Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human ...melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma ( approximately 30-40%). In vitro testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other KIT mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (P = 0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (DeltaDeltaGbind = -2.52 kcal/mol) but not for dasatinib (DeltaDeltaGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography (PET) imaging after dasatinib treatment. These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas.
Delayed systemic recurrence of uveal melanoma Kolandjian, Nathalie A; Wei, Caimiao; Patel, Sapna P ...
American journal of clinical oncology,
10/2013, Volume:
36, Issue:
5
Journal Article
Peer reviewed
Open access
Metastatic uveal melanoma recurrence after ≥10 years is not well studied in the clinical literature. This study describes the clinical characteristics and natural history of patients with delayed ...tumor recurrence.
To describe the characteristics of patients with delayed systemic recurrence of uveal melanoma and the natural history of the disease after recurrence.
This is a chart review of patients treated between 1994 and 2008 at The University of Texas, MD Anderson Cancer Center for uveal melanoma whose disease recurred ≥10 years after treatment of the primary tumor.
Of 463 patients treated for metastatic uveal melanoma, 305 developed systemic recurrence within 5 years from the time of diagnosis of primary melanoma, 97 developed systemic recurrences between 5 and 10 years, whereas 61 patients developed metastasis after ≥10 years. The interval between primary to first systemic metastasis was a significant independent predictor of survival time from first systemic metastasis. The median survival time for patients with delayed metastatic recurrence after ≥10 years was significantly longer than for patients who had intermediate or early systemic recurrence. Levels of lactate dehydrogenase, serum alkaline phosphatase, serum albumin, age, M-stage, and performance status at time of recurrence, as well as sex were also independent predictors of survival time from systemic recurrence.
Longer time interval between primary and first systemic metastasis is significantly correlated with prolonged survival. Patients who survive ≥10 years without tumor metastasis after treatment for primary uveal melanoma cannot be considered cured. Prognosis remains poor for patients with metastatic uveal melanoma.
The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and ...dacarbazine CVD) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b.
Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks.
Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects.
Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.
Pharmacologic blockade of the myostatin (Mstn)/activin receptor pathway is being pursued as a potential therapy for several muscle wasting disorders. The functional benefits of blocking this pathway ...are under investigation, in particular given the findings that greater muscle hypertrophy results from Mstn deficiency arising from genetic ablation compared to post‐developmental Mstn blockade. Using high‐resolution MS coupled with SILAC mouse technology, we quantitated the relative proteomic changes in gastrocnemius muscle from Mstn knockout (Mstn−/−) and mice treated for 2‐weeks with REGN1033, an anti‐Mstn antibody. Relative to wild‐type animals, Mstn−/− mice had a two‐fold greater muscle mass and a >1.5‐fold change in expression of 12.0% of 1137 quantified muscle proteins. In contrast, mice treated with REGN1033 had minimal changes in muscle proteome (0.7% of 1510 proteins >1.5‐fold change, similar to biological difference 0.5% of 1310) even though the treatment induced significant 20% muscle mass increase. Functional annotation of the altered proteins in Mstn−/− mice corroborates the mutiple physiological changes including slow‐to‐fast fiber type switch. Thus, the proteome‐wide protein expression differs between Mstn−/− mice and mice subjected to specific Mstn blockade post‐developmentally, providing molecular‐level insights to inform mechanistic hypotheses to explain the observed functional differences.
Venous thromboembolism (VTE) is a frequent complication in melanoma patients with brain metastases (BM). The management of these patients is challenging because of the high risk of intracranial ...hemorrhage (ICH) and the limited data available on the safety of anticoagulation in this scenario. We reviewed the treatments and outcomes among melanoma patients with BM and VTE at our institution to determine the safety of anticoagulation in these patients. A retrospective chart review was performed to identify melanoma patients with BM who were diagnosed with VTE. The clinical characteristics of the BM and the VTE, the treatments given for VTE, subsequent ICH, and overall survival (OS) were determined. The characteristics and outcomes were compared between patients who received systemic anticoagulation and those who did not. A total of 74 evaluable melanoma patients with BM and VTE were identified. Fifty-seven (77%) patients received systemic anticoagulation. There was no significant difference in the number (P=0.40) or the maximum diameter (P=0.55) of brain metastasis between the patients who received anticoagulation and those who did not. Two (4%) patients who received anticoagulation developed ICH, which was not statistically different from the patients who did not receive anticoagulation (0%, P=1.00). There was a trend toward longer OS from VTE among patients who received systemic anticoagulation (median OS: 4.2 vs. 1.2 months, P=0.06). Anticoagulation for VTE did not significantly increase the risk of ICH or decrease OS in patients with melanoma BM. These data support the safety of systemic anticoagulation for VTE in these patients.
Melanoma that metastasizes to distant sites is associated with a grave prognosis. The objectives of the study were (1) to identify predictive factors for the development of brain metastases from the ...time of diagnosis of stage III/IV disease, (2) to identify predictive factors for the development of central nervous system (CNS) metastases from the time of diagnosis of primary melanoma, and (3) to assess whether the incidence of brain metastasis is more frequent in patients who had no tumor response to systemic therapy for stage III/IV disease compared with those who had partial or complete response.
We collected and retrospectively analyzed information of 740 patients with advanced metastatic melanoma treated at MD Anderson Cancer Center over 15 years. Three hundred and twenty-nine patients had CNS metastases. The characteristics of these patients in terms of median age, sex, primary site, Breslow thickness, stage at first visit, baseline serum parameters, and response to systemic therapy were compared with those of patients who did not develop CNS metastasis. Cox proportional hazards models were used to analyze the cause-specific hazard function for CNS metastasis and deaths without CNS metastasis.
We identified that M-stage stage M1b vs. stage III or M1a, hazard ratio (HR)=2.64; stage M1c vs. stage III or M1a, HR=2.13, P<0.0001 and lactic acid dehydrogenase (LDH) (elevated vs. normal LDH, HR=1.51, P<0.001) at diagnosis of unresectable stage III/IV disease can independently predict the risk of developing CNS metastasis from the time of diagnosis of stage III/IV disease. Older age (HR=1.01, P=0.076), chemoresistance (stable disease+progressive disease vs. complete response+partial response HR=2.91, P<0.0001), low level of albumin (vs. normal HR=2.87, P<0.0001), elevated LDH (vs. normal HR=1.55, P=0.0004), and M-stage (M1c disease vs. stage III or M1a HR=1.89, P<0.0001) can independently predict shorter time to death without CNS metastasis from the diagnosis of stage III/IV disease. The location (head and neck vs. limbs HR=1.56, P=0.028; trunk and abdomen vs. limbs HR=1.45, P=0.029; unknown site vs. limbs HR=8.43, P=0.036) and pathology Clark level (CL)=3 and/or BR2 to 4 mm vs. CL≤2 and/or BR<2 mm HR=1.60, P=0.037; CL>3 and/or BR> 4 mm vs. CL≤2 and/or BR<2 mm HR=2.03, P=0.001) of the primary melanoma can independently predict CNS metastasis-free interval from the time of diagnosis of primaries. Age (HR=1.012, P=0.034) and pathology of the primary melanoma (CL>3 and/or BR>4 mm vs. CL≤2 and/or BR<2 mm HR=1.54, P=0.024) can independently predict time to death without CNS metastasis from primaries.
We identified the predictive factors associated with the development of CNS metastasis in patients with unresectable metastatic melanoma.
Isotype Determination of Antibodies Hornbeck, Peter; Fleisher, Thomas A; Papadopoulos, Nicholas M
Current protocols in immunology,
February 2017, Volume:
116
Journal Article
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