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Melanoma: HELP
Articles by Takami Sato
Based on 42 articles published since 2008
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Between 2008 and 2019, Takami Sato wrote the following 42 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Successes and setbacks of early investigational drugs for melanoma. 2015

Orloff, Marlana / Valsecchi, Matias E / Sato, Takami. ·Thomas Jefferson University, Department of Medical Oncology , 1015 Walnut Street, Philadelphia, PA 19107 , USA +1 215 955 1195 ; +1 215 923 0797 ; Marlana.Orloff@jefferson.edu. ·Expert Opin Investig Drugs · Pubmed #26068553.

ABSTRACT: Treatment of advanced and metastatic melanoma is a rapidly changing field. Over the past 10 years, there have been six new drugs approved by the FDA for the treatment of metastatic melanoma. These approved drugs include a number of immune checkpoint inhibitors and MAPK-pathway-targeted therapies. The discovery of such agents as ipilimumab, pembrolizumab, nivolumab, vemurafenib, trametininb and dabrafenib have revolutionized the way in which melanoma in managed. While these agents have succeeded in both early and later phase clinical trials, a large number of investigational therapies have not yet been developed or researched past Phase I clinical studies. Furthermore, there are dozens of potential agents in Phase I and Phase II clinical development that appear promising and are currently being explored. The field currently aims to determine the optimal sequence and combination of these therapies to best overcome such setbacks as toxicity and resistance and build upon the successes previously seen.

2 Editorial Tumor necrosis factor-α blockade and development of uveal melanoma: expected adverse effect or just coincidence? 2014

Sato, Takami. ·Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA. Electronic address: takami.sato@jefferson.edu. ·Mayo Clin Proc · Pubmed #25444483.

ABSTRACT: -- No abstract --

3 Editorial Uveal melanoma trapped in the temple of doom. 2012

Shields, Carol L / Ganguly, Arupa / O'Brien, Joan / Sato, Takami / Shields, Jerry A. · ·Am J Ophthalmol · Pubmed #22813447.

ABSTRACT: -- No abstract --

4 Review Autologous melanoma cell vaccine using monocyte-derived dendritic cells (NBS20/eltrapuldencel-T). 2016

Javed, Asad / Sato, Shingo / Sato, Takami. ·Department of Medical Oncology, Thomas Jefferson University, 925 Chestnut street, Philadelphia, PA 19107, USA. ·Future Oncol · Pubmed #26837440.

ABSTRACT: Targeted therapy and immunotherapy have revolutionized the treatment of advanced melanoma. Despite recent advances, lack of long-term efficacy from targeted therapy and serious immune-related toxicity are major concerns. There is unmet need for 'durable' and 'safe' treatment options for advanced melanoma. Cancer vaccine therapy in melanoma has been investigated for many years with modest clinical efficacy. More recently, dendritic cell-based vaccine products have become available for clinical use and have been the focus of investigation. CLBS20 (NBS20/eltrapuldencel-T) is a novel dendritic cell-based vaccine product that has shown promising results in early phase trials in advanced melanoma. This cancer vaccine approach could play an important role in providing a sustainable survival benefit, targeting cancer cells themselves and avoiding off-target immune-related toxicity.

5 Review Biology of advanced uveal melanoma and next steps for clinical therapeutics. 2015

Luke, Jason J / Triozzi, Pierre L / McKenna, Kyle C / Van Meir, Erwin G / Gershenwald, Jeffrey E / Bastian, Boris C / Gutkind, J Silvio / Bowcock, Anne M / Streicher, Howard Z / Patel, Poulam M / Sato, Takami / Sossman, Jeffery A / Sznol, Mario / Welch, Jack / Thurin, Magdalena / Selig, Sara / Flaherty, Keith T / Carvajal, Richard D. ·Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. ·Pigment Cell Melanoma Res · Pubmed #25113308.

ABSTRACT: Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherapies are reviewed, and next steps in the development of clinical therapeutics are discussed.

6 Review The potential role of sunitinib targeting melanomas. 2013

Valsecchi, Matias E / Sato, Takami. ·Thomas Jefferson University, Department of Medical Oncology , 1015 Walnut Street, Philadelphia, PA 19107 , USA Takami.Sato@jefferson.edu. ·Expert Opin Investig Drugs · Pubmed #24050392.

ABSTRACT: INTRODUCTION: Metastatic melanoma - independently of its cutaneous, uveal or mucosal origin - represents an exceptionally aggressive tumor with poor prognosis. Molecular and genetics investigations permitted to identify several important driver mutations: BRAF, NRAS, c-Kit, GNA11 and GNAQ. Additionally, hypervascular and immunlogenic characteristics of metastatic melanoma make in this tumor a unique therapeutic target. In this regard, the antiangiogenic, antiproliferative and immunomodulator properties of sunitinib make it an attractive drug to explore in melanoma. AREAS COVERED: In this article, the currently available data on sunitinib in terms of its pharmacokinetics and mechanisms of action is summarized. The reader will also be updated on current clinical experience using this drug in the treatment of cutaneous, mucosal and uveal melanomas. Special attention is placed on the scientific rationales behind its development in melanoma including the potentiality to broadly attack receptor-tyrosine kinases as well as its remarkable but certainly still unexplored immunomodulatory qualities. EXPERT OPINION: Given its wide spectrum of actions and the encouraging results obtained from the limited clinical experience, sunitinib remains as a promising drug, especially for mucosal and uveal melanoma, that deserves further exploration in properly designed clinical trials.

7 Review Locoregional management of hepatic metastasis from primary uveal melanoma. 2010

Sato, Takami. ·Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 19107, USA. Takami.Sato@jefferson.edu ·Semin Oncol · Pubmed #20494705.

ABSTRACT: Uveal melanoma is the most common primary ocular malignancy in adults and has a significant predilection for metastasis to the liver. Despite successful treatment of the primary uveal melanoma, up to 50% of patients will subsequently develop a systemic metastasis, with the liver involved in up to 90% of these individuals. Metastatic uveal melanoma has proven to be resistant to currently available systemic chemotherapies. Recognition of the poor prognosis associated with liver metastasis has led to the evaluation of various locoregional treatment modalities primarily designed to control tumor progression in the liver, including surgical resection, hepatic arterial chemotherapy, transarterial chemoembolization (TACE), immunoembolization, radiosphere, drug-eluting beads, isolated hepatic perfusion (IHP), and percutaneous hepatic perfusion. This article reviews the efficacies, and morbidities of currently available locoregional therapies.

8 Review The biology and management of uveal melanoma. 2008

Sato, Takami / Han, Fei / Yamamoto, Akira. ·Department of Medical Oncology, Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA 19107, USA. t_sato @mail.jci.tju.edu ·Curr Oncol Rep · Pubmed #18706273.

ABSTRACT: Uveal melanoma is the most common primary intraocular malignancy in adults. Overall mortality rate remains high because of the frequent development of metastatic disease, especially hepatic metastasis. While traditional systemic chemotherapies provide only marginal benefit to patients, local treatments for hepatic metastases, such as immunoembolization, have improved patient prognoses. Progress has also been made in identifying potential targets in the pathways involved in apoptosis, proliferation, invasion, metastasis, and angiogenesis of uveal melanoma. Among these pathways, the c-Kit, c-Met, and IGF-1R signal pathways and the PTEN-related PI3K-Akt pathway are the most important targets. Clinical trials using blockades of these pathways in conjunction with strategies to facilitate apoptosis is a direction for future clinical trials. Application of these approaches in the adjuvant setting after primary therapy for high-risk uveal melanoma patients is also a future consideration to improve the clinical outcome of this disease.

9 Clinical Trial Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. 2017

Williams, Noelle L / Wuthrick, Evan J / Kim, Hyun / Palmer, Joshua D / Garg, Shivank / Eldredge-Hindy, Harriet / Daskalakis, Constantine / Feeney, Kendra J / Mastrangelo, Michael J / Kim, Lyndon J / Sato, Takami / Kendra, Kari L / Olencki, Thomas / Liebner, David A / Farrell, Christopher J / Evans, James J / Judy, Kevin D / Andrews, David W / Dicker, Adam P / Werner-Wasik, Maria / Shi, Wenyin. ·Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. · Department of Radiation Oncology, Ohio State University, Columbus, Ohio. · Department of Radiation Oncology, Baystate Medical Center, Springfield, Massachusetts. · Department of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. · Division of Medical Oncology, Ohio State University, Columbus, Ohio. · Department of Neurosurgery, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. · Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. Electronic address: Wenyin.Shi@jefferson.edu. ·Int J Radiat Oncol Biol Phys · Pubmed #28816150.

ABSTRACT: PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

10 Clinical Trial Health-related quality of life during trans-arterial chemoembolization with drug-eluting beads loaded with doxorubicin (DEBDOX) for unresectable hepatic metastases from ocular melanoma. 2017

Rostas, Jack W / Tam, Alda L / Sato, Takami / Scoggins, Charles R / McMasters, Kelly M / Martin, Robert C G. ·University of Louisville, Department of General Surgery, Division of Surgical Oncology, Louisville, KY, USA. · Department of Interventional Radiology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA. · Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA. · University of Louisville, Department of General Surgery, Division of Surgical Oncology, Louisville, KY, USA. Electronic address: Robert.martin@louisville.edu. ·Am J Surg · Pubmed #28754534.

ABSTRACT: BACKGROUND: We have previously reported favorable response and survival rates using drug-eluting beads loaded with doxorubicin (DEBDOX) for unresectable hepatic metastases. This study investigates the quality of life (QoL) impact of DEBDOX for the treatment of unresectable hepatic metastases from melanoma. METHODS: A multi-center, prospective, non-controlled clinical trial was reviewed. QoL was assessed at baseline and after each treatment, and doxorubicin-specific effects were assessed after each treatment. RESULTS: Twenty patients received 61 DEBDOX treatments. After each treatment, at least 83% of patients reported "little" to "none" doxorubicin-related symptoms. For the 8 FACT-Hep subscales, QoL scores were unchanged through 3 treatments for 18 of 24 total time points by ANOVA, with a small-to-moderate ES change through the last treatment in 36 of 40 time points. CONCLUSIONS: Hepatic arterial therapy with DEBDOX is safe with minimal QOL changes in treating unresectable liver-dominant melanoma metastasis. CLINICAL TRIAL: NCT01010984.

11 Clinical Trial Image-Guided Transarterial Chemoembolization With Drug-Eluting Beads Loaded with Doxorubicin (DEBDOX) for Unresectable Hepatic Metastases from Melanoma: Technique and Outcomes. 2017

Rostas, Jack / Tam, Alda / Sato, Takami / Kelly, Larry / Tatum, Cliff / Scoggins, Charles / McMasters, Kelly / Martin, Robert C G. ·Division of Surgical Oncology, Department of General Surgery, University of Louisville, 315 E. Broadway M10 Rm #312, Louisville, KY, 40202, USA. · Department of Radiology, MD Anderson Cancer Center, Houston, TX, USA. · Department of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA. · Department of Radiology and Interventional Radiology, Norton Healthcare, Louisville, KY, USA. · Division of Surgical Oncology, Department of General Surgery, University of Louisville, 315 E. Broadway M10 Rm #312, Louisville, KY, 40202, USA. Robert.martin@louisville.edu. ·Cardiovasc Intervent Radiol · Pubmed #28508253.

ABSTRACT: PURPOSE: Hepatic metastasis from melanoma represents a therapeutic dilemma, with limited effective options for the 85% of cases deemed unresectable. Systemic agents confer toxicity and, along with traditional local hepatic arterial-directed therapies such as transarterial chemoembolization, have not led to a significant increase in survival. The aim of this study was to investigate the safety and dose-limiting toxicity of DEBDOX for the treatment of unresectable hepatic metastases from melanoma. METHODS: A multicenter (University of Louisville, Thomas Jefferson University, MD Anderson Cancer Center), prospective, non-controlled treatment trial (NCT01010984) of hepatic-directed therapy with DEBDOX for the treatment of melanoma liver metastasis was reviewed. Primary endpoints were response rates by modified response evaluation criteria in solid tumors, hepatic progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty patients received a total of 61 DEBDOX treatments from January 2010 to March 2013. The median hepatic tumor burden was 40% (range 20-55), 18 patients (90%) had bilobar disease, and 13 patients (65%) had concomitant extrahepatic disease. At median assessment of 2.5 months, 11 patients (55%) exhibited a tumor response and 16 (80%) exhibited disease control. Median follow-up was 5 months (range 1.1-34.3 months). Median hepatic PFS was 3 months (95% CI 1.4, 3.4), and OS was 5 months (95% CI 3.3, 10.5). CONCLUSIONS: Directed arterial therapy with DEBDOX is effective in managing unresectable liver-dominant metastasis from melanoma and should be considered a therapeutic option in the multidisciplinary treatment of this disease. Concurrent systemic therapy is merited given the high rate of extrahepatic progression. CLINICAL TRIAL: NCT01010984.

12 Clinical Trial Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. 2017

Atkinson, Thomas M / Hay, Jennifer L / Shoushtari, Alexander / Li, Yuelin / Paucar, Daniel J / Smith, Sloane C / Kudchadkar, Ragini R / Doyle, Austin / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Schwartz, Gary K / Carvajal, Richard D. ·Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. atkinsot@mskcc.org. · Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. · Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA. · Winship Cancer Institute of Emory University, Atlanta, GA, USA. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. · Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. · Mayo Clinic, Rochester, MN, USA. · University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Princess Margaret Hospital University Health Network, Toronto, ON, Canada. · Penn Medicine, Philadelphia, PA, USA. · University of Chicago, Chicago, IL, USA. · Mount Sinai Medical Center, Miami Beach, FL, USA. · University of Michigan, Ann Arbor, MI, USA. · Minnesota Oncology, Woodbury, MN, USA. · Univeristy of Wisconsin School of Medicine and Public Health, Madison, WI, USA. · Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. · University of Colorado - Denver, Denver, CO, USA. · Columbia University Medical Center, New York, NY, USA. ·J Cancer Res Clin Oncol · Pubmed #27921276.

ABSTRACT: PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

13 Clinical Trial Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. 2014

Carvajal, Richard D / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Kudchadkar, Ragini R / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Doyle, Austin / Ancell, Kristin / Panageas, Katherine S / Bluth, Mark / Hedvat, Cyrus / Erinjeri, Joseph / Ambrosini, Grazia / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Wolchok, Jedd D / Chapman, Paul B / Schwartz, Gary K. ·Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York. · Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee. · Mayo Clinic, Rochester, Minnesota. · University of Iowa Hospital and Clinics, Iowa City. · Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · H. Lee Moffitt Cancer Center, Tampa, Florida. · Washington University, St Louis, Missouri. · University of Chicago, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Winship Cancer Institute of Emory University, Atlanta, Georgia. · University of Michigan, Ann Arbor. · Metro Minnesota Community Clinical Oncology Program, St Louis Park. · University of Wisconsin, Madison. · Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. · University of Colorado, Aurora. · Investigational Drug Branch, National Cancer Institute, Rockville, Maryland. · Memorial Sloan-Kettering Cancer Center, New York, New York. ·JAMA · Pubmed #24938562.

ABSTRACT: IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.

14 Clinical Trial A pilot study of sunitinib malate in patients with metastatic uveal melanoma. 2012

Mahipal, Amit / Tijani, Lukman / Chan, Kathryn / Laudadio, MaryAnn / Mastrangelo, Michael J / Sato, Takami. ·Clinical Research Unit, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. ·Melanoma Res · Pubmed #23114504.

ABSTRACT: The prognosis of patients with metastatic uveal melanoma is poor and there are limited therapeutic options. C-kit is expressed in the majority of patients with metastatic uveal melanoma. In this pilot trial, we examined the toxicity and efficacy of sunitinib malate, a multitarget tyrosine kinase inhibitor, in patients with metastatic uveal melanoma. Twenty patients with metastatic uveal melanoma expressing c-kit, 17 of whom failed previous treatments, were included in this study. Patients received sunitinib malate 37.5 mg daily continuously in 4-week cycles. The evaluation of response was carried out every 8 weeks. The overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier survival curves and differences in survivals were tested using the log-rank test. There was one partial response and 12 stable disease (SD) after sunitinib treatment. The median OS and PFS were 8.2 and 4.2 months, respectively. Three patients had SD for more than 12 months with sunitinib after failing previous treatments. The most common adverse events were fatigue (90%), diarrhea (60%), hemorrhage (55%), anorexia (45%), hand-foot syndrome (25%), hypothyroidism (25%), and rash (25%). Eleven patients required a dose reduction to 25 mg daily secondary to grade 3 adverse events. The degree of c-kit expression in melanoma cells was not associated with longer PFS or OS. Patients who developed systemic metastases after more than 5 years of their initial diagnosis had better PFS (median PFS: 5.8 vs. 2.6 months, P=0.005). Sunitinib was safely administered and showed potential clinical benefit in patients with metastatic uveal melanoma. The lack of a correlation between c-kit expression and clinical outcomes requires further investigation on the mechanism of sunitinib in metastatic uveal melanoma.

15 Clinical Trial A phase 1-2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma. 2010

Weber, Jeffrey S / Samlowski, Wolfram E / Gonzalez, Rene / Ribas, Antoni / Stephenson, Joe / O'Day, Steven / Sato, Takami / Dorr, Robert / Grenier, Kathryn / Hersh, Evan. ·Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida 33612, USA. Jeffrey.weber@moffitt.org ·Cancer · Pubmed #20564083.

ABSTRACT: BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study.

16 Article Adjuvant Sunitinib in High-Risk Patients with Uveal Melanoma: Comparison with Institutional Controls. 2018

Valsecchi, Matias E / Orloff, Marlana / Sato, Rino / Chervoneva, Inna / Shields, Carol L / Shields, Jerry A / Mastrangelo, Michael J / Sato, Takami. ·Department of Medical Oncology, Sidney Kimmel Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania; Huntington Internal Medicine Group, Huntington, West Virginia. · Department of Medical Oncology, Sidney Kimmel Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. · Ocular Oncology Service, Wills Eye Hospital, Philadelphia, Pennsylvania. · Department of Medical Oncology, Sidney Kimmel Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: Takami.sato@jefferson.edu. ·Ophthalmology · Pubmed #28935400.

ABSTRACT: PURPOSE: To compare overall survival in high-risk patients with primary uveal melanoma who received adjuvant sunitinib with institutional controls. DESIGN: Retrospective cohort. PARTICIPANTS: Selection criteria were (1) monosomy 3 and 8q amplification by cytogenetic or DecisionDx-UM Class 2 and (2) monosomy 3 and large tumor size (T3-4 by American Joint Committee on Cancer classification). Exclusion criteria were date of diagnosis before 2007 or after 2013 and age <18 years. METHODS: A cohort of patients who intended to receive adjuvant sunitinib for 6 months was compared with institutional historical controls with the same risk factors. Kaplan-Meier and Cox proportional hazards models were used to analyze the outcome. Propensity score was used to adjust for nonrandom assignment to sunitinib. MAIN OUTCOME MEASURES: Overall survival. RESULTS: From the Wills Eye Hospital Oncology Service Uveal Melanoma Cytogenetic Database (N = 1172), 128 patients fulfilled the selection and exclusion criteria. Median follow-up was 52.7 months (range, 0.26-108 months). A total of 54 patients received sunitinib. Their median age was 56 years (range, 29-81 years), and 48% were men. A total of 74 historical controls in the same risk category were identified. Their median age was 62 years (21-80 years), and 48% were men. Patients in the sunitinib group had worse cytogenetic or molecular features (monosomy 3 and 8q amplification or class 2 87% vs. 57%; P < 0.001), had smaller tumor sizes (T3-4 56% vs. 83%; P = 0.001), and were younger. There were 51 deaths, 14 (26%) in the sunitinib group and 37 (50%) in the control group. In the univariate analysis, the sunitinib group had longer overall survival (hazard ratio, 0.53; 95% confidence interval, 0.29-0.99; P = 0.041). In multivariate Cox regression analysis, interaction between use of sunitinib and age as a dichotomous variable was highly significant (P = 0.003). The following variables were statistically associated with prediction of overall survival: cytogenetic/molecular status (P = 0.015), T-size category (P = 0.022), gender (P = 0.040), and adjuvant sunitinib in patients aged <60 years (P = 0.004). Results were confirmed by propensity score analysis. CONCLUSIONS: In this retrospective study, the use of sunitinib in the adjuvant setting was associated with better overall survival.

17 Article PD-L1 expression in tumor metastasis is different between uveal melanoma and cutaneous melanoma. 2017

Javed, Asad / Arguello, David / Johnston, Curtis / Gatalica, Zoran / Terai, Mizue / Weight, Ryan M / Orloff, Marlana / Mastrangelo, Michael J / Sato, Takami. ·Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA. · Caris Life Sciences, Phoenix, AZ 85040, USA. ·Immunotherapy · Pubmed #29185395.

ABSTRACT: AIM: To compare PD-L1 expression between metastatic uveal melanoma (MUM) and metastatic cutaneous melanoma (MCM). MATERIALS & METHODS: A total of 295 MCM and 78 MUM specimens were analyzed for tumor cell PD-L1 expression. Additionally, 91 MCM and 45 MUM specimens were analyzed for PD-1 expression on tumor-infiltrating lymphocytes. RESULTS: A total of 77/295 (26.1%) MCM specimens expressed PD-L1 as compared to 4/78 (5.1%) MUM specimens (p < 0.0001). PD-1 expression on tumor-infiltrating lymphocytes was greater in MCM (73.6%; 67/91) than in MUM (51.1%; 23/45), respectively (p = 0.009). CONCLUSION: Significant differences exist in PD-L1 expression between MCM and MUM. The lower PD-L1 expression in MUM may provide a rationale for failure of PD-1 inhibitor therapy and suggests that immune evasion in this disease may occur via alternative mechanisms.

18 Article A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. 2017

Krepler, Clemens / Sproesser, Katrin / Brafford, Patricia / Beqiri, Marilda / Garman, Bradley / Xiao, Min / Shannan, Batool / Watters, Andrea / Perego, Michela / Zhang, Gao / Vultur, Adina / Yin, Xiangfan / Liu, Qin / Anastopoulos, Ioannis N / Wubbenhorst, Bradley / Wilson, Melissa A / Xu, Wei / Karakousis, Giorgos / Feldman, Michael / Xu, Xiaowei / Amaravadi, Ravi / Gangadhar, Tara C / Elder, David E / Haydu, Lauren E / Wargo, Jennifer A / Davies, Michael A / Lu, Yiling / Mills, Gordon B / Frederick, Dennie T / Barzily-Rokni, Michal / Flaherty, Keith T / Hoon, Dave S / Guarino, Michael / Bennett, Joseph J / Ryan, Randall W / Petrelli, Nicholas J / Shields, Carol L / Terai, Mizue / Sato, Takami / Aplin, Andrew E / Roesch, Alexander / Darr, David / Angus, Steve / Kumar, Rakesh / Halilovic, Ensar / Caponigro, Giordano / Jeay, Sebastien / Wuerthner, Jens / Walter, Annette / Ocker, Matthias / Boxer, Matthew B / Schuchter, Lynn / Nathanson, Katherine L / Herlyn, Meenhard. ·Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA. · Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA. · Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA. · Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA. · Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA. · Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA 19107, USA. · Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107. · Department of Dermatology, University Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany; German Consortium of Translational Cancer Research, Heidelberg, Germany. · Lineberger Cancer Center, University of North Carolina Chapel Hill, NC 27514, USA. · Glaxosmithkline, Collegeville, PA 19426, USA. · Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. · Bayer Pharma AG, Berlin 13353, Germany. · National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA. · Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: herlynm@wistar.org. ·Cell Rep · Pubmed #29141225.

ABSTRACT: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.

19 Article Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis. 2017

Kageyama, Ken / Ohara, Masahiro / Saito, Kengo / Ozaki, Shinji / Terai, Mizue / Mastrangelo, Michael J / Fortina, Paolo / Aplin, Andrew E / Sato, Takami. ·Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Ste. 1024, Philadelphia, PA, 19107, USA. · Department of Radiology, Osaka City University, 1-4-3 Asahimachi Abenoku, Osaka, Osaka, 545-8585, Japan. · Department of Surgery, National Hospital Organization, Kure Medical Center/Chugoku Cancer Center, 3-1 Aoyamacho Kure, Hiroshima, 737-0023, Japan. · Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Ste. 1024, Philadelphia, PA, 19107, USA. · Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, Ste. 1024, Philadelphia, PA, 19107, USA. Takami.Sato@jefferson.edu. ·J Transl Med · Pubmed #28645290.

ABSTRACT: BACKGROUND: Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice. RESULTS: By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice. CONCLUSIONS: Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.

20 Article Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma. 2017

Cheng, Hanyin / Chua, Vivian / Liao, Connie / Purwin, Timothy J / Terai, Mizue / Kageyama, Ken / Davies, Michael A / Sato, Takami / Aplin, Andrew E. ·Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Andrew.Aplin@Jefferson.edu. · Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. ·Mol Cancer Ther · Pubmed #28138035.

ABSTRACT: Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver.

21 Article Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment. 2017

Kemp, Daria Marley / Pidich, Alyson / Larijani, Mary / Jonas, Rebecca / Lash, Elizabeth / Sato, Takami / Terai, Mizue / De Pizzol, Maria / Allegretti, Marcello / Igoucheva, Olga / Alexeev, Vitali. ·Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA. · Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA. · Dompé Farmaceutici SpA, Via Campo di Pile, L'Aquila, Italy. ·Oncotarget · Pubmed #28129639.

ABSTRACT: CXCR1 and CXCR2 chemokine receptors and their ligands (CXCL1/2/3/7/8) play an important role in tumor progression. Tested to date CXCR1/2 antagonists and chemokine-targeted antibodies were reported to affect malignant cells in vitro and in animal models. Yet, redundancy of chemotactic signals and toxicity hinder further clinical development of these approaches. In this pre-clinical study we investigated the capacity of a novel small molecule dual CXCR1/2 inhibitor, Ladarixin (LDX), to attenuate progression of experimental human melanomas. Our data showed that LDX-mediated inhibition of CXCR1/2 abrogated motility and induced apoptosis in cultured cutaneous and uveal melanoma cells and xenografts independently of the molecular defects associated with the malignant phenotype. These effects were mediated by the inhibition of AKT and NF-kB signaling pathways. Moreover, systemic treatment of melanoma-bearing mice with LDX also polarized intratumoral macrophages to M1 phenotype, abrogated intratumoral de novo angiogenesis and inhibited melanoma self-renewal. Collectively, these studies outlined the pre-requisites of the successful CXCR1/2 inhibition on malignant cells and demonstrated multifactorial effects of Ladarixin on cutaneous and uveal melanomas, suggesting therapeutic utility of LDX in treatment of various melanoma types.

22 Article Immune Check Point Inhibitors Combination in Melanoma: Worth the Toxicity? 2016

Orloff, Marlana / Weight, Ryan / Valsecchi, Matias E / Sato, Takami. ·Department of Medical Oncology, Thomas Jefferson University, Philadelphia PA, USA. Marlana.Orloff@jefferson.edu. ·Rev Recent Clin Trials · Pubmed #27028970.

ABSTRACT: The combination of immune checkpoint inhibitors ipilimumab and nivolumab has been recently been FDA approved for first line treatment of unresectable and metastatic BRAF wild type melanoma. The approval came following the impressive results of the CheckMate 067, where the combination of ipilimumab and nivolumab appeared to outperform each as a single agent in regards to response rate and progression free survival. Though we await final overall survival data, the combination will likely be adapted by many oncologists and integrated into the ever changing melanoma treatment algorithm. In this article we aim to summarize the data leading up to the recent FDA approval and publication by Larkin et al. that presents the results from the CheckMate 067 trial. We will also further explore the feasibility, challenges, and applicability of combination immune checkpoint inhibitor therapy.

23 Article Establishment and Characterization of Orthotopic Mouse Models for Human Uveal Melanoma Hepatic Colonization. 2016

Ozaki, Shinji / Vuyyuru, Raja / Kageyama, Ken / Terai, Mizue / Ohara, Masahiro / Cheng, Hanyin / Manser, Tim / Mastrangelo, Michael J / Aplin, Andrew E / Sato, Takami. ·Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Breast Surgery, National Hospital Organization, Kure Medical Center/Chugoku Cancer Center, Kure-shi, Japan. · Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. · Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: takami.sato@jefferson.edu. ·Am J Pathol · Pubmed #26613897.

ABSTRACT: Uveal melanoma (UM) is a rare type of melanoma, although it is the most common primary ocular malignant tumor in adults. Nearly one-half the patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, no treatment is effective for UM hepatic metastasis, and the prognosis is universally poor. The main challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We developed two orthotopic mouse models for human UM hepatic metastases: direct hepatic implantation model (intrahepatic dissemination model) and splenic-implantation model (hematogenous dissemination model) and investigated the tumorgenesis in the liver. A human UM cell line, established from a hepatic metastasis and nonobese diabetic severe combined immunodeficient γ mice, were used for development of in vivo tumor models. In the direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about one-half of cases. However, in the splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently seeded intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver.

24 Article Yttrium-90 Microsphere Brachytherapy for Liver Metastases From Uveal Melanoma: Clinical Outcomes and the Predictive Value of Fluorodeoxyglucose Positron Emission Tomography. 2016

Eldredge-Hindy, Harriet / Ohri, Nitin / Anne, Pramila R / Eschelman, David / Gonsalves, Carin / Intenzo, Charles / Bar-Ad, Voichita / Dicker, Adam / Doyle, Laura / Li, Jun / Sato, Takami. ·*Department of Radiation Oncology ‡Department of Radiology, Division of Interventional Radiology §Department of Radiology, Division of Nuclear Medicine ∥Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA †Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY. ·Am J Clin Oncol · Pubmed #24441583.

ABSTRACT: OBJECTIVES: To report outcomes after yttrium-90 microsphere brachytherapy for unresectable liver metastases from uveal melanoma and to evaluate factors predictive for overall survival (OS) and hepatic progression-free survival (PFS). METHODS: A total of 71 patients were consecutively treated with microsphere brachytherapy for unresectable liver metastases from uveal melanoma between 2007 and 2012. Clinical, radiographic, and positron emission tomography-derived, functional tumor parameters were evaluated by log-rank test in univariate analysis and backwards stepwise multivariate Cox proportional hazards regression. OS and hepatic PFS were estimated by Kaplan-Meier analysis. RESULTS: A total of 134 procedures were performed in 71 patients with a median age of 63 years (range, 23 to 91 y). Fifty-eight patients (82%) received microsphere brachytherapy as a salvage therapy. Median hepatic PFS and OS after microsphere brachytherapy were 5.9 months (range, 1.3 to 19.1 mo) and 12.3 months (range, 1.9 to 49.3 mo), respectively. Median OS times after diagnosis of liver metastases was 23.9 months (range, 6.2 to 69.0 mo). In univariate analysis, female sex, pretreatment metabolic tumor volume, and total glycolic activity (TGA) were significantly correlated with hepatic PFS and OS. In multivariate analysis, female sex and TGA retained significance as independent predictors of hepatic PFS and OS. A low pretreatment TGA (<225 g) was associated with a significantly longer median OS than was a TGA≥225 g (17.2 vs. 9.7 mo, P=0.01). CONCLUSIONS: Yttrium-90 microsphere brachytherapy provided favorable survival times in patients with unresectable liver metastases from uveal melanoma. Metabolic tumor volume and TGA are predictive functional tumor parameters, which may aid patient selection and risk stratification.

25 Article Arterial Blood, Rather Than Venous Blood, is a Better Source for Circulating Melanoma Cells. 2015

Terai, Mizue / Mu, Zhaomei / Eschelman, David J / Gonsalves, Carin F / Kageyama, Ken / Chervoneva, Inna / Orloff, Marlana / Weight, Ryan / Mastrangelo, Michael J / Cristofanilli, Massimo / Sato, Takami. ·Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA. · Department of Radiology, Division of Interventional Radiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA. · Department of Pharmacology and Experimental Therapeutics, Division of Biostatistics, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA. ·EBioMedicine · Pubmed #26870807.

ABSTRACT: BACKGROUND: CTCs provide prognostic information and their application is under investigation in multiple tumor types. Of the multiple variables inherent in any such process, none is more important to outcome than the appropriateness of the sample source. To address this question, we investigated CTCs in paired peripheral venous and arterial blood specimens obtained from stage IV uveal melanoma patients. METHODS: Blood specimens were obtained from both common femoral arteries and antecubital veins in 17 uveal melanoma patients with multiple hepatic metastases for CTC measurements. FINDING: CTCs were detectable with greater frequency (100%) and in larger numbers (median 5, range 1 to 168) in all arterial blood specimens than in venous samples (52.9%; median 1, range 0 to 8). Patients with hepatic as well as extra-hepatic metastasis showed higher number of arterial CTCs, compared to patients with liver-only metastasis (p = 0.003). There was no significant association between the number of arterial CTCs and the tumor burden within the liver in patients who had liver-only metastases. INTERPRETATION: Our data indicate that arterial blood specimens might be a better source of circulating uveal melanoma cells. Although less conveniently processed, perhaps arterial blood should be evaluated as sample source for measurement of CTCs.

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