[Show abstract][Hide abstract] ABSTRACT: Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ∼11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
[Show abstract][Hide abstract] ABSTRACT: Background:
Melanoma patients with palpable nodal disease in more than one basin have a worse prognosis than those with single-basin disease. Little is known about the outcome of patients with microscopically positive nodal disease in more than one basin, or how they are currently managed at tertiary referral centers.
We identified 97 patients with positive sentinel lymph nodes (SLNs) in more than one lymph node basin from 1994 to 2010 from three tertiary care centers. Clinical and pathologic outcome variables were analyzed.
Ninety-seven patients (72 men, 25 women) were identified with at least one positive SLN in at least two node basins. Most primary tumors were truncal (68, 70 %) followed by extremity (16, 17 %) and head/neck (13, 13 %). The median Breslow depth was 3.2 mm (range 0.8-12 mm), and 49 (51 %) were ulcerated. The most frequently involved nodal basins were the axilla (112, 57 %), neck (40, 20 %), and groin (24, 12 %). Seventy-seven percent (153 of 198) of all positive SLN basins underwent completion lymph node dissection (CLND). Most patients (54, 56 %) developed recurrent disease, with a median time to recurrence of 20 months. The majority of first recurrences were distant (42, 43 %), followed by regional nonnodal metastases (17, 18 %) and regional nodal metastases (16, 16 %). There was no significant difference in median overall survival between CLND versus no-CLND groups (45 vs. 30 months, respectively).
Most melanoma patients with more than one SLN-positive basin are currently managed with CLND. Outcomes after CLND and no CLND are similarly poor; therefore, consideration of close nodal observation may be more appropriate.
No preview · Article · Jun 2014 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Background:
The brain is a common site of recurrence in melanoma patients. Brain recurrence may present as a seizure, hemorrhage, or death. We sought to determine predictors of brain metastases in patients with primary and regional melanoma in order to facilitate targeted screening.
Prospectively maintained databases were used to identify patients treated for local or regional melanoma who developed stage IV melanoma with and without brain metastasis at initial recurrence. One hundred twenty patients were identified with brain relapse and compared to 487 patients without brain recurrence.
On univariate analysis, patients with brain metastases were younger (55 vs. 59yrs, P = 0.04) but did not differ in primary site (head and neck 23% vs. 21%, P = 0.20). Brain metastasis patients had thinner primaries (mean 3.4 vs. 4.5 mm, P = 0.01). There were no other pathologic differences including ulceration (55% vs. 53%, P = 0.75), mitoses (7 vs.7.5, P = 0.61) or histologic subtype. Younger age and decreased Breslow thickness were independently associated with brain metastases at stage IV recurrence (OR = 1.10 P = 0.01 and OR = 1.02 P = 0.02, respectively).
Our analysis, the largest to date, demonstrates that thinner Breslow depth and younger age were associated with brain recurrence at first presentation with Stage IV disease.
No preview · Article · Jun 2014 · Journal of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: The benefit of completion lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) remains unknown.
We identified patients with a positive SLN from 1994 to 2012. Patient and tumor characteristics, reasons for not undergoing CLND, patterns of recurrence, and melanoma-specific survival data were analyzed.
Of 4,310 patients undergoing SLN biopsy (SLNB), 495 (11 %) had a positive SLN-167 (34 %) patients underwent nodal observation and 328 (66 %) had immediate CLND. Patients in the no-CLND group were older (66 vs. 56 years; p < 0.001) and more likely to have lower extremity lesions (57 vs. 42 %; p = 0.006). There were no differences in tumor thickness, Clark level of invasion, ulceration, or SLN tumor burden. Median follow-up was 23 and 80 months for the no-CLND and CLND groups, respectively, and median time to recurrence was similar at 9 and 12 months, respectively (p = 0.48). There was no difference in local and in transit recurrence rates between groups (16 %, no CLND, and 18 %, CLND; p = 0.48). Nodal disease as a site of first recurrence occurred in 15 % of patients in the no-CLND group and 6 % of CLND patients (p = 0.002). In contrast, systemic recurrences occurred in 8 % of no-CLND patients compared with 27 % of CLND patients (p < 0.001). While median recurrence-free survival was higher after CLND (34.5 vs. 20.9 months; p = 0.02), melanoma-specific survival was similar (not reached, no CLND vs. 110 months, CLND; p = 0.09).
Immediate CLND after a positive SLNB is associated with fewer initial nodal basin recurrences but similar melanoma-specific survival. These results support ongoing equipoise in the Multicenter Selective Lymphadenectomy Trial II (MSLT-II).
Full-text · Article · May 2014 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: RAF inhibitors selectively block ERK signaling in BRAF-mutant melanomas and have defined a genotype-guided approach to care for this disease. RAF inhibitors have the opposite effect in BRAF wild-type tumor cells, where they cause hyperactivation of ERK signaling. Here, we predict that RAF inhibitors can enhance T cell activation, based upon the observation that these agents paradoxically activate ERK signaling in BRAF wild-type cells. To test this hypothesis, we have evaluated the effects of the RAF inhibitor BMS908662 on T cell activation and signaling in vitro and in vivo. We observe that T cell activation is enhanced in a concentration-dependent manner and that this effect corresponds with increased ERK signaling, consistent with paradoxical activation of the pathway. Furthermore, we find that the combination of BMS908662 with CTLA-4 blockade in vivo potentiates T cell expansion, corresponding with hyperactivation of ERK signaling in T cells detectable ex vivo. Lastly, this combination demonstrates superior anti-tumor activity, compared to either agent alone, in two transplantable tumor models. This study provides clear evidence that RAF inhibitors can modulate T cell function by potentiating T cell activation in vitro and in vivo. Paradoxical activation of ERK signaling in T cells offers one mechanism to explain the enhanced antitumor activity seen when RAF inhibitors are combined with CTLA-4 blockade in preclinical models.
[Show abstract][Hide abstract] ABSTRACT: The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF(V600E) melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.
No preview · Article · Feb 2014 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Malignant melanoma is the most fatal type of skin cancer. Traditional melanoma classification has been based on histological subtype or anatomical location. However, recent evidence suggests that melanoma comprises a group of diseases characterized by distinct molecular mutations. These mutations affect disease behavior but provide unique opportunities for targeted therapy.
In this review, several signaling pathways in melanoma are described as well as how mutations of BRAF, NRAS, KIT, GNAQ, and GNA11 genes cause aberrant signaling and malignant transformation.
Multiple genes affecting both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway are mutated in melanoma. Melanomas harboring the BRAF V600E mutation have demonstrated sensitivity to both RAF and MAPK/extracellular signal regulated kinase (ERK) inhibitors in vitro and in vivo. In addition, KIT-mutant melanomas, often arising from mucosal, acral, and chronically sun-damaged skin surfaces, have shown clinical response to several inhibitors of the type III transmembrane receptor tyrosine kinase KIT. Uveal melanoma, which often harbors GNAQ or GNA11 mutations, may also be sensitive to MAPK/ERK or protein kinase C/PI3K pathway inhibition.
Emerging knowledge of these molecular alterations has led to clinical advances in patients with melanoma. The study of known mutations and identification of new potential targets must continue in an effort to develop more effective therapies for this disease.
No preview · Article · Oct 2013 · Cancer control: journal of the Moffitt Cancer Center
[Show abstract][Hide abstract] ABSTRACT: The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune-related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted.
[Show abstract][Hide abstract] ABSTRACT: Acral melanoma (AM) is an unusual malignancy with poor survival. This study defines a cohort of patients, treated at a single institution, and the factors associated with survival and comparison with nonacral cutaneous melanoma (NACM).
All patients with AM presenting from 1995 to 2010 were identified from a prospectively maintained database. Analysis of clinicopathologic features of AM associated with disease-specific survival (DSS) was performed. A stratified, stage-matched survival analysis compared the outcome of 281 acral to 843 extremity NACM patients.
A total of 281 AM patients (170 volar, 111 subungual) were identified. Pathologic stage (p < 0.001), ulceration (p < 0.001), Breslow thickness (p < 0.001), and a positive sentinel lymph node (p < 0.001) were found to be poor prognostic indicators associated with DSS. In stage-matched analysis, AM had a worse DSS compared with NACM (hazard ratio 1.8; 95 % CI 1.2-2.7; p < 0.01).
This study represents the largest, single-institution series describing the characteristics and outcomes of AM. AM tumors exhibit aggressive histopathologic features associated with a poorer survival outcome. AM patients have an inferior survival than extremity NACM when matched for stage, perhaps reflecting inherent alterations in tumor biology. This warrants further investigation into the differences between acral and cutaneous melanoma.
No preview · Article · Jul 2013 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Background:
In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.
We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.
Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).
Full-text · Article · Jun 2013 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Background:
The tumor microenvironment after treatment with ipilimumab is not well described. Furthermore, the safety of surgery for patients being treated with ipilimumab for metastatic melanoma has not been well reported. This study analyzed the safety of surgery and the immune phenotype of tumors resected while on ipilimumab.
From our prospective melanoma database, we identified patients undergoing surgery for any indication within 30 days of receiving a dose of induction ipilimumab or while on maintenance ipilimumab therapy. Surgical toxicity was graded 1-5 by the Clavien classification. Tumor-infiltrating lymphocytes were classified by flow cytometry and compared with peripheral blood.
23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipilimumab (1-123 weeks). Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures. Grade 1 or 2 wound complications were seen in 22% of patients. No Grade 3-5 complications were seen. Analysis of the T cell infiltrate and matched peripheral blood from ten patients showed an elevated % of CD4+FOXP3+ T-regulatory cells and a 2.8-fold lower ratio of CD8+/CD4+FOXP3+ in the tumor compared with blood (p=0.02). In addition, all CD8+ T cells had a higher expression of PD-1 in the tumor, compared with peripheral blood.
Surgery for patients on ipilimumab is safe. This study highlights the immunosuppressive phenotype in tumors not responding to immunotherapy. The high percentage of T-regulatory cells and low T-effector cells in progressive tumors suggests a possible mechanism of immune escape.
Full-text · Article · May 2013 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: : Anatomic site is a predictive factor in subtypes of cutaneous and mucosal melanoma.
: The aim of this study was to examine the clinical relevance of location of origin of anorectal melanoma as a prognostic factor.
: With the use of a prospectively maintained database, clinical characteristics, management, and outcomes were compared according to the site of origin. SETTINGS, PATIENTS, INTERVENTIONS:: A retrospective review was conducted of patients diagnosed with anorectal melanoma from 1994 to 2010. Tumors were defined as anal, anorectal, or rectal melanoma according to their anatomic relationship to the dentate line.
: Clinicopathologic factors were compared by χ test. Time-to-event analysis was performed by Kaplan-Meier analysis.
: Of the 96 patients included (41 with anal melanoma, 32 with anorectal melanoma, 23 with rectal melanoma), patients with rectal and anorectal mucosal melanoma had advanced primary tumors (median Breslow thickness, 12 mm and 8 mm, p = 0.002), whereas anal lesions could be found at earlier depths (median thickness, 6.5 mm). Patients with anal tumors more commonly underwent transanal excision (p < 0.02) and sentinel lymph node biopsy (p = 0.004) versus anorectal and rectal tumors. Patterns of recurrence were also distinct; nearly two-thirds of anorectal and rectal tumors recurred systemically, whereas anal melanoma more often recurred within the lymph nodes first (63%; p < 0.02). Recurrence occurred in 24 (59%) patients with anal tumors, 23 (72%) patients with anorectal tumors, and 16 (70%) patients with rectal tumors. Median overall survival was 22 months for anal melanoma, 28 months for anorectal melanoma, and 27 months for rectal melanoma. Recurrence and survival were not statistically different between the groups.
: This study is limited by small sample size and its retrospective nature.
: This study represents the only series describing the outcomes of anorectal melanoma by anatomic location. Lesions at or proximal to the dentate line present with more advanced disease, possibly related to a delay in diagnosis. Lesions distal to the dentate line more commonly recur within lymph nodes, which may represent differences in nodal drainage. Irrespective of location, the long-term prognosis remains poor for all cases of anorectal melanoma.
Full-text · Article · Feb 2013 · Diseases of the Colon & Rectum
[Show abstract][Hide abstract] ABSTRACT: Background:
The effect of lymph node metastasis on local tumor control and distant failure in patients with anorectal melanoma has not been fully studied. Understanding the significance of lymphatic dissemination might assist in stratifying patients for either organ preservation or radical surgery.
A retrospective review of all patients with anorectal melanoma who underwent surgery at our institution between 1985 and 2010. Abdominoperineal resection (APR) was performed in 25 patients (39 %), and wide local excision (WLE) in 40 (61%). Extent of primary surgery and locoregional lymphadenectomy (mesorectal vs. inguinal vs. none) and pattern of treatment failure were analyzed. Recurrence-free survival (RFS) and disease-specific survival (DSS) were calculated.
In patients undergoing APR, DSS was not associated with presence (29 %) or absence (71 %) of metastatic melanoma in mesorectal lymph nodes. There was a trend toward improved DSS in patients with clinically negative inguinal lymph nodes (n = 17) compared with patients with proven inguinal metastasis (n = 6; P = 0.12). Type of surgery (WLE vs. APR) was not associated with subsequent development of distant disease. Twelve patients (18 %) had synchronous local and distant recurrence. Synchronous recurrence was not associated with surgical strategy used to treat primary tumor (P = 0.28). Perineural invasion (PNI) was significantly correlated with RFS (P = 0.002).
Outcome following resection of anorectal melanoma is independent of locoregional lymph node metastasis; lymphadenectomy should be reserved for gross symptomatic disease. PNI is a powerful prognostic marker warranting further exploration in clinical trials.
No preview · Article · Jan 2013 · Annals of Surgical Oncology
[Show abstract][Hide abstract] ABSTRACT: Patients undergoing sentinel lymph node (SLN) mapping for lower extremity melanoma may have drainage to pelvic nodes (DPN) in addition to superficial inguinal nodes. These nodes are not sampled routinely at SLN biopsy. Factors predicting DPN and its prognostic significance were assessed in a large cohort of patients undergoing an SLN biopsy. Three hundred and twenty five patients with single primary melanomas of the lower extremity or buttocks who underwent SLN mapping were identified from our prospective melanoma database (December 1995-October 2008). Associations of clinical and pathologic factors with DPN and time to melanoma recurrence (TTR) were analyzed by logistic and Cox regression, respectively. DPN was common, occurring in 23% of cases. Increased Breslow's thickness (P=0.007) and age (P=0.01) were associated with DPN by multivariate analysis. Patients with DPN were not more likely to have a positive SLN; however, SLN- patients with DPN showed a shorter TTR (P=0.02) in a multivariable model including thickness and ulceration. With age included in the model, DPN remained marginally associated with TTR in this group (P=0.08). The pelvic recurrence rates observed were similar in recurrent patients with DPN compared with those without DPN (39% in both groups). In conclusion, DPN occurs in almost one-quarter of patients with lower extremity melanoma and is marginally associated with a shorter TTR in SLN- patients.
No preview · Article · Dec 2012 · Melanoma research
[Show abstract][Hide abstract] ABSTRACT: First-degree relatives (FDRs) of melanoma survivors are at heightened risk for developing melanoma, but use sun protection inconsistently. To develop appropriate interventions, in this article we identify factors related to sun protection inconsistency in melanoma FDRs using ethnographic decision tree modeling. We conducted in-home interviews with 25 melanoma FDRs balanced across gender and sunbathing attitudes and identified factors related to daily decision making about use of sunscreen, shade seeking, hats, and clothing. Results indicated primary facilitators for sun protection involved water settings and sunny weather. Physical activities such as exercise served to promote as well as inhibit sun protection. If participants anticipated shade cover, they tended to forgo other sun protection. The use of hats and clothing was often dictated by nonsun-protection goals. Understanding factors related to inconsistent sun protection with detail and nuance is an important prerequisite to interventions aimed to improve sun-protection maintenance in this population.
No preview · Article · Jul 2012 · Qualitative Health Research