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Melanoma: HELP
Articles by Donald L. Morton
Based on 60 articles published since 2008
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Between 2008 and 2019, D. Morton wrote the following 60 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

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.

2 Review Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. 2012

Morton, Donald L. ·John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA. mortond@JCWI.org ·Clin Exp Metastasis · Pubmed #22729520.

ABSTRACT: This short review offers an update on the first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) for patients with melanoma, and briefly traces the development of intraoperative lymphatic mapping and sentinel node biopsy.

3 Review Surgery for distant melanoma metastasis. 2012

Leung, Anna M / Hari, Danielle M / Morton, Donald L. ·Department of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. ·Cancer J · Pubmed #22453019.

ABSTRACT: Traditionally, distant metastatic melanoma has a poor prognosis owing to lack of efficacious, U.S. Food and Drug Administration-approved systemic therapy and the limited use of surgical resection as a therapeutic option. More recently, new biological therapies such as vemurafenib (Zelboraf) and ipilimumab (Yervoy) have shown strong promise and dramatically improved the landscape of stage IV melanoma therapy. Although there are numerous single-institution studies advocating the role for therapeutic surgical intervention, many remain skeptical of nonpalliative surgery for metastatic melanoma. Surgical resection of advanced melanoma has been proven to be effective as long as all disease is removed (R0). Patient selection is paramount. The combination of newer systemic therapies and surgical resection is currently under investigation. Understanding the tumor biology of melanoma and its mechanism of metastatic spread is essential to developing the most efficacious treatment strategy.

4 Review Unique patterns of metastases in common and rare types of malignancy. 2011

Leong, Stanley P L / Nakakura, Eric K / Pollock, Raphael / Choti, Michael A / Morton, Donald L / Henner, W David / Lal, Anita / Pillai, Raji / Clark, Orlo H / Cady, Blake. ·Center for Melanoma Research and Treatmnet and Department of Surgery, California Pacific Medical Center and Research Institute, San Francisco, California 94115, USA. leongSX@cpmcri.org ·J Surg Oncol · Pubmed #21480255.

ABSTRACT: This review on the unique patterns of metastases by common and rare types of cancer addresses regional lymphatic metastases but also demonstrates general principles by consideration of vital organ metastases. These general features of successfully treated metastases are relationships to basic biological behavior as illustrated by disease-free interval, organ-specific behavior, oligo-metastatic presentation, genetic control of the metastatic pattern, careful selection of patients for surgical resection, and the necessity of complete resection of the few patients eligible for long-term survival after resection of vital organ metastasis. Lymph node metastases, while illustrating these general features, are not related to overall survival because lymph node metastases themselves do not destroy a vital organ function, and therefore have no causal relationship to overall survival. When a cancer cell spreads to a regional lymph node, does it also simultaneously spread to the systemic site or sites? Alternatively, does the cancer spread to the regional lymph node first and then it subsequently spreads to the distant site(s) after an incubation period of growth in the lymph node? Of course, if the cancer is in its incubation stage in the lymph node, then removal of the lymph node in the majority of cases with cancer cells may be curative. The data from the sentinel lymph node era, particularly in melanoma and breast cancer, is consistent with the spectrum theory of cancer progression to the sentinel lymph node in the majority of cases prior to distant metastasis. Perhaps, different subsets of cancer may be better defined with relevant biomarkers so that mechanisms of metastasis can be more accurately defined on a molecular and genomic level.

5 Review Sentinel node biopsy in melanoma: technical considerations of the procedure as performed at the John Wayne Cancer Institute. 2010

Bagaria, Sanjay P / Faries, Mark B / Morton, Donald L. ·John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California 90404, USA. ·J Surg Oncol · Pubmed #20512942.

ABSTRACT: Since its first description in 1990, sentinel node (SN) biopsy has become the standard for accurate staging of a melanoma-draining regional lymphatic basin. This minimally invasive, multidisciplinary technique can detect occult metastases by selective sampling and focused pathologic analysis of the first nodes on the afferent lymphatic pathway from a primary cutaneous melanoma. An understanding of preoperative lymphoscintigraphy, intraoperative lymphatic mapping, and the definition of SN are critical for surgical expertise with SN biopsy.

6 Clinical Trial Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. 2017

Faries, Mark B / Mozzillo, Nicola / Kashani-Sabet, Mohammed / Thompson, John F / Kelley, Mark C / DeConti, Ronald C / Lee, Jeffrey E / Huth, James F / Wagner, Jeffrey / Dalgleish, Angus / Pertschuk, Daniel / Nardo, Christopher / Stern, Stacey / Elashoff, Robert / Gammon, Guy / Morton, Donald L / Anonymous10680923. ·John Wayne Cancer Institute, Santa Monica, CA, USA. mfaries@theangelesclinic.org. · Istituto Nazionale dei Tumori de Napoli, Naples, Italy. · Mt. Zion Medical Center, University of California, San Francisco, San Francisco, CA, USA. · Royal Prince Alfred Hospital, Sydney, Australia. · Vanderbilt University, Nashville, TN, USA. · H. Lee Moffitt Cancer Center, Tampa, FL, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Southwestern Medical Center at Dallas, University of Texas, Dallas, TX, USA. · Wagner & Associates, Indianapolis, IN, USA. · St. George's Hospital Medical School, London, Great Britain. · CancerVax Corp, Carlsbad, CA, USA. · John Wayne Cancer Institute, Santa Monica, CA, USA. · UCLA Life Sciences, Biomathematics, Los Angeles, CA, USA. ·Ann Surg Oncol · Pubmed #29019177.

ABSTRACT: BACKGROUND: This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma. METHODS: After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156). RESULTS: Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; p = 0.260). Positive DTH skin testing correlated with increased survival. DISCUSSION: In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

7 Clinical Trial Final trial report of sentinel-node biopsy versus nodal observation in melanoma. 2014

Morton, Donald L / Thompson, John F / Cochran, Alistair J / Mozzillo, Nicola / Nieweg, Omgo E / Roses, Daniel F / Hoekstra, Harold J / Karakousis, Constantine P / Puleo, Christopher A / Coventry, Brendon J / Kashani-Sabet, Mohammed / Smithers, B Mark / Paul, Eberhard / Kraybill, William G / McKinnon, J Gregory / Wang, He-Jing / Elashoff, Robert / Faries, Mark B / Anonymous4460784. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #24521106.

ABSTRACT: BACKGROUND: Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial. METHODS: We evaluated outcomes in 2001 patients with primary cutaneous melanomas randomly assigned to undergo wide excision and nodal observation, with lymphadenectomy for nodal relapse (observation group), or wide excision and sentinel-node biopsy, with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). Results No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population (20.8% with and 79.2% without nodal metastases). Mean (± SE) 10-year disease-free survival rates were significantly improved in the biopsy group, as compared with the observation group, among patients with intermediate-thickness melanomas, defined as 1.20 to 3.50 mm (71.3 ± 1.8% vs. 64.7 ± 2.3%; hazard ratio for recurrence or metastasis, 0.76; P=0.01), and those with thick melanomas, defined as >3.50 mm (50.7 ± 4.0% vs. 40.5 ± 4.7%; hazard ratio, 0.70; P=0.03). Among patients with intermediate-thickness melanomas, the 10-year melanoma-specific survival rate was 62.1 ± 4.8% among those with metastasis versus 85.1 ± 1.5% for those without metastasis (hazard ratio for death from melanoma, 3.09; P<0.001); among patients with thick melanomas, the respective rates were 48.0 ± 7.0% and 64.6 ± 4.9% (hazard ratio, 1.75; P=0.03). Biopsy-based management improved the 10-year rate of distant disease-free survival (hazard ratio for distant metastasis, 0.62; P=0.02) and the 10-year rate of melanoma-specific survival (hazard ratio for death from melanoma, 0.56; P=0.006) for patients with intermediate-thickness melanomas and nodal metastases. Accelerated-failure-time latent-subgroup analysis was performed to account for the fact that nodal status was initially known only in the biopsy group, and a significant treatment benefit persisted. CONCLUSIONS: Biopsy-based staging of intermediate-thickness or thick primary melanomas provides important prognostic information and identifies patients with nodal metastases who may benefit from immediate complete lymphadenectomy. Biopsy-based management prolongs disease-free survival for all patients and prolongs distant disease-free survival and melanoma-specific survival for patients with nodal metastases from intermediate-thickness melanomas. (Funded by the National Cancer Institute, National Institutes of Health, and the Australia and New Zealand Melanoma Trials Group; ClinicalTrials.gov number, NCT00275496.).

8 Clinical Trial Association between circulating tumor cells and prognosis in patients with stage III melanoma with sentinel lymph node metastasis in a phase III international multicenter trial. 2012

Hoshimoto, Sojun / Shingai, Tatsushi / Morton, Donald L / Kuo, Christine / Faries, Mark B / Chong, Kelly / Elashoff, David / Wang, He-Jing / Elashoff, Robert M / Hoon, Dave S B. ·John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA 90404, USA. ·J Clin Oncol · Pubmed #23008288.

ABSTRACT: PURPOSE: The outcomes of patients with melanoma who have sentinel lymph node (SLN) metastases can be highly variable, which has precluded establishment of consensus regarding treatment of the group. The detection of high-risk patients from this clinical setting may be helpful for determination of both prognosis and management. We report the utility of multimarker reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) detection of circulating tumor cells (CTCs) in patients with melanoma diagnosed with SLN metastases in a phase III, international, multicenter clinical trial. PATIENTS AND METHODS: Blood specimens were collected from patients with melanoma (n = 331) who were clinically disease-free after complete lymphadenectomy (CLND) before entering onto a randomized adjuvant melanoma vaccine plus bacillus Calmette-Guérin (BCG) versus BCG placebo trial from 30 melanoma centers (United States and international). Blood was assessed using a verified multimarker RT-qPCR assay (MART-1, MAGE-A3, and GalNAc-T) of melanoma-associated proteins. Cox regression analyses were used to evaluate the prognostic significance of CTC status for disease recurrence and melanoma-specific survival (MSS). RESULTS: Individual CTC biomarker detection ranged from 13.4% to 17.5%. There was no association of CTC status (zero to one positive biomarkers v two or more positive biomarkers) with known clinical or pathologic prognostic variables. However, two or more positive biomarkers was significantly associated with worse distant metastasis disease-free survival (hazard ratio [HR] = 2.13, P = .009) and reduced recurrence-free survival (HR = 1.70, P = .046) and MSS (HR = 1.88, P = .043) in a multivariable analysis. CONCLUSION: CTC biomarker status is a prognostic factor for recurrence-free survival, distant metastasis disease-free survival, and MSS after CLND in patients with SLN metastasis. This multimarker RT-qPCR analysis may therefore be useful in discriminating patients who may benefit from aggressive adjuvant therapy or stratifying patients for adjuvant clinical trials.

9 Clinical Trial Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. 2012

Hoshimoto, Sojun / Faries, Mark B / Morton, Donald L / Shingai, Tatsushi / Kuo, Christine / Wang, He-Jing / Elashoff, Robert / Mozzillo, Nicola / Kelley, Mark C / Thompson, John F / Lee, Jeffrey E / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. ·Ann Surg · Pubmed #22202581.

ABSTRACT: OBJECTIVE: To verify circulating tumor cell (CTC) prognostic utility in stage IV resected melanoma patients in a prospective international phase III clinical trial. BACKGROUND: Our studies of melanoma patients in phase II clinical trials demonstrated prognostic significance for CTCs in patients with AJCC stage IV melanoma. CTCs were assessed to determine prognostic utility in follow-up of disease-free stage IV patients pre- and during treatment. METHODS: After complete metastasectomy, patients were prospectively enrolled in a randomized trial of adjuvant therapy with a whole-cell melanoma vaccine, Canvaxin, plus Bacille Calmette-Guerin (BCG) versus placebo plus BCG. Blood specimens obtained pretreatment (n = 244) and during treatment (n = 214) were evaluated by quantitative real-time reverse-transcriptase polymerase chain reaction (qPCR) for expression of MART-1, MAGE-A3, and PAX3 mRNA biomarkers. Univariate and multivariate Cox analyses examined CTC biomarker expression with respect to clinicopathological variables. RESULTS: CTC biomarker(s) (≥ 1) was detected in 54% of patients pretreatment and in 86% of patients over the first 3 months. With a median follow-up of 21.9 months, 71% of patients recurred and 48% expired. CTC levels were not associated with known prognostic factors or treatment arm. In multivariate analysis, pretreatment CTC (> 0 vs. 0 biomarker) status was significantly associated with disease-free survival (DFS; HR 1.64, P = 0.002) and overall survival (OS; HR 1.53, P = 0.028). Serial CTC (>0 vs. 0 biomarker) status was also significantly associated with DFS (HR 1.91, P = 0.02) and OS (HR 2.57, P = 0.012). CONCLUSION: CTC assessment can provide prognostic discrimination before and during adjuvant treatment for resected stage IV melanoma patients.

10 Clinical Trial Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. 2009

Faries, Mark B / Hsueh, Eddy C / Ye, Xing / Hoban, Mary / Morton, Donald L. ·Sonya Valley Ghidossi Vaccine Laboratory of the Roy E. Coats Research Laboratories of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. fariesm@jwci.org ·Clin Cancer Res · Pubmed #19903777.

ABSTRACT: PURPOSE: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine. EXPERIMENTAL DESIGN: Ninety-seven patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular melanoma vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined. RESULTS: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antimelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF. CONCLUSION: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution.

11 Article Analysis of the in vivo proliferative capacity of a whole cell cancer vaccine. 2016

Petricciani, John / Koren, Eugene / Morton, Donald. ·CancerVax Corp., Carlsbad, CA, USA. Electronic address: jpmdpsca@aol.com. · CancerVax Corp., Carlsbad, CA, USA. · John Wayne Cancer Institute, Santa Monica, CA, USA. ·Biologicals · Pubmed #26806533.

ABSTRACT: A polyvalent therapeutic cancer cell vaccine containing three viable, irradiated, replication-incompetent melanoma cell lines (Canvaxin) was administered to over 2500 patients in various clinical studies. This study examines the fate of Canvaxin cells in 16 patients with Stage II, III or IV melanoma, with special attention on assessing the capacity of the vaccine cells to replicate. The survival time and the potential proliferative capacity of irradiated Canvaxin cells in humans was studied by histologic examination of biopsies of injection sites over a two-week period. The overall results show that the vaccine cell mitotic index in skin biopsies (0.12%) was approximately 6 times lower than the control value (0.71%). Similarly, there was an overall trend toward a decrease in mitotic figures during the two week observation periods. Also, there was a trend towards a decrease in the number of vaccine cells and mitotic figures with increasing cycles. The data indicate that Canvaxin cells do not proliferate after intra-dermal injection, and that cells typically associated with an immune response are present at the inoculation sites.

12 Article Inflammatory Marker Testing Identifies CD74 Expression in Melanoma Tumor Cells, and Its Expression Associates with Favorable Survival for Stage III Melanoma. 2016

Ekmekcioglu, Suhendan / Davies, Michael A / Tanese, Keiji / Roszik, Jason / Shin-Sim, Myung / Bassett, Roland L / Milton, Denái R / Woodman, Scott E / Prieto, Victor G / Gershenwald, Jeffrey E / Morton, Donald L / Hoon, Dave S / Grimm, Elizabeth A. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. sekmekcioglu@mdanderson.org egrimm@mdanderson.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Dermatology, School of Medicine, Keio University, Tokyo, Japan. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California. · Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Pathology and Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ·Clin Cancer Res · Pubmed #26783288.

ABSTRACT: PURPOSE: Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues. EXPERIMENTAL DESIGN: Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or recurrence-free survival (RFS) in the retrospective discovery tissue microarray (TMA; n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. RESULTS: Expression of CD74 on melanoma cells was unique, and in the discovery TMA, it associated with favorable patient outcome (OS: HR, 0.53; P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation data set confirmed the CD74 prognostic significance and revealed that the absence of macrophage migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (P = 0.003) with OS in the melanoma TCGA data set. CONCLUSIONS: Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue. Clin Cancer Res; 22(12); 3016-24. ©2016 AACR.

13 Article Brain metastasis is predetermined in early stages of cutaneous melanoma by CD44v6 expression through epigenetic regulation of the spliceosome. 2015

Marzese, Diego M / Liu, Michelle / Huynh, Jamie L / Hirose, Hajime / Donovan, Nicholas C / Huynh, Kelly T / Kiyohara, Eiji / Chong, Kelly / Cheng, David / Tanaka, Ryo / Wang, Jinhua / Morton, Donald L / Barkhoudarian, Garni / Kelly, Daniel F / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA. ·Pigment Cell Melanoma Res · Pubmed #25169209.

ABSTRACT: Melanoma brain metastasis (MBM) is frequent and has a very poor prognosis with no current predictive factors or therapeutic molecular targets. Our study unravels the molecular alterations of cell-surface glycoprotein CD44 variants during melanoma progression to MBM. High expression of CD44 splicing variant 6 (CD44v6) in primary melanoma (PRM) and regional lymph node metastases from AJCC Stage IIIC patients significantly predicts MBM development. The expression of CD44v6 also enhances the migration of MBM cells by hyaluronic acid and hepatocyte growth factor exposure. Additionally, CD44v6-positive MBM migration is reduced by blocking with a CD44v6-specific monoclonal antibody or knocking down CD44v6 by siRNA. ESRP1 and ESRP2 splicing factors correlate with CD44v6 expression in PRM, and ESRP1 knockdown significantly decreases CD44v6 expression. However, an epigenetic silencing of ESRP1 is observed in metastatic melanoma, specifically in MBM. In advanced melanomas, CD44v6 expression correlates with PTBP1 and U2AF2 splicing factors, and PTBP1 knockdown significantly decreases CD44v6 expression. Overall, these findings open a new avenue for understanding the high affinity of melanoma to progress to MBM, suggesting CD44v6 as a potential MBM-specific factor with theranostic utility for stratifying patients.

14 Article DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations. 2014

Marzese, Diego M / Scolyer, Richard A / Roqué, Maria / Vargas-Roig, Laura M / Huynh, Jamie L / Wilmott, James S / Murali, Rajmohan / Buckland, Michael E / Barkhoudarian, Garni / Thompson, John F / Morton, Donald L / Kelly, Daniel F / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California (D.M.M., J.L.H., D.S.B.H.) · Department of Tissue Oncology and Diagnostic Pathology (R.A.S., M.E.B., J.F.T.) and Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, Australia (J.F.T.) · Sydney Medical School, The University of Sydney, Sydney, Australia (R.A.S., J.S.W., M.E.B., J.F.T.) · Melanoma Institute Australia, Sydney, Australia (R.A.S., J.S.W.) · Cellular and Molecular Biology Laboratory, Institute of Histology and Embryology, Mendoza, Argentina (M.R.) · Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo, Mendoza, Argentina (L.M.V.-R.) · Department of Pathology (R.M.), Center for Molecular Oncology (R.M.), and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (R.M.) · Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, California (D.L.M.) · Brain Tumor Center, Saint John's Health Center, Santa Monica, California (G.B., D.F.K.). ·Neuro Oncol · Pubmed #24968695.

ABSTRACT: BACKGROUND: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. METHODS: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. RESULTS: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. CONCLUSIONS: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.

15 Article A 20-year experience of hepatic resection for melanoma: is there an expanding role? 2014

Faries, Mark B / Leung, Anna / Morton, Donald L / Hari, Danielle / Lee, Ji-Hey / Sim, Myung-shin / Bilchik, Anton J. ·Department of Surgical Oncology, The John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA. Electronic address: mark.faries@jwci.org. · Department of Surgical Oncology, The John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA. · Department of Biostatistics, The John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA. ·J Am Coll Surg · Pubmed #24952441.

ABSTRACT: BACKGROUND: Melanoma liver metastasis is most often fatal, with a 4- to 6-month median overall survival (OS). Over the past 20 years, surgical techniques have improved in parallel with more effective systemic therapies. We reviewed our institutional experience of hepatic melanoma metastases. STUDY DESIGN: Overall and disease-specific survivals were calculated from hepatic metastasis diagnosis. Potential prognostic factors including primary tumor type, depth, medical treatment response, location, and surgical approach were evaluated. RESULTS: Among 1,078 patients with melanoma liver metastases treated at our institution since 1991, 58 (5.4%) received surgical therapy (resection with or without ablation). Median and 5-year OS were 8 months and 6.6 %, respectively, for 1,016 nonsurgical patients vs 24.8 months and 30%, respectively, for surgical patients (p < 0.001). Median OS was similar among patients undergoing ablation (with or without resection) relative to those undergoing surgery alone. On multivariate analysis of surgical patients, completeness of surgical therapy (hazard ratio [HR] 3.4, 95% CI 1.4 to 8.1, p = 0.007) and stabilization of melanoma on therapy before surgery (HR 0.38, 95% CI 0.19 to 0.78, p = 0.008) predicted OS. CONCLUSIONS: In this largest single-institution experience, patients selected for surgical therapy experienced markedly improved survival relative to those receiving only medical therapy. Patients whose disease stabilized on medical therapy enjoyed particularly favorable results, regardless of the number or size of their metastases. The advent of more effective systemic therapy in melanoma may substantially increase the fraction of patients who are eligible for surgical intervention, and this combination of treatment modalities should be considered whenever it is feasible in the context of a multidisciplinary team.

16 Article Genome-wide characterization of circulating tumor cells identifies novel prognostic genomic alterations in systemic melanoma metastasis. 2014

Chiu, Connie G / Nakamura, Yoshitaka / Chong, Kelly K / Huang, Sharon K / Kawas, Neal P / Triche, Timothy / Elashoff, David / Kiyohara, Eiji / Irie, Reiko F / Morton, Donald L / Hoon, Dave S B. ·Department of Molecular Oncology and Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA; · Department of Molecular Oncology and. · Center for Personalized Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA; · Department of Medicine Statistics Core, UCLA School of Medicine, Los Angeles, CA; · Department of Biotechnology, John Wayne Cancer Institute, Santa Monica, CA. · Division of Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA; · Department of Molecular Oncology and hoon@jwci.org. ·Clin Chem · Pubmed #24718909.

ABSTRACT: BACKGROUND: Circulating tumor cells (CTC) have been found in patients with metastatic melanoma and are associated with advanced melanoma stage and poor patient outcome. We hypothesize that CTC harbor genomic changes critical in the development of distant systemic metastasis. Here, we present the first genome-wide copy-number aberration (CNA) and loss of heterozygosity (LOH)-based characterization of melanoma CTC. METHODS: CTC were isolated from peripheral blood monocytes of 13 melanoma patients with regional metastasis stage IIIB/C using antibodies against melanoma-associated cell surface gangliosides. RESULTS: We characterized 251 CNA in CTC. Comparative analysis demonstrated >90% concordance in single-nucleotide polymorphism profiles between paired CTC and tumor metastases. In particular, there were notable recurring CNA across patients. In exploratory studies, the presence of several top CTC-associated CNA was verified in distant metastasis (stage IV) from 27 patients, suggesting that certain genomic changes are propagated from regional metastasis to CTC and to distant systemic metastases. Lastly, an exploratory biomarker panel derived from 5 CTC-associated CNA [CSMD2 (CUB and Sushi multiple domains 2), 1p35.1; CNTNAP5 (contactin associated protein-like 5), 2q14.3; NRDE2 (NRDE-2, necessary for RNA interference, domain containing), 14q32.11; ADAM6 (ADAM metallopeptidase domain 6, pseudogene), 14q32.33; and TRPM2 (transient receptor potential cation channel, subfamily m, member 2), 21q22.3] conferred prognostic utility for melanoma recurrence [hazard ratio (HR), 1.14; CI, 1.00-1.44; P = 0.0471] and death (HR, 2.86; CI, 1.23-14.42; P = 0.0014) in 35 patients with stage IIIB/C melanoma, with a 5-year disease-free survival of 13% vs 69% (P = 0.0006) and overall survival of 28% vs 94% between high-risk and low-risk groups defined by the biomarker panel, respectively. CONCLUSIONS: This study provides the first detailed CNA-based profile of melanoma CTC and illustrates how CTC may be used as a novel approach for identification of systemic metastasis.

17 Article Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. 2014

Balch, Charles M / Thompson, John F / Gershenwald, Jeffrey E / Soong, Seng-Jaw / Ding, Shouluan / McMasters, Kelly M / Coit, Daniel G / Eggermont, Alexander M M / Gimotty, Phyllis A / Johnson, Timothy M / Kirkwood, John M / Leong, Stanley P / Ross, Merrick I / Byrd, David R / Cochran, Alistair J / Mihm, Martin C / Morton, Donald L / Atkins, Michael B / Flaherty, Keith T / Sondak, Vernon K. ·Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA, balch@asoeditorial.org. ·Ann Surg Oncol · Pubmed #24531700.

ABSTRACT: PURPOSE: We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. METHODS: The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. RESULTS: Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20-40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). CONCLUSIONS: Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.

18 Article Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis. 2014

Marzese, Diego M / Scolyer, Richard A / Huynh, Jamie L / Huang, Sharon K / Hirose, Hajime / Chong, Kelly K / Kiyohara, Eiji / Wang, Jinhua / Kawas, Neal P / Donovan, Nicholas C / Hata, Keisuke / Wilmott, James S / Murali, Rajmohan / Buckland, Michael E / Shivalingam, Brindha / Thompson, John F / Morton, Donald L / Kelly, Daniel F / Hoon, Dave S B. ·Department of Molecular Oncology. ·Hum Mol Genet · Pubmed #24014427.

ABSTRACT: Melanoma brain metastasis (MBM) represents a frequent complication of cutaneous melanoma. Despite aggressive multi-modality therapy, patients with MBM often have a survival rate of <1 year. Alteration in DNA methylation is a major hallmark of tumor progression and metastasis; however, it remains largely unexplored in MBM. In this study, we generated a comprehensive DNA methylation landscape through the use of genome-wide copy number, DNA methylation and gene expression data integrative analysis of melanoma progression to MBM. A progressive genome-wide demethylation in low CpG density and an increase in methylation level of CpG islands according to melanoma progression were observed. MBM-specific partially methylated domains (PMDs) affecting key brain developmental processes were identified. Differentially methylated CpG sites between MBM and lymph node metastasis (LNM) from patients with good prognosis were identified. Among the most significantly affected genes were the HOX family members. DNA methylation of HOXD9 gene promoter affected transcript and protein expression and was significantly higher in MBM than that in early stages. A MBM-specific PMD was identified in this region. Low methylation level of this region was associated with active HOXD9 expression, open chromatin and histone modifications associated with active transcription. Demethylating agent induced HOXD9 expression in melanoma cell lines. The clinical relevance of this finding was verified in an independent large cohort of melanomas (n = 145). Patients with HOXD9 hypermethylation in LNM had poorer disease-free and overall survival. This epigenome-wide study identified novel methylated genes with functional and clinical implications for MBM patients.

19 Article Staging of regional lymph nodes in melanoma: a case for including nonsentinel lymph node positivity in the American Joint Committee on Cancer staging system. 2013

Leung, Anna M / Morton, Donald L / Ozao-Choy, Junko / Hari, Danielle M / Shin-Sim, Myung / Difronzo, Andrew L / Faries, Mark B. ·Melanoma Research Program, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California. ·JAMA Surg · Pubmed #23903435.

ABSTRACT: IMPORTANCE: Survival varies widely in patients with stage III melanoma. The existence of clinical significance for positive nonsentinel lymph node (NSLN) status would warrant consideration for incorporation into the American Joint Committee on Cancer staging system and better prediction of survival. OBJECTIVE: To evaluate whether disease limited to sentinel lymph nodes (SLNs) represents different clinical significance than disease spread into NSLNs. DESIGN, SETTING, AND PARTICIPANTS: The database of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California, was queried for all patients with SLNs positive for cutaneous melanoma who subsequently underwent completion lymph node dissection. MAIN OUTCOMES AND MEASURES: Disease-free survival, melanoma-specific survival (MSS), and overall survival. RESULTS: A total of 4223 patients underwent SLN biopsy from 1986 to 2012. Of these patients, 329 had a tumor-positive SLN. Of the 329, 250 patients (76.0%) had no additional positive nodes and 79 (24.0%) had a tumor-positive NSLN. Factors predictive of NSLN positivity included older age (P = .04), greater Breslow thickness (P < .001), and ulceration (P < .02). Median overall survival was 178 months for the SLN-only positive group and 42.2 months for the NSLN positive group (5-year overall survival, 72.3% and 46.4%, respectively). Median MSS was not reached for the SLN-only positive group and was 60 months for the NSLN positive group (5-year MSS, 77.8% and 49.5%, respectively). On multivariate analysis, NSLN positivity had a strong association with recurrence (hazard ratio [HR], 1.75; 95% CI, 1.23-2.50; P = .002), shorter overall survival (HR, 2.24; 95% CI, 1.48-3.40; P < .001), and shorter MSS (HR, 2.23; 95% CI, 1.46-3.07; P < .001). To further control for the effects of total positive lymph nodes, comparison was done for patients with only N2 disease (2-3 total positive lymph nodes); the results of this comparison confirmed the independent effect of NSLN status (MSS; P = .04). CONCLUSIONS AND RELEVANCE: Nonsentinel lymph node positivity is one of the most significant prognostic factors in patients with stage III melanoma. Subclassification of melanoma by NSLN tumor status should be considered for the American Joint Committee on Cancer staging system.

20 Article Age as a prognostic factor in patients with localized melanoma and regional metastases. 2013

Balch, Charles M / Soong, Seng-jaw / Gershenwald, Jeffrey E / Thompson, John F / Coit, Daniel G / Atkins, Michael B / Ding, Shouluan / Cochran, Alistair J / Eggermont, Alexander M M / Flaherty, Keith T / Gimotty, Phyllis A / Johnson, Timothy M / Kirkwood, John M / Leong, Stanley P / McMasters, Kelly M / Mihm, Martin C / Morton, Donald L / Ross, Merrick I / Sondak, Vernon K. ·Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA, charles.balch@utsouthwestern.edu. ·Ann Surg Oncol · Pubmed #23838920.

ABSTRACT: BACKGROUND: We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable. MATERIALS AND METHODS: The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate. RESULTS: With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients <20 and >80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients >70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous. CONCLUSIONS: Melanomas in patients at the extremes of age have a distinct natural history.

21 Article Late recurrence in melanoma: clinical implications of lost dormancy. 2013

Faries, Mark B / Steen, Shawn / Ye, Xing / Sim, Myung / Morton, Donald L. ·John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. mark.faries@jwci.org ·J Am Coll Surg · Pubmed #23643694.

ABSTRACT: BACKGROUND: For patients with melanoma, if there has been no recurrence of disease 10 years after initial treatment, additional disease is believed to be very unlikely. However, such late recurrences are known to occur. The frequency of this phenomenon and its clinical significance are not well characterized due to the difficulty in obtaining relevant data. We examined a large, mature, institutional database to evaluate late recurrence. STUDY DESIGN: The late recurrence cohort was defined as having a disease-free interval of 10 or more years after potentially curative treatment and was compared with an early recurrence cohort recurring within 3 years. Actuarial late recurrence frequency and factors associated with late recurrence were examined. Post-recurrence overall and melanoma-specific survival and prognostic variables were analyzed. RESULTS: Among all patients, 408 exhibited late recurrence (mean disease-free interval 15.7 years). For patients who received primary treatment at our institution with 10 or more years follow-up, 327 of 4,731 (6.9%) showed late recurrence. On an actuarial basis, late recurrence rates were 6.8% and 11.3% at 15 and 20 years, respectively, for those with no recurrence at 10 years. Late recurrence was associated with both tumor (thin, non-ulcerated, non-head/neck, node negative) and patient (younger age, less male predominant) characteristics. Multivariate analysis confirmed younger age, thinner and node negative tumors in the late recurrence group. Late recurrences were more likely to be distant, but were associated with better post-recurrence survival on univariate and multivariate analyses. CONCLUSIONS: Late melanoma recurrence is not rare. It occurs more frequently in certain clinical groups and is associated with improved post-recurrence survival.

22 Article B7-H3 associated with tumor progression and epigenetic regulatory activity in cutaneous melanoma. 2013

Wang, Jinhua / Chong, Kelly K / Nakamura, Yoshitaka / Nguyen, Linhda / Huang, Sharon K / Kuo, Christine / Zhang, Wang / Yu, Hua / Morton, Donald L / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute (JWCI), Santa Monica, California 90404, USA. ·J Invest Dermatol · Pubmed #23474948.

ABSTRACT: B7-H3, a cell surface transmembrane glycoprotein, was assessed for its functional and prognostic role in cutaneous melanoma progression. B7-H3 expression in melanoma cells was shown to be related to specific downstream signal transduction events as well as associated with functional epigenetic activity. B7-H3 expression and prognostic utility were shown by reverse transcription and real-time PCR and immunohistochemistry analysis on individual melanoma specimens and then verified in clinically annotated melanoma stage III and stage IV metastasis tissue microarrays in a double-blind study. B7-H3 messenger RNA expression was shown to be significantly increased with stage of melanoma (P<0.0001) and significantly associated with melanoma-specific survival in both stage III (P<0.0001) and stage IV (P<0.012) melanoma patients. B7-H3 expression was related to migration and invasion; overexpression of B7-H3 increased migration and invasion, whereas knockdown of B7-H3 reduced cell migration and invasion. MiR-29c expression was shown to inversely regulate B7-H3 expression. Furthermore, we demonstrated that melanoma B7-H3 expression was correlated to phosphorylated signal transducer and activator of transcription-3 activity level in melanoma tissues and cell lines. These studies demonstrate that B7-H3 is a significant factor in melanoma progression and events of metastasis.

23 Article BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. 2013

Haq, Rizwan / Yokoyama, Satoru / Hawryluk, Elena B / Jönsson, Göran B / Frederick, Dennie Tompers / McHenry, Kevin / Porter, Dale / Tran, Thanh-Nga / Love, Kevin T / Langer, Robert / Anderson, Daniel G / Garraway, Levi A / Duncan, Lyn McDivitt / Morton, Donald L / Hoon, Dave S B / Wargo, Jennifer A / Song, Jun S / Fisher, David E. ·Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02115, USA. ·Proc Natl Acad Sci U S A · Pubmed #23447565.

ABSTRACT: Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in ∼30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.

24 Article Combined intralesional Bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma. 2012

Kidner, Travis B / Morton, Donald L / Lee, Delphine J / Hoban, Mary / Foshag, Leland J / Turner, Roderick R / Faries, Mark B. ·Department of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404, USA. ·J Immunother · Pubmed #23090081.

ABSTRACT: The introduction of numerous immunotherapeutic agents into the clinical arena has allowed the long-time promise of immunotherapy to begin to become reality. Intralesional immunotherapy has demonstrated activity in multiple tumor types, and as the number of locally applicable agents has increased, so has the opportunity for therapeutic combinations. Both intralesional Bacille Calmette-Guérin (ILBCG) and topical 5% imiquimod cream have been used as single agents for the treatment of dermal/subcutaneous lymphatic metastases or in-transit melanoma, but the combination has not previously been reported. We used this combination regimen in 9 patients during the period from 2004 to 2011 and report their outcomes here. All patients were initially treated with ILBCG, followed by topical imiquimod after development of an inflammatory response to BCG. In this retrospective study, we examined their demographics, tumor characteristics, clinical and pathologic response to treatment, associated morbidities, local and distant recurrence, and overall survival. The 9 patients (8 male) had a mean age of 72 years (range, 56-95 y). Mild, primarily local toxicities were noted. Five patients (56%) had complete regression of their in-transit disease and 1 had a partial response. The 3 others had "surgical" complete responses with resection of solitary resistant lesions. The mean interval between the first treatment and complete resolution of in-transit disease was of 6.5 months (range, 2-12 mo). With a mean follow-up of 35 months (range 12-58 mo), 7 patients (78%) had not developed recurrent in-transit disease. Two patients (22%) have died of nonmelanoma causes, and none have died due to melanoma.

25 Article Preoperative imaging of pulmonary metastases in patients with melanoma: implications for minimally invasive techniques. 2012

Kidner, Travis B / Yoon, Jeong / Faries, Mark B / Morton, Donald L. ·Department of Surgical Oncology, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA 90404, USA. ·Arch Surg · Pubmed #22987185.

ABSTRACT: HYPOTHESIS: Preoperative imaging underestimates the number of pulmonary melanoma metastases. Although thoracoscopic resection is less invasive than resection via thoracotomy, it does not allow manual palpation of the lung to identify any metastases not visible on the preoperative scan or at the time of resection. DESIGN: Retrospective review of a prospectively maintained database. SETTING: Tertiary referral center. PATIENTS: A total of 170 patients who underwent preoperative computed tomography of the chest, followed within 30 days by thoracotomy for resection of pulmonary metastatic melanoma. MAIN OUTCOME MEASURES: Number of pathology-confirmed pulmonary metastases detected by preoperative chest computed tomography vs intraoperative manual palpation. RESULTS: The mean age of the patients was 49.5 years at initial diagnosis of melanoma and 57.1 years at diagnosis of pulmonary metastases; 69% of patients were male. A total of 334 pulmonary metastases were resected; the mean lesion size was 2.0 cm (range, 0.1-14.0 cm). In 49 of 190 pulmonary resections (26%), manual palpation of the subpleural parenchyma revealed lesions not identified during preoperative imaging. The rate of 5-year overall survival was 33%. CONCLUSIONS: Preoperative imaging underestimates the number of pulmonary lesions in patients with metastatic melanoma. Because incomplete resection of metastatic disease is associated with worse outcomes, we recommend caution when considering a minimally invasive approach for the resection of pulmonary metastatic melanoma.

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