David H Lawson

Emory University, Atlanta, Georgia, United States

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Publications (56)385.19 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Here we demonstrate a “synthetic lethal” interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukaemia cells. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, active BRAF upregulates HMGCL through an octamer transcription factor Oct-1, leading to increased intracellular levels of HMGCL product, acetoacetate, which selectively enhances binding of BRAF V600E but not BRAF wild type to MEK1 in V600E-positive cancer cells to promote activation of MEK-ERK signaling. These findings reveal a novel mutation-specific mechanism by which oncogenic BRAF V600E “rewires” metabolic and cell signaling networks and signals through the Oct-1-HMGCL-acetoacetate axis to selectively promote BRAF V600E-dependent tumor development.
    Molecular Cell 07/2015; · 14.46 Impact Factor
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    ABSTRACT: Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Neuro-Oncology 05/2015; DOI:10.1093/neuonc/nov093 · 5.29 Impact Factor
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    ABSTRACT: We compared the safety and efficacy of ipilimumab and stereotactic radiosurgery (SRS) to SRS alone for newly diagnosed melanoma brain metastases (MBM). We reviewed records of newly diagnosed MBM patients treated with SRS from 2009 to 2013. The primary endpoint of overall survival (OS), and secondary endpoints of local control, distant intracranial failure, and radiation necrosis were compared using Kaplan-Meier method. Univariate and multivariate analysis were performed using the Cox proportional hazards method. Fifty-four consecutive MBM patients were identified, with 20 (37.0%) receiving ipilimumab within 4 months of SRS. Ipilimumab-treated and non-ipilimumab-treated patients had similar baseline characteristics. No difference in symptomatic radiation necrosis or hemorrhage was identified between cohorts. Compared with patients in the nonipilimumab group, 1 year local control (71.4% vs. 92.3%, P=0.40) and intracranial control (12.7% vs. 29.1%, P=0.59) were also statistically similar. The ipilimumab cohort also had no difference in 1-year OS (37.1% vs. 38.5%, P=0.84). Patients administered ipilimumab within 14 days of SRS had higher 1-year (42.9%) and 2-year OS (42.9%) relative to ipilimumab delivered >14 days (33.8%, 16.9%) and SRS alone (38.5%, 25.7%) but these difference were not statistically significant. Univariate analysis and multivariate analysis both confirmed single brain metastasis, controlled primary, and active systemic disease as predictors for OS. Use of ipilimumab within 4 months of SRS seems to be safe, with no increase in radiation necrosis or hemorrhage; however, our retrospective institutional experience with this treatment regimen was not associated with improved outcomes.
    American journal of clinical oncology 05/2015; DOI:10.1097/COC.0000000000000199 · 2.61 Impact Factor
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    ABSTRACT: A gene expression profile (GEP) test able to accurately identify risk of metastasis for patients with cutaneous melanoma has been clinically validated. We aimed for assessment of the prognostic accuracy of GEP and sentinel lymph node biopsy (SLNB) tests, independently and in combination, in a multicenter cohort of 217 patients. Reverse transcription polymerase chain reaction (RT-PCR) was performed to assess the expression of 31 genes from primary melanoma tumors, and SLNB outcome was determined from clinical data. Prognostic accuracy of each test was determined using Kaplan-Meier and Cox regression analysis of disease-free, distant metastasis-free, and overall survivals. GEP outcome was a more significant and better predictor of each end point in univariate and multivariate regression analysis, compared with SLNB (P < .0001 for all). In combination with SLNB, GEP improved prognostication. For patients with a GEP high-risk outcome and a negative SLNB result, Kaplan-Meier 5-year disease-free, distant metastasis-free, and overall survivals were 35%, 49%, and 54%, respectively. Within the SLNB-negative cohort of patients, overall risk of metastatic events was higher (∼30%) than commonly found in the general population of patients with melanoma. In this study cohort, GEP was an objective tool that accurately predicted metastatic risk in SLNB-eligible patients. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
    Journal of the American Academy of Dermatology 03/2015; 72(5). DOI:10.1016/j.jaad.2015.01.009 · 5.00 Impact Factor
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    ABSTRACT: The National Comprehensive Cancer Network (NCCN) 2014 guidelines are unclear about the role of radiotherapy in the management of desmoplastic melanoma. The guidelines specify that radiotherapy can be 'considered' for select patients with desmoplastic melanoma with narrow surgical margins. Patient selection criteria, including margins, are not well defined, causing considerable differences in practice patterns across the country. There are also several conflicting reports about the role of radiotherapy in improving postsurgical outcomes when other adverse pathological risks factors, such as increased Clark level, head and neck involvement, perineural invasion, positive margins, or recurrent disease, are also present. Recent data provide further clarification and insights into the role of radiotherapy. Thus, in light of the NCCN guidelines and the recently published series, we critically review the role of radiotherapy for desmoplastic melanoma. In our review, we highlight the published risk factors that predict for increased risk of recurrence after surgery. We also provide a comparison of surgical and radiation outcomes data, and then address areas for further research.
    Melanoma Research 01/2015; 25(2). DOI:10.1097/CMR.0000000000000139 · 2.10 Impact Factor
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    ABSTRACT: The development of a genetic signature for the identification of high-risk cutaneous melanoma tumors would provide a valuable prognostic tool with value for stage I and II patients who represent a remarkably heterogeneous group with a 3% to 55% chance of disease progression and death 5 years from diagnosis. A prognostic 28-gene signature was identified by analysis of microarray expression data. Primary cutaneous melanoma tumor tissue was evaluated by RT-PCR for expression of the signature, and radial basis machine (RBM) modeling was performed to predict risk of metastasis. RBM analysis of cutaneous melanoma tumor gene expression reports low risk (class 1) or high risk (class 2) of metastasis. Metastatic risk was predicted with high accuracy in development (ROC = 0.93) and validation (ROC = 0.91) cohorts of primary cutaneous melanoma tumor tissue. Kaplan-Meier analysis indicated that the 5-year disease-free survival (DFS) rates in the development set were 100% and 38% for predicted classes 1 and 2 cases, respectively (P < 0.0001). DFS rates for the validation set were 97% and 31% for predicted classes 1 and 2 cases, respectively (P < 0.0001). Gene expression profile (GEP), American Joint Committee on Cancer stage, Breslow thickness, ulceration, and age were independent predictors of metastatic risk according to Cox regression analysis. The GEP signature accurately predicts metastasis risk in a multicenter cohort of primary cutaneous melanoma tumors. Preliminary Cox regression analysis indicates that the signature is an independent predictor of metastasis risk in the cohort presented. Clin Cancer Res; 21(1); 175-83. ©2015 AACR. ©2015 American Association for Cancer Research.
    Clinical Cancer Research 01/2015; 21(1):175-83. DOI:10.1158/1078-0432.CCR-13-3316 · 8.19 Impact Factor
  • Cancer Epidemiology Biomarkers & Prevention 11/2014; 23(11 Supplement):C26-C26. DOI:10.1158/1538-7755.DISP13-C26 · 4.32 Impact Factor
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    ABSTRACT: To investigate survival, efficacy, and safety of selective internal yttrium-90 radioembolization therapy (Y-SIRT) in patients with unresectable metastatic melanoma (MM) to liver refractory to systemic therapy.
    American Journal of Clinical Oncology 08/2014; DOI:10.1097/COC.0000000000000109 · 2.61 Impact Factor
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    ABSTRACT: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation.
    JAMA The Journal of the American Medical Association 06/2014; 311(23):2397-405. DOI:10.1001/jama.2014.6096 · 30.39 Impact Factor
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    ABSTRACT: This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011). Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily. Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation. This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.
    The Cancer Journal 01/2014; 20(1):18-24. DOI:10.1097/PPO.0000000000000024 · 3.61 Impact Factor
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    ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts-including physicians, nurses, and patient advocates-to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.
    Nature Reviews Clinical Oncology 08/2013; DOI:10.1038/nrclinonc.2013.153 · 15.70 Impact Factor
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    ABSTRACT: Metastatic melanoma is difficult to treat, and often portends a grim prognosis. For patients with cerebral metastases, the prognosis is even more dire. Systemic immunotherapy and targeted agents are emerging as the mainstay of treatment for metastatic melanoma. Although immunotherapy has been shown to prolong relapse-free survival and long-term control of micrometastatic disease, the response rate is suboptimal, prompting the need to optimize and improve therapy. Accumulating evidence suggests that in addition to effective locoregional control, radiation therapy (RT) may induce immune activation and expansion of T lymphocytes recognizing melanocyte-specific antigens including activated cytotoxic T lymphocytes that can potentially kill melanoma cells. In some cases, RT contributes to the clearance of metastatic disease in distant, nonirradiated regions, a bystander phenomenon called the abscopal effect. Here, we evaluate the potential promise of ablative radiation treatment in the era of modern immunotherapy by presenting a patient with metastatic melanoma who remained disease free for over 3 years after an initial diagnosis of advanced metastatic melanoma with brain, subcutaneous tissue, mesenteric, pelvic, and retroperitoneal involvement. The patient failed initial stereotactic radiosurgery, but responded to whole-brain RT in combination with interleukin-2 immunotherapy. Thus, combination RT with immunotherapy may be synergistic by promoting the release and processing of melanoma antigens that can be presented by dendritic cells. This in turn may augment the response to therapies that center on expansion and/or activation of antitumor T cells.
    American journal of clinical oncology 05/2013; 38(1). DOI:10.1097/COC.0b013e3182940dc3 · 2.61 Impact Factor
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    ABSTRACT: Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, two weeks prior to, and during IL-2 treatment [720 000 units/kg q8 hrs X 5 days (1 cycle) every 3 weeks X 4 cycles]. Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms [Hamilton Depression Rating Scale (HDRS) score]. Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both groups [ESC (n=9), placebo (n=11)] exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Though ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, i.e., a maximal difference of ~3 points on the HDRS, which, though not statistically significant (in part due to small sample size), represents a clinically significant difference according to National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2- induced neurobehavioral changes.Neuropsychopharmacology accepted article preview online, 10 April 2013; doi:10.1038/npp.2013.85.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2013; 38(10). DOI:10.1038/npp.2013.85 · 7.83 Impact Factor
  • H.J. Prajapati, D.H. Lawson, H.S. Kim
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    ABSTRACT: Purpose To investigate the correlation of imaging findings with survivals in patients (pts) with unresectable metastatic melanoma (MM) to liver, refractory to systemic therapy , treated with selective internal yttrium-90 radioembolization therapy (90-Y SIRT). Materials and Methods Consecutive pts with unresectable MM to liver, who failed with systemic therapy, treated with resin-based 90Y SIRT in last 9 years, and who had cross sectional imaging (PET in 75% and chest abdomen pelvis CT or MR in 25% of pts) before 90-Y SIRT were evaluated retrospectively. Imaging findings were correlated with progression free survival (PFS) and overall survival (OS). RECIST 1.1 criteria were used for liver disease. The OS times were calculated from diagnosis of primary melanoma (OS-dx), from first 90Y SIRT (OS–90-Y) and from MM to liver (OS-MM). Absence of progression of MM to liver was considered as PFS. Kaplan Meir method tested with log rank test and Cox proportional hazard model were used for survival analysis. Results 24 pts (mean age 48.8 years, SD 14.5) with MM to liver underwent 42 90-Y SIRTs. The median OS-dx, OS-MM and OS-90Y were 121.4, 27.9 and 13.4 months(m) respectively. The median PFS was 10.1 m. PFS in partially responded (n=3), stable disease (n=15) and progressive disease (n=6) according RECIST 1.1 criteria were 19.6, 10.3 and 1.3 m respectively (p=0.001). Before 90-Y SIRT, the pts had Child-Pugh class A (n=21), B (n=2) and C (n=1) with corresponding median OS-90Y of 15, 2.6 and 0.9 m (p=0.02) respectively. More than 8 MM lesions to liver were present in 29.2% pts and had median OS–90-Y of 5.5 m vs 17.7 m in pts with <8 MM to liver (p=0.001). Before 90-Y SIRT, extrahepatic MM disease was present in lungs (12.5%), bones (33.3%), bones and lungs (8.3%), soft tissue or lymph nodes (20.9%) and no extrahepatic metastasis in 25% of the pts with corresponding median OS–90-Y of 5.9, 10.9, 4.8, 12.9 and 21.4, respectively (p=007). Conclusion RECIST 1.1 responses, less than 8 MM to liver lesions and absence of extrahepatic MM disease before 90Y SIRT were found predictor of prolonged survival.
    Journal of Vascular and Interventional Radiology 04/2013; 24(4):S36. DOI:10.1016/j.jvir.2013.01.077 · 2.15 Impact Factor
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    ABSTRACT: OBJECTIVES:: Brain metastases (BM) cause significant morbidity and mortality in patients with melanoma. We aimed to identify prognostic factors for overall survival (OS) in patients undergoing stereotactic radiosurgery (SRS) for BM from melanoma. METHODS:: We identified 135 patients treated with SRS at Emory University between 1998 and 2010 for BM from melanoma. We recorded patient age, number and size of all BM, Karnofsky Performance Status (KPS), presence of extracranial metastases, serum lactate dehydrogenase (LDH), use of whole-brain radiation therapy (WBRT), use of temozolomide, and surgical resection of BM. We used the Kaplan-Meier method to calculate OS, and we compared time-to-event data with the log-rank test. We performed Cox multivariate analysis to identify factors independently associated with OS. RESULTS:: Median OS for all patients was 6.9 months. Patients with KPS≥90, 70 to 80, and <70 had median OS of 10.4, 6.1, and 4.5 months, respectively (P=0.02). Patients with LDH<240 had median OS of 7.8 months versus 3.5 months for LDH≥240 (P=0.01). Patients receiving WBRT had median OS of 7.3 months versus 6.5 months for patients not receiving WBRT (P=0.05). KPS and LDH (but not WBRT) were significantly associated with OS on multivariate analysis. CONCLUSIONS:: In addition to previously identified prognostic factors for OS in patients with BM from melanoma, serum LDH is independently associated with OS. If this finding is confirmed in a prospective manner, the serum LDH level should be included in future prognostic algorithms for patients with melanoma and BM who are to receive SRS.
    American journal of clinical oncology 02/2013; DOI:10.1097/COC.0b013e318280d7be · 2.61 Impact Factor
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    ABSTRACT: Background. While it is established that the incidence of cutaneous melanoma has risen over time in the United States, the incidence trend for mucosal melanoma of the head and neck (MMHN) is unknown. Methods. We used the Surveillance, Epidemiology, and End Results (SEER) database to determine incidence trends for MMHN from 1987 to 2009 in the United States. We determined annual percent change (APC) by weighted least squares and joinpoint regression analysis. Results. MMHN incidence increased from 1987 to 2009 (APC 2.4%; P < 0.01). Nasal cavity lesions increased in incidence (APC 2.7%; P < 0.01) over this duration, while the incidence of non-nasal cavity lesions remained stable. The highest rate of increase was in white females ages 55 to 84 (APC 5.1%; P = 0.01). Conclusions. The incidence of MMHN in the United States has been rising since 1987. This trend is driven primarily by increased incidence of nasal cavity melanomas.
    12/2012; 2012:231693. DOI:10.1155/2012/231693
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    ABSTRACT: BACKGROUND: CTLA4 blocking monoclonal antibodies provide a low frequency but durable tumor responses in patients with metastatic melanoma, which led to the regulatory approval of ipilimumab based on two randomized clinical trials with overall survival advantage. The similarly fully human anti-CTLA4 antibody tremelimumab had been developed in the clinic at a fixed rate infusion, resulting in very prolonged infusion times. A new formulation of tremelimumab allowed testing a shorter infusion time. METHODS: A phase 1 multi-center study to establish the safety and tolerability of administering tremelimumab as a 1-hour infusion to patients with metastatic melanoma. Secondary endpoints included pharmacokinetic and clinical effects of tremelimumab. RESULTS: No grade 3 or greater infusion-related adverse events or other adverse events preventing the administration of the full tremelimumab dose were noted in 44 treated patients. The overall side effect profile was consistent with prior experiences with anti-CTLA4 antibodies. Objective tumor responses were noted in 11% of evaluable patients with metastatic melanoma, which is also consistent with the prior experience with CTLA4 antagonistic antibodies. CONCLUSIONS: This study did not identify any safety concerns when tremelimumab was administered as a 1-hour infusion. These data support further clinical testing of the 1-hour infusion of tremelimumab. (Clinical trial registration number NCT00585000).
    Journal of Translational Medicine 11/2012; 10(1):236. DOI:10.1186/1479-5876-10-236 · 3.99 Impact Factor
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    ABSTRACT: To investigate the prognostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in predicting survival in patients with unresectable metastatic melanoma to the liver undergoing yttrium-90 ((90)Y) radioembolization. A retrospective review of 12 patients with unresectable hepatic melanoma metastases (5 patients with cutaneous metastases, 7 patients with ocular metastases) who underwent (18)F-FDG PET-CT before (90)Y was performed. Metabolically significant tumors, defined as having a long-axis diameter ≥ 1 cm and maximum standardized uptake value (SUV(max)) ≥ 2.5, were identified on (18)F-FDG PET-CT. SUV(max), glycolytic activity, and volume were determined for each tumor. Overall SUV(max), total tumor glycolytic activity (TGA), total metabolic tumor volume (MTV), and metabolic tumor burden (MTB) based on percentage of liver involvement (MTV/total liver volume) were calculated. Kaplan-Meier method, life-table analysis, and Cox proportional hazards model were used for statistical analysis. Median SUV(max) was 10.9 (range, 4.6-15.3), median TGA was 377.0 SUV/cm(3) (range, 53.6-20,393.4 SUV/cm(3)), median MTV was 85.4 cm(3) (range, 11.5-2,504.1 cm(3)), and median MTB was 5.5% (range, 0.1%-54.0%). MTB was found to be a significant negative prognostic marker of survival on univariate (P = .020) and multivariate (P = .018) analyses accounting for age and duration from metastatic diagnosis to first (90)Y treatment. A 60th percentile MTB of 7.0% (hazard ratio, 5.704; P = .040) was a statistically significant cutoff. Median survivals from first (90)Y treatment in patients with MTB < 7.0% and ≥ 7.0% were 10.8 months (95% confidence interval [CI], 6.8-14.8) and 4.7 months (95% CI, 1.6-7.8), respectively. SUV(max) (P = .422), TGA (P = .064), and MTV (P = .065) were not found to be statistically significant. MTB based on (18)F-FDG PET-CT performed before treatment was found to be a negative prognostic factor for patient survival after (90)Y radioembolization for unresectable metastatic melanoma to liver.
    Journal of vascular and interventional radiology: JVIR 05/2012; 23(7):943-8. DOI:10.1016/j.jvir.2012.04.010 · 2.15 Impact Factor
  • Fuel and Energy Abstracts 10/2011; 81(2). DOI:10.1016/j.ijrobp.2011.06.827
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    ABSTRACT: α(v) integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α(v)-integrin monoclonal antibody. In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1:1:1:1 to 1000 mg m(-2) dacarbazine+placebo (n=32), 1000 mg m(-2) dacarbazine+10 mg kg(-1) intetumumab (n=32), 10 mg kg(-1) intetumumab (n=33), or 5 mg kg(-1) intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics. No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg(-1) intetumumab, and 5 mg kg(-1) intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab-dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1-2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22-30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16-73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred. With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.
    British Journal of Cancer 07/2011; 105(3):346-52. DOI:10.1038/bjc.2011.183 · 4.82 Impact Factor