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1.  Adjuvant High-Dose Interferon for Cutaneous Melanoma is Most Beneficial for Patients with Early Stage III Disease 
Cancer  2008;112(9):2030-2037.
Evidence from randomized trials in the pre-sentinel node biopsy era indicate that adjuvant treatment with high-dose interferon-α (IFN) increases relapse-free survival (RFS) in patients with high-risk melanoma. However, the role of this treatment in selected patients with early stage III disease has not been well studied.
We evaluated clinical and pathologic characteristics of 486 patients undergoing surgical treatment for stage III melanoma and compared outcomes for those given adjuvant treatment with IFN with those who had surgery alone. A particular focus was on the effect of IFN therapy on RFS and overall survival (OS) among those with stage IIIA disease.
Median follow-up for the entire cohort was 5.2 years; 5-year RFS and OS for the entire group were 41% and 53%, respectively. Adjuvant IFN was given to 141 patients (29%). In multivariate analysis, IFN was the only independent predictor for RFS in stage IIIA disease (hazard ratio 0.4, 95% confidence interval 0.2–0.9, P = 0.02). IFN was not associated with increased RFS in patients with more advanced nodal disease (stage IIIB and IIIC). IFN had no effect on OS in any patient with stage III disease.
Adjuvant treatment with IFN improves RFS in melanoma patients with early stage III disease. These results should help guide management when considering adjuvant treatment for these patients.
PMCID: PMC4207058  PMID: 18320602
High-dose interferon; adjuvant therapy; stage III melanoma
2.  Prospective Assessment of Lymphedema Incidence and Lymphedema-associated Symptoms Following Lymph Node Surgery for Melanoma 
Melanoma research  2013;23(4):10.1097/CMR.0b013e3283632c83.
We sought to prospectively assess limb volume change (LVC) and associated symptoms in patients with melanoma undergoing sentinel lymph node (SLN) biopsy and/or therapeutic lymph node dissection (TLND).
Limb volume was measured pre-operatively and post-operatively at 6 and 12 months using a perometer (JUZO 1000M). LVC calculated and used to define 3 groups: <5%, 5-10%, and >10%. A 19-item lymphedema symptom questionnaire was administered at baseline, 6-month and 12-months.
One hundred eighty-two patients were enrolled. Twelve months after axillary surgery, 9% had LVC 5-10%, and 13% had LVC >10%. Twelve months after inguino-femoral surgery, 10% had LVC 5-10%, and 13% had LVC >10%. There was a significant 7- to 9-fold increase in symptoms for patients with LVC greater than >10% compared to those with LVC <5% (P<.05). By multivariate analysis, TLND versus SLN biopsy (odds ratio [OR] = 3.18 P<0.01) and borderline significance for lower-versus upper-extremity procedures (OR=1.72; P=0.07) were associated with LVC >5%.
LVC greater than 5% is common at 12 months following nodal surgery for melanoma and is associated with symptoms. Informed consent for melanoma patients undergoing lymph node surgery should include a discussion of the risks of post-operative lymphedema.
PMCID: PMC3881422  PMID: 23752305
melanoma; lymphedema; perometry; symptom assessment
3.  Variants in melanocortin 1 receptor gene contribute to risk of melanoma – a direct sequencing analysis in a Texas population 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12070.
In this study, we directly sequenced the Melanocortin 1 Receptor (MC1R) gene in 2,212 individuals to detect all variants and assessed their associations with cutaneous melanoma (CM) risk in a hospital-based study of 1,106 CM patients and 1,106 control subjects. Of 61 MC1R variants identified, 16 rare variants have not been previously reported by others; three MC1R variants were associated with a significant CM risk [c.451C>T (OR = 1.78, 95% CI = 1.44–2.20), c.478C>T (OR = 1.31, 95% CI = 1.05–1.63), and c.880G>C (OR = 1.69, 95% CI = 1.15–2.48)]; and two with borderline CM risk [c.942A>G (OR =1.23, 95% CI =1.00–1.51, and c.274G>A (OR = 1.23,95% CI = 0.99–1.53)] under a dominant model. When combined these five MC1R variants for cumulative effect analysis, we found that subjects with an increased number of variant genotypes from any of these five variants had significantly increased risk of CM with ORs of 1.68 (95% CI = 1.39–2.04), 1.61 (95% CI = 1.27–2.04), and 2.64 (95% CI = 1.72–4.05) for one, two, and three or more variant genotypes, respectively (trend test: P <0.001). Further haplotype and diplotype analyses based on the above-mentioned five SNPs suggested that the c.451T allele contributed to the high risk of CM and that the five variants may have joint effects on the risk of CM. Additional analysis suggests that the three most significant SNPs may be the molecular mechanisms underlying the known risk factors of the colors of the eyes, skin and hair in this study population. In conclusion, our study provided confirmatory evidence that both common and rare variants in the MC1R coding region may be biomarkers for susceptibility to CM in US populations.
PMCID: PMC3721512  PMID: 23360207
melanocortin 1 receptor gene; direct sequencing; interaction; melanoma; case-control
4.  Microscopic Tumor Burden in Sentinel Lymph Nodes Predicts Synchronous Nonsentinel Lymph Node Involvement in Patients With Melanoma 
Journal of Clinical Oncology  2008;26(26):4296-4303.
We and others have demonstrated that additional positive lymph nodes (LNs) are identified in only 8% to 33% of patients with melanoma who have positive sentinel LNs (SLNs) and undergo complete therapeutic LN dissection (cTLND). We sought to determine predictors of additional regional LN involvement in patients with positive SLNs.
Patients and Methods
Patients with clinically node-negative melanoma who underwent SLN biopsy (1991 to 2003) and had positive SLNs were identified. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs.
Overall, 359 (16.3%) of the 2,203 patients identified had a positive SLN. Positive non-SLNs were identified in 48 (14.0%) of the 343 patients with positive SLNs who underwent cTLND. On univariate analysis, several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness more than 2 mm, age older than 50 years, and Clark level higher than III were predictive of positive non-SLNs; primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs; tumor thickness more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement.
In melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group at low risk for positive non-SLNs and be spared the potential morbidity of a cTLND.
PMCID: PMC2653121  PMID: 18606982
5.  Randomized Controlled Trial of a Sun Protection Intervention for Children of Melanoma Survivors 
We studied whether a melanoma survivor-centered intervention was more effective than materials available to the general public in increasing children’s sun protection.
In a randomized controlled trial, melanoma survivors (n=340) who had a child ≤12 years received a targeted sun protection intervention (DVD and booklets) or standard education. Primary outcomes were children’s sunburns, children’s sun protection, and survivors’ psychosocial factors at baseline and postintervention (1 and 4 months).
The intervention increased children’s sunscreen reapplication at 1 month (P = 0.002) and use of wide-brimmed hats at 4 months (P = 0.045). There were no effects on other behaviors or sunburns. The intervention improved survivors’ hats/clothing self-efficacy at both follow-up assessments (P = 0.026, 0.009). At 4 months, the intervention improved survivors’ clothing intentions (P = 0.029), knowledge (P = 0.010), and outcome expectations for hats (P = 0.002) and clothing (P = 0.037). Children’s sun protection increased with survivors’ intervention use. The intervention was less effective in survivors who were female or who had a family history, older children, or children with higher baseline sun protection scores.
A melanoma survivor-centered sun protection intervention can improve some child and survivor outcomes. The intervention may be more effective in survivors who have younger children or less experience with sun protection. Intervention delivery must be enhanced to maximize use.
This is the first study to examine a sun protection intervention for children of melanoma survivors. Findings will guide interventions for this important population at increased melanoma risk.
PMCID: PMC3929920  PMID: 24097199
Melanoma; Prevention & Control; Survivors; Child; Health Behavior
6.  Polymorphisms of Nucleotide Excision Repair Genes Predict Melanoma Survival 
Melanoma is the most highly malignant skin cancer, and nucleotide excision repair (NER) is involved in melanoma susceptibility. In this analysis of 1042 melanoma patients, we evaluated whether genetic variants of NER genes may predict survival outcome of melanoma patients. We used genotyping data of 74 tagging single nucleotide polymorphisms (tagSNPs) in eight core NER genes from our genome-wide association study (including 2 in XPA, 14 in XPC, 3 in XPE, 4 in ERCC1, 10 in ERCC2, 8 in ERCC3, 14 in ERCC4, and 19 in ERCC5) and evaluated their associations with prognosis of melanoma patients. Using the Cox proportional hazards model and Kaplan-Meier analysis, we found a predictive role of XPE rs28720291, ERCC5 rs4150314, XPC rs2470458 and ERCC2 rs50871 SNPs in prognosis of melanoma patients (rs28720291: AG vs. GG, adjusted hazard ratio [adjHR] = 11.2, 95% confidence interval [CI] 3.04–40.9, P = 0.0003; rs4150314: AG vs. GG, adjHR = 4.76, 95% CI 1.09–20.8, P = 0.038; rs2470458: AA vs. AG/GG, adjHR = 2.11, 95% CI 1.03–4.33, P = 0.040; and rs50871: AA vs. AC/CC adjHR =2.27, 95% CI 1.18–4.35, P = 0.015). Patients with an increasing number of unfavorable genotypes had dramatically increased death risk. Genetic variants of NER genes, particularly XPE rs28720291, ERCC5 rs4150314, XPC rs2470458 and ERCC2 rs50871, may independently or jointly modulate survival outcome of melanoma patients. Because our results were based on a median follow-up of 3 years without multiple test corrections, additional large prospective studies are needed to confirm our findings.
PMCID: PMC3660504  PMID: 23407396
melanoma; nucleotide excision repair; survival; association
7.  Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients 
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
Experimental Design
Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined.
Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified.
These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.
PMCID: PMC3525747  PMID: 23032743
melanoma; tumor-infiltrating lymphocytes; adoptive cell therapy
8.  Variability in melanoma post-treatment surveillance practices by country and physician specialty: A systematic review 
Melanoma research  2012;22(5):10.1097/CMR.0b013e328357d796.
There are no evidence-based guidelines for surveillance of patients with melanoma following surgical treatment. We performed a systematic review to identify current stage-specific surveillance practices for patients with melanoma by country and physician specialty.
Three major medical indices, MEDLINE, the Cochrane Library database, and Scopus, were reviewed to identify articles published in January 1970 to October 2011 that included detailed information about surveillance of patients with melanoma after initial surgical treatment. Data on surveillance intervals and recommended evaluation were extracted and categorized by country and, when reported, physician specialty.
One hundred four articles from 10 countries and 4 physician specialties (dermatology, surgical oncology, medical oncology, and general practice) met the inclusion criteria, including 43 providing specific patient-level data. The articles showed wide variation with respect to surveillance intervals and recommended evaluations. Variation was greatest for patients with stage I disease, for whom follow-up frequency ranged from 1 to 6 visits per year during years 1 and 2 after treatment. All 4 physician specialties agreed that for years 1–3, the follow-up frequency should be 4 times per year for all patients. For years 4 and 5, surgical oncologists recommended 2 follow-up visits per year, whereas general practitioners, dermatologists, and medical oncologists recommended 4 visits per year. Recommended imaging and laboratory evaluations were most intense in the United Kingdom and most minimalist in The Netherlands. While general practitioners did not recommend routine laboratory or imaging tests for surveillance, all other specialties utilized both in their surveillance practice. Self skin-examination was recommended for surveillance in all countries and by all practitioner specialties.
There is significant intercountry and interspecialty variation in surveillance of patients with melanoma. As the number of melanoma survivors increases, it will be critical to examine the benefits and costs of various follow-up strategies to establish consensus guidelines for melanoma post-treatment surveillance.
PMCID: PMC3858181  PMID: 22914178
melanoma; post-treatment surveillance; patient care; systematic review
9.  Influence of single nucleotide polymorphisms in the MMP1 promoter region on cutaneous melanoma progression 
Melanoma Research  2012;22(2):169-175.
Recently, we reported on the associations of seven single-nucleotide polymorphisms (SNPs) in the promoter region of MMP1 gene with susceptibility to cutaneous melanoma (CM). Considering the reported correlation between MMP1 expression and melanoma progression, we hypothesized that these promoter SNPs might affect CM progression and prognosis. In this study, we examined the associations of the seven SNPs with overall survival as well as six clinicopathologic factors in 754 patients with CM. After adjustment for 11 covariates, we observed significant association of the SNP −422A > T (rs475007) with ulceration status (P = 0.012), primary tumor thickness (P = 0.040), and anatomic site (P = 0.030). We also observed significant association of the SNP −755T > G (rs498186) with ulceration status (P = 0.038) and anatomic site (P = 0.003). Two SNPs −839G > A and −519A > G were marginally associated with primary tumor thickness, ulceration status, and anatomic site. Furthermore, the frequency of haplotype 2G-G-G-A-A-G-T was higher in patients with ulceration (odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.08–4.40, P = 0.030) than that in those without ulceration. However, we did not find significant associations of these SNPs with overall survival and other clinical factors. Since primary tumor thickness and ulceration status are two important indicators of tumor progression and have significant associations with melanoma prognosis, our results suggested that these promoter SNPs in MMP1 might have potential effects on melanoma progression and prognosis by influencing related clinical factors.
PMCID: PMC3296883  PMID: 22198560
Genotypes; Melanoma; Survival; Tumor characters; Molecular epidemiology
10.  Genome-wide association study identifies novel loci predisposing to cutaneous melanoma† 
Human Molecular Genetics  2011;20(24):5012-5023.
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10−10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
PMCID: PMC3298855  PMID: 21926416
11.  Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy 
Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors.
Experimental Design
We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment).
Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; p=0.01) and female patients (71% vs. 57% for males; p=0.04) having the highest rate of success. Systemic therapy 30 days prior to tumor harvest negatively impacted initial TIL outgrowth compared to patients who never received systemic therapy (47% versus 71%, p=0.02). Biochemotherapy within 0–60 days of tumor harvest negatively impacted the initial TIL outgrowth with a success rate of only 16% (p<0.0001).
Parameters such as age, sex, and the type and timing of prior systemic therapy significantly affect the success rate of the initial TIL outgrowth from tumor fragments for ACT; these parameters may be helpful in selecting patients for melanoma ACT.
PMCID: PMC3139726  PMID: 21632855
12.  Contemporary Diagnostic Imaging Modalities for the Staging and Surveillance of Melanoma Patients: a Meta-analysis 
Meta-analyses were performed to examine the utility of ultrasonography, computed tomography (CT), positron emission tomography (PET), and a combination of both (PET-CT) for the staging and surveillance of melanoma patients.
Patient-level data from 74 studies containing 10 528 patients (between January 1, 1990, and June, 30, 2009) were used to derive characteristics of the diagnostic tests used. Meta-analyses were conducted by use of Bayesian bivariate binomial models to estimate sensitivity and specificity. Diagnostic odds ratios [ie, true-positive results/false-negative results)/(false-positive results/true-negative results)] and their 95% credible intervals (CrIs) and positive predictive values were used as indicators of test performance.
Among the four imaging methods examined for the staging of regional lymph nodes, ultrasonography had the highest sensitivity (60%, 95% CrI = 33% to 83%), specificity (97%, 95% CrI = 88% to 99%), and diagnostic odds ratio (42, 95% CrI = 8.08 to 249.8). For staging of distant metastases, PET-CT had the highest sensitivity (80%, 95% CrI = 53% to 93%), specificity (87%, 95% CrI = 54% to 97%), and diagnostic odds ratio (25, 95% CrI = 3.58 to 198.7). Similar trends were observed for melanoma surveillance of lymph node involvement, with ultrasonography having the highest sensitivity (96%, 95% CrI = 85% to 99%), specificity (99%, 95% CrI = 95% to 100%), and diagnostic odds ratio (1675, 95% CrI = 226.6 to 15,920). For distant metastases, PET-CT had the highest sensitivity (86%, 95% CrI = 76% to 93%), specificity (91%, 95% CrI = 79% to 97%), and diagnostic odds ratio (67, 95% CrI = 20.42 to 229.7). Positive predictive values were likewise highest for ultrasonography in lymph node staging and for PET-CT in detecting distant metastases.
Among the compared modalities, ultrasonography was superior for detecting lymph node metastases, and PET-CT was superior for the detection of distant metastases in both the staging and surveillance of melanoma patients.
PMCID: PMC3022618  PMID: 21081714
13.  Promoter Polymorphisms in Matrix Metallopeptidase 1 and Risk of Cutaneous Melanoma 
Matrix Metallopeptidase 1 (MMP1) is one of the interstitial collagens in the extracellular matrix metalloproteinase family and involved in tumor behaviors. However, there is no report on the role of genetic variation in MMP1 in risk of cutaneous melanoma (CM). We investigated the association between genotypes and haplotypes of seven reported MMP1 promoter polymorphisms (-1607 G ins/del, -839G>A, -755T>G, -519A>G, -422A>T, -340A>G, and -320T>C, genotyped by the TaqMan assay) and CM risk in 872 patients and 873 cancer-free controls. These seven polymorphisms were not in linkage disequilibrium among each other (r2 < 0.63). Compared to their common homozygous genotypes, the variant -519GG was associated with significantly decreased CM risk (adjusted odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.52-0.99), whereas variant -422TT and -320CC were associated with significantly increased CM risk (OR = 1.50, 95% CI = 1.11-2.03 and OR = 1.72, 95% CI = 1.05-2.81, respectively) after adjustment for age, sex, family history, and sun-exposure related risk factors. The number of risk alleles of these three polymorphisms was associated with CM risk in a dose- response manner (Ptrend = 0.0002). In the stratification analysis, we found that the associations of these polymorphisms with CM risk were modified by some of the risk factors. Furthermore, the haplotypes Gdel-A-G-A-T-G-T and G-G-G-A-T-A-T were associated with significantly increased CM risk (ORs = 1.56 and 2.13, 95% CIs = 1.02-2.38 and 1.22-3.70, respectively). These findings suggest that MMP1 promoter polymorphisms may individually or jointly play roles in the development of CM.
PMCID: PMC2987546  PMID: 20655738
genotypes; haplotypes; genetic susceptibility; molecular epidemiology; skin neoplasms
14.  Prospective Assessment of Postoperative Complications and Associated Costs Following Inguinal Lymph Node Dissection (ILND) in Melanoma Patients 
Annals of surgical oncology  2010;17(10):2764-2772.
We prospectively assessed the incidence, risk factors, and costs associated with wound complications and lymphedema in melanoma patients undergoing inguinal lymph node dissection (ILND).
Materials and Methods
A total of 53 melanoma patients were accrued to 2 trials (June 2005 to July 2008) that included prospective evaluations of postoperative complications; 30-day wound complications included infection, seroma, and/or dehiscence. There were 20 patients who underwent limb volume measurement and completed a 19-item lymphedema symptom assessment questionnaire preoperatively and 3 months postoperatively. A multivariate analysis was performed to evaluate potential risk factors for complications. A microcosting analysis was also performed to evaluate the direct costs associated with wound complications.
The 30-day wound complications were noted in 77.4% of patients. A BMI ≥ 30 (n = 28) increased the risk for wound complications (odds ratio [OR] = 11.4, 95% confidence interval [95%CI] 1.6–78.5, P = .01), while advanced nodal disease approached significance (OR = 9.0, 95%CI: 0.79–103.1, P = .08). Other risk factors, including diabetes, smoking, and the addition of a deep pelvic (iliac/obturator) dissection to ILND, were not significant. Of 20 patients, 9 (45%) developed limb volume change (LVC) ≥5% at 3 months, with associated mean symptom scores of 6.1 versus 4.6 for those without LVC. Costs for patients with wound complications were significantly higher than for those without wound complications.
Postoperative wound complications and early onset lymphedema occur frequently following ILND for melanoma. Obesity is an adverse risk factor for 30-day wound complications that can significantly increase postoperative costs, as is likely the case for advanced disease. Risk reduction practices and novel treatment approaches are needed to reduce postoperative morbidity.
PMCID: PMC2943041  PMID: 20336388
15.  Conditional survival estimates improve over time for patients with advanced melanoma: results from a population-based analysis 
Cancer  2010;116(9):2234-2241.
Conditional survival (CS) has emerged as a clinically relevant measure of prognosis for cancer survivors. The objective of this analysis was to provide melanoma-specific CS estimates to help clinicians promote more informed patient decision-making.
Patients with melanoma and at least 5 years of follow-up were identified from the Surveillance Epidemiology and End Results (SEER) registry (1988–2000). Using the methods of Kaplan and Meier, stage-specific 5-year CS estimates were independently calculated for survivors for each year following diagnosis. Stage-specific multivariate Cox regression models including baseline survivor functions were used to calculate adjusted melanoma-specific CS for different subgroups of patients further stratified by age, gender, race, marital status, anatomic tumor location, and tumor histology.
Five-year CS estimates for stage I patients remained constant at 97% annually, while for patients with stages II, III and IV disease, 5-year CS estimates from time 0 (diagnosis) to 5 years improved from 72% to 86%, 51% to 87%, and 19% to 84%, respectively. Multivariate CS analysis revealed that differences in stages II through IV CS based on age, gender and race decreased over time.
Five-year melanoma-specific CS estimates improve dramatically over time for survivors with advanced stages of disease. These prognostic data are critical to patients for both treatment and non-treatment related life decisions.
PMCID: PMC2860044  PMID: 20187100
melanoma; conditional survival; SEER
16.  Genetic Variants and Haplotypes of the Caspase-8 and Caspase-10 Genes Contribute to Susceptibility to Cutaneous Melanoma 
Human mutation  2008;29(12):1443-1451.
Caspase-8 (CASP8) and caspase-10 (CASP10) play key roles in regulating apoptosis, and functional polymorphisms of them may alter apoptosis and cancer risk. However, no reported studies have investigated the association between such polymorphisms and the risk of cutaneous melanoma (CM). In a hospital-based study of 805 non-Hispanic white patients with CM and 835 cancer-free age- sex- and ethnicity-matched controls, we genotyped three reported putatively functional polymorphisms of CASP8 and CASP10--CASP8 D302H (rs1045485:G>C), CASP8-652 6N del (rs3834129:–/CTTACT), and CASP10 I522L (rs13006529:A>T)--and assessed their associations with risk of CM and interactions with known risk factors for CM. We also calculated the false-positive-report probability (FPRP) for significant findings. CASP8 302H variant genotypes (DH: adjusted odds ratio [OR], 0.70 [95% confidence interval (CI), 0.50-0.98]; DH+HH: unadjusted OR, 0.78 [95% CI, 0.62-0.98]; FPRP, 0.79) and CASP8 -652 6N del variant genotypes (ins/del: OR, 0.74 [95% CI, 0.57-0.97]; ins/del+del/del: OR, 0.76 [95% CI, 0.61-0.95]; FPRP, 0.61) were associated with significantly lower CM risk than were the ins/ins genotypes. The CASP10 522L variant genotypes were not associated with significantly altered CM risk. Also, the D-del-I haplotype was associated with a significantly lower CM risk (OR, 0.52 [95% CI, 0.37-0.74]; FPRP, 0.116) than was the most common haplotype, D-ins-I. Furthermore, multivariate logistic regression analysis revealed that CASP8 D302H, CASP8 -652 6N del, and CASP10 I522L were independent risk factors for CM. Therefore, these CASP8 and CASP10 variant polymorphisms may be biomarkers for susceptibility to CM.
PMCID: PMC2937220  PMID: 18563783
apoptosis; death pathway; genetic susceptibility; molecular epidemiology; skin cancer
17.  Haplotype and Genotypes of the VDR Gene and Cutaneous Melanoma Risk in Non-Hispanic Whites in Texas: A Case-Control Study 
In a hospital-based case-control study of 805 non-Hispanic whites with cutaneous melanoma and 841cancer-free age-, sex- and ethnicity-matched control subjects, three VDR polymorphisms (i.e., TaqI, BsmI, and FokI) were genotyped using blood samples collected between 1994 and 2006. We tested the hypothesis that the haplotypes and combined genotypes of these polymorphisms were associated with melanoma risk by interacting with known risk factors. Haplotypes t-B-F (adjusted odds ratio [OR], 0.52; 95 percent confidence interval [CI], 0.34–0.80) and t-B-f (adjusted OR, 0.51; CI, 0.27–0.94) were associated with a reduced risk when compared with T-b-f. The combined genotypes Tt+tt/Bb+BB/Ff+ff (adjusted OR, 0.69; CI, 0.52, 0.90) and Tt+tt/Bb+BB/FF (adjusted OR, 0.58; CI, 0.43, 0.78) were also associated with reduced risk, whereas the combined genotype TT/Bb+BB/Ff+ff genotype (adjusted OR, 2.35; CI, 1.13, 4.98) was associated with increased risk when compared with TT/bb/Ff+ff genotypes. On multivariate analysis, only the TaqI polymorphism was an independent risk factor, while the FokI polymorphism interacted with skin color (p = 0.029), moles (p = 0.017), and first-degree relatives with any cancer (p = 0.013) in modifying risk. Together, these findings suggest that VDR polymorphisms may directly effect or modify the risk associated with known melanoma risk factors. Larger, population-based studies are needed to replicate our findings.
PMCID: PMC2938035  PMID: 18183598
case-control studies; vitamin D receptor; genetic polymorphisms; genotypes; melanoma
18.  Polymorphisms of TP53 Arg72Pro, but not p73 G4C14>A4TA4 and p21 Ser31Arg, contribute to risk of cutaneous melanoma 
PMCID: PMC2938047  PMID: 18049450
case-control study; cell cycle; DNA repair; genetic polymorphism; skin cancer
19.  Lymph Node Ratio Predicts Disease-Specific Survival in Melanoma Patients 
Cancer  2009;115(11):2505-2513.
The objectives of this analysis were to compare various measures associated with lymph node (LN) dissection and to identify threshold values associated with disease-specific survival (DSS) outcomes in patients with melanoma.
Patients with node positive melanoma who underwent therapeutic LN dissection of the neck, axilla, and inguinal region were identified from the SEER database (1988–2005). We performed Cox multivariate analyses to determine the impact of the total number of LNs removed, number of negative LNs removed, and LN ratio on DSS. Multivariate cut-point analyses were conducted for each anatomic region to identify the threshold values associated with the largest improvement in DSS.
The LN ratio was significantly associated with DSS for all LN regions. The LN ratio thresholds resulting in the greatest difference in 5-year DSS were 0.07, 0.13, and 0.18 for neck, axillary, and inguinal regions, respectively, corresponding to 15, 8, and 6 LNs removed per positive node. After adjustment for other clinicopathologic factors, the hazard ratios (HRs) were 0.53 (95% confidence intervals (CIs), 0.40 to 0.71) in the neck, 0.52 (95% CI, 0.42 to 0.65) in the axillary, and 0.47 (95% CI, 0.36 to 0.61) in the inguinal regions for patients in whom the LN ratio threshold was met.
Among the prognostic factors examined, LN ratio was the best indicator of the extent of LN dissection, regardless of anatomic nodal region. These data provide evidence-based guidelines for defining adequate LN dissections in melanoma patients.
PMCID: PMC2755291  PMID: 19309746
melanoma; lymphadenectomy; lymph node ratio; disease-specific survival
20.  Fibrin sealant does not decrease seroma output or time to drain removal following inguino-femoral lymph node dissection in melanoma patients: A randomized controlled trial (NCT00506311) 
This study assessed the impact of closed suction drains and evaluated whether the intraoperative use of a fibrin sealant decreased time to drain removal and wound complications in melanoma patients undergoing inguino-femoral lymph node dissection.
A pilot study (n = 18) assessed the impact of a closed suction drain following inguino-femoral lymph node dissection. A single-institution, prospective trial was then performed in which patients were randomized to a group that received intraoperative application of a fibrin sealant following inguino-femoral lymph node dissection or to a control group that did not receive sealant.
The majority of the patients enrolled felt the drains caused moderate or severe discomfort and difficulties with activities of daily living. Thirty patients were then randomized; the median time to drain removal in the control group (n = 14) was 30 days (range, 13–74) compared to 29 days (range, 11–45) in the fibrin sealant group (n = 16; P = 0.6). Major and minor complications were similar in the two groups.
Postoperative closed suction drains were associated with major patient inconvenience. Applying a fibrin sealant at the time of inguino-femoral lymph node dissection in melanoma patients did not reduce the time to drain removal or postoperative morbidity. Alternative strategies are needed.
PMCID: PMC2464595  PMID: 18564433
21.  Crystal Structures of Beta- and Gammaretrovirus Fusion Proteins Reveal a Role for Electrostatic Stapling in Viral Entry 
Journal of Virology  2014;88(1):143-153.
Membrane fusion is a key step in the life cycle of all envelope viruses, but this process is energetically unfavorable; the transmembrane fusion subunit (TM) of the virion-attached glycoprotein actively catalyzes the membrane merger process. Retroviral glycoproteins are the prototypical system to study pH-independent viral entry. In this study, we determined crystal structures of extramembrane regions of the TMs from Mason-Pfizer monkey virus (MPMV) and xenotropic murine leukemia virus-related virus (XMRV) at 1.7-Å and 2.2-Å resolution, respectively. The structures are comprised of a trimer of hairpins that is characteristic of class I viral fusion proteins and now completes a structural library of retroviral fusion proteins. Our results allowed us to identify a series of intra- and interchain electrostatic interactions in the heptad repeat and chain reversal regions. Mutagenesis reveals that charge-neutralizing salt bridge mutations significantly destabilize the postfusion six-helix bundle and abrogate retroviral infection, demonstrating that electrostatic stapling of the fusion subunit is essential for viral entry. Our data indicate that salt bridges are a major stabilizing force on the MPMV and XMRV retroviral TMs and likely provide the key energetics for viral and host membrane fusion.
PMCID: PMC3911763  PMID: 24131724
22.  Genetic variants in Fanconi Anemia Pathway Genes BRCA2 and FANCA Predict Melanoma Survival 
Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi Anemia (FA) pathway involved in DNA crosslinks repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2339 common single nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 [AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confident interval (CI)=1.16-2.95, P=0.010], rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.
PMCID: PMC4289462  PMID: 25243787
cutaneous melanoma; Fanconi Anemia pathway; survival; single nucleotide polymorphisms; Cox regression
23.  Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk Germline RET Proto-Oncogene Mutations 
Thyroid  2014;24(7):1096-1106.
Background: Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy.
Methods: From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs. no MTC after thyroidectomy or no clinical evidence of MTC if thyroid intact). Data were used to estimate the cumulative prevalence of MTC and/or assess likelihood of MTC stratified by codon. After exclusion of cases with missing data or small representation, 503 patients with mutations in codons 533, 609, 611, 618, 620, 791, and 804 were analyzed.
Results: 236 patients had MTC. Cumulative prevalence and median time to MTC varied by codon and within ATA risk levels (p<0.0001). Patients with a codon 620 mutation were 2.8–6.9 times more likely to have MTC than other level B mutation carriers, and 5.1–21.7 times more likely than level A mutation carriers included in our focus population. The youngest median time to MTC was 19 years for codon 620 and the oldest was 56 years for codon 611. Cumulative prevalence of MTC by age 20 was 10% or lower for codons 533, 609, 611, 791, and 804. By age 50, it ranged from 18% for codon 791 to 95% for codon 620. An elevated preoperative calcitonin level strongly predicted MTC on final pathology, though false-negative rates varied by codon (p<0.0001). Positive predictive values ranged from 76% to 100% by codon with an overall positive predictive value of 87% across codons.
Conclusions: This study offers a better understanding of the age-related development of MTC in lower risk RET mutation carriers, provides evidence of further distinctions between lower risk mutations within ATA subgroups, and clarifies the clinical significance of codon 791 mutations. The data support individualized “codon-based” management approaches coupled with clinical data such as calcitonin levels.
PMCID: PMC4080849  PMID: 24617864
24.  Mitochondrial DNA Copy Number in Peripheral Blood and Melanoma Risk 
PLoS ONE  2015;10(6):e0131649.
Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure).
PMCID: PMC4482392  PMID: 26110424
25.  Identification of DRG-1 As a Melanoma-Associated Antigen Recognized by CD4+ Th1 Cells 
PLoS ONE  2015;10(5):e0124094.
Immunotherapy has emerged as a promising strategy for the treatment of metastatic melanoma. Clinical studies have demonstrated the feasibility of cancer immunotherapy using tumor antigens recognized by CD8+ T cells. However, the overall immune responses induced by these antigens are too weak and transient to induce tumor regression in the majority of patients who received immunization. A growing body of evidence suggests that CD4+ T helper (Th) cells play an important role in antitumor immunity. Therefore, the identification of MHC class II-restricted tumor antigens capable of stimulating CD4+ T cells may provide opportunities for developing effective cancer vaccines. To this end, we describe the identification of developmentally regulated GTP-binding protein 1 (DRG-1) as a melanoma-associated antigen recognized by HLA-DR11-restricted CD4+ Th1 cells. Epitope mapping analysis showed that the DRG1248-268 epitope of DRG-1 was required for T cell recognition. Reverse transcription-polymerase chain reaction revealed that DRG-1 was highly expressed in melanoma cell lines but not in normal tissues. DRG-1 knockdown by lentiviral-based shRNA suppressed melanoma cell proliferation and soft agar colony formation. Taken together, these data suggest that DRG-1 plays an important role in melanoma cell growth and transformation, indicating that DRG1 may represent a novel target for CD4+ T cell-mediated immunotherapy in melanoma.
PMCID: PMC4439028  PMID: 25993655

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