primary melanomas are attempting to generate insights into low-penetrance susceptibility genes.
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Cicchiello, Mark; Lin, Matthew J; Pan, Yan; McLean, Catriona; Kelly, John W
2016-05-01
Missed opportunities in the diagnosis of nodular melanoma (NM) carry high prognostic penalties due to the rapid rate of NM growth. To date, an assessment of the pathways to diagnosis of NM versus superficial spreading melanoma (SSM) specifically comparing numbers of opportunities missed to undertake biopsy has not been performed. A retrospective questionnaire of 120 patients (60 NM patients, age and sex matched to 60 SSM patients) from the Victorian Melanoma Service (VMS) database was undertaken to assess pathways to diagnosis. The numbers of opportunities missed to undertake a biopsy and doctor behaviour at such encounters were recorded. Diagnostic delay (overall, patient's and doctor's delay) in terms of time was assessed. Significant differences in opportunities missed to make a diagnosis of NM compared to SSM were found. In all, 43% of NM were biopsied at a first encounter compared to 70% of SSM. All SSM were diagnosed within three reviews. Overall, 33% of NM required at least three and up six reviews until biopsy. Patients with NM were more likely than those with SSM to be reassured that their lesions were benign. No significant differences in terms of time delay to diagnosis between NM and SSM were found. NM contributes disproportionately to melanoma mortality in Australia. Addressing earlier diagnosis of NM with renewed focus may make the biggest impact on the overall mortality of melanoma. The message that a period of observation is not appropriate for patients re-presenting with lesions of concern must be more effectively communicated. © 2015 The Australasian College of Dermatologists.
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Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma.
Calero, R; Morchon, E; Martinez-Argudo, I; Serrano, R
2017-10-10
Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors. We also found high expression of HSP90 and the PI3K/AKT/mTOR pathway proteins, 4EBP1 and AKT compared with healthy tissue and this correlated with poor overall survival of melanoma patients. The combination of the HSP90 inhibitor 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 showed a synergistic activity decreasing melanoma cell growth, inducing apoptosis and targeting simultaneously the MAPK and PI3K/AKT/mTOR pathways. These results demonstrate that the combination of HSP90 and PI3K/mTOR inhibitors could be an effective therapeutic strategy that target the main survival pathways in melanoma and must be considered to overcome resistance to BRAF inhibitors in melanoma patients. Copyright © 2017 Elsevier B.V. All rights reserved.
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Uveal Melanoma: From Diagnosis to Treatment and the Science in Between
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
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Aziz, Hassan A; Singh, Nakul; Bena, James; Wilkinson, Allan; Singh, Arun D
2016-06-01
Vision loss following episcleral brachytherapy for uveal melanoma is difficult to predict for individual patients. To generate a risk calculator for vision loss following episcleral brachytherapy for uveal melanoma. A retrospective review of data was conducted at a multispecialty tertiary care center in Cleveland, Ohio. All patients with primary ciliary body or choroidal melanoma treated with iodine 125 or ruthenium 106 episcleral brachytherapy between January 1, 2004, and December 30, 2013, were included. Univariate and multivariable Cox proportional hazards were used to determine the influence of baseline patient factors on vision loss. Kaplan-Meier curves (log-rank analyses) were used to estimate freedom from vision loss. Bootstrap resampling was performed to bias correct this estimate. Vision loss (to visual acuity [VA] worse than 20/50 and worse than 20/200). A total of 311 patients were included in the study, with a mean (SD) age of 62 (14.7) years at start of treatment and a median follow-up of 36 months (interquartile range, 18-60 months). At presentation, VA was better than or equal to 20/50 in 199 patients (64%) and better than or equal to 20/200 in 289 patients (93%). By Kaplan-Meier analysis, VA less than 20/200 at 3 years was not associated with sex, diabetes, systemic hypertension, or hypercholesterolemia but was associated with history of ocular comorbidities, type of isotope (ruthenium 106 or iodine 125), and initial VA ( >20/50 or <20/50). By multivariable analysis, age (hazard ratio [HR], 0.97; 95% CI, 0.94-1.00; P = .06), largest basal diameter (HR, 1.25; 95% CI, 1.16-1.34; P = <.001), total radiation dose to the fovea (HR, 1.03; 95% CI, 1.01-1.04; P = .001) and optic disc (HR, 1.01; 95% CI, 1.00-1.01; P = .005), and initial VA worse than 20/50 (HR, 1.85; 95% CI, 1.20-2.85; P = .005) were predictive of vision loss to a VA of less than 20/200. The concordance index for the full data set was 0.77. Using these data, an online risk calculator was developed to predict vision loss following episcleral brachytherapy. The vision prognostication tool presented herein needs to be validated by independent data sets. This tool may improve counseling for patients being evaluated for episcleral brachytherapy. At-risk individuals identified by this tool could be considered for inclusion into trials exploring prevention or treatment of radiation retinopathy and alternative therapies of uveal melanoma.
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Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients
Saint-Jean, Mélanie; Volteau, Christelle; Quéreux, Gaëlle; Peuvrel, Lucie; Brocard, Anabelle; Saiagh, Soraya; Nguyen, Jean-Michel; Bedane, Christophe; Basset-Seguin, Nicole
2018-01-01
Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n = 4) or IV (n = 6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation. PMID:29750176
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Malignant Melanoma of the Anus Found during Routine Colonoscopy in Ulcerative Colitis.
Seo, Kwang Il; Moon, Won; Kim, Sung Eun; Park, Moo In; Park, Seun Ja
2017-06-25
Inflammatory bowel disease (IBD) is characterized by recurrent or chronic inflammation of the gastrointestinal tract, which results in increased risk of developing cancer. Anorectal malignant melanoma is often misdiagnosed as either hemorrhoids or benign anorectal conditions in inflammatory bowel disease. Therefore, the overall prognosis and survival of IBD are poor. To date, the best treatment strategy remains controversial. Only early diagnosis and complete excision yield survival benefit. Here, we report a 64-year-old woman with ulcerative colitis, who was found to have anal malignant melanoma on routine colonoscopy. The lesion was confined to the mucosa with no distant metastasis. She underwent complete trans-anal excision. There was no recurrence at the four-year follow-up. Physicians should be aware of increased risk of cancer development in IBD patients and remember the importance of meticulous inspection of the anal canal.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Smith, P.J.; Greene, M.H.; Adams, D.
The dysplastic nevus syndrome (DNS) is a preneoplastic melanocyte abnormality which occurs in families affected by hereditary cutaneous malignant melanoma (HCMM). A putative role of host-environmental interactions in the etiology of hereditary melanoma has been strengthened by the recent finding that fibroblasts derived from HCMM/DNS patients demonstrated enhanced sensitivity to u.v.-irradiation in vitro. An extension of these studies is reported in which we have examined the invitro responses to a model environmental carcinogen, 4-nitroquinoline 1-oxide (4NQO), of six non-tumor skin fibroblast strains from HCMM/DNS patients representing five families. Three of the six HCMM/DNS strains showed enhanced cell killing with sensitivitiesmore » greater than that of a xeroderma pigmentosum (XP) variant strain but less than those of ataxia telangiectasia and XP Group D cell strains. The inhibition and recovery of de novo DNA synthesis, together with the expression of repair synthesis, following 4NQO exposure appeared to be normal in HCMM/DNS strains, irrespective of their subsequent clonogenic potential. The data point to a metabolic anomaly which may contribute to the carcinogenic risk of the melanoma prone preneoplastic state presented by some DNS patients.« less
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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.
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Anorectal melanoma: not a haemorrhoid.
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.
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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
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Caini, Saverio; Masala, Giovanna; Saieva, Calogero; Kvaskoff, Marina; Savoye, Isabelle; Sacerdote, Carlotta; Hemmingsson, Oskar; Hammer Bech, Bodil; Overvad, Kim; Tjønneland, Anne; Petersen, Kristina E N; Mancini, Francesca Romana; Boutron-Ruault, Marie-Christine; Cervenka, Iris; Kaaks, Rudolf; Kühn, Tilman; Boeing, Heiner; Floegel, Anna; Trichopoulou, Antonia; Valanou, Elisavet; Kritikou, Maria; Tagliabue, Giovanna; Panico, Salvatore; Tumino, Rosario; Bueno-de-Mesquita, H B As; Peeters, Petra H; Veierød, Marit B; Ghiasvand, Reza; Lukic, Marko; Quirós, José Ramón; Chirlaque, Maria-Dolores; Ardanaz, Eva; Salamanca Fernández, Elena; Larrañaga, Nerea; Zamora-Ros, Raul; Maria Nilsson, Lena; Ljuslinder, Ingrid; Jirström, Karin; Sonestedt, Emily; Key, Timothy J; Wareham, Nick; Khaw, Kay-Tee; Gunter, Marc; Huybrechts, Inge; Murphy, Neil; Tsilidis, Konstantinos K; Weiderpass, Elisabete; Palli, Domenico
2017-05-15
In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma. © 2017 UICC.
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In vivo coherent Raman imaging of the melanomagenesis-associated pigment pheomelanin
NASA Astrophysics Data System (ADS)
Wang, Hequn; Osseiran, Sam; Igras, Vivien; Nichols, Alexander J.; Roider, Elisabeth M.; Pruessner, Joachim; Tsao, Hensin; Fisher, David E.; Evans, Conor L.
2016-11-01
Melanoma is the most deadly form of skin cancer with a yearly global incidence over 232,000 patients. Individuals with fair skin and red hair exhibit the highest risk for developing melanoma, with evidence suggesting the red/blond pigment known as pheomelanin may elevate melanoma risk through both UV radiation-dependent and -independent mechanisms. Although the ability to identify, characterize, and monitor pheomelanin within skin is vital for improving our understanding of the underlying biology of these lesions, no tools exist for real-time, in vivo detection of the pigment. Here we show that the distribution of pheomelanin in cells and tissues can be visually characterized non-destructively and noninvasively in vivo with coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. We validated our CARS imaging strategy in vitro to in vivo with synthetic pheomelanin, isolated melanocytes, and the Mc1re/e, red-haired mouse model. Nests of pheomelanotic melanocytes were observed in the red-haired animals, but not in the genetically matched Mc1re/e; Tyrc/c (“albino-red-haired”) mice. Importantly, samples from human amelanotic melanomas subjected to CARS imaging exhibited strong pheomelanotic signals. This is the first time, to our knowledge, that pheomelanin has been visualized and spatially localized in melanocytes, skin, and human amelanotic melanomas.
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Jannot, Anne-Sophie; Meziani, Roubila; Bertrand, Guylene; Gérard, Benedicte; Descamps, Vincent; Archimbaud, Alain; Picard, Catherine; Ollivaud, Laurence; Basset-Seguin, Nicole; Kerob, Delphine; Lanternier, Guy; Lebbe, Celeste; Saiag, P; Crickx, Beatrice; Clerget-Darpoux, Françoise; Grandchamp, Bernard; Soufir, Nadem; Melan-Cohort
2005-08-01
The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.
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Family history of melanoma and Parkinson disease risk
Gao, X; Simon, K C.; Han, J; Schwarzschild, M A.; Ascherio, A
2009-01-01
Background: Co-occurrence of Parkinson disease (PD) and melanoma has been reported in numerous studies. If this was due to common genetic mechanisms, a positive family history of melanoma would be associated with an excessive PD risk, independent of environmental risk factors for PD. Methods: We prospectively examined associations between a family history of melanoma and PD among 157,036 men and women free of PD at baseline (1990 for men and 1982 for women) who participated in 2 ongoing US cohorts: the Health Professional Follow-up Study and the Nurses' Health Study. Information on family history of melanoma in parents or siblings was assessed via questionnaire. Relative risks and 95% confidence intervals were estimated using Cox proportional hazards models and pooled using a fixed-effects model. Results: During 14–20 years follow-up, we identified 616 incident PD cases. A family history of melanoma in a first-degree relative was associated with a higher risk of PD (multivariate relative risk = 1.85; 95% confidence interval: 1.2, 2.8; p = 0.004), after adjusting for smoking, ethnicity, caffeine intake, and other covariates. In contrast, we did not observe significant associations between a family history of colorectal, lung, prostate, or breast cancer and PD risk. Interactions between melanoma family history and age, smoking, or caffeine intake were not significant and subgroup analyses according to these factors generated similar results. Conclusions: Our findings support the notion that melanoma and Parkinson disease (PD) share common genetic components. The genetic determinants of melanoma could therefore be explored as susceptibility candidate genes for PD. GLOSSARY BMI = body mass index; CDK = cyclin dependent kinase; CI = confidence interval; HPFS = Health Professional Follow-up Study; NHS = Nurses' Health Study; OR = odds ratio; PD = Parkinson disease; RR = relative risk; SER = standardized event ratio. PMID:19841380
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Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma.
Strom, Tobin; Torres-Roca, Javier F; Parekh, Akash; Naghavi, Arash O; Caudell, Jimmy J; Oliver, Daniel E; Messina, Jane L; Khushalani, Nikhil I; Zager, Jonathan S; Sarnaik, Amod; Mulé, James J; Trotti, Andy M; Eschrich, Steven A; Sondak, Vernon K; Harrison, Louis B
2017-04-01
Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P =.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P <.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P =.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P <.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance. Copyright © 2017 by the National Comprehensive Cancer Network.
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Impact of sentinel lymphadenectomy on survival in a murine model of melanoma.
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.
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Mucosal melanoma of the head and neck.
Ascierto, Paolo Antonio; Accorona, Remo; Botti, Gerardo; Farina, Davide; Fossati, Piero; Gatta, Gemma; Gogas, Helen; Lombardi, Davide; Maroldi, Roberto; Nicolai, Piero; Ravanelli, Marco; Vanella, Vito
2017-04-01
Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery. Many new treatment options in the last years, in particular targeted therapies (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) and immunotherapies (anti CTLA-4 and anti PD-1/PD-L1 antibodies), have changed the history of cutaneous melanoma. Despite the different biology, mucosal melanoma is currently treated in the same way as cutaneous melanoma; however, patients with mucosal melanoma were excluded from the majority of recent clinical trials. Recent molecular findings offer new hope for the development of more effective systemic therapy. Copyright © 2017 Elsevier B.V. All rights reserved.
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Correlation between fertility drugs use and malignant melanoma incidence: the state of the art.
Tomao, Federica; Papa, Anselmo; Lo Russo, Giuseppe; Zuber, Sara; Spinelli, Gian Paolo; Rossi, Luigi; Caruso, Davide; Prinzi, Natalie; Stati, Valeria; Benedetti Panici, Pierluigi; Tomao, Silverio
2014-09-01
The relationship between fertility, reproductive hormones, and risk of malignant melanoma has acquired much interest in recent years. Melanocytes are hormonally responsive cells, and some in vitro studies demonstrated that estrogen hormones stimulate the growth of melanocytes. Moreover, estrogen receptors have been identified in melanoma cells, as well as in melanocytic nevi and in normal skin. Some evidences suggest a possible link between fertility treatments and the increased risk of malignant melanoma. This article addresses this association through a scrupulous search of the literature published thus far. The aim of this review is to determine the incidence of malignant melanoma in women treated with fertility drugs and to examine if the exposure to fertility treatments really increases the risk of malignant melanoma. In particular, our analysis focused on the different types of drugs and different treatment schedules used. Finally, this study provides additional insights regarding the long-term relationships between fertility drugs and the risk of malignant melanoma.
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Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq
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
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Feasibility of Proton Beam Therapy for Ocular Melanoma Using a Novel 3D Treatment Planning Technique
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hartsell, William F., E-mail: whartsell@chicagocancer.org; Kapur, Rashmi; Hartsell, Siobhan O'Connor
Purpose: We evaluated sparing of normal structures using 3-dimensional (3D) treatment planning for proton therapy of ocular melanomas. Methods and Materials: We evaluated 26 consecutive patients with choroidal melanomas on a prospective registry. Ophthalmologic work-up included fundoscopic photographs, fluorescein angiography, ultrasonographic evaluation of tumor dimensions, and magnetic resonance imaging of orbits. Three tantalum clips were placed as fiducial markers to confirm eye position for treatment. Macula, fovea, optic disc, optic nerve, ciliary body, lacrimal gland, lens, and gross tumor volume were contoured on treatment planning compute tomography scans. 3D treatment planning was performed using noncoplanar field arrangements. Patients were typicallymore » treated with 3 fields, with at least 95% of planning target volume receiving 50 GyRBE in 5 fractions. Results: Tumor stage was T1a in 10 patients, T2a in 10 patients, T2b in 1 patient, T3a in 2 patients, T3b in 1 patient, and T4a in 2 patients. Acute toxicity was mild. All patients completed treatment as planned. Mean optic nerve dose was 10.1 Gy relative biological effectiveness (RBE). Ciliary body doses were higher for nasal (mean: 11.4 GyRBE) than temporal tumors (5.8 GyRBE). Median follow-up was 31 months (range: 18-40 months). Six patients developed changes which required intraocular bevacizumab or corticosteroid therapy, but only 1 patient developed neovascular glaucoma. Five patients have since died: 1 from metastatic disease and 4 from other causes. Two patients have since required enucleation: 1 due to tumor and 1 due to neovascular glaucoma. Conclusions: 3D treatment planning can be used to obtain appropriate coverage of choroidal melanomas. This technique is feasible with relatively low doses to anterior structures, and appears to have acceptable rates of local control with low risk of enucleation. Further evaluation and follow-up is needed to determine optimal dose-volume relationships for organs at risk to decrease complications rates.« less
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The value of FDG PET/CT for follow-up of patients with melanoma: a retrospective analysis
Vensby, Philip H; Schmidt, Grethe; Kjær, Andreas; Fischer, Barbara M
2017-01-01
The incidence of melanoma (MM) is among the fastest rising cancers in the western countries. Positron Emission Tomography with Computed Tomography (PET/CT) is a valuable non-invasive tool for the diagnosis and staging of patients with MM. However, research on the value of PET/CT in follow-up of melanoma patients is limited. This study assesses the diagnostic value of PET/CT for follow-up after melanoma surgery. This retrospective study includes patients with MM who performed at least one PET/CT scan after initial surgery and staging. PET/CT findings were compared to histology, MRI or fine needle aspiration (FNA) to estimate the diagnostic accuracy. The diagnostic performance of PET/CT performed in patients with and without a clinical suspicion of relapse was compared. 238 patients (526 scans) were included. Of the 526 scans 130 (25%) scans were PET-positive, 365 (69%) PET-negative, and 28 (5%) had equivocal findings. Sensitivity was 89% [0.82-0.94], specificity 92% [0.89-0.95], positive and negative predictive values of 78% [0.70-0.84] and 97% [0.94-0.98] respectively. When stratified for reason of referral there was no statistical significant difference in the diagnostic accuracy of PET/CT between patients referred with or without a clinical suspicion of relapse. This study demonstrates that PET/CT despite a moderate sensitivity has a high negative predictive value in the follow-up of melanoma patients. Thus, a negative PET/CT-scan essentially rules out relapse. However, the frequency of false positive findings is relatively high, especially among patients undergoing a “routine” PET/CT with no clinical suspicion of relapse, potentially causing anxiety and leading to further diagnostic procedures. PMID:29348980
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The value of FDG PET/CT for follow-up of patients with melanoma: a retrospective analysis.
Vensby, Philip H; Schmidt, Grethe; Kjær, Andreas; Fischer, Barbara M
2017-01-01
The incidence of melanoma (MM) is among the fastest rising cancers in the western countries. Positron Emission Tomography with Computed Tomography (PET/CT) is a valuable non-invasive tool for the diagnosis and staging of patients with MM. However, research on the value of PET/CT in follow-up of melanoma patients is limited. This study assesses the diagnostic value of PET/CT for follow-up after melanoma surgery. This retrospective study includes patients with MM who performed at least one PET/CT scan after initial surgery and staging. PET/CT findings were compared to histology, MRI or fine needle aspiration (FNA) to estimate the diagnostic accuracy. The diagnostic performance of PET/CT performed in patients with and without a clinical suspicion of relapse was compared. 238 patients (526 scans) were included. Of the 526 scans 130 (25%) scans were PET-positive, 365 (69%) PET-negative, and 28 (5%) had equivocal findings. Sensitivity was 89% [0.82-0.94], specificity 92% [0.89-0.95], positive and negative predictive values of 78% [0.70-0.84] and 97% [0.94-0.98] respectively. When stratified for reason of referral there was no statistical significant difference in the diagnostic accuracy of PET/CT between patients referred with or without a clinical suspicion of relapse. This study demonstrates that PET/CT despite a moderate sensitivity has a high negative predictive value in the follow-up of melanoma patients. Thus, a negative PET/CT-scan essentially rules out relapse. However, the frequency of false positive findings is relatively high, especially among patients undergoing a "routine" PET/CT with no clinical suspicion of relapse, potentially causing anxiety and leading to further diagnostic procedures.
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Li, Wei; Yu, Yalian; Wang, Hailong; Yan, Aihui; Jiang, Xuejun
2015-10-21
Head and neck mucosal melanoma (HNMM) is a rare type of malignant tumor that frequently exhibits postoperative recurrence and distant metastasis. Many clinicians administer postoperative adjuvant radiotherapy to improve patient prognosis and enhance quality of life; however, the effects of this treatment remain controversial. Therefore, in this study, a meta-analysis was performed to evaluate the practical value of postoperative adjuvant radiotherapy for head and neck mucosal melanoma. Articles in the PubMed, MEDLINE, Cochrane Library, Web of Science and EMBASE databases were systematically retrieved. Analyses were conducted to compare the impact of treatments involving postoperative radiotherapy with treatments entailing surgery alone on patient overall survival time, local recurrence and distant metastasis. The hazard ratio (HR) was used to evaluate the time-to-event data employing RevMan version 5.2 and Stata/SE version 13.0 software according to the principles specified for systematic reviews of interventions in the Cochrane handbook. Twelve cohort studies involving 1593 patients satisfied the desired conditions. In comparing surgery alone with postoperative radiotherapy, there was no significant difference regarding a decrease in the death risk in HNMM patients (HR, 1.07; 95 % CI, 0.95-1.2; p = 0.903; low heterogeneity, I(2) = 0); this was also the case for sinonasal melanoma after subgroup meta-analysis (HR, 1.04; 95 % CI, 0.8-1.36; p = 0.983; low heterogeneity, I(2) = 0 %). A sensitivity analysis and subgroup meta-analysis showed that disease progression was the main source of the instability in the results. Surgery combined with postoperative radiotherapy reduced the risk of local recurrence (HR, 0.51; 95 % CI, 0.35-0.76; p = 0.155) but did not reduce the risk of distant metastasis (HR, 2.26; 95 % CI, 1.01-5.05; p = 0.006). This study demonstrated that for HNMM patients surgery is recommended if indicated, and surgery combined with postoperative radiotherapy is also recommended for dramatically improved local control of the tumor bed. For patients not suitable for surgical treatment, radiotherapy is still advised. To control distant metastasis and finally lower the risk of death, immunological therapy is another potential option whose therapeutic effect needs to be proved with more data from clinical trials.
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Identifying and targeting determinants of melanoma cellular invasion.
Jayachandran, Aparna; Prithviraj, Prashanth; Lo, Pu-Han; Walkiewicz, Marzena; Anaka, Matthew; Woods, Briannyn L; Tan, BeeShin; Behren, Andreas; Cebon, Jonathan; McKeown, Sonja J
2016-07-05
Epithelial-to-mesenchymal transition is a critical process that increases the malignant potential of melanoma by facilitating invasion and dissemination of tumor cells. This study identified genes involved in the regulation of cellular invasion and evaluated whether they can be targeted to inhibit melanoma invasion. We identified Peroxidasin (PXDN), Netrin 4 (NTN4) and GLIS Family Zinc Finger 3 (GLIS3) genes consistently elevated in invasive mesenchymal-like melanoma cells. These genes and proteins were highly expressed in metastatic melanoma tumors, and gene silencing led to reduced melanoma invasion in vitro. Furthermore, migration of PXDN, NTN4 or GLIS3 siRNA transfected melanoma cells was inhibited following transplantation into the embryonic chicken neural tube compared to control siRNA transfected melanoma cells. Our study suggests that PXDN, NTN4 and GLIS3 play a functional role in promoting melanoma cellular invasion, and therapeutic approaches directed toward inhibiting the action of these proteins may reduce the incidence or progression of metastasis in melanoma patients.
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Identifying and targeting determinants of melanoma cellular invasion
Jayachandran, Aparna; Prithviraj, Prashanth; Lo, Pu-Han; Walkiewicz, Marzena; Anaka, Matthew; Woods, Briannyn L.; Tan, BeeShin
2016-01-01
Epithelial-to-mesenchymal transition is a critical process that increases the malignant potential of melanoma by facilitating invasion and dissemination of tumor cells. This study identified genes involved in the regulation of cellular invasion and evaluated whether they can be targeted to inhibit melanoma invasion. We identified Peroxidasin (PXDN), Netrin 4 (NTN4) and GLIS Family Zinc Finger 3 (GLIS3) genes consistently elevated in invasive mesenchymal-like melanoma cells. These genes and proteins were highly expressed in metastatic melanoma tumors, and gene silencing led to reduced melanoma invasion in vitro. Furthermore, migration of PXDN, NTN4 or GLIS3 siRNA transfected melanoma cells was inhibited following transplantation into the embryonic chicken neural tube compared to control siRNA transfected melanoma cells. Our study suggests that PXDN, NTN4 and GLIS3 play a functional role in promoting melanoma cellular invasion, and therapeutic approaches directed toward inhibiting the action of these proteins may reduce the incidence or progression of metastasis in melanoma patients. PMID:27172792
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Burgard, Barbara; Schöpe, Jakob; Holzschuh, Isabel; Schiekofer, Claudia; Reichrath, Sandra; Stefan, Wagenpfeil; Pilz, Stefan; Ordonez-Mena, Jose; März, Winfried; Vogt, Thomas; Reichrath, Jörg
2018-02-01
There is an ongoing debate whether solarium use (indoor tanning/artificial UV) may increase the risk for primary cutaneous malignant melanoma. A systematic literature search was conducted using MEDLINE and ISI Web of Science. Included studies were critically assessed regarding their risk of bias, and methodological shortcomings. Levels of evidence and grades of recommendation were determined according to guidelines of the Oxford Centre for Evidence-Based Medicine. Summary risk estimates and 95% confidence intervals for four different outcomes (ever exposure, exposure at younger age, high/low exposure vs. non-exposure) were derived from random-effects meta-analyses to account for possible heterogeneity across studies. Two cohort and twenty-nine case-control studies were eligible. Overall, quality of included studies was poor as a result of severe limitations, including possible recall and selection bias, and due to lack of interventional trials. Summary risk estimates suggested a weak association (odds ratio (OR)=1.19, 95% confidence interval (CI)=1.04-1.35, p=0.009) for ever-exposure to UV radiation from a solarium with melanoma risk. However, sensitivity analyses did not show an association for studies from Europe (OR=1.10; 95%CI=0.95-1.27, p=0.218), studies with low risk of bias (OR=1.15; 95%CI=0.94-1.41, p=0.179), and studies conducted after 1990 (OR 1.09; 95%CI=0.93-1.29, p=0.295). Moreover, moderate associations were found for first exposure to UV radiation from a solarium at younger age (<25 years) and high exposure (>10 sessions in lifetime) with melanoma risk. However, for all outcomes analyzed, overall study quality and resulting levels of evidence (3a-) and grades of recommendation (D) were low due to lack of interventional studies and severe limitations including unobserved or unrecorded confounding. Current scientific knowledge is mainly based on observational studies with poor quality data, which report associations but do not prove causality. At present, there is no convincing evidence that moderate/responsible solarium use increases melanoma risk. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anterior segment sparing to reduce charged particle radiotherapy complications in uveal melanoma
NASA Technical Reports Server (NTRS)
Daftari, I. K.; Char, D. H.; Verhey, L. J.; Castro, J. R.; Petti, P. L.; Meecham, W. J.; Kroll, S.; Blakely, E. A.; Chatterjee, A. (Principal Investigator)
1997-01-01
PURPOSE: The purpose of this investigation is to delineate the risk factors in the development of neovascular glaucoma (NVG) after helium-ion irradiation of uveal melanoma patients and to propose treatment technique that may reduce this risk. METHODS AND MATERIALS: 347 uveal melanoma patients were treated with helium-ions using a single-port treatment technique. Using univariate and multivariate statistics, the NVG complication rate was analyzed according to the percent of anterior chamber in the radiation field, tumor size, tumor location, sex, age, dose, and other risk factors. Several University of California San Francisco-Lawrence Berkeley National Laboratory (LBNL) patients in each size category (medium, large, and extralarge) were retrospectively replanned using two ports instead of a single port. By using appropriate polar and azimuthal gaze angles or by treating patients with two ports, the maximum dose to the anterior segment of the eye can often be reduced. Although a larger volume of anterior chamber may receive a lower dose by using two ports than a single port treatment. We hypothesize that this could reduce the level of complications that result from the irradiation of the anterior chamber of the eye. Dose-volume histograms were calculated for the lens, and compared for the single and two-port techniques. RESULTS: NVG developed in 121 (35%) patients. The risk of NVG peaked between 1 and 2.5 years posttreatment. By univariate and multivariate analysis, the percent of lens in the field was strongly correlated with the development of NVG. Other contributing factors were tumor height, history of diabetes, and vitreous hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques demonstrate that for some patients in the medium and large category tumor groups, a significant decrease in dose to the structures in the anterior segment of the eye could have been achieved with the use of two ports. CONCLUSION: The development of NVG after helium-ion irradiation is correlated to the amount of lens, anterior chamber in the treatment field, tumor height, proximity to the fovea, history of diabetes, and the development of vitreous hemorrhage. Although the influence of the higher LET deposition of helium-ions is unclear, this study suggests that by reducing the dose to the anterior segment of the eye may reduce the NVG complications. Based on this retrospective analysis of LBNL patients, we have implemented techniques to reduce the amount of the anterior segment receiving a high dose in our new series of patients treated with protons using the cyclotron at the UC Davis Crocker Nuclear Laboratory (CNL).
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Ipilimumab-induced colitis in patients with metastatic melanoma.
De Felice, Kara M; Gupta, Arjun; Rakshit, Sagar; Khanna, Sahil; Kottschade, Lisa A; Finnes, Heidi D; Papadakis, Konstantinos A; Loftus, Edward V; Raffals, Laura E; Markovic, Svetomir N
2015-08-01
Ipilimumab is used for the treatment of metastatic melanoma and is associated with serious immune-related colitis. We aimed to report the clinical features, treatment, and outcomes of patients with ipilimumab-induced colitis. In this retrospective observational study, we identified patients with unresectable melanoma treated with ipilimumab between March 2011 and September 2013. Diarrhea was assessed using the Common Terminology Criteria for Adverse Events, v3.0. Colitis was defined by diarrhea (grade≥2) requiring steroids with or without endoscopic/histologic/radiologic evidence of colitis. A total of 103 patients with metastatic melanoma treated with ipilimumab were identified. Of these, 30 patients (29%) developed diarrhea (all grades), and 23 patients (22%) developed colitis requiring systemic corticosteroid therapy. The median number of ipilimumab doses before onset of diarrhea was 2 (range, 1-4). Six of 23 patients responded to less than 1 mg/kg daily prednisone alone. Fifteen patients required high-dose oral and/or intravenous prednisone (1-2 mg/kg body weight). Six patients had diarrhea refractory to prednisone; five required rescue therapy with budesonide (9-12 mg daily) and one was treated with infliximab (5 mg/kg, three doses). There was one case of severe diarrhea (grade 3) treated successfully with high-dose budesonide (12 mg) monotherapy. Ipilimumab-induced colitis requires early and aggressive medical therapy. Most patients can be successfully managed with systemic corticosteroids. High-dose budesonide is an attractive steroid-sparing agent, however further studies of its efficacy in this setting are needed. Infliximab should be used in refractory cases to avoid colectomy. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma Patients
Logozzi, Mariantonia; De Milito, Angelo; Lugini, Luana; Borghi, Martina; Calabrò, Luana; Spada, Massimo; Perdicchio, Maurizio; Marino, Maria Lucia; Federici, Cristina; Iessi, Elisabetta; Brambilla, Daria; Venturi, Giulietta; Lozupone, Francesco; Santinami, Mario; Huber, Veronica; Maio, Michele; Rivoltini, Licia; Fais, Stefano
2009-01-01
Background Metastatic melanoma is an untreatable cancer lacking reliable and non-invasive markers of disease progression. Exosomes are small vesicles secreted by normal as well as tumor cells. Human tumor-derived exosomes are involved in malignant progression and we evaluated the presence of exosomes in plasma of melanoma patients as a potential tool for cancer screening and follow-up. Methodology/Principal Findings We designed an in-house sandwich ELISA (Exotest) to capture and quantify exosomes in plasma based on expression of housekeeping proteins (CD63 and Rab-5b) and a tumor-associated marker (caveolin-1). Western blot and flow cytometry analysis of exosomes were used to confirm the Exotest-based findings. The Exotest allowed sensitive detection and quantification of exosomes purified from human tumor cell culture supernatants and plasma from SCID mice engrafted with human melanoma. Plasma levels of exosomes in melanoma-engrafted SCID mice correlated to tumor size. We evaluated the levels of plasma exosomes expressing CD63 and caveolin-1 in melanoma patients (n = 90) and healthy donors (n = 58). Consistently, plasma exosomes expressing CD63 (504±315) or caveolin-1 (619±310) were significantly increased in melanoma patients as compared to healthy donors (223±125 and 228±102, respectively). While the Exotest for CD63+ plasma exosomes had limited sensitivity (43%) the Exotest for detection of caveolin-1+ plasma exosomes showed a higher sensitivity (68%). Moreover, caveolin-1+ plasma exosomes were significantly increased with respect to CD63+ exosomes in the patients group. Conclusions/Significance We describe a new non-invasive assay allowing detection and quantification of human exosomes in plasma of melanoma patients. Our results suggest that the Exotest for detection of plasma exosomes carrying tumor-associated antigens may represent a novel tool for clinical management of cancer patients. PMID:19381331
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Single institution experience of paediatric melanoma in Victoria, Australia.
Le, Quynh; Norris, Diana; McClean, Catriona A; Mcguiness, Myra; Meani, Rowena; Kelly, John W; Pan, Yan
2017-05-01
Paediatric melanoma is an uncommon presentation of melanoma that accounts for 3% of all paediatric cancers. The objective was to describe a series of paediatric melanoma cases presenting to a state-wide tertiary referral service over the past 19 years. A search of the Victorian Melanoma Service database was performed to identify all patients under the age of 20 years diagnosed with melanoma from 1994 to 2013. Histological, demographic and phenotypical information for each patient was collected. Patients were matched against the Victorian Death Registry to identify those who had died. Fisher's exact test was used to examine associations. Melanoma-specific survival was estimated using the Kaplan-Meier method. A total of 65 paediatric melanoma patients were included for analysis, in whom 72.3% of melanomas were diagnosed when they were 16-19 years of age with a mean age at diagnosis of 16 years. The mean Breslow thickness was 1.4 mm. It was greatest (3.4 mm) in the youngest age group (< 12 years of age). Ten patients developed nodal metastatic disease, eight of which progressed to visceral metastatic disease. The 5-year melanoma-specific survival rate was 96.8%. This is the first descriptive epidemiological study of paediatric melanoma in Victoria. Further large, population-based, multi-institutional studies of paediatric melanoma are warranted to provide a clearer understanding of this group of melanoma patients. © 2016 The Australasian College of Dermatologists.
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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.
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Real-time sun protection decisions in first-degree relatives of melanoma patients.
Hay, Jennifer L; Shuk, Elyse; Schofield, Elizabeth; Loeb, Rebecca; Holland, Susan; Burkhalter, Jack; Li, Yuelin
2017-09-01
Melanoma is the most serious skin cancer, and consistent use of sun protection is recommended to reduce risk. Yet sun protection use is generally inconsistent. Understanding the decisional factors driving sun protection choices could aid in intervention development to promote sun protection maintenance. In 59 first-degree relatives of melanoma patients, an interactive voice response system (IVRS) on participants' cell phones was used to assess twice daily (morning, afternoon) real-time sun protection usage (sunscreen, shade, hats, protective clothing) and decision factors (weather, type of activity, convenience, social support) over a 14-day summer interval where morning and afternoon outdoor exposures were anticipated. Generalized estimating equations and hierarchical linear models were used to examine the effect of demographics and decisional factors on sun protection choices over time. Sun protection use was inconsistent (e.g., 61% used sunscreen inconsistently). Most strategies were used independently, with the exception of moderate overlap of sunscreen and hat usage. Decision factors were highly relevant for sun protection. For instance, sunscreen use was related to the perception of having adequate time to apply it, whereas shade and hat usage were each related to convenience. Few findings emerged by gender, age, time of day, or year. Significant within-subject variation remained, however. The findings support continued examination of decision factors in understanding sun protection consistency in real time. Interventions where cues to action and environmental supports work together in varied settings can be developed to improve sun protection maintenance in populations at risk for this common disease. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
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Ghiasvand, Reza; Rueegg, Corina S; Weiderpass, Elisabete; Green, Adele C; Lund, Eiliv; Veierød, Marit B
2017-02-01
Indoor tanning is associated with increased risk of melanoma, but most evidence comes from case-control studies. Using data from the Norwegian Women and Cancer Study, a large prospective cohort study, we investigated the associations of age at initiation of indoor tanning, duration of tanning-device use, and dose response with melanoma risk and examined the role of indoor tanning in age at melanoma diagnosis. We used Poisson regression to estimate relative risks and 95% confidence intervals for the relationship of indoor tanning to melanoma risk and linear regression to examine age of indoor tanning initiation in relation to age at diagnosis. During follow-up of 141,045 women (1991-2012; mean duration follow-up = 13.7 years), 861 women were diagnosed with melanoma. Melanoma risk increased with increasing cumulative number of tanning sessions (for highest tertile of use vs. never use, adjusted relative risk = 1.32, 95% confidence interval (CI): 1.08, 1.63); P-trend = 0.006. Age at initiation <30 years was associated with a higher risk in comparison with never use (adjusted relative risk = 1.31, 95% CI: 1.07, 1.59). Moreover, women who started indoor tanning prior to 30 years of age were 2.2 years (95% CI: 0.9, 3.4) younger at diagnosis, on average, than never users. This cohort study provides strong evidence of a dose-response association between indoor tanning and risk of melanoma and supports the hypothesis that vulnerability to the harmful effects of indoor tanning is greater at a younger age. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Epacadostat and Vaccine Therapy in Treating Patients With Stage III-IV Melanoma
2018-01-09
Mucosal Melanoma; Recurrent Melanoma; Recurrent Uveal Melanoma; Stage IIIA Skin Melanoma; Stage IIIA Uveal Melanoma; Stage IIIB Skin Melanoma; Stage IIIB Uveal Melanoma; Stage IIIC Skin Melanoma; Stage IIIC Uveal Melanoma; Stage IV Skin Melanoma; Stage IV Uveal Melanoma
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Melanoma risk and survival among organ transplant recipients
Robbins, Hilary A.; Clarke, Christina A.; Arron, Sarah T.; Tatalovich, Zaria; Kahn, Amy R.; Hernandez, Brenda Y.; Paddock, Lisa; Yanik, Elizabeth L.; Lynch, Charles F.; Kasiske, Bertram L.; Snyder, Jon; Engels, Eric A.
2015-01-01
Solid organ transplant recipients, who are medically immunosuppressed to prevent graft rejection, have increased melanoma risk, but risk factors and outcomes are incompletely documented. We evaluated melanoma incidence among 139,991 non-Hispanic white transplants using linked U.S. transplant-cancer registry data (1987–2010). We used standardized incidence ratios (SIRs) to compare incidence to the general population, and incidence rate ratios (IRRs) from multivariable Poisson models to assess risk factors. Separately, we compared post-melanoma survival among transplant recipients (N=182) and non-recipients (N=131,358) using multivariable Cox models. Among transplant recipients, risk of invasive melanoma (N=519) was elevated (SIR=2.20, 95%CI 2.01-2.39), especially for regional stage tumors (SIR=4.11, 95%CI 3.27–5.09). Risk of localized tumors was stable over time after transplantation, but higher with azathioprine maintenance therapy (IRR=1.35, 95%CI 1.03–1.77). Risk of regional/distant stage tumors peaked within 4 years following transplantation and increased with polyclonal antibody induction therapy (IRR=1.65, 95%CI 1.02–2.67). Melanoma-specific mortality was higher among transplant recipients than non-recipients (HR 2.98, 95%CI 2.26–3.93). Melanoma exhibits increased incidence and aggressive behavior under transplant-related immunosuppression. Some localized melanomas may result from azathioprine, which acts synergistically with ultraviolet radiation, while T-cell depleting induction therapies may promote late stage tumors. Our findings support sun safety practices and skin screening for transplant recipients. PMID:26270022
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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
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Naturally occurring melanomas in dogs as models for non-UV pathways of human melanomas.
Gillard, Marc; Cadieu, Edouard; De Brito, Clotilde; Abadie, Jérôme; Vergier, Béatrice; Devauchelle, Patrick; Degorce, Frédérique; Dréano, Stephane; Primot, Aline; Dorso, Laetitia; Lagadic, Marie; Galibert, Francis; Hédan, Benoit; Galibert, Marie-Dominique; André, Catherine
2014-01-01
Spontaneously occurring melanomas are frequent in dogs. They appear at the same localizations as in humans, i.e. skin, mucosal sites, nail matrix and eyes. They display variable behaviors: tumors at oral localizations are more frequent and aggressive than at other anatomical sites. Interestingly, dog melanomas are associated with strong breed predispositions and overrepresentation of black-coated dogs. Epidemiological analysis of 2350 affected dogs showed that poodles are at high risk of developing oral melanoma, while schnauzers or Beauce shepherds mostly developped cutaneous melanoma. Clinical and histopathological analyses were performed on a cohort of 153 cases with a 4-yr follow-up. Histopathological characterization showed that most canine tumors are intradermal and homologous to human rare morphological melanomas types - 'nevocytoid type' and 'animal type'-. Tumor cDNA sequencing data, obtained from 95 dogs for six genes, relevant to human melanoma classification, detected somatic mutations in oral melanoma, in NRAS and PTEN genes, at human hotspot sites, but not in BRAF. Altogether, these findings support the relevance of the dog model for comparative oncology of melanomas, especially for the elucidation of non-UV induced pathways. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Axitinib in Treating Patients With Melanoma That is Metastatic or Cannot Be Removed by Surgery
2018-05-08
Extraocular Extension Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIA Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIB Melanoma; Stage IIIC Intraocular Melanoma; Stage IIIC Melanoma; Stage IV Intraocular Melanoma; Stage IV Melanoma
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Patterns of Ultraviolet Radiation Exposure and Skin Cancer Risk: the E3N-SunExp Study.
Savoye, Isabelle; Olsen, Catherine M; Whiteman, David C; Bijon, Anne; Wald, Lucien; Dartois, Laureen; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Kvaskoff, Marina
2018-01-05
While ultraviolet (UV) radiation exposure is a recognized risk factor for skin cancer, associations are complex and few studies have allowed a direct comparison of exposure profiles associated with cutaneous melanoma, basal-cell carcinoma (BCC), and squamous-cell carcinoma (SCC) within a single population. We examined associations between UV exposures and skin cancer risk in a nested case-control study within E3N, a prospective cohort of 98,995 French women born in 1925-1950. In 2008, a lifetime UV exposure questionnaire was sent to all reported skin cancer cases and three controls per case, which were matched on age, county of birth, and education. Analyses were performed using conditional logistic regression and included 366 melanoma cases, 1,027 BCC cases, 165 SCC cases, and 3,647 controls. A history of severe sunburns <25 years was associated with increased risks of all skin cancers (melanoma: OR 2.7; BCC: OR 1.7; SCC: OR 2.0 for ≥6 sunburns vs. none), while sunburns ≥25 years were associated with BCC and SCC only. While high-sun protection factor sunscreen use before age 25 was associated with lower BCC risk (P trend = 0.02), use since age 25 and reapplication of sunscreen were associated with higher risks of all three types of skin cancer. There were positive linear associations between total UV score and risks of BCC (P trend = 0.01) and SCC (P trend = 0.09), but not melanoma. While recreational UV score was strongly associated with BCC, total and residential UV scores were more strongly associated with SCC. Melanoma, BCC, and SCC are associated with different sun exposure profiles in women.
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Abel, G A; Shelton, J; Johnson, S; Elliss-Brookes, L; Lyratzopoulos, G
2015-03-31
Although overall sociodemographic and cancer site variation in the risk of cancer diagnosis through emergency presentation has been previously described, relatively little is known about how this risk may vary differentially by sex, age and deprivation group between patients with a given cancer. Data from the Routes to Diagnosis project on 749,645 patients (2006-2010) with any of 27 cancers that can occur in either sex were analysed. Crude proportions and crude and adjusted odds ratios were calculated for emergency presentation, and interactions between sex, age and deprivation with cancer were examined. The overall proportion of patients diagnosed through emergency presentation varied greatly by cancer. Compared with men, women were at greater risk for emergency presentation for bladder, brain, rectal, liver, stomach, colon and lung cancer (e.g., bladder cancer-specific odds ratio for women vs men, 1.50; 95% CI 1.39-1.60), whereas the opposite was true for oral/oropharyngeal cancer, lymphomas and melanoma (e.g., oropharyngeal cancer-specific odds ratio for women vs men, 0.49; 95% CI 0.32-0.73). Similarly, younger patients were at higher risk for emergency presentation for acute leukaemia, colon, stomach and oesophageal cancer (e.g., colon cancer-specific odds ratio in 35-44- vs 65-74-year-olds, 2.01; 95% CI 1.76-2.30) and older patients for laryngeal, melanoma, thyroid, oral and Hodgkin's lymphoma (e.g., melanoma specific odds ratio in 35-44- vs 65-74-year-olds, 0.20; 95% CI 0.12-0.33). Inequalities in the risk of emergency presentation by deprivation group were greatest for oral/oropharyngeal, anal, laryngeal and small intestine cancers. Among patients with the same cancer, the risk for emergency presentation varies notably by sex, age and deprivation group. The findings suggest that, beyond tumour biology, diagnosis through an emergency route may be associated both with psychosocial processes, which can delay seeking of medical help, and with difficulties in suspecting the diagnosis of cancer after presentation.
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MITF E318K's effect on melanoma risk independent of, but modified by, other risk factors.
Berwick, Marianne; MacArthur, Jamie; Orlow, Irene; Kanetsky, Peter; Begg, Colin B; Luo, Li; Reiner, Anne; Sharma, Ajay; Armstrong, Bruce K; Kricker, Anne; Cust, Anne E; Marrett, Loraine D; Gruber, Stephen B; Anton-Culver, Hoda; Zanetti, Roberto; Rosso, Stefano; Gallagher, Richard P; Dwyer, Terence; Venn, Alison; Busam, Klaus; From, Lynn; White, Kirsten; Thomas, Nancy E
2014-05-01
A rare germline variant in the microphthalmia-associated transcription factor (MITF) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma [odds ratio (OR) 1.7, 95% confidence interval (CI) = 1.1, 2.7, P = 0.03]; adjusted for age, sex, center, age × sex interaction, pigmentation characteristics, family history of melanoma, and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (P for interaction, 0.03) and in those with no moles than some or many moles (P for interaction, <0.01). There was no evidence of interaction between MC1R 'red hair variants' and MITF E318K. Moreover, risk of melanoma among carriers with 'low risk' phenotypes was as great or greater than among those with 'at risk' phenotypes with few exceptions. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Diagnosing malignant melanoma in ambulatory care: a systematic review of clinical prediction rules.
Harrington, Emma; Clyne, Barbara; Wesseling, Nieneke; Sandhu, Harkiran; Armstrong, Laura; Bennett, Holly; Fahey, Tom
2017-03-06
Malignant melanoma has high morbidity and mortality rates. Early diagnosis improves prognosis. Clinical prediction rules (CPRs) can be used to stratify patients with symptoms of suspected malignant melanoma to improve early diagnosis. We conducted a systematic review of CPRs for melanoma diagnosis in ambulatory care. Systematic review. A comprehensive search of PubMed, EMBASE, PROSPERO, CINAHL, the Cochrane Library and SCOPUS was conducted in May 2015, using combinations of keywords and medical subject headings (MeSH) terms. Studies deriving and validating, validating or assessing the impact of a CPR for predicting melanoma diagnosis in ambulatory care were included. Data extraction and methodological quality assessment were guided by the CHARMS checklist. From 16 334 studies reviewed, 51 were included, validating the performance of 24 unique CPRs. Three impact analysis studies were identified. Five studies were set in primary care. The most commonly evaluated CPRs were the ABCD, more than one or uneven distribution of Colour, or a large (greater than 6 mm) Diameter (ABCD) dermoscopy rule (at a cut-point of >4.75; 8 studies; pooled sensitivity 0.85, 95% CI 0.73 to 0.93, specificity 0.72, 95% CI 0.65 to 0.78) and the 7-point dermoscopy checklist (at a cut-point of ≥1 recommending ruling in melanoma; 11 studies; pooled sensitivity 0.77, 95% CI 0.61 to 0.88, specificity 0.80, 95% CI 0.59 to 0.92). The methodological quality of studies varied. At their recommended cut-points, the ABCD dermoscopy rule is more useful for ruling out melanoma than the 7-point dermoscopy checklist. A focus on impact analysis will help translate melanoma risk prediction rules into useful tools for clinical practice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Sentinel lymph node biopsy from the vantage point of an oncologic surgeon.
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.
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The Effect of Exposure to Ultraviolet Radiation in Infancy on Melanoma Risk.
Gefeller, Olaf; Fiessler, Cornelia; Radespiel-Tröger, Martin; Uter, Wolfgang; Pfahlberg, Annette B
2016-01-01
Evidence on the effect of ultraviolet radiation (UVR) exposure in infancy on melanoma risk in later life is scarce. Three recent studies suffering from methodological shortcomings suggested that people born in spring carry a higher melanoma risk. Data from the Bavarian population-based cancer registry on 28374 incident melanoma cases between 2002 and 2012 were analyzed to reexamine this finding. Crude and adjusted analyses - using negative binomial regression models - were performed addressing the relationship. In the crude analysis, the birth months March - May were significantly overrepresented among melanoma cases. However, after additionally adjusting for the birth month distribution of the Bavarian population, the ostensible seasonal effect disappeared. Similar results emerged in all subgroup analyses. Our large registry-based study provides no evidence that people born in spring carry a higher risk for developing melanoma in later life and thus lends no support to the hypothesis of higher UVR-susceptibility during the first months of life.
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Chang, Chih-Chao; Chang, Chih-Hsien; Shen, Chih-Chieh; Chen, Chuan-Lin; Liu, Ren-Shyan; Lin, Ming-Hsien; Wang, Hsin-Ell
2015-05-01
Malignant melanoma expresses a highly aggressive metastasis. Early diagnosis of malignant melanoma is important for patient survival. Radiolabeled benzamides and nicotinamides have been reported to be attractive candidates for malignant melanoma diagnosis as they bind to melanin, a characteristic substance that displays in malignant melanoma, and show high tumor accumulation and retention. Herein, we designed and synthesized a novel (123/131)I-labeled nicotinamide derivative that specifically binds to melanin. (123/131)I-Iochlonicotinamide was prepared with good radiochemical yield (50-70%, decay corrected) and high specific radioactivity (50-80 GBq/μmol). (131)I-Iochlonicotinamide exhibited good in vitro stability (radiochemical purity >95% after a 24-h incubation) in human serum. High uptake of (123/131)I-Iochlonicotinamide in B16F0 melanoma cells compared to that in A375 amelanotic cells demonstrated its selective binding to melanin. Intravenous administration of (123/131)I-Iochlonicotinamide in a melanoma-bearing mouse model revealed high uptake in melanotic melanoma and high tumor-to-muscle ratio. MicroSPECT scan of (123/131)I-Iochlonicotinamide injected mice also displayed high contrast tumor imaging as compared with normal organs. The radiation-absorbed dose projection for the administration of (131)I-Iochlonicotinamide to human was based on the results of biodistribution study. The effective dose appears to be approximately 0.44 mSv/MBq(-1). The specific binding of (123/131)I-Iochlonicotinamide to melanin along with a prolonged tumor retention and acceptable projected human dosimetry suggest that it may be a promising theranostic agent for treating malignant melanoma. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Ong, Eugene Liat Hui; Goldacre, Raph; Goldacre, Michael
2014-09-01
There is evidence that people with Parkinson's disease (PD) have a decreased risk of developing cancer. PD has also variably been shown to be associated with an increased risk of cancers like melanoma and breast. We investigated this relationship in a very large cohort of PD patients. We constructed two cohorts of people from an all-England record-linked hospital and mortality dataset spanning 1999-2011. One cohort comprised people with a record of PD; the other comprised people without a record of PD. We 'followed up' these two cohorts to determine observed and expected numbers of people with subsequent primary cancers in each, based on person-years at risk, and calculated standardised rate ratios (RRs). In 219,194 people with PD, the RR for all subsequent primary malignant cancers combined was 0.92 (95% confidence interval (CI) 0.91-0.93). Increased RRs (p<0.05) were found for six out of the 31 cancer types investigated, including breast, melanoma, uterus, kidney, and neurological malignancies. Decreased RRs were found for 11 cancer sites, including lung and colon cancer. We corroborate the findings of a reduced risk for the development of cancers in PD patients shown in smaller studies, including cancers associated and not known to be associated with smoking; and of an increased risk of melanoma and breast cancer. To the best of our knowledge, this is the first study to report an association between PD and elevated rates of uterine and renal cancer. Further work is warranted to understand the mechanisms behind these findings. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts.
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.
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van Rooijen, Ellen; Fazio, Maurizio; Zon, Leonard I
2017-07-01
Melanoma is the most aggressive and deadliest form of skin cancer. A detailed knowledge of the cellular, molecular, and genetic events underlying melanoma progression is highly relevant to diagnosis, prognosis and risk stratification, and the development of new therapies. In the last decade, zebrafish have emerged as a valuable model system for the study of melanoma. Pathway conservation, coupled with the availability of robust genetic, transgenic, and chemical tools, has made the zebrafish a powerful model for identifying novel disease genes, visualizing cancer initiation, interrogating tumor-microenvironment interactions, and discovering new therapeutics that regulate melanocyte and melanoma development. In this review, we will give an overview of these studies, and highlight recent advancements that will help unravel melanoma pathogenesis and impact human disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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AZD2171 in Treating Patients With Recurrent or Stage IV Melanoma
2015-06-01
Acral Lentiginous Malignant Melanoma; Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Intraocular Melanoma; Iris Melanoma; Lentigo Maligna Malignant Melanoma; Recurrent Melanoma; Stage, Intraocular Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma
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Long-term effects of laser-imiquimod combination in the treatment of late-stage melanoma patients
NASA Astrophysics Data System (ADS)
Naylor, Mark F.; Le, Henry; Li, Xiaosong; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.
2012-03-01
Topical application of a potent immunological modulator, imiquimod, followed by laser irradiation has been used for the treatment of late-stage melanoma patients. This novel approach, laser-assisted laser immunotherapy (LIT), targets the root course of melanoma, a highly metastatic cancer. We started a phase I clinical trial in 2006 with promising initial outcomes. The laser-imiquimod combination showed significant palliative effects for these patients with multiple treatment cycles. For the returning patients, we found that the recurrent tumors were less aggressive than usually seen in untreated patients. The current protocol uses a light-absorbing dye for selective laser photothermal interaction with a non-invasive treatment mode. It has limitations for patient treatment, particularly for large, deeper tumors, and for patients with dark pigmented skins. This study provides some information on the treated patients (both stage IV and stage IV) during the past several years. We also discuss the future directions of LIT, particularly in the area of photothermal treatment mode with a new approach of interstitial irradiation. The current results in melanoma treatment using LIT indicate that the combination of photothermal therapy and immunological stimulation may hold the key for the treatment of late-stage, metastatic cancers, not only for cutaneous cancers such as melanoma and breast cancer, but also for deep and internal tumors using different operations modes such as interstitial laser irradiation.
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Vaccine Therapy in Treating Patients With Stage IIC-IV Melanoma
2014-05-20
Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Iris Melanoma; Metastatic Intraocular Melanoma; Mucosal Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage IIC Melanoma; Stage IIIA Intraocular Melanoma; Stage IIIA Melanoma; Stage IIIB Intraocular Melanoma; Stage IIIB Melanoma; Stage IIIC Intraocular Melanoma; Stage IIIC Melanoma; Stage IV Intraocular Melanoma; Stage IV Melanoma
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Quantitative Proteomics Identifies Activation of Hallmark Pathways of Cancer in Patient Melanoma.
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.
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Non-melanoma Skin Cancer in Canada Chapter 2: Primary Prevention of Non-melanoma Skin Cancer.
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.
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Sun exposure and risk of melanoma
Oliveria, S A; Saraiya, M; Geller, A C; Heneghan, M K; Jorgensen, C
2006-01-01
Background As skin cancer education programmes directed to children and adolescents continue to expand, an epidemiological basis for these programmes is necessary to target efforts and plan for further evaluation. Aims To summarise the epidemiological evidence on sun exposure during childhood and adolescence and melanoma risk. Methods A literature review was conducted using Medline (1966 to December 2004) to identify articles relating to sun exposure and melanoma. The review was restricted to studies that included sun exposure information on subjects 18 years of age or younger. Results Migrant studies generally indicate an increased melanoma risk in individuals who spent childhood in sunny geographical locations, and decreasing melanoma risk with older age at arrival. Individuals who resided in geographical locations close to the equator or close to the coast during childhood and/or adolescence have an increased melanoma risk compared to those who lived at higher latitudes or never lived near the coast. The intermittent exposure hypothesis remains controversial; some studies indicate that children and adolescents who received intermittent sun exposure during vacation, recreation, or occupation are at increased melanoma risk as adults, but more recent studies suggest intermittent exposure to have a protective effect. The majority of sunburn studies suggest a positive association between early age sunburn and subsequent risk of melanoma. Conclusion Future research efforts should focus on: (1) clarifying the relation between sun exposure and melanoma; (2) conducting prospective studies; (3) assessing sun exposure during different time periods of life using a reliable and quantitative method; (4) obtaining information on protective measures; and (5) examining the interrelations between ability to tan, propensity to burn, skin type, history of sunburns, timing and pattern of sun exposure, number of nevi, and other host factors in the child and adolescent populations. PMID:16326797
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2015-04-14
Ciliary Body and Choroid Melanoma, Medium/Large Size; Extraocular Extension Melanoma; Iris Melanoma; Stage IIB Melanoma; Stage IIC Melanoma; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma
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Recombinant Interferon Alfa-2b in Treating Patients With Melanoma
2016-05-17
Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma
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Sentinel Lymph Node Biopsy in Nonmelanoma Skin Cancer Patients
Matthey-Giè, Marie-Laure; Boubaker, Ariane; Letovanec, Igor; Demartines, Nicolas; Matter, Maurice
2013-01-01
The management of lymph nodes in nonmelanoma skin cancer patients is currently still debated. Merkel cell carcinoma (MCC), squamous cell carcinoma (SCC), pigmented epithelioid melanocytoma (PEM), and other rare skin neoplasms have a well-known risk to spread to regional lymph nodes. The use of sentinel lymph node biopsy (SLNB) could be a promising procedure to assess this risk in clinically N0 patients. Metastatic SNs have been observed in 4.5–28% SCC (according to risk factors), in 9–42% MCC, and in 14–57% PEM. We observed overall 30.8% positive SNs in 13 consecutive patients operated for high-risk nonmelanoma skin cancer between 2002 and 2011 in our institution. These high rates support recommendation to implement SLNB for nonmelanoma skin cancer especially for SCC patients. Completion lymph node dissection following positive SNs is also a matter of discussion especially in PEM. It must be remembered that a definitive survival benefit of SLNB in melanoma patients has not been proven yet. However, because of its low morbidity when compared to empiric elective lymph node dissection or radiation therapy of lymphatic basins, SLNB has allowed sparing a lot of morbidity and could therefore be used in nonmelanoma skin cancer patients, even though a significant impact on survival has not been demonstrated. PMID:23476781
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[Mucosal melanomas of the head and neck: State of the art and current controversies].
Troussier, Idriss; Baglin, Anne-Catherine; Marcy, Pierre-Yves; Even, Caroline; Moya-Plana, Antoine; Krengli, Marco; Thariat, Juliette
2015-06-01
Mucosal melanomas of the head and neck (sinonasal and oral cavity) account for 1% of neoplasms, 4% of all melanomas and over 50% of all mucosal melanomas. They have a high metastatic potential. Five-year overall survival does not exceed 30%. Diagnosis may be difficult and includes adequate immunohistochemical staining. Risk factors, presentation and molecular biology are different from those of cutaneous melanomas. The mainstay of treatment is surgery and postoperative radiotherapy. Endoscopic surgery should be evaluated prospectively. Neck dissection is recommended for N0 oral cavity melanomas, while it can generally be omitted for sinonasal melanomas. Inoperable tumors can be treated with exclusive radiotherapy. Molecular guidance for metastatic cases is a relevant option despite low level of evidence, based on the rarity of disease and low response rates to chemotherapy. c-KIT inhibitors and immunotherapy appear promising. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.
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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.
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Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients.
Labarrière, Nathalie; Pandolfino, Marie-Christine; Gervois, Nadine; Khammari, Amir; Tessier, Marie-Hélène; Dréno, Brigitte; Jotereau, Francine
2002-11-01
Adoptive therapy for cancer using tumor-infiltrating lymphocytes (TIL) has mainly been investigated in cancer patients with advanced stage disease. The limited clinical success has not been encouraging, although this might be explained by poor TIL specificity and/or high tumor burden. To re-evaluate the effectiveness of adoptive therapy, we analyzed the capacity of tumor-reactive TIL injection in preventing the further development of disease in stage III melanoma patients after complete tumor resection. A phase II/III randomized trial was performed on 88 melanoma patients, who received autologous TIL plus interleukin-2 (IL-2) or IL-2 only. The duration of relapse-free survival was analyzed, taking into account the immunological specificity of injected TIL and the number of metastatic lymph nodes removed before treatment. Kaplan-Meyer analysis revealed that the injection of tumor-reactive TIL was statistically correlated with prolonged relapse-free survival in patients with only one metastatic lymph node. Therefore, improved clinical outcome could be obtained after adoptive therapy by selecting appropriate groups of patients and monitoring the specificity of the injected TIL populations.
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Human Papilloma Virus in Melanoma Biopsy Specimens and Its Relation to Melanoma Progression
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
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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
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Do We Know What Causes Melanoma Skin Cancer?
... Skin Cancer Causes, Risk Factors, and Prevention What Causes Melanoma Skin Cancer? Many risk factors for melanoma have been found, ... it’s not always clear exactly how they might cause cancer. For example, while most moles never turn into ...
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Rare Presentations of Primary Melanoma and Special Populations: A Systematic Review
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
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Stefanaki, Irene; Panagiotou, Orestis A; Kodela, Elisavet; Gogas, Helen; Kypreou, Katerina P; Chatzinasiou, Foteini; Nikolaou, Vasiliki; Plaka, Michaela; Kalfa, Iro; Antoniou, Christina; Ioannidis, John P A; Evangelou, Evangelos; Stratigos, Alexander J
2013-01-01
Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value. Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs. Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982--SLC45A2, rs12203592--IRF4, rs258322--CDK10, rs1805007--MC1R, rs1805008--MC1R, rs910873--PIGU, rs17305573--PIGU, and rs1885120--MTAP) and higher for one SNP (rs6001027--PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22-2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34-0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03-9.43; P = 2×10⁻⁵). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66). Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.
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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
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Association between family cancer history and risk of pancreatic cancer.
Schulte, Annaka; Pandeya, Nirmala; Fawcett, Jonathan; Fritschi, Lin; Klein, Kerenaftali; Risch, Harvey A; Webb, Penelope M; Whiteman, David C; Neale, Rachel E
2016-12-01
Family history of pancreatic adenocarcinoma is an established risk factor for the disease. However, associations of pancreatic cancer with other familial cancers are less clear. We analyzed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, to investigate associations between family history of various cancer types and risk of pancreatic cancer. Our study included 591 pancreatic cancer patients and 646 controls, all of whom self-reported the histories of cancer in their first-degree relatives. We used logistic regression to estimate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Based on our results, we conducted a systematic literature review using the Medline (OVID) database to identify articles pertaining to the association between family history of melanoma and risk of pancreatic cancer. A meta-analysis including associations in five published studies, unpublished results from a study co-author and the QPCS results was then performed using the DerSimonian and Laird random-effects model. Cases were more likely than controls to report a family history of pancreatic cancer (OR 2.20, 95% CI 1.16-4.19) and melanoma (OR 1.74, 95% CI 1.03-2.95), but not of breast, ovarian, respiratory, other gastrointestinal or prostate cancer. Meta-analysis of melanoma family history and pancreatic cancer risk yielded an OR of 1.22 (95% CI 1.00-1.51). Our results yield further evidence of increased risk of pancreatic cancer in those with family histories of the disease. We also provide suggestive evidence of an association between family history of melanoma and risk of pancreatic cancer. Copyright © 2016. Published by Elsevier Ltd.
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Sentinel lymph node biopsy in thick malignant melanoma: A 16-year single unit experience.
Hunger, Robert E; Michel, Aude; Seyed Jafari, S Morteza; Shafighi, Maziar
2015-01-01
The role of sentinel lymph node biopsy (SLNB) and its benefits in patients with thick melanoma is still controversial. We evaluated the clinical effect of SLNB in patients with thick melanoma. We performed a retrospective cohort review (1996-2012) of thick melanomas. Collected data included the patient and tumour characteristics. Locoregional recurrence, distant metastases, disease free and overall survival were compared between the patients with positive and negative SLNB. 126 thick melanomas with a mean age of 64.09 years were included in the study. Positive SLNB were found in 47 (37.3%) patients. Significantly more locoregional recurrence (P = 0.002) and distant metastases (P = 0.030) were detected in the patients with positive SLNB. Furthermore, the patients with negative SLNB showed significantly better disease free survival (P = 0.021). Positive SLNB might be prognostic factor in thick melanoma and aggravates the outcome of thick melanomas.
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TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma.
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.
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Loquai, C; Scheurich, V; Syring, N; Schmidtmann, I; Müller-Brenne, T; Werner, A; Grabbe, S; Beutel, M E
2014-12-01
Although psychosocial distress has been evaluated well in cancer entities like breast or prostate cancer, its impact on melanoma patients still needs to be characterized. The objectives of this study were to (i) evaluate psychosocial distress in melanoma patients using an expert rating instrument [basic documentation for psycho-oncology short version (PO-Bado SF)]; (ii) determine associated demographic and clinical variables; and (iii) assess the acceptance of using PO-Bado SF as a routine procedure in a skin cancer unit. A cross-sectional group of 696 melanoma patients was recruited. During the routine contact, doctors assessed the patients subjective distress using PO-Bado SF. Sociodemographic data, tumour data, treatment and the course of the disease were extracted from the patients' charts. PO-Bado SF was completed in 688 of 696 (99%) participating patients, revealing a high acceptance. In 51 (7%) patients, the PO-Bado SF cut-off score indicated the potential need of psychosocial support. Patients with previous or ongoing radiotherapy, a history of major surgery due to organ metastases, younger age and shorter time since diagnosis were considered significantly more distressed than patients without these criteria. Patients were most distressed by suffering from anxiety/worries and/or tensions. In younger patients emotional variables and other problems like social or family problems were deemed more relevant while functional limitations in daily living were reasons for higher distress in older patients. PO-Bado SF is a useful, well-accepted, practical and economic screening tool to identify distressed melanoma patients. Although most melanoma patients seem to cope well with their disease, special attention should be given to young patients in the first years after initial diagnosis and to patients with advanced disease, radiotherapy and major surgery due to their disease. Combination of expert rating tools with self-report screening instruments could further characterize the specific sources of distress to optimize psychosocial support. © 2014 European Academy of Dermatology and Venereology.
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Dry Eye Syndrome After Proton Therapy of Ocular Melanomas
DOE Office of Scientific and Technical Information (OSTI.GOV)
Thariat, Juliette, E-mail: jthariat@gmail.com; Maschi, Celia; Lanteri, Sara
Purpose: To investigate whether proton therapy (PT) performs safely in superotemporal melanomas, in terms of risk of dry-eye syndrome (DES). Methods and Materials: Tumor location, DES grade, and dose to ocular structures were analyzed in patients undergoing PT (2005-2015) with 52 Gy (prescribed dose, not accounting for biologic effectiveness correction of 1.1). Prognostic factors of DES and severe DES (sDES, grades 2-3) were determined with Cox proportional hazard models. Visual acuity deterioration and enucleation rates were compared by sDES and tumor locations. Results: Median follow-up was 44 months (interquartile range, 18-60 months). Of 853 patients (mean age, 64 years), 30.5% had temporal and 11.4% superotemporalmore » tumors. Five-year incidence of DES and sDES was 23.0% (95% confidence interval [CI] 19.0%-27.7%) and 10.9% (95% CI 8.2%-14.4%), respectively. Multivariable analysis showed a higher risk for sDES in superotemporal (hazard ratio [HR] 5.82, 95% CI 2.72-12.45) and temporal tumors (HR 2.63, 95% CI 1.28-5.42), age ≥70 years (HR 1.90, 95% CI 1.09-3.32), distance to optic disk ≥5 mm (HR 2.71, 95% CI 1.52-4.84), ≥35% of retina receiving 12 Gy (HR 2.98, 95% CI 1.54-5.77), and eyelid rim irradiation (HR 2.68, 95% CI 1.49-4.80). The same risk factors were found for DES. Visual acuity deteriorated more in patients with sDES (0.86 ± 1.10 vs 0.64 ± 0.98 logMAR, P=.034) but not between superotemporal/temporal and other locations (P=.890). Enucleation rates were independent of sDES (P=.707) and tumor locations (P=.729). Conclusions: Severe DES was more frequent in superotemporal/temporal melanomas. Incidence of vision deterioration and enucleation was no higher in patients with superotemporal melanoma than in patients with tumors in other locations. Tumor location should not contraindicate PT.« less
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2016-05-06
Acral Lentiginous Malignant Melanoma; Lentigo Maligna Malignant Melanoma; Nodular Malignant Melanoma; Recurrent Melanoma; Solar Radiation-related Skin Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma
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Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades
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
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Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades.
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.
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Aya-Bonilla, Carlos A; Marsavela, Gabriela; Freeman, James B; Lomma, Chris; Frank, Markus H; Khattak, Muhammad A; Meniawy, Tarek M; Millward, Michael; Warkiani, Majid E; Gray, Elin S; Ziman, Mel
2017-09-15
Circulating Tumour Cells (CTCs) are promising cancer biomarkers. Several methods have been developed to isolate CTCs from blood samples. However, the isolation of melanoma CTCs is very challenging as a result of their extraordinary heterogeneity, which has hindered their biological and clinical study. Thus, methods that isolate CTCs based on their physical properties, rather than surface marker expression, such as microfluidic devices, are greatly needed in melanoma. Here, we assessed the ability of the slanted spiral microfluidic device to isolate melanoma CTCs via label-free enrichment. We demonstrated that this device yields recovery rates of spiked melanoma cells of over 80% and 55%, after one or two rounds of enrichment, respectively. Concurrently, a two to three log reduction of white blood cells was achieved with one or two rounds of enrichment, respectively. We characterised the isolated CTCs using multimarker flow cytometry, immunocytochemistry and gene expression. The results demonstrated that CTCs from metastatic melanoma patients were highly heterogeneous and commonly expressed stem-like markers such as PAX3 and ABCB5. The implementation of the slanted microfluidic device for melanoma CTC isolation enables further understanding of the biology of melanoma metastasis for biomarker development and to inform future treatment approaches.
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CD200 is induced by ERK and is a potential therapeutic target in melanoma
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
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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
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2018-04-26
Ciliary Body and Choroid Melanoma, Medium/Large Size; Extraocular Extension Melanoma; Iris Melanoma; Metastatic Intraocular Melanoma; Recurrent Intraocular Melanoma; Recurrent Melanoma; Stage III Melanoma; Stage IV Melanoma
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Use of Ruthenium-106 Brachytherapy for Iris Melanoma: The Scottish Experience.
Agraval, Umiya; Sobti, Manvi; Russell, Heather C; Lockington, David; Ritchie, Diana; Cauchi, Paul; Kemp, Ewan G; Chadha, Vikas
2018-01-01
To analyse long-term outcomes of ruthenium-106 ( 106 Ru) plaque brachytherapy for the treatment of iris melanoma. We retrospectively reviewed medical records of 19 consecutive patients with pure iris melanoma treated with 106 Ru plaque brachytherapy between 1998 and 2016 at the Scottish Ophthalmic Oncology Service, Glasgow. The iris melanoma was treated with a ruthenium plaque placed on the corneal surface to deliver a surface dose of 555 Gy. We analysed vision preservation, local tumour control, radiation-related complications, eye retention rates, symptomatic metastasis and melanoma-related mortality. The mean largest basal diameter of the lesions was 3.50±1.42 mm (range 1.6-6.5 mm), and the mean maximum height was 1.47±0.65 mm (range 0.7-2.8 mm). The tumour control and eye retention were 100% at a mean follow-up of 62 months (range 6-195 months). A 62% reduction in tumour height was observed on ultrasonography. Complications included cataract (68%), dry eye (47%), uveitis (37%) and scleral thinning (5%). At the final follow-up visit, the mean loss of Snellen visual acuity was 1.11±2.90 lines and vision of 6/9 or better was maintained in 53% of patients. None of the patients had evidence of symptomatic metastasis (non-imaged) or melanoma-related mortality. 106 Ru plaque treatment for iris melanoma was highly effective a high tumour control, no tumour recurrences and a relatively a low complication rate. © 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.
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Validation of the VE1 Immunostain for the BRAF V600E Mutation in Melanoma
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
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Sutton, Selina K; Carter, Daniel R; Kim, Patrick; Tan, Owen; Arndt, Greg M; Zhang, Xu Dong; Baell, Jonathan; Noll, Benjamin D; Wang, Shudong; Kumar, Naresh; McArthur, Grant A; Cheung, Belamy B; Marshall, Glenn M
2016-08-09
There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease.
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Sutton, Selina K.; Carter, Daniel R.; Kim, Patrick; Tan, Owen; Arndt, Greg M.; Zhang, Xu Dong; Baell, Jonathan; Noll, Benjamin D.; Wang, Shudong; Kumar, Naresh; McArthur, Grant A.; Cheung, Belamy B.; Marshall, Glenn M.
2016-01-01
There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease. PMID:27447557
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Lobo, João; Pinto, Carla; Freitas, Micaela; Pinheiro, Manuela; Vizcaino, Rámon; Oliva, Esther; Teixeira, Manuel R; Jerónimo, Carmen; Bartosch, Carla
2017-03-01
Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient's uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.
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Kim, Sun-Hee; Hashimoto, Yuuri; Cho, Sung-Nam; Roszik, Jason; Milton, Denái R.; Dal, Fulya; Kim, Sangwon F.; Menter, David G.; Yang, Peiying; Ekmekcioglu, Suhendan; Grimm, Elizabeth A.
2016-01-01
Summary COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy. PMID:26801201
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Ragan, Agnieszka R; Lesniak, Anna; Bochynska-Czyz, Marta; Kosson, Anna; Szymanska, Hanna; Pysniak, Kazimiera; Gajewska, Marta; Lipkowski, Andrzej W; Sacharczuk, Mariusz
2013-09-01
Both chronic stress conditions and hyperergic reaction to environmental stress are known to enhance cancer susceptibility. We described two mouse lines that displayed high (HA) and low (LA) swim stress-induced analgesia (SSIA) to investigate the relationship between inherited differences in sensitivity to stress and proneness to an increased growth rate of subcutaneously inoculated melanoma. These lines display several genetic and physiological differences, among which distinct sensitivity to mutagens and susceptibility to cancer are especially noticeable. High analgesic mice display high proneness both to stress and a rapid local spread of B16F0 melanoma. However, stress-resistant LA mice do not develop melanoma tumors after inoculation, or if so, tumors regress spontaneously. We found that the chronic mild stress (CMS) procedure leads to enhanced interlinear differences in melanoma susceptibility. Tumors developed faster in stress conditions in both lines. However, LA mice still displayed a tendency for spontaneous regression, and 50% of LA mice did not develop a tumor, even under stressed conditions. Moreover, we showed that chronic stress, but not tumor progression, induces depressive behavior, which may be an important clue in cancer therapy. Our results clearly indicate how the interaction between genetic susceptibility to stress and environmental stress determine the risk and progression of melanoma. To our knowledge, HA/LA mouse lines are the first animal models of distinct melanoma progression mediated by inherited differences in stress reactivity.
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Kähler, Katharina C; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Müller-Brenne, Tina; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; Augustin, Matthias
2018-05-25
After more than two decades with interferon alfa-2a and 2b (IFN) as the only approved drugs in the adjuvant setting for melanoma, new treatment approaches like immune checkpoint inhibitors and BRAF-MEK inhibitors improve the progression free survival (PFS) and also the overall survival (OS). We compared physicians' preferences ("utilities") for health states associated with IFN therapy to their patients' preferences. Utilities describe a preference for a specific health state on a scale of 0 (as bad as death) to 1.0 (perfect health). We assessed utilities for health states associated with adjuvant IFN using the standard gamble technique in 108 physicians and 130 melanoma patients. Four IFN toxicity scenarios and three outcome scenarios were given to the participants. Both groups were asked for the 5-year disease free survival (DFS) they would need to accept the described IFN-related side effects. In both groups, utilities for melanoma relapse were significantly lower than for IFN side effects, showing that toxicity was more acceptable than relapse. Physicians indicated higher utilities for each scenario and needed lower 5-year DFS both in case of mild-to-moderate and severe side effects. Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, while physicians only required a chance of 40% and 50%, respectively. Both physicians and patients rated melanoma recurrence much lower than even severe IFN side effects. In direct comparison, physicians rated cancer-related scenarios more positively and accepted IFN toxicity for an even lower treatment benefit.
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Endometriosis and the risk of skin cancer: a prospective cohort study.
Farland, Leslie V; Lorrain, Simon; Missmer, Stacey A; Dartois, Laureen; Cervenka, Iris; Savoye, Isabelle; Mesrine, Sylvie; Boutron-Ruault, Marie-Christine; Kvaskoff, Marina
2017-10-01
Endometriosis has been associated with an increased risk of skin melanoma. However, associations with other skin cancer types and how they compare with melanoma are unclear. Our objective was to prospectively investigate the relationships between endometriosis and risk of non-melanoma and melanoma skin cancers. E3N is a prospective cohort of 98,995 French women aged 40-65 years in 1990. Data on surgically confirmed endometriosis and skin cancer diagnoses were collected every 2-3 years through self-report, with skin cancer cases confirmed through pathology reports. Hazard Ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox regression models. Between 1990 and 2008, 535 melanoma, 247 squamous-cell carcinoma (SCC), and 1,712 basal-cell carcinoma (BCC) cases were ascertained. Endometriosis was associated with an increased overall risk of skin cancer (HR 1.28, 95% CI 1.05-1.55). When considering skin cancer type, endometriosis was associated with melanoma risk (HR 1.64, 95% CI 1.15-2.35), but not with SCC (HR 1.21, 95% CI 0.62-2.36) or BCC (HR 1.16, 95% CI 0.91-1.48) (non-melanoma skin cancers combined: HR 1.17, 95% CI 0.93-1.46), although no heterogeneity was detected across skin cancer types (Phomogeneity = 0.13). These data support an association between a personal history of endometriosis and the risk of skin cancer and suggest that the association is strongest for melanoma.
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Mayer, Simone; Teufel, Martin; Schaeffeler, Norbert; Keim, Ulrike; Garbe, Claus; Eigentler, Thomas Kurt; Zipfel, Stephan; Forschner, Andrea
2017-09-01
Despite an increasing number of promising treatment options, only a limited number of studies concerning melanoma patients' psycho-oncological distress have been carried out. However, multiple screening tools are in use to assess the need for psycho-oncological support. This study aimed first to identify parameters in melanoma patients that are associated with a higher risk for being psycho-oncologically distressed and second to compare patients' self-evaluation concerning the need for psycho-oncological support with the results of established screening tools.We performed a cross-sectional study including 254 melanoma patients from the Center for Dermatooncology at the University of Tuebingen. The study was performed between June 2010 and February 2013. Several screening instruments were included: the Distress Thermometer (DT), Hospital Anxiety and Depression Scale and the patients' subjective evaluation concerning psycho-oncological support. Binary logistic regression was performed to identify factors that indicate the need for psycho-oncological support.Patients' subjective evaluation concerning the need for psycho-oncological support, female gender, and psychotherapeutic or psychiatric treatment at present or in the past had the highest impact on values above threshold in the DT. The odds ratio of patients' self-evaluation (9.89) was even higher than somatic factors like female gender (1.85), duration of illness (0.99), or increasing age (0.97). Patients' self-evaluation concerning the need for psycho-oncological support indicated a moderate correlation with the results of the screening tools included.In addition to the results obtained by screening tools like the DT, we could demonstrate that patients' self-evaluation is an important instrument to identify patients who need psycho-oncological support.
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Association between month of birth and melanoma risk: fact or fiction?
Fiessler, Cornelia; Pfahlberg, Annette B; Keller, Andrea K; Radespiel-Tröger, Martin; Uter, Wolfgang; Gefeller, Olaf
2017-04-01
Evidence on the effect of ultraviolet radiation (UVR) exposure in infancy on melanoma risk in later life is scarce. Three recent studies suggest that people born in spring carry a higher melanoma risk. Our study aimed at verifying whether such a seasonal pattern of melanoma risk actually exists. Data from the population-based Cancer Registry Bavaria (CRB) on the birth months of 28 374 incident melanoma cases between 2002 and 2012 were analysed and compared with data from the Bavarian State Office for Statistics and Data Processing on the birth month distribution in the Bavarian population. Crude and adjusted analyses using negative binomial regression models were performed in the total study group and supplemented by several subgroup analyses. In the crude analysis, the birth months March-May were over-represented among melanoma cases. Negative binomial regression models adjusted only for sex and birth year revealed a seasonal association between melanoma risk and birth month with 13-21% higher relative incidence rates for March, April and May compared with the reference December. However, after additionally adjusting for the birth month distribution of the Bavarian population, these risk estimates decreased markedly and no association with the birth month was observed any more. Similar results emerged in all subgroup analyses. Our large registry-based study provides no evidence that people born in spring carry a higher risk for developing melanoma in later life and thus lends no support to the hypothesis of higher UVR susceptibility during the first months of life. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
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A UV-independent pathway to melanoma carcinogenesis in the redhair-fairskin background
Mitra, Devarati; Luo, Xi; Morgan, Ann; Wang, Jin; Hoang, Mai P.; Lo, Jennifer; Guerrero, Candace R.; Lennerz, Jochen K.; Mihm, Martin C.; Wargo, Jennifer A.; Robinson, Kathleen C.; Devi, Suprabha P.; Vanover, Jillian C.; D’Orazio, John A.; McMahon, Martin; Bosenberg, Marcus W.; Haigis, Kevin M.; Haber, Daniel A.; Wang, Yinsheng; Fisher, David E.
2012-01-01
People with pale skin, red hair, freckles, and an inability to tan—the “redhair/fairskin” phenotype— are at highest risk of developing melanoma, compared to all other pigmentation types1. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the Melanocortin 1 receptor (MC1R) gene. MC1R encodes a cAMP stimulating G-protein coupled receptor that controls pigment production. Minimal receptor activity, as in redhair/fairskin polymorphisms, produces red/yellow pheomelanin pigment, while increasing MC1R activity stimulates production of black/brown eumelanin2. Pheomelanin has weak UV shielding capacity relative to eumelanin and has been shown to amplify UVA-induced reactive oxygen species (ROS) 3–5. Several observations, however, complicate the assumption that melanoma risk is completely UV dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and UV signature mutations are infrequently oncogenic drivers6. While linkage of melanoma risk to UV exposure is beyond doubt, UV-independent events are also likely to play a significant role1,7. Here, we introduced into mice carrying an inactivating mutation in the Mc1r gene (who exhibit a phenotype analogous to redhair/fairskin humans), a conditional, melanocyte-targeted allele of the most commonly mutated melanoma oncogene, BRafV600E. We observed a high incidence of invasive melanomas without providing additional gene aberrations or UV exposure. To investigate the mechanism of UV-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1re/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1re/e mouse skin. These data suggest that the pheomelanin pigment pathway produces UV-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. While UV protection remains important, additional strategies may be required for optimal melanoma prevention. PMID:23123854
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2017-06-05
Recurrent Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma
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2015-01-23
Recurrent Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Skin Melanoma
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Pedersen, Sidsel Arnspang; Schmidt, Sigrun Alba Johannesdottir; Klausen, Siri; Pottegård, Anton; Friis, Søren; Hölmich, Lisbet Rosenkrantz; Gaist, David
2018-05-01
The nationwide Danish Cancer Registry and the Danish Melanoma Database both record data on melanoma for purposes of monitoring, quality assurance, and research. However, the data quality of the Cancer Registry and the Melanoma Database has not been formally evaluated. We estimated the positive predictive value (PPV) of melanoma diagnosis for random samples of 200 patients from the Cancer Registry (n = 200) and the Melanoma Database (n = 200) during 2004-2014, using the Danish Pathology Registry as "gold standard" reference. We further validated tumor characteristics in the Cancer Registry and the Melanoma Database. Additionally, we estimated the PPV of in situ melanoma diagnoses in the Melanoma Database, and the sensitivity of melanoma diagnoses in 2004-2014. The PPVs of melanoma in the Cancer Registry and the Melanoma Database were 97% (95% CI = 94, 99) and 100%. The sensitivity was 90% in the Cancer Registry and 77% in the Melanoma Database. The PPV of in situ melanomas in the Melanoma Database was 97% and the sensitivity was 56%. In the Melanoma Database, we observed PPVs of ulceration of 75% and Breslow thickness of 96%. The PPV of histologic subtypes varied between 87% and 100% in the Cancer Registry and 93% and 100% in the Melanoma Database. The PPVs for anatomical localization were 83%-95% in the Cancer Registry and 93%-100% in the Melanoma Database. The data quality in both the Cancer Registry and the Melanoma Database is high, supporting their use in epidemiologic studies.
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2017-11-15
Stage 0 Skin Melanoma; Stage I Skin Melanoma; Stage IA Skin Melanoma; Stage IB Skin Melanoma; Stage II Skin Melanoma; Stage IIA Skin Melanoma; Stage IIB Skin Melanoma; Stage IIC Skin Melanoma; Stage III Skin Melanoma; Stage IIIA Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma
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Ferrucci, Leah M.; Vogel, Rachel Isaksson; Cartmel, Brenda; Lazovich, DeAnn; Mayne, Susan T.
2014-01-01
Background Indoor tanning increases skin cancer risk. Beyond early research describing melanoma and sun lamps, few recent reports describe where individuals indoor tan and whether skin cancer risk varies by location (business, home-based). Objective Assess where individuals tanned indoors and skin cancer risk by tanning device location. Methods Multivariate logistic regression in two US case-control studies of melanoma (1,161 cases, 1,083 controls, ages 25–59) and early-onset basal cell carcinoma (BCC) (375 cases, 382 controls, under age 40) conducted between 2004 and 2010. Results Most indoor tanners (86.4–95.1%), especially younger individuals, tanned exclusively in businesses. Persons who used indoor tanning exclusively in businesses were at increased risk of melanoma (OR=1.82, 95% CI=1.47–2.26) and BCC (OR=1.69, 95% CI=1.15–2.48) compared to non-users. Melanoma risk was also increased in the small number who reported tanning indoors only at home relative to non-users (OR=4.14, 95% CI=1.75–9.78); 67.6% used sun lamps. Limitations Self-reported tanning, potential recall bias. Conclusion Business only tanning, despite claims of “safe" tanning, was positively associated with a significant risk of melanoma and BCC. Home tanning was uncommon and mostly from sun lamps which were rarely used by younger participants. Regardless of location, indoor tanning was associated with increased risk of skin cancer. PMID:25062934
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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.
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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
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3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines.
Qin, J-Z; Xin, H; Nickoloff, B J
2010-05-28
Clinicians successfully utilize high uptake of radiolabeled glucose via PET scanning to localize metastases in melanoma patients. To take advantage of this altered metabolome, 3-bromopyruvate (BrPA) was used to overcome the notorious resistance of melanoma to cell death. Using four melanoma cell lines, BrPA triggered caspase independent necrosis in two lines, whilst the other two lines were resistant to killing. Mechanistically, sensitive cells differed from resistant cells by; constitutively lower levels of glutathione, reduction of glutathione by BrPA only in sensitive cells; increased superoxide anion reactive oxygen species, loss of outer mitochondrial membrane permeability, and rapid ATP depletion. Sensitive cell killing was blocked by N-acetylcysteine or glutathione. When glutathione levels were reduced in resistant cell lines, they became sensitive to killing by BrPA. Taken together, these results identify a metabolic-based Achilles' heel in melanoma cells to be exploited by use of BrPA. Future pre-clinical and clinical trials are warranted to translate these results into improved patient care for individuals suffering from metastatic melanoma. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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3-Bromopyruvate induces necrotic cell death in sensitive melanoma cell lines
DOE Office of Scientific and Technical Information (OSTI.GOV)
Qin, J.-Z.; Xin, H.; Nickoloff, B.J., E-mail: bnickol@lumc.edu
2010-05-28
Clinicians successfully utilize high uptake of radiolabeled glucose via PET scanning to localize metastases in melanoma patients. To take advantage of this altered metabolome, 3-bromopyruvate (BrPA) was used to overcome the notorious resistance of melanoma to cell death. Using four melanoma cell lines, BrPA triggered caspase independent necrosis in two lines, whilst the other two lines were resistant to killing. Mechanistically, sensitive cells differed from resistant cells by; constitutively lower levels of glutathione, reduction of glutathione by BrPA only in sensitive cells; increased superoxide anion reactive oxygen species, loss of outer mitochondrial membrane permeability, and rapid ATP depletion. Sensitive cellmore » killing was blocked by N-acetylcysteine or glutathione. When glutathione levels were reduced in resistant cell lines, they became sensitive to killing by BrPA. Taken together, these results identify a metabolic-based Achilles' heel in melanoma cells to be exploited by use of BrPA. Future pre-clinical and clinical trials are warranted to translate these results into improved patient care for individuals suffering from metastatic melanoma.« less
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Clinical impact of sentinel lymph node biopsy in patients with thick (>4 mm) melanomas.
White, Ian; Fortino, Jeanine; Curti, Brendan; Vetto, John
2014-05-01
The role of sentinel lymph node status (SLNS) in thick melanoma is evolving. The purpose of this study was to determine the prognostic value of SLNS in thick melanoma. A retrospective analysis of 120 prospectively collected clinically node-negative thick melanomas over 5 years was performed. Patient (age/sex) and tumor (thickness, ulceration, SLNS, mitoses, metastases, and recurrence) features were collected. Multivariate analysis was performed using Cox proportional hazard model. Factors predictive of positive SLN included male sex, ulceration, and high mitoses. Factors associated with positive SLN had higher local-regional recurrence and metastases than negative SLN. SLNS and tumor thickness impacted 5-year disease-free survival (DFS) and overall survival (OS). Positive SLN, ulceration, age, and mitoses were independent predictors of DFS/OS. Nonulcerated/lower mitoses thick melanomas had lower positive SLN rates. Positive SLN develop recurrence and metastases and have worse OS/DFS. SLNS is an important prognosticator for OS/DFS. Sentinel lymph node biopsy delineates prognostic groups in thick melanomas and can impact management. Copyright © 2014 Elsevier Inc. All rights reserved.
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Tataru, CP; Pop, MD
2012-01-01
Rationale: Enucleation implants are covered with a material that allows the fixation of the extraocular rectus muscles. Usually, the implants are covered in donor sclera, which implies the risk of infection transmission, inflammation and implant rejection, being also an expensive procedure. The new materials used for implant meshing should be tested and a safer and cost effective solution should be researched. Objective: This study presents the results obtained after a 15-year use of an original prosthesis for the reconstruction of the orbital cavity after enucleation surgery. Methods and results: 42 eyes of 42 patients who underwent enucleation surgery for choroidal malignant melanoma were included in the study. The surgical technique was very similar to the classic enucleation, the major difference being the implant of a prosthesis made out of a Polymethyl methacrylate (PMMA) ball covered by a Polyethylene terephthalate (dacron) shell used in cardiovascular surgery. All the patients had a very good technical result, without the inflammation of the orbital cavity, conjunctiva or eyelids, which demonstrates a very high material tolerability and an excellent cosmetic result. Late implant expulsion appeared in 7.14% of the patients (3 cases). Discussion: The particularly good results obtained by using this technique, the absence of an inflammatory reaction after surgery, and the long lasting stability of the implant, recommend the method as being safe, with no major complications and a good esthetic result. AbbreviationsPolymethyl methacrylate (PMMA), Malignant choroidal melanoma (CMM) PMID:22802888
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Nagore, E; Botella-Estrada, R; Requena, C; Serra-Guillén, C; Martorell, A; Hueso, L; Llombart, B; Sanmartín, O; Guillén, C
2009-04-01
Melanomas arising in areas with comparable levels of sun exposure have been shown to have similar genetic profiles. The aim of this study was to characterize the clinical features of melanoma patients according to the pattern of sun exposure: chronic, intermittent, or none. From our melanoma database, we selected 789 consecutive patients with melanoma diagnosed in our center since January 2000. Epidemiologic data, phenotype, and personal and family history of cancer were retrieved. The observed frequency of each variable was compared. Most melanoma patients presented tumors on areas exposed intermittently to sunlight. In addition, these patients presented higher numbers of common and atypical melanocytic nevi and the melanoma very frequently arose in a pre-existing nevus. The second largest group was formed by patients with tumors on areas chronically exposed to sun and that had all the clinical lesions (solar lentigines and actinic keratoses) and epidemiological characteristics typical of these areas. Finally, patients with melanomas on areas not exposed to sun were older, as occurred in the group with chronic exposure, and the diagnosis was made at more advanced stages of the disease. There are many patients who did not fit these patterns of melanoma development. Clinical and biological characterization is therefore necessary to determine alternative pathways of development in order to establish specific preventive measures.
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Omata, W; Tsutsumida, A; Namikawa, K; Takahashi, A; Oashi, K; Yamazaki, N
2017-01-01
By the recent introduction of molecular targeting drugs against BRAF mutation and immune checkpoint inhibitors, the prognosis of patients with melanoma in advanced stage is now improving, but still in the minority. Mucosal melanoma lacks the BRAF mutations, and hence conventional chemotherapeutic regimens must be improved. We have conventionally used dacarbazine (DTIC) for patients with metastatic mucosal melanoma. However, the efficacy of DTIC in patients with metastatic mucosal melanoma has been limited. Therefore, we explored other possibilities to improve the prognosis of patients suffering from metastatic mucosal melanoma. In this communication, we present a retrospective analysis of the sequential combination chemotherapy of DTIC with carboplatin and paclitaxel (CP) for metastatic mucosal melanoma of nasal cavity and paranasal sinuses. The objective response rate of seven patients is 14.3% by RECIST 1.1 and the overall survival (OS) is 12.5 months. These data indicate that the sequential combination chemotherapy of DTIC with CP could be an option for patients with metastatic mucosal melanoma of nasal cavity and paranasal sinuses who are currently ending into dismal prognosis.
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Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.
Long, Georgina V; Hauschild, Axel; Santinami, Mario; Atkinson, Victoria; Mandalà, Mario; Chiarion-Sileni, Vanna; Larkin, James; Nyakas, Marta; Dutriaux, Caroline; Haydon, Andrew; Robert, Caroline; Mortier, Laurent; Schachter, Jacob; Schadendorf, Dirk; Lesimple, Thierry; Plummer, Ruth; Ji, Ran; Zhang, Pingkuan; Mookerjee, Bijoyesh; Legos, Jeff; Kefford, Richard; Dummer, Reinhard; Kirkwood, John M
2017-11-09
Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).
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Chiarugi, Alessandra; Nardini, Paolo; Borgognoni, Lorenzo; Brandani, Paola; Gerlini, Gianni; Rubegni, Pietro; Lamberti, Arianna; Salvini, Camilla; Lo Scocco, Giovanni; Cecchi, Roberto; Sirna, Riccardo; Lorenzi, Stefano; Gattai, Riccardo; Battistini, Silvio; Crocetti, Emanuele
2017-03-14
The epidemiologic trends of cutaneous melanoma are similar in several countries with a Western-type life style, where there is a progressive increasing incidence and a low but not decreasing mor- tality, or somewhere an increase too, especially in the older age groups. Also in Tuscany there is a steady rise in incidence with prevalence of in situ and invasive thin melanomas, with also an increase of thick melanomas. It is necessary to reduce the frequency of thick melanomas to reduce specific mortality. The objective of the current survey has been to compare, in the Tuscany population, by a case- case study, thin and thick melanoma cases, trying to find out those personal and tumour characteristics which may help to customize preventive interventions. RESULTS The results confirmed the age and the lower edu- cation level are associated with a later detection. The habit to perform skin self-examination is resulted protec- tive forward thick melanoma and also the diagnosis by a doctor. The elements emerging from the survey allow to hypothesize a group of subjects resulting at higher risk for a late diagnosis, aged over 50 and carrier of a fewer constitutional and environmental risk factors: few total and few atypical nevi, and lower sun exposure and burning. It is assumable that a part of people did not be reached from messages of prevention because does not recognize oneself in the categories of people at risk for skin cancers described in educational cam- paigns. If we want to obtain better results on diagnosis of skin melanoma we have to think a new strategy. At least to think over the educational messages discriminating people more at risk of incidence of melanoma from people more at risk to die from melanoma, and to renewed active involvement of the Gen- eral Practitioners .
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Donat-Vargas, Carolina; Berglund, Marika; Glynn, Anders; Wolk, Alicja; Åkesson, Agneta
2017-02-01
For malignant melanoma, other risk factors aside from sun exposure have been hardly explored. Polychlorinated biphenyls (PCBs)-mainly from fatty fish- may affect melanogenesis and promote melanoma progression, while long-chain n-3 polyunsaturated fatty acids seem to exert antineoplastic actions in melanoma cells. We aimed to assess the association of validated estimates of dietary PCB exposure as well as the intake of eicosapentaenoic acid and docosahexaenoic acid (EPA-DHA), accounting for sun habits and skin type, with the risk of malignant melanoma in middle-aged and elderly women. We included 20,785 women at baseline in 2009 from the prospective population-based Swedish Mammography Cohort. Validated estimates of dietary PCB exposure and EPA-DHA intake were obtained via a food frequency questionnaire. Incident melanoma cases were ascertained through register-linkage. During 4.5 years of follow-up, we ascertained 67 incident cases of melanoma. After multivariable adjustments, exposure to dietary PCBs was associated with four-fold increased risk of malignant melanoma (hazard ratio [HR], 4.0 [95% confidence interval {CI}, 1.2-13; P for trend = 0.02]), while EPA-DHA intake was associated with 80% lower risk (HR, 0.2 [95% CI, 0.1-0.8; P for trend = 0.03]), comparing the highest exposure tertiles with the lowest. While we found a direct association between dietary PCB exposure and risk of melanoma, EPA-DHA intake showed to have a substantial protective association. Question of benefits and risk from fish consumption is very relevant and further prospective studies in the general population verifying these findings are warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.
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TGF-β-Induced Transcription Sustains Amoeboid Melanoma Migration and Dissemination
Cantelli, Gaia; Orgaz, Jose L.; Rodriguez-Hernandez, Irene; Karagiannis, Panagiotis; Maiques, Oscar; Matias-Guiu, Xavier; Nestle, Frank O.; Marti, Rosa M.; Karagiannis, Sophia N.; Sanz-Moreno, Victoria
2015-01-01
Summary Cell migration underlies metastatic dissemination of cancer cells, and fast “amoeboid” migration in the invasive fronts of tumors is controlled by high levels of actomyosin contractility. How amoeboid migration is regulated by extracellular signals and sustained over time by transcriptional changes is not fully understood. Transforming growth factor β (TGF-β) is well known to promote epithelial-to-mesenchymal transition (EMT) and contribute to metastasis, but melanocytes are neural crest derivatives that have undergone EMT during embryonic development. Surprisingly, we find that in melanoma, TGF-β promotes amoeboid features such as cell rounding, membrane blebbing, high levels of contractility, and increased invasion. Using genome-wide transcriptomics, we find that amoeboid melanoma cells are enriched in a TGF-β-driven signature. We observe that downstream of TGF-β, SMAD2 and its adaptor CITED1 control amoeboid behavior by regulating the expression of key genes that activate contractile forces. Moreover, CITED1 is highly upregulated during melanoma progression, and its high expression is associated with poor prognosis. CITED1 is coupled to a contractile-rounded, amoeboid phenotype in a panel of 16 melanoma cell lines, in mouse melanoma xenografts, and in 47 human melanoma patients. Its expression is also enriched in the invasive fronts of lesions. Functionally, we show how the TGF-β-SMAD2-CITED1 axis promotes different steps associated with progression: melanoma detachment from keratinocytes, 2D and 3D migration, attachment to endothelial cells, and in vivo lung metastatic initial colonization and outgrowth. We propose a novel mechanism by which TGF-β-induced transcription sustains actomyosin force in melanoma cells and thereby promotes melanoma progression independently of EMT. PMID:26526369
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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.
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Kaidar-Person, Orit; Zagar, Timothy M; Deal, Allison; Moschos, Stergios J; Ewend, Matthew G; Sasaki-Adams, Deanna; Lee, Carrie B; Collichio, Frances A; Fried, David; Marks, Lawrence B; Chera, Bhishamjit S
2017-07-01
Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.
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Sunbeds and sunlamps: who used them and their risk for melanoma
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
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Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S; Wunderlich, John R; Dudley, Mark E; Rosenberg, Steven A
2013-09-01
Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3(+) T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8(+) cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ~50 × 10(9) T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3(+)CD8(+) cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I-mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I-mediated up-regulation of CD137 (4-1BB) expression on CD8(+) cells suggested that 0-3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells.
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Turcotte, Simon; Gros, Alena; Hogan, Katherine; Tran, Eric; Hinrichs, Christian S.; Wunderlich, John R.; Dudley, Mark E.
2013-01-01
Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate cancer regression in patients with metastatic melanoma, but whether this approach can be applied to common epithelial malignancies remains unclear. In this study, we compared the phenotype and function of TILs derived from liver and lung metastases from patients with gastrointestinal (GI) cancers (n = 14) or melanoma (n = 42). Fewer CD3+ T cells were found to infiltrate GI compared with melanoma metastases, but the proportions of CD8+ cells, T cell differentiation stage, and expression of costimulatory molecules were similar for both tumor types. Clinical-scale expansion up to ∼50 × 109 T cells on average was obtained for all patients with GI cancer and melanoma. From GI tumors, however, TIL outgrowth in high-dose IL-2 yielded 22 ± 1.4% CD3+CD8+ cells compared with 63 ± 2.4% from melanoma (p < 0.001). IFN-γ ELISA demonstrated MHC class I–mediated reactivity of TIL against autologous tumor in 5 of 7 GI cancer patients tested (9% of 188 distinct TIL cultures) and in 9 of 10 melanoma patients (43% of 246 distinct TIL cultures). In these assays, MHC class I–mediated up-regulation of CD137 (4-1BB) expression on CD8+ cells suggested that 0–3% of TILs expanded from GI cancer metastases were tumor-reactive. This study implies that the main challenge to the development of TIL adoptive cell transfer for metastatic GI cancers may not be the in vitro expansion of bulk TILs, but the ability to select and enrich for tumor-reactive T cells. PMID:23904171
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Melanocytic nevi, nevus genes and melanoma risk in a large case-control study in the United Kingdom
Newton-Bishop, Julia A; Chang, Yu-Mei; Iles, Mark M; Taylor, John C; Bakker, Bert; Chan, May; Leake, Susan; Karpavicius, Birute; Haynes, Sue; Fitzgibbon, Elaine; Elliott, Faye; Kanetsky, Peter A.; Harland, Mark; Barrett, Jennifer H; Bishop, D Timothy
2010-01-01
Background Increased number of melanocytic nevi is a potent melanoma risk factor. We have carried out a large population-based case-control study to explore the environmental and genetic determinants of nevi and the relationship with melanoma risk. Methods We report nevus phenotype in relation to differing patterns of sun exposure, inherited variation at loci shown in recent genome-wide association studies to be nevus genes, and risk. Results Increased numbers of nevi were associated with holiday sun exposure, particularly on intermittently sun-exposed body sites (test for trend p<0.0001). Large nevi were also associated with holiday sun exposure (p=0.002). Single nucleotide polymorphisms (SNPs) on chromosomes 9 and 22 were associated with increased numbers of nevi (p=0.04 and p=0.002 respectively) and larger nevi (p=0.03 and p=0.002), whereas that on chromosome 6 was associated only with large nevi (p=0.01). Melanoma risk was associated with increased nevus count, large nevi and atypical nevi for tumors in all body sites (including rare sites) irrespective of age. The risk persisted when adjusted for inheritance of nevus SNPs. Conclusions The at-risk nevus phenotype is associated with behaviors known to increase melanoma risk (holiday sun exposure). Although SNPs on chromosomes 6, 9 and 22 were shown to be nevus genes they explained only a small proportion of melanoma risk and nevus phenotype; therefore a number of nevus genes likely remain to be identified. Impact This paper confirms the importance of nevi in melanoma pathogenesis and increases understanding of their genetic determinants. PMID:20647408
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Nevus density and melanoma risk in women: a pooled analysis to test the divergent pathway hypothesis
Olsen, Catherine M.; Zens, Michael S.; Stukel, Therese A.; Sacerdote, Carlotta; Chang, Yu-mei; Armstrong, Bruce K.; Bataille, Veronique; Berwick, Marianne; Elwood, J. Mark; Holly, Elizabeth A.; Kirkpatrick, Connie; Mack, Thomas; Bishop, Julia Newton; Østerlind, Anne; Swerdlow, Anthony J.; Zanetti, Roberto; Green, Adèle C.; Karagas, Margaret R.; Whiteman, David C
2009-01-01
A “divergent pathway” model for the development of cutaneous melanoma has been proposed. The model hypothesizes that melanomas occurring in people with a low tendency to develop nevi will, on average, arise more commonly on habitually sun-exposed body sites such as the head and neck. In contrast, people with an inherent propensity to develop nevi will tend to develop melanomas most often on body sites with large melanocyte populations, such as on the back. We conducted a collaborative analysis to test this hypothesis using the original data from ten case-control studies of melanoma in women (2406 cases and 3119 controls), with assessment of the potential confounding effects of socioeconomic, pigmentary, and sun exposure-related factors. Higher nevus count on the arm was associated specifically with an increased risk of melanoma of the trunk (p for trend=0.0004) and limbs (both upper and lower limb p for trends=0.01), but not of the head and neck (p for trend=0.25). The pooled odds ratios for the highest quartile of non-zero nevus count versus none were 4.6 (95% confidence interval (CI) 2.7–7.6) for melanoma of the trunk, 2.0 (95% CI 0.9–4.5) for the head and neck, 4.2 (95% CI 2.3–7.5) for the upper limbs and 3.4 (95% CI 1.5–7.9) for the lower limbs. Aggregate data from these studies suggest that high nevus counts are strongly associated with melanoma of the trunk but less so if at all of the head and neck. This finding supports different etiologic pathways of melanoma development by anatomic site. PMID:19035450
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El Sayed, Salah Mohamed; Mohamed, Walaa Gamal; Seddik, Minnat-Allah Hassan; Ahmed, Al-Shimaa Ahmed; Mahmoud, Asmaa Gamal; Amer, Wael Hassan; Helmy Nabo, Manal Mohamed; Hamed, Ahmed Roshdi; Ahmed, Nagwa Sayed; Abd-Allah, Ali Abdel-Rahman
2014-07-01
3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.
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El Sayed, Salah Mohamed; Mohamed, Walaa Gamal; Seddik, Minnat-Allah Hassan; Ahmed, Al-Shimaa Ahmed; Mahmoud, Asmaa Gamal; Amer, Wael Hassan; Helmy Nabo, Manal Mohamed; Hamed, Ahmed Roshdi; Ahmed, Nagwa Sayed; Abd-Allah, Ali Abdel-Rahman
2014-01-01
3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects. PMID:24636230
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Outcomes of patients with a pretransplant history of early-stage melanoma.
Puza, Charles J; Barbas, Andrew S; Mosca, Paul J
2018-06-25
A history of melanoma within the preceding 5 years is commonly considered a contraindication to solid organ transplantation. We investigated how a pretransplant history of melanoma impacts patient survival and melanoma recurrence. Institutional Review Board approval was obtained, and Duke's retrospective database was used to identify 4552 patients who underwent a solid organ transplant at Duke University from 1 January 2001 to 31 December 2016. Data with regard to the transplant, melanoma characteristics, rejection episodes, and survival were recorded. Of 4552 patients who underwent a solid organ transplant, 12 (0.3%) had a history of melanoma before transplant (six with melanoma in situ and six with stage I disease). The median time between melanoma diagnosis and transplant was 4.13 years (range: 1.1-13.3 years). The study cohort consisted of four liver transplants, four lung transplants, one kidney transplant, one heart transplant, one small bowel transplant, and one multivisceral transplant. At the median follow-up time of 2.8 years, 10 (83.3%) patients were alive. In nonmelanoma cohorts, the 3-year survival is 70% for thoracic transplants, 78% for liver transplants, and 88% for kidney transplants. In well-selected patients with a history of early-stage melanoma and an appropriate time interval between melanoma treatment and transplant, post-transplant outcomes are favorable.
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Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma
NASA Astrophysics Data System (ADS)
Sun, Chong; Wang, Liqin; Huang, Sidong; Heynen, Guus J. J. E.; Prahallad, Anirudh; Robert, Caroline; Haanen, John; Blank, Christian; Wesseling, Jelle; Willems, Stefan M.; Zecchin, Davide; Hobor, Sebastijan; Bajpe, Prashanth K.; Lieftink, Cor; Mateus, Christina; Vagner, Stephan; Grernrum, Wipawadee; Hofland, Ingrid; Schlicker, Andreas; Wessels, Lodewyk F. A.; Beijersbergen, Roderick L.; Bardelli, Alberto; di Nicolantonio, Federica; Eggermont, Alexander M. M.; Bernards, Rene
2014-04-01
Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a `drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
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Promoter Methylation of PTEN Is a Significant Prognostic Factor in Melanoma Survival.
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.
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Hamilton, Sarah Nicole; Scali, Elena P; Yu, Irene; Gusnowski, Eva; Ingledew, Paris-Ann
2015-09-01
This study describes how melanoma patients used the Internet as a melanoma information source and how it impacted their clinical encounter and treatment decision. From 2010 to 2013, melanoma patients were invited to complete a 23-question paper survey with open- and close-ended questions. Thirty-one of the 62 patients approached completed the survey. The majority (90 %) of respondents used the Internet as a melanoma information source. Most (90 %) had used the search engine Google. The most commonly searched topics were melanoma treatment (96 %), screening (64 %), and prevention (64 %). While most respondents (85 %) found the Internet was a useful melanoma information source, over half (54 %) found melanoma websites at least somewhat difficult to understand. Many (78 %) believed it increased their understanding of their diagnosis, 71 % thought it influenced their treatment decision, and 59 % felt it impacted their specialist consultation. This study informs health care professionals that many melanoma patients search the Internet for information regarding their diagnosis and that it may impact their disease understanding and treatment decisions.
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McPherson, Iain; Kirk, Alan
2017-01-01
Background Immunosuppression helps prevent acute rejection post-cardiac transplant but has been linked to malignancy development. This may be due to a reduction in T-lymphocyte function, a direct oncogenic effect or the increased impact of environmental carcinogens. There has been shown to be significant increases in non-melanoma skin cancers and post-transplant lympho-proliferative disorders, particularly in those treated with OKT3. Aim To investigate the survival and incidence of malignancy in the Scottish cardiac transplant population and whether rates of non-melanoma skin cancers justify the provision of specialist dermatological follow-up. Methods and results Retrospective case note analysis of patients transplanted (363) or followed up (2) in Scotland from 1992 to 2016. Kaplan-Meier survival analysis generated a survival curve. Patients had a 1-year survival of 82% and a median survival of 10.9 years. There were 60 (95% CI 47.5, 75.2) NMSCs and 8 (3.7, 12.4) post-transplant lympho-proliferative disorders diagnosed in the cohort (3110 person years follow-up). Fisher's exact test was employed to analyse the association between induction therapy (via OKT3 or rabbit antithymocyte globulin) and post-transplant lympho-proliferative disorder development. Patients treated with OKT3 had a 6.7 times greater risk ( P = 0.014) and a shorter experience of patients treated with rabbit antithymocyte globulin has so far shown no significantly altered risk ( P = 1.00) of developing a post-transplant lympho-proliferative disorder. Conclusion Incidences of non-melanoma skin cancers and post-transplant lympho-proliferative disorders were increased in the Scottish cardiac transplant population and there was a significant association between post-transplant lympho-proliferative disorder development and OKT3 therapy but not rabbit antithymocyte globulin therapy. These findings in Scottish patients reflect what is published in wider literature and support the provision of a dedicated post-transplant dermatology clinic.
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Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
Chapman, Paul B; Hauschild, Axel; Robert, Caroline; Haanen, John B; Ascierto, Paolo; Larkin, James; Dummer, Reinhard; Garbe, Claus; Testori, Alessandro; Maio, Michele; Hogg, David; Lorigan, Paul; Lebbe, Celeste; Jouary, Thomas; Schadendorf, Dirk; Ribas, Antoni; O'Day, Steven J; Sosman, Jeffrey A; Kirkwood, John M; Eggermont, Alexander M M; Dreno, Brigitte; Nolop, Keith; Li, Jiang; Nelson, Betty; Hou, Jeannie; Lee, Richard J; Flaherty, Keith T; McArthur, Grant A
2011-06-30
Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).
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Mazzarella, Tonia; Cambiaghi, Valeria; Rizzo, Nathalie; Pilla, Lorenzo; Parolini, Danilo; Orsenigo, Elena; Colucci, Annalisa; Modorati, Giulio; Doglioni, Claudio; Parmiani, Giorgio; Maccalli, Cristina
2012-08-01
Tumor-infiltrating lymphocytes (TILs) have been successfully used for adoptive cell transfer (ACT) immunotherapy; however, due to their scarce availability, this therapy is possible for a limited fraction of cutaneous melanoma patients. We assessed whether an effective protocol for ex vivo T-cell expansion from peripheral blood mononuclear cells (PBMCs), suitable for ACT of both cutaneous and ocular melanoma patients, could be identified. PBMCs from both cutaneous and ocular melanoma patients were stimulated in vitro with autologous, irradiated melanoma cells (mixed lymphocyte tumor cell culture; MLTCs) in the presence of IL-2 and IL-15 followed by the rapid expansion protocol (REP). The functional activity of these T lymphocytes was characterized and compared with that of TILs. In addition, the immune infiltration in vivo of ocular melanoma lesions was analyzed. An efficient in vitro MLTC expansion of melanoma reactive T cells was achieved from all PBMC's samples obtained in 7 cutaneous and ocular metastatic melanoma patients. Large numbers of melanoma-specific T cells could be obtained when the REP protocol was applied to these MLTCs. Most MLTCs were enriched in non-terminally differentiated T(EM) cells homogeneously expressing co-stimulatory molecules (e.g., NKG2D, CD28, CD134, CD137). A similar pattern of anti-tumor activity, in association with a more variable expression of co-stimulatory molecules, was detected on short-term in vitro cultured TILs isolated from the same patients. In these ocular melanoma patients, we observed an immune infiltrate with suppressive characteristics and a low rate of ex vivo growing TILs (28.5% of our cases). Our MLTC protocol overcomes this limitation, allowing the isolation of T lymphocytes with effector functions even in these patients. Thus, anti-tumor circulating PBMC-derived T cells could be efficiently isolated from melanoma patients by our novel ex vivo enrichment protocol. This protocol appears suitable for ACT studies of cutaneous and ocular melanoma patients.
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Yen, Hsi; Li, Wen-Qing; Dhana, Ashar; Li, Tricia; Qureshi, Abrar; Cho, Eunyoung
2018-04-24
Red and processed meat consumption has been associated with increased risk for several cancers, but the association with cutaneous melanoma risk has been inconclusive. To investigate the association between red and processed meat intake and melanoma risk. Dietary information was assessed by using food frequency questionnaires in 2 prospective cohorts: 75,263 women from the Nurses' Health Study (1984-2010) and 48,523 men from the Health Professionals Follow-up Study (1986-2010). Melanoma cases were confirmed by reviewing pathology records. Pooled multivariable hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. A total of 679 female and 639 male melanoma cases were documented during follow-up. Red and processed meat intake was inversely associated with melanoma risk (P = .002 for trend); the pooled hazard ratios (95% confidence intervals) of the 2 cohorts were 1.00 (reference), 1.00 (0.87-1.14), 0.98 (0.86-1.13), 0.89 (0.77-1.02), and 0.81 (0.70-0.95) for increasing quintiles of intake. Findings might have limited generalizability, considering that the cohorts were limited to white health professionals. Red and processed meat intake was inversely associated with melanoma risk in these 2 cohorts. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
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Dabrafenib in metastatic melanoma: a monocentric ‘real life’ experience
Cocorocchio, E; Gandini, S; Alfieri, S; Battaglia, A; Pennacchioli, E; Tosti, G; Spadola, G; Barberis, M; Leo, M Di; Riviello, C; Pala, L; Intelisano, A; Martinoli, C; Ferrucci, PF
2016-01-01
Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3–4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts. PMID:26981153
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Gaudy-Marqueste, Caroline; Monestier, Sandrine; Franques, Jérome; Cantais, Emmanuel; Richard, Marie-Aleth; Grob, Jean-Jacques
2013-01-01
Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 recently approved for the treatment of metastatic melanoma and currently under investigation in the adjuvant setting of high-risk stage III melanoma. The blockade of CTLA-4 induces activation of T cells, with an expected increase in the immunological reaction directed to cancer. We report a case of ipilimumab-induced Guillain-Barré syndrome revealed by an occlusive enteric neuropathy. Two weeks after the second dose of ipilimumab, our patient started to complain of abdominal meteorism and nausea. Within a few days, an occlusive syndrome developed. Wall biopsies during colonoscopy revealed a slight edema of the mucosa and a high number of lymphocytic follicles, leading to the diagnosis of ipilimumab-induced immune colitis. A respiratory failure occurred and a neurological deficiency developed rapidly. The diagnosis of polyradiculoneuritis was retained. Despite IV steroids, tacrolimus than plasmatic exchanges, the patient died within a few days because of multivisceral failure. Polyradiculoneuritis is a rare but very severe immune-mediated complication of ipilimumab. Occlusive enteric neuropathy may mimic the digestive symptoms of colitis, which is so frequent under ipilimumab.
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Faião-Flores, F; Alves-Fernandes, D K; Pennacchi, P C; Sandri, S; Vicente, A L S A; Scapulatempo-Neto, C; Vazquez, V L; Reis, R M; Chauhan, J; Goding, C R; Smalley, K S; Maria-Engler, S S
2017-01-01
BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFβ/SMAD (transforming growth factor-β/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients. PMID:27748762
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Faião-Flores, F; Alves-Fernandes, D K; Pennacchi, P C; Sandri, S; Vicente, A L S A; Scapulatempo-Neto, C; Vazquez, V L; Reis, R M; Chauhan, J; Goding, C R; Smalley, K S; Maria-Engler, S S
2017-03-30
BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFβ/SMAD (transforming growth factor-β/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.
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Caffeine Intake, Coffee Consumption, and Risk of Cutaneous Malignant Melanoma.
Wu, Shaowei; Han, Jiali; Song, Fengju; Cho, Eunyoung; Gao, Xiang; Hunter, David J; Qureshi, Abrar A
2015-11-01
Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies. We evaluated the association among caffeine intake, coffee consumption, and melanoma risk among three large cohort studies. The analysis used data from 89,220 women in the Nurses' Health Study II (1991-2009), 74,666 women in the Nurses' Health Study (1980-2008), and 39,424 men in the Health Professionals Follow-up Study (1986-2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) of melanoma associated with dietary intakes. We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/day vs. <60 mg/day: HR = 0.78, 95% CI = 0.64, 0.96; Ptrend = 0.048). The association was more apparent in women (≥393 mg/day vs. <60 mg/day: HR = 0.70, 95% CI = 0.58, 0.85; Ptrend = 0.001) than in men (HR = 0.94, 95% CI = 0.75, 1.2; Ptrend = 0.81), and more apparent for melanomas occurring on body sites with higher continuous sun exposure (head, neck, and extremities; ≥393 mg/day vs. <60 mg/day: HR = 0.71, 95% CI = 0.59, 0.86; Ptrend = 0.001) than for melanomas occurring on body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen, and chest; HR = 0.90, 95% CI = 0.70, 1.2; Ptrend = 0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk. Increasing caffeine intake and caffeinated coffee consumption is associated with decreased risk of cutaneous malignant melanomas.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Howell, J.N.; Greene, M.H.; Corner, R.C.
Because of a possible etiologic link between mutations and carcinogenesis, the authors compared fibroblasts derived from skin biopsies of several patients with hereditary cutaneous malignant melanoma and the dysplastic nevus syndrome for sensitivity to the mutagenic and/or cytotoxic effect of broad-spectrum simulated sunlight and of a UV mimetic carcinogen, 4-nitroquinoline 1-oxide (4NQO). The genetic marker was resistant to 6-thioguanine; loss of colony-forming ability was the assay for cytotoxicity. All five strains tested were more sensitive than normal to the killing effect of 4NQO (slopes of survival curves were 2- to 3-fold steeper), but only one strain was hypersensitive to killingmore » by Sun Lamp radiation. Two strains were tested for mutagenicity. The response of each to the mutagenic action of these agents corresponded to its response to cell killing. Both strains were hypermutable after exposure to 4NQO, but only one showed a higher than normal frequency of mutants induced by simulated sunlight. The finding that nonmalignant fibroblasts from patients with a hereditary variant of malignant fibroblasts from patients with a hereditary variant of malignant melanoma are abnormally susceptible to carcinogen-induced mutations suggests that hypersensitivity to mutagens contributes to risk of melanoma in patients. It also supports the somatic cell mutation hypothesis for the origin of cancer. 46 references, 3 figures.« less
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A case-control study: occupational cooking and the risk of uveal melanoma
2010-01-01
Background A European-wide population based case-control study (European rare cancer study) undertaken in nine European countries examined risk factors for uveal melanoma. They found a positive association between cooks and the risk of uveal melanoma. In our study we examine whether cooks or people who worked in cook related jobs have an increased uveal melanoma risk. Methods We conducted a case-control study during 2002 and 2005. Overall, 1653 eligible subjects (age range: 20-74 years, living in Germany) participated. Interviews were conducted with 459 incident uveal melanoma cases, 827 population controls, 180 ophthalmologist controls and 187 sibling controls. Data on occupational exposure were obtained from a self-administered postal questionnaire and a computer-assisted telephone interview. We used conditional logistic regression to estimate odds ratios adjusting for the matching factors. Results Overall, we did not observe an increased risk of uveal melanoma among people who worked as cooks or who worked in cook related jobs. When we restricted the source population of our study to the population of the Federal State of Northrhine-Westphalia, we observed an increased risk among subjects who were categorized as cooks in the cases-control analysis. Conclusion Our results are in conflict with former results of the European rare cancer study. Considering the rarity of the disease laboratory in vitro studies of human uveal melanoma cell lines should be done to analyze potential exposure risk factors like radiation from microwaves, strong light from incandescent ovens, or infrared radiation. PMID:20969762
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Changing presentation of cutaneous malignant melanoma.
Klit, Anders; Lassen, Cecilie Brandt; Olsen, Caroline Holkmann; Lock-Andersen, Jørgen
2015-10-01
The incidence of cutaneous malignant melanoma is rapidly increasing in Denmark like in other Northern and Western European countries. Our objective was to investigate the characteristics of current patients suffering from cutaneous malignant melanoma. We evaluated patient and tumour characteristics in a cross-sectional study based on data from the Danish Melanoma Register. We included all patients diagnosed with cutaneous malignant melanoma in Healthcare Region Zealand in 2012 and 2013. We identified 520 patients with invasive cutaneous malignant melanoma. More females than males suffered from cutaneous malignant melanoma. Furthermore, females were younger than males, and the anatomical distribution of malignant melanoma varied between the genders. Outcome of sentinel lymph node biopsy was associated with tumour thickness. When comparing findings in our study with earlier Danish studies, we see a trend towards an increase in age at diagnosis. Furthermore, tumour thickness is decreasing and the topical distribution of cutaneous malignant melanoma in females changes towards a male pattern. none. The study has been approved by the Danish National Data Protection Agency.
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Prognostic role of the histological subtype of melanoma on the hands and feet in Caucasians.
Carrera, Cristina; Gual, Adrià; Díaz, Alba; Puig-Butillé, Joan A; Noguès, Susanna; Vilalta, Antonio; Conill, Carlos; Rull, Ramón; Vilana, Ramon; Arguis, Pedro; Vidal-Sicart, Sergi; Alós, Llucia; Palou, Josep; Castel, Teresa; Malvehy, Josep; Puig, Susana
2017-08-01
Acral melanoma (AM) is associated with a poor prognosis in part because of delayed diagnosis, but probably also because of other intrinsic characteristics of location. The aim of this study was to review the specific characteristics and outcome of AM in Caucasians. This was a cross-sectional retrospective clinical-pathological study of 274 patients identified with AM in the database of a referral unit in Europe from 1986 to 2010. The mean age of the patients was 56.6 (SD 17.7) years. 269 cases could be histologically classified and included in the study. In all, 222 (82.5%) were located on feet. According to melanoma subtype, 165 (61.3%) were acral lentiginous melanoma (ALM), 84 (31.2%) were superficial spreading melanoma (SSM), and 20 (7.5%) were nodular melanoma (NM). SSM patients were characterized by female predominance (77.4%), younger age, and classic melanoma-risk phenotype (fair skin and multiple nevi). Among the 198 invasive cases with a mean follow-up of 56.2 months, the mean (SD) Breslow's thickness was 3.1 (3.6) mm, being 1.4 (1.4) mm in SSM, 3.5 (4.1) mm in ALM and 4.9 (2.9) mm in NM (P<0.001). Ulceration was present in 33.3%, 2.9% in SSM, 38.6% in ALM, and 76.9% in NM (P<0.001). A total of 29.3% relapsed (7.3% of SSM, 35% of ALM and 55% of NM) and 24.2% died because of AM. In multivariate analysis, age at diagnosis, Breslow, and histopathological subtype were independent prognostic factors for both disease-free and AM-specific survival. The ALM and NM subtypes presented poorer outcome after weighting Breslow and age (P=0.02). Histological subtype of AM could have an impact on biological behavior, ALM and NM subtypes presenting a poorer prognosis after adjusting for age and Breslow's thickness.
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Paradisi, Andrea; Didona, Biagio; Tabolli, Stefano; Ricci, Francesco; Sobrino, Luciano; Panebianco, Annarita; Abeni, Damiano
2017-08-01
Chronic inflammatory conditions, such as psoriasis, may pose an increased risk of cancer due to impaired immunosurveillance resulting from chronic inflammation and immunosuppressive medications. To compare the risk of non-melanoma skin cancer (NMSC) in a retrospective cohort of 72,739 psoriasis patients and 25,956 non-dermatological patients. A record linkage was performed for data on hospitalizations, and the occurrence of NMSC was compared by computing the relative risk (RR) and modelled using multiple logistic regression. Overall, the occurrence of NMSC was 9.6‰ (95% CI: 8.9-10.3‰) in psoriasis patients and 19.6‰ (95% CI: 18.0-21.4‰) in non-dermatological patients (RR = 0.49; 95% CI: 0.44-0.55). The simultaneous adjustment for gender, age, and phototherapy yielded a RR of 0.84 (95% CI: 0.75-0.95). With regards to phototherapy, the occurrence of NMSC was significantly higher among psoriasis patients who underwent phototherapy relative to those who did not (27.0‰ vs. 9.3‰). In this large retrospective study, we found that patients with psoriasis had a 16% lower probability of having NMSC when compared to a group of non-dermatological patients. Further studies, preferably with a prospective longitudinal design to collect more precise data, are needed to corroborate our findings.
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Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K
2014-08-01
Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.