Stage IV metastatic melanoma patients historically have a poor prognosis with 5-10% 5-year survival. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4), is one of the ...first treatments to provide beneficial durable responses in advanced melanoma. However, less than 25% of those treated benefit, treatment is expensive, and side effects can be fatal. Since soluble (s) CTLA4 may mediate inhibitory effects previously ascribed to the membrane-bound isoform (mCTLA4), we hypothesized patients benefiting from ipilimumab have higher serum levels of sCTLA4. We found that higher sCTLA4 levels correlated both with response and improved survival in patients treated with ipilimumab in a small patient cohort patients with (n = 9) and without (n = 5) clinical benefit. sCTLA4 levels were statistically higher in ipilimumab-treated patients with response to ipilimumab. In contrast, sCTLA4 levels did not correlate with survival in patients who did not receive ipilimumab (n = 11). These preliminary observations provide a previously unrecognized link between serum sCTLA4 levels and response to ipilimumab as well as to improved survival in ipilimumab-treated melanoma patients and a potential mechanism by which ipilimumab functions.
Purpose: The purpose of the study was to clarify the incidence of B-raf oncogene ( BRAF ) mutations in primary cutaneous melanomas, their relation to tumor progression, and effect on disease outcome. ...Somatic mutations
of BRAF kinase, a component of the Ras -mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase pathway, are frequently
reported (>65%) in nevi and malignant melanomas.
Experimental Design: W e assessed BRAF mutation frequency in exons 11 and 15 in primary ( n = 59) and metastatic ( n = 68) melanomas. Direct sequencing of PCR products was performed on DNA isolated and purified from microdissected tumors.
Results: Eighteen mutations (31%) at exon 15 were detected in primary melanoma with a significantly ( P = 0.001) higher frequency in patients < 60 years old. Incidence of BRAF mutation did not correlate with Breslow thickness. Presence of BRAF mutation of primary tumors did not effect overall disease-free survival. BRAF mutation frequency in metastatic lesions was 57% and significantly ( P = 0.0024) higher than primary melanomas.
Conclusions: The study suggests that BRAF mutation may be acquired during development of metastasis but is not a significant factor for primary tumor development and
disease outcome.
Abstract A vaccine is typically defined as any preparation used as a preventive inoculation to confer immunity against a specific disease. Vaccines for infectious diseases are highly effective, ...acting by inducing antigen-specific immunity that prevents subsequent infection. Unfortunately, the success of vaccines in infectious diseases has not been mirrored in oncology. This failure is the result of several challenges facing cancer vaccines, including the conceptual shift from disease prevention to disease treatment, tumor-induced immunosuppression and other mechanisms of immune escape, the similarity between tumor antigens and self antigens to which the patient is tolerant, unfavorable effector-to-target ratios in patients with established tumors, and financial and regulatory issues. Despite this, cancer remains a promising target for vaccine therapy. Melanoma in particular is known for its inherent immunogenicity on the basis of many anecdotal reports of spontaneous immune-based tumor regression, and thus has been the focus of immunotherapeutic approaches. Rare but significant vaccine-induced clinical regression of melanoma has spurred intensive investigations to augment vaccine efficacy. This review explores the many vaccine strategies that have been clinically tested for the treatment of melanoma and considers future approaches of cancer immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Melanoma brain metastasis (MBM) represents a frequent complication of cutaneous melanoma. Despite aggressive multi-modality therapy, patients with MBM often have a survival rate of <1 year. ...Alteration in DNA methylation is a major hallmark of tumor progression and metastasis; however, it remains largely unexplored in MBM. In this study, we generated a comprehensive DNA methylation landscape through the use of genome-wide copy number, DNA methylation and gene expression data integrative analysis of melanoma progression to MBM. A progressive genome-wide demethylation in low CpG density and an increase in methylation level of CpG islands according to melanoma progression were observed. MBM-specific partially methylated domains (PMDs) affecting key brain developmental processes were identified. Differentially methylated CpG sites between MBM and lymph node metastasis (LNM) from patients with good prognosis were identified. Among the most significantly affected genes were the HOX family members. DNA methylation of HOXD9 gene promoter affected transcript and protein expression and was significantly higher in MBM than that in early stages. A MBM-specific PMD was identified in this region. Low methylation level of this region was associated with active HOXD9 expression, open chromatin and histone modifications associated with active transcription. Demethylating agent induced HOXD9 expression in melanoma cell lines. The clinical relevance of this finding was verified in an independent large cohort of melanomas (n = 145). Patients with HOXD9 hypermethylation in LNM had poorer disease-free and overall survival. This epigenome-wide study identified novel methylated genes with functional and clinical implications for MBM patients.
The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) ...for staging the regional nodal basin of patients with early-stage melanoma.
Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases.
After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (> or =1 mm with Clark level > or =III, or any thickness with Clark level > or =IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients.
Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications.
LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.
Background Melanoma liver metastasis is most often fatal, with a 4- to 6-month median overall survival (OS). Over the past 20 years, surgical techniques have improved in parallel with more effective ...systemic therapies. We reviewed our institutional experience of hepatic melanoma metastases. Study Design Overall and disease-specific survivals were calculated from hepatic metastasis diagnosis. Potential prognostic factors including primary tumor type, depth, medical treatment response, location, and surgical approach were evaluated. Results Among 1,078 patients with melanoma liver metastases treated at our institution since 1991, 58 (5.4%) received surgical therapy (resection with or without ablation). Median and 5-year OS were 8 months and 6.6 %, respectively, for 1,016 nonsurgical patients vs 24.8 months and 30%, respectively, for surgical patients (p < 0.001). Median OS was similar among patients undergoing ablation (with or without resection) relative to those undergoing surgery alone. On multivariate analysis of surgical patients, completeness of surgical therapy (hazard ratio HR 3.4, 95% CI 1.4 to 8.1, p = 0.007) and stabilization of melanoma on therapy before surgery (HR 0.38, 95% CI 0.19 to 0.78, p = 0.008) predicted OS. Conclusions In this largest single-institution experience, patients selected for surgical therapy experienced markedly improved survival relative to those receiving only medical therapy. Patients whose disease stabilized on medical therapy enjoyed particularly favorable results, regardless of the number or size of their metastases. The advent of more effective systemic therapy in melanoma may substantially increase the fraction of patients who are eligible for surgical intervention, and this combination of treatment modalities should be considered whenever it is feasible in the context of a multidisciplinary team.
Surgery for distant melanoma metastasis Leung, Anna M; Hari, Danielle M; Morton, Donald L
The cancer journal (Sudbury, Mass.),
2012 Mar-Apr, 2012-03-00, 20120301, Volume:
18, Issue:
2
Journal Article
Peer reviewed
Open access
Traditionally, distant metastatic melanoma has a poor prognosis owing to lack of efficacious, U.S. Food and Drug Administration-approved systemic therapy and the limited use of surgical resection as ...a therapeutic option. More recently, new biological therapies such as vemurafenib (Zelboraf) and ipilimumab (Yervoy) have shown strong promise and dramatically improved the landscape of stage IV melanoma therapy. Although there are numerous single-institution studies advocating the role for therapeutic surgical intervention, many remain skeptical of nonpalliative surgery for metastatic melanoma. Surgical resection of advanced melanoma has been proven to be effective as long as all disease is removed (R0). Patient selection is paramount. The combination of newer systemic therapies and surgical resection is currently under investigation. Understanding the tumor biology of melanoma and its mechanism of metastatic spread is essential to developing the most efficacious treatment strategy.
•Studies have shown that direct peer pressure and conversations affect young driver behavior.•Impact of a non-interacting passenger and subtle modes of peer influence on driver behavior are ...unknown.•Driver attention was affected by Passenger Presence.•Driver characteristics were associated with driving performance with a passenger.
Studies have shown that teenage drivers are less attentive, more frequently exhibit risky driving behavior, and have a higher fatal crash risk in the presence of peers. The effects of direct peer pressure and conversation on young drivers have been examined. Little is known about the impact on driving performance of the presence of a non-interacting passenger and subtle modes of peer influence, such as perceived social norms. The goal of this study was to examine if teenagers would engage in more risky driving practices and be less attentive in the presence of a passenger (vs. driving alone) as well as with a risk-accepting (vs. risk-averse) passenger. A confederate portrayed the passenger's characteristics mainly by his non-verbal attitude. The relationship between driver characteristics and driving behavior in the presence of a passenger was also examined. Thirty-six male participants aged 16–17 years old were randomly assigned to drive with a risk-accepting or risk-averse passenger. Main outcomes included speed, headway, gap acceptance, eye glances at hazards, and horizontal eye movement. Driver characteristics such as tolerance of deviance, susceptibility to peer pressure, and self-esteem were measured. Compared to solo driving, the presence of a passenger was associated with significantly fewer eye glances at hazards and a trend for fewer horizontal eye movements. Contrary to the hypothesis, however, Passenger Presence was associated with waiting for a greater number of vehicles to pass before initiating a left turn. Results also showed, contrary to the hypothesis, that participants with the risk-accepting passenger maintained significantly longer headway with the lead vehicle and engaged in more eye glances at hazards than participants with the risk-averse passenger. Finally, when driving with the passenger, earlier initiation of a left turn in a steady stream of oncoming vehicles was significantly associated with higher tolerance of deviance and susceptibility to peer pressure, while fewer eye glances at hazards was linked to lower self-esteem. While the results of this study were mixed, they suggest that the presence of a teenage passenger can affect some aspects of teenage driver behavior even in the absence of overt pressure and distraction. Results are discussed in relation to theoretical concepts of social influence and social facilitation models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background
We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable.
Materials ...and Methods
The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate.
Results
With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients <20 and >80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients >70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous.
Conclusions
Melanomas in patients at the extremes of age have a distinct natural history.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Age-related outcomes have become increasingly common in evaluating patients with melanoma. For instance, as age increases, sentinel node (SN) nonidentification increases and SN positivity ...decreases. Furthermore, advanced age is a risk factor for in-transit disease. We hypothesized that increasing age is accompanied by alterations in lymphatic function, possibly explaining these findings.
Methods
Our center’s melanoma database was queried to identify patients who underwent successful sentinel node biopsy after lymphoscintigraphy. Records of those treated between 2000 and 2005 were reviewed for age, sex, drainage basin, intraoperative radioactivity, and SN pathology.
Results
The 858 patients had a mean age of 55 years; 59% were men. Mean radioactivity in the hottest SN was 5232 counts per second; 179 patients (21%) had SN metastases. SN count rates were significantly and inversely related to age (
P
< .001 by Pearson correlation, analysis of variance, and χ
2
test). Mean counts per second were 6105, 5883, and 2720 for axillary, inguinal, and cervical basins, respectively (
P
< .01), and count rates in these basins were consistently lower with increasing age (neck and axilla,
P
< .001; groin,
P
= .060; Pearson correlation). Multivariate analysis confirmed an independent inverse association between age and count rates (
P
< .001), overall and within each primary tumor site.
Conclusions
Lymphatic function, as assessed by radiocolloid transit to and uptake within the SN, declines with age. Altered lymphatic function in older patients may modify metastatic patterns; knowledge of this may help clarify findings of reduced nodal positivity and increased in-transit disease in this population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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