%0 Journal Article
%~ PubMed
%A Carlino, Matteo S
%A Saunders, Catherine A B
%A Haydu, Lauren E
%A Menzies, Alexander M
%A Martin Curtis, C
%A Lebowitz, Peter F
%A Kefford, Richard F
%A Long, Georgina V
%T (18)F-labelled fluorodeoxyglucose-positron emission tomography (FDG-PET) heterogeneity of response is prognostic in dabrafenib treated BRAF mutant metastatic melanoma.
%B European Journal of Cancer
%D 2013
%C United Kingdom
%I Pergamon
%V 49
%N 2
%P 395-402
%@ 1879-0852
%X 
%Z FOR Codes: 110313


%0 Journal Article
%~ PubMed
%A Klein, Oliver
%A Clements, Arthur
%A Menzies, Alexander M
%A O'Toole, Sandra
%A Kefford, Richard F
%A Long, Georgina V
%T BRAF inhibitor activity in V600R metastatic melanoma.
%B European Journal of Cancer
%D 2013
%C United Kingdom
%I Pergamon
%V 49
%N 5
%P 1073-1079
%@ 1879-0852
%X 
%Z FOR Codes: 111204


%0 Journal Article
%~ PubMed
%A Long, Georgina V
%A Wilmott, James S
%A Capper, David
%A Preusser, Matthias
%A Zhang, Yuxiao E
%A Thompson, John F
%A Kefford, Richard F
%A von Deimling, Andreas
%A Scolyer, Richard A
%T Immunohistochemistry Is Highly Sensitive and Specific for the Detection of V600E BRAF Mutation in Melanoma.
%B American Journal of Surgical Pathology
%D 2013
%C United States
%I Lippincott Williams & Wilkins
%V 37
%N 1
%P 61-65
%@ 1532-0979
%X 
%Z FOR Codes: 1112


%0 Journal Article
%~ PubMed
%A Zimmer, Lisa
%A Hillen, Uwe
%A Livingstone, Elisabeth
%A Lacouture, Mario E
%A Busam, Klaus
%A Carvajal, Richard D
%A Egberts, Friederike
%A Hauschild, Axel
%A Kashani-Sabet, Mohammed
%A Goldinger, Simone M
%A Dummer, Reinhard
%A Long, Georgina V
%A McArthur, Grant
%A Scherag, Andr??
%A Sucker, Antje
%A Schadendorf, Dirk
%T Atypical Melanocytic Proliferations and New Primary Melanomas in Patients With Advanced Melanoma Undergoing Selective BRAF Inhibition.
%B Journal of Clinical Oncology
%D 2012
%C United States
%I American Society of Clinical Oncology
%V 30
%N 19
%P 2375-2383
%@ 1527-7755
%X PURPOSESelective inhibition of mutant BRAF by using class I RAF inhibitors in patients with metastatic melanoma has resulted in impressive clinical activity. However, there is also evidence that RAF inhibitors might induce carcinogenesis or promote tumor progression via stimulation of MAPK signaling in RAF wild-type cells. We analyzed melanocytic lesions arising under class I RAF inhibitor treatment for dignity, specific genetic mutations, or expression of signal transduction molecules. PATIENTS AND METHODSIn all, 22 cutaneous melanocytic lesions that had either developed or considerably changed in morphology in 19 patients undergoing treatment with selective BRAF inhibitors for BRAF-mutant metastatic melanoma at seven international melanoma centers within clinical trials in 2010 and 2011 were analyzed for mutations in BRAF and NRAS genes and immunohistologically assessed for expression of various signal transduction molecules in comparison with 22 common nevi of 21 patients with no history of BRAF inhibitor treatment.ResultsTwelve newly detected primary melanomas were confirmed in 11 patients within 27 weeks of selective BRAF blockade. In addition, 10 nevi developed of which nine were dysplastic. All melanocytic lesions were BRAF wild type. Explorations revealed that expression of cyclin D1 and pAKT was increased in newly developed primary melanomas compared with nevi (P = .01 and P = .03, respectively). There was no NRAS mutation in common nevi, but BRAF mutations were frequent. CONCLUSIONMalignant melanocytic tumors might develop with increased frequency in patients treated with selective BRAF inhibitors supporting a mechanism of BRAF therapy-induced growth and tumorigenesis. Careful surveillance of melanocytic lesions in patients receiving class I RAF inhibitors seems warranted.
%Z FOR Codes: 801


%0 Journal Article
%~ PubMed
%A Murali, Rajmohan
%A Haydu, Lauren E
%A Long, Georgina V
%A Quinn, Michael J
%A Saw, Robyn P M
%A Shannon, Kerwin
%A Spillane, Andrew J
%A Stretch, Jonathan R
%A Kefford, Richard F
%A Thompson, John F
%A Scolyer, Richard A
%T Clinical and Pathologic Factors Associated with Distant Metastasis and Survival in Patients with Thin Primary Cutaneous Melanoma.
%B Annals of Surgical Oncology
%D 2012
%C United States
%I Springer New York LLC
%V 19
%N 6
%P 1782-1789
%@ 1068-9265
%X BACKGROUND: Approximately 3-5% of patients with thin (?1 mm) cutaneous melanomas develop distant metastases. We sought to identify clinical and pathologic factors associated with distant metastasis and survival in a large number of patients with thin melanoma treated at a single institution. METHODS: We identified patients with a single invasive melanoma ?1 mm in thickness diagnosed between January 1983 and December 2003 who developed distant metastasis (cases), and matched patients with no recorded recurrence during follow-up (control subjects). Cases and control subjects were matched for age, sex, and year of primary melanoma diagnosis. Associations of clinical and pathologic parameters with distant metastasis-free survival and melanoma-specific survival were analyzed. RESULTS: A total of 178 cases and 178 control subjects were identified. Factors associated with development of distant metastasis were: increasing Breslow thickness (P < 0.001), increasing Clark level of invasion (P < 0.001), increasing mitotic rate (P = 0.001), ulceration (P = 0.025), and American Joint Committee on Cancer T subcategory (P < 0.001). Multivariable models including Breslow thickness (but not Clark level) showed that factors independently associated with poorer distant metastasis-free survival were increasing age [hazard ratio (HR) 1.01, 95% confidence interval (CI) 1.00-1.02]; increasing Breslow thickness (HR 3.21, 95% CI 1.73-5.94, and HR 3.77, 95% CI 2.11-6.74 for 0.51-0.75 mm and 0.76-1.00 mm, respectively, compared with 0.01-0.50 mm); ulceration (HR 1.87, 95% CI 1.14-3.06) and mitotic rate (HR 1.13, 95% CI 1.05-1.21). Similar associations with melanoma-specific survival were found. CONCLUSIONS: Clinical and pathologic predictors of distant metastasis and survival identified in this large study of patients with thin primary cutaneous melanomas will enable more accurate stratification of risk of distant metastasis and poor survival in such patients, and will assist in formulating clinical management and follow-up regimens based on the level of risk.
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Flaherty, Keith T
%A Infante, Jeffery R
%A Daud, Adil
%A Gonzalez, Rene
%A Kefford, Richard F
%A Sosman, Jeffrey
%A Hamid, Omid
%A Schuchter, Lynn
%A Cebon, Jonathan
%A Ibrahim, Nageatte
%A Kudchadkar, Ragini
%A Burris, Howard A
%A Falchook, Gerald
%A Algazi, Alain
%A Lewis, Karl
%A Long, Georgina V
%A Puzanov, Igor
%A Lebowitz, Peter
%A Singh, Ajay
%A Little, Shonda
%A Sun, Peng
%A Allred, Alicia
%A Ouellet, Daniele
%A Kim, Kevin B
%A Patel, Kiran
%A Weber, Jeffrey
%T Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
%B The New England journal of medicine
%D 2012
%C United States
%I Massachusetts Medical Society
%V 367
%N 18
%P 1694-1703
%@ 1533-4406
%X 
%Z FOR Codes: 111204 111205


%0 Journal Article
%~ PubMed
%A Wilmott, James S
%A Scolyer, Richard A
%A Long, Georgina V
%A Hersey, Peter
%T Combined targeted therapy and immunotherapy in the treatment of advanced melanoma.
%B Oncoimmunology
%D 2012
%C United States
%I Landes Bioscience
%V 1
%N 6
%P 997-999
%@ 2162-402X
%X 
%Z FOR Codes: 111204


%0 Journal Article
%~ PubMed
%A Anforth, R M
%A Blumetti, T C M P
%A Kefford, R F
%A Sharma, R
%A Scolyer, R A
%A Kossard, S
%A Long, G V
%A Fernandez-Pe??as, P
%T Cutaneous Manifestations of Dabrafenib (GSK2118436): A Selective Inhibitor of Mutant BRAF in patients with Metastatic Melanoma.
%B British Journal of Dermatology
%D 2012
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 167
%N 5
%P 1153-1160
%@ 1365-2133
%X Background:??? Inhibitors of mutant BRAF (BRAFi) are emerging as standard of care in patients with metastatic melanoma carrying relevant oncogenic mutations. Cutaneous reactions are frequent and significant. We conducted a systematic prospective dermatologic review of all patients enrolled at a single institution in the phase I/II clinical trial of the mutant BRAFi dabrafenib (GSK2118436). Objectives:??? To identify the cutaneous manifestations of the BRAFi dabrafenib; To form a diagnostic criterion to standardise the diagnosis of verrucal keratotic squmoproliferative lesions; To bring awareness to the medical community of the importance of dermatological assessment of patients taking dabrafenib. Methods:??? Patients enrolled in the phase I/II trial (N=43) were monitored for the development of new skin lesions. Each new lesion was photographed, a clinical diagnosis recorded and, where appropriate, a biopsy taken. Human papilloma virus (HPV) and p16 immunohistochemistry analysis were performed. Results:??? The most frequently observed lesions were verrucal keratotic squamoproliferative lesions (49%), Grover''s disease (27%) and reactive hyperkeratotic lesions on the soles, at points of friction (22%). Eighteen squamous cell carcinomas (SCC) occurred in 20% of patients. Most SCCs appeared between weeks six and 24 following commencement of therapy on both sun-damaged and non sun-damaged skin. All SCCs were well differentiated, five were of the keratoacanthoma-type, and two were SCC in situ. Other lesions observed included seborrheic keratoses, epidermal cysts, acneiform eruptions, hair loss and changes in hair structure. HPV was negative in 15 of the 16 tissues studied and p16 expression was higher in SCCs compared to verrucal keratoses. Conclusion:??? Administration of the mutant BRAFi dabrafenib is associated with induction of keratinocytic proliferation, which in some cases develops features of low-grade malignancy. Highly oncogenic HPV infection is unlikely to be a contributor to the formation of SCCs or verrucal keratoses.
%Z FOR Codes: 699


%0 Journal Article
%~ PubMed
%A Menzies, Alexander M
%A Long, Georgina V
%A Murali, Rajmohan
%T Dabrafenib and its potential for the treatment of metastatic melanoma.
%B Drug Design, Development and Therapy
%D 2012
%C United Kingdom
%I Dove Medical Press Ltd.
%V 6
%N 
%P 391-405
%@ 1177-8881
%X 
%Z FOR Codes: 111204


%0 Journal Article
%~ PubMed
%A Long, Georgina V
%A Trefzer, Uwe
%A Davies, Michael A
%A Kefford, Richard F
%A Ascierto, Paolo A
%A Chapman, Paul B
%A Puzanov, Igor
%A Hauschild, Axel
%A Robert, Caroline
%A Algazi, Alain
%A Mortier, Laurent
%A Tawbi, Hussein
%A Wilhelm, Tabea
%A Zimmer, Lisa
%A Switzky, Julie
%A Swann, Suzanne
%A Martin, Anne-Marie
%A Guckert, Mary
%A Goodman, Vicki
%A Streit, Michael
%A Kirkwood, John M
%A Schadendorf, Dirk
%T Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial.
%B The Lancet Oncology
%D 2012
%C United Kingdom
%I The Lancet Publishing Group
%V 13
%N 11
%P 1087-1095
%@ 1474-5488
%X 
%Z FOR Codes: 1103 1112


%0 Journal Article
%~ PubMed
%A Falchook, Gerald S
%A Long, Georgina V
%A Kurzrock, Razelle
%A Kim, Kevin B
%A Arkenau, Tobias H
%A Brown, Michael P
%A Hamid, Omid
%A Infante, Jeffrey R
%A Millward, Michael
%A Pavlick, Anna C
%A O'Day, Steven J
%A Blackman, Samuel C
%A Curtis, C Martin
%A Lebowitz, Peter
%A Ma, Bo
%A Ouellet, Daniele
%A Kefford, Richard F
%T Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.
%B The Lancet
%D 2012
%C United Kingdom
%I The Lancet Publishing Group
%V 379
%N 9829
%P 1893-1901
%@ 0140-6736
%X Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases.
%Z FOR Codes: 111209


%0 Journal Article
%~ PubMed
%A Menzies, Alexander M
%A Haydu, Lauren E
%A Visintin, Lydia
%A Carlino, Matteo S
%A Howle, Julie R
%A Thompson, John F
%A Kefford, Richard F
%A Scolyer, Richard A
%A Long, Georgina V
%T Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma.
%B Clinical Cancer Research
%D 2012
%C United States
%I American Association for Cancer Research
%V 18
%N 12
%P 3242-3249
%@ 1078-0432
%X PURPOSE: Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma.Methods: A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival.RESULTS: Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade (P < 0.001). All patients <30 years and only 25% ?70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. Non-V600E genotypes comprised <20% in patients <50 years and >40% in those ?70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type melanoma (37%, P < 0.001).CONCLUSION: Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior. Clin Cancer Res; 1-8. ©2012 AACR.
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Wilmott, James Samuel
%A Tembe, Varsha
%A Howle, Julie R
%A Sharma, Raghwa
%A Thompson, John F
%A Rizos, Helen
%A Lo, Roger S
%A Kefford, Richard F
%A Scolyer, Richard A
%A Long, Georgina V
%T Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine.
%B Molecular Cancer Therapeutics
%D 2012
%C United States
%I American Association for Cancer Research
%V 11
%N 12
%P 2704-2708
%@ 1538-8514
%X Targeted therapies are increasingly being used to treat a variety of cancers. Their efficacy depends upon the accurate detection and targeting of a specific mutation or aberration in the tumour. All cancers such as melanoma are molecularly heterogeneous, with drug resistant subclones present prior to treatment or emerging as a result of targeted therapies. Here we show intra-lesional molecular heterogeneity in a progressing V600E BRAF-mutant melanoma metastasis from a patient treated for 7 months with the BRAF inhibitor vemurafenib. In the single metastasis, two distinct subclones were observed, both V600E BRAF-mutant, and only one with an additional G13R NRAS-mutation. Molecular heterogeneity even at the intra-lesional level demonstrates that personalising or adjusting therapies based on genotyping of a portion of a single lesion, might not accurately depict the molecular profile or drivers of oncogenesis across the entire patient''s melanoma.
%Z FOR Codes: 60103 110399


%0 Journal Article
%~ PubMed
%A Shi, Hubing
%A Moriceau, Gatien
%A Kong, Xiangju
%A Lee, Mi-Kyung
%A Lee, Hane
%A Koya, Richard C
%A Ng, Charles
%A Chodon, Thinle
%A Scolyer, Richard A
%A Dahlman, Kimberly B
%A Sosman, Jeffrey A
%A Kefford, Richard F
%A Long, Georgina V
%A Nelson, Stanley F
%A Ribas, Antoni
%A Lo, Roger S
%T Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance.
%B Nature Communications
%D 2012
%C United Kingdom
%I Nature Publishing Group
%V 3
%N 2
%P 724
%@ 2041-1723
%X The development of acquired drug resistance hampers the long-term success of B-RAF inhibitor therapy for melanoma patients. Here we show (V600E)B-RAF copy-number gain as a mechanism of acquired B-RAF inhibitor resistance in 4 out of 20 (20%) patients treated with B-RAF inhibitor. In cell lines, (V600E)B-RAF overexpression and knockdown conferred B-RAF inhibitor resistance and sensitivity, respectively. In (V600E)B-RAF amplification-driven (versus mutant N-RAS-driven) B-RAF inhibitor resistance, extracellular signal-regulated kinase reactivation is saturable, with higher doses of vemurafenib down-regulating phosho-extracellular signal-regulated kinase and re-sensitizing melanoma cells to B-RAF inhibitor. These two mechanisms of extracellular signal-regulated kinase reactivation are sensitive to the MEK1/2 inhibitor AZD6244/selumetinib or its combination with the B-RAF inhibitor vemurafenib. In contrast to mutant N-RAS-mediated (V600E)B-RAF bypass, which is sensitive to C-RAF knockdown, (V600E)B-RAF amplification-mediated resistance functions largely independently of C-RAF. Thus, alternative clinical strategies may potentially overcome distinct modes of extracellular signal-regulated kinase reactivation underlying acquired B-RAF inhibitor resistance in melanoma.
%Z FOR Codes: 801


%0 Journal Article
%~ PubMed
%A Murali, Rajmohan
%A Brown, Philip T
%A Kefford, Richard F
%A Scolyer, Richard A
%A Thompson, John F
%A Atkins, Michael B
%A Long, Georgina V
%T Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma.
%B Cancer
%D 2012
%C United States
%I John Wiley & Sons, Inc.
%V 118
%N 18
%P 4519-4529
%@ 0008-543X
%X BACKGROUND: A history of multiple primary melanomas (PMs) has been associated with improved survival in patients with early stage melanoma, but whether it also is correlated with survival in patients with metastatic melanoma is unknown. The authors sought to address the latter question in the current study. METHODS: Patients with metastatic melanoma diagnosed at the Melanoma Institute Australia between 1983 and 2008 were identified. Overall survival (OS) was calculated from date of first distant metastasis. Survival analysis was performed using the Kaplan-Meier method, log-rank tests, and multivariate Cox proportional hazards models. RESULTS: Of 2942 patients with metastatic melanoma, 2634 (89.5%) had 1 PM and 308 (10.5%) had >1 PM. Factors that were associated independently with shorter OS were site of metastasis, including the brain (hazard ratio [HR], 2.41; 95% confidence interval [CI], 2.07-2.81; P < .001) and nonlung viscera (HR, 1.92; 95% CI, 1.67-2.22; P < .001, vs lymph node/subcutaneous/soft tissue), age >60 years (HR, 1.23; 95% CI, 1.12-1.36; P < .001), shorter disease-free interval from PM to first distant metastasis (???12 months vs >36 months: HR, 1.62; 95% CI, 1.39-1.89; P < .001), and fewer PMs (1 vs >1; HR, 1.26; 95% CI, 1.08-1.47; P = .004). CONCLUSIONS: A history of multiple PM was an independent predictor of improved survival for patients with metastatic melanoma. The results indicate that a history of multiple PMs should be incorporated into multivariate analyses of prognostic factors and treatment outcomes. Cancer 2012. ?? 2012 American Cancer Society.
%Z FOR Codes: 111201


%0 Journal Article
%~ PubMed
%A Shi, Hubing
%A Moriceau, Gatien
%A Kong, Xiangju
%A Koya, Richard C
%A Nazarian, Ramin
%A Pupo, Gulietta M
%A Bacchiocchi, Antonella
%A Dahlman, Kimberly B
%A Chmielowski, Bartosz
%A Sosman, Jeffrey A
%A Halaban, Ruth
%A Kefford, Richard F
%A Long, Georgina V
%A Ribas, Antoni
%A Lo, Roger S
%T Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors.
%B Cancer Discovery
%D 2012
%C United States
%I American Association for Cancer Research
%V 2
%N 5
%P 414-424
%@ 2159-8290
%X BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced (V600E/K)BRAF melanomas. Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with (V600E/K)BRAF may be selected for by BRAFi. We sequenced MEK1/2 exon 3 in melanomas at baseline and upon disease progression. Of 31 baseline (V600E/K)BRAF melanomas, 5 (16%) carried concurrent somatic BRAF/MEK1 activating mutations. Three of 5 patients with BRAF/MEK1 double-mutant baseline melanomas showed objective tumor responses, consistent with the overall 60% frequency. No MEK1 mutation was found in disease progression melanomas, except when it was already identified at baseline. MEK1-mutant expression in (V600E/K)BRAF melanoma cell lines resulted in no significant alterations in p-ERK1/2 levels or growth-inhibitory sensitivities to BRAFi, MEK1/2 inhibitor (MEKi), or their combination. Thus, activating MEK1 exon 3 mutations identified herein and concurrent with (V600E/K)BRAF do not cause BRAFi resistance in melanoma. Cancer Discov; 2(5); 414-24. ??2012 AACR.
%Z FOR Codes: 111207 111209 60408


%0 Journal Article
%~ PubMed
%A Wilmott, James Samuel
%A Long, Georgina V
%A Howle, Julie R
%A Haydu, Lauren E
%A Sharma, Raghwa
%A Thompson, John F
%A Kefford, Richard F
%A Hersey, Peter
%A Scolyer, Richard A
%T Selective BRAF inhibitors induce marked T cell infiltration into human metastatic melanoma.
%B Clinical Cancer Research
%D 2012
%C United States
%I American Association for Cancer Research
%V 18
%N 5
%P 1386-1394
%@ 1078-0432
%X PURPOSE:  To evaluate the effects of treatment with the potent mutant BRAF inhibitors GSK 2118436 or vemurafenib (PLX4720) on immune responses to metastatic melanoma in tissues taken before and after treatment. Patients and Methods: Thirty-seven tumor biopsies were collected from fifteen unresectable American Joint Committee on Cancer stage III or IV melanoma patients immediately before and approximately seven days after the commencement of BRAF inhibitor treatment and at the time of tumor progression. Immunohistochemical staining was performed on the biopsies using specific antibodies for CD8, CD4, CD20, CD1a, and Granzyme B. RESULTS:  Tumor infiltration by CD4+ and CD8+ lymphocytes increased markedly following BRAF inhibitor treatment (both ??=0???015). There was a correlation between the degree of tumor infiltration by CD8+ and Granzyme B expressing lymphocytes in post BRAF inhibitor treated biopsies (r=0???690, ??=0???013). Increased intratumoral CD8+ lymphocyte expression correlated with a reduction in tumor size and an increase in necrosis in post treatment biopsies (r= -0???793, ??=0???011 and r=0???761, ??=0???004, respectively). CONCLUSION:  The increase in tumor infiltrating lymphocytes (TILS) induced by treatment with BRAF inhibitors provides strong support for conducting trials that combine BRAF inhibitors with immunotherapy in the hope of prolonging clinical responses.
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Carlino, Matteo S
%A Fogarty, Gerald B
%A Long, Georgina V
%T Treatment of melanoma brain metastases: a new paradigm.
%B Cancer Journal
%D 2012
%C United States
%I Lippincott Williams & Wilkins
%V 18
%N 2
%P 208-212
%@ 1540-336X
%X Brain metastases occur commonly in patients with metastatic melanoma, are associated with a poor prognosis, and cause significant morbidity. Both surgery and stereotactic radiosurgery are used to control brain metastases and, in selected patients, improve survival. In those with extensive brain involvement, whole-brain radiotherapy can alleviate symptoms. Historically, systemic therapy has had little role to play in the management of melanoma brain metastases; however, early clinical trials of BRAF inhibitors have shown promising activity. This review examines the evidence for local and systemic treatments in the management of patients with melanoma brain metastases. We present a new treatment algorithm for melanoma patients with brain metastases, which integrates the evolving evidence for the use of BRAF inhibitors.
%Z FOR Codes: 801


%0 Journal Article
%~ PubMed
%A Scolyer, Richard A
%A Long, Georgina V
%A Thompson, John F
%T Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care.
%B Molecular oncology
%D 2011
%C Netherlands
%I Elsevier BV
%V 5
%N 2
%P 124-36
%@ 1878-0261
%X In the initial period after melanoma was recognised as a disease entity in the early 1800''s, it was subclassified on the basis of its presumed origin (from a precursor naevus, from a melanocytic precursor lesion acquired during adult life or in previously blemish-fee skin). In 1967 the eminent American pathologist, Dr Wallace Clark, proposed a histogenetic classification for melanoma in which the disease was subdivided predominantly on the basis of histopathological features of the intra-epidermal component of the tumour adjacent to any dermal invasive component. The subtypes were superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) and nodular melanoma (NM). Whilst additional entities, including acral lentiginous melanoma, mucosal melanoma, desmoplastic melanoma and naevoid melanoma have since been recognised, SSM, LMM and NM remain in the latest (2006) version of the WHO melanoma classification. Clark''s histogenetic classification has been criticised because the criteria upon which it is based include clinical features (such as the site of the melanoma) and non-tumourous histopathological features (such as the character of the associated epidermis and the degree of solar elastosis) and also because of overlap in defining features, lack of an independent association with patient outcome and minimal relevance as a determinant of clinical management. However, such criticisms fail to acknowledge its importance in highlighting the myriad of clinical and histological guises of melanoma, which if not recognized by clinicians and pathologists will inevitably lead to a delay in diagnosis and a concomitant adverse clinical outcome. Recently, mutually exclusive oncogenic mutations in melanomas involving NRAS (15-20%), BRAF (50%), CKIT (2%), and GNAQ/GNA11 (50% of uveal melanomas) have been identified. This might herald the beginning of a new molecular classification of melanoma in which the biologically distinct subsets share a common oncogenic mechanism, behave clinically in a similar fashion and require similar clinical management. These discoveries are already being successfully exploited as therapeutic targets in clinical trials of metastatic melanoma patients with promising activity. Whilst there remains much to be discovered in this rapidly evolving field, there is already great optimism that more rational and effective therapies for melanoma patients will soon be widely available.
%Z FOR Codes: 1112


%0 Journal Article
%~ PubMed
%A Long, Georgina V
%A Menzies, Alexander M
%A Nagrial, Adnan M
%A Haydu, Lauren E
%A Hamilton, Anne L
%A Mann, Graham J
%A Hughes, T Michael
%A Thompson, John F
%A Scolyer, Richard A
%A Kefford, Richard F
%T Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma.
%B Journal of Clinical Oncology
%D 2011
%C United States
%I American Society of Clinical Oncology
%V 29
%N 10
%P 1239-1246
%@ 1527-7755
%X To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.
%Z FOR Codes: 110316


%0 Journal Article
%~ PubMed
%A Arkenau, H-T
%A Kefford, R
%A Long, G V
%T Targeting BRAF for patients with melanoma.
%B British journal of cancer
%D 2011
%C United Kingdom
%I Nature Publishing Group
%V 104
%N 3
%P 392-8
%@ 0007-0920
%X The prognosis of patients with metastatic melanoma is poor and not influenced by systemic therapy with cytotoxic drugs. New targeted agents directed against the RAS-RAF-MEK-ERK pathway show promising activity in early clinical development and particular interest is focused on selective inhibitors of mutant BRAF, which is present in one half of the cases of metastatic melanoma. The majority of patients on early trials of these drugs develop secondary resistance and subsequent disease progression and it is, therefore, critical to understand the underlying escape mechanisms leading to resistance.
%Z FOR Codes: 111207 110399


%0 Journal Article
%A Long, Georgina
%T Book review: The Molecular Biology of Cancer
%B CancerForum
%D 2007
%C Australia
%I Cancer Council Australia
%V 31
%N 2
%P 121
%@ 0311-306X
%X 
%Z FOR Codes: 111201


%0 Journal Article
%~ PubMed
%A Long, Georgina
%A Tattersall, Martin H
%T Lung encasement by metastatic osteoblastic sarcoma.
%B The Medical journal of Australia
%D 2007
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 186
%N 2
%P 100-100
%@ 1326-5377
%X 
%Z FOR Codes: 111201