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Melanoma: HELP
Articles by Alistair J. Cochran
Based on 46 articles published since 2009
(Why 46 articles?)
||||

Between 2009 and 2019, A. J. Cochran wrote the following 46 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. 2018

Wong, Sandra L / Faries, Mark B / Kennedy, Erin B / Agarwala, Sanjiv S / Akhurst, Timothy J / Ariyan, Charlotte / Balch, Charles M / Berman, Barry S / Cochran, Alistair / Delman, Keith A / Gorman, Mark / Kirkwood, John M / Moncrieff, Marc D / Zager, Jonathan S / Lyman, Gary H. ·Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · The Angeles Clinic and Research Institute, Santa Monica, CA, USA. · American Society of Clinical Oncology, Alexandria, VA, USA. guidelines@asco.org. · St Luke's Cancer Center, Easton, PA, USA. · Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Broward Health, Fort Lauderdale, FL, USA. · Los Angeles Center for Health Services, University of California, Los Angeles, CA, USA. · Emory University, Atlanta, GA, USA. · , Silver Spring, MD, USA. · University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. · Norfolk and Norwich University Hospital, Norwich, UK. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. · Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ·Ann Surg Oncol · Pubmed #29236202.

ABSTRACT: PURPOSE: To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. METHODS: An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. RESULTS: Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. RECOMMENDATIONS: Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or <0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline.

2 Guideline Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. 2018

Wong, Sandra L / Faries, Mark B / Kennedy, Erin B / Agarwala, Sanjiv S / Akhurst, Timothy J / Ariyan, Charlotte / Balch, Charles M / Berman, Barry S / Cochran, Alistair / Delman, Keith A / Gorman, Mark / Kirkwood, John M / Moncrieff, Marc D / Zager, Jonathan S / Lyman, Gary H. ·Sandra L. Wong, Dartmouth-Hitchcock Medical Center, Lebanon, NH · Mark B. Faries, The Angeles Clinic and Research Institute, Santa Monica · Alistair Cochran, University of California, Los Angeles Center for Health Services, Los Angeles, CA · Erin B. Kennedy, American Society of Clinical Oncology, Alexandria, VA · Sanjiv S. Agarwala, St Luke's Cancer Center, Easton · John M. Kirkwood, University of Pittsburgh Cancer Institute, Pittsburgh, PA · Timothy J. Akhurst, Peter MacCallum Cancer Centre, Victoria, Australia · Charlotte Ariyan, Memorial Sloan Kettering Cancer Center, New York, NY · Charles M. Balch, MD Anderson Cancer Center, Houston, TX · Barry S. Berman, Broward Health, Fort Lauderdale · Jonathan S. Zager, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Keith A. Delman, Emory University, Atlanta, GA · Mark Gorman, Silver Spring, MD · Marc D. Moncrieff, Norfolk and Norwich University Hospital, Norwich, United Kingdom · and Gary H. Lyman, Fred Hutchinson Cancer Research Center, Seattle, WA. ·J Clin Oncol · Pubmed #29232171.

ABSTRACT: Purpose To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. Methods An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. Results Nine new observational studies, two systematic reviews, and an updated randomized controlled trial of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. Recommendations Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (nonulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of > 1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors and details of the reference patient populations are included within the guideline. Additional information is available at www.asco.org/melanoma-guidelines and www.asco.org/guidelineswiki .

3 Guideline Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. 2012

Wong, Sandra L / Balch, Charles M / Hurley, Patricia / Agarwala, Sanjiv S / Akhurst, Timothy J / Cochran, Alistair / Cormier, Janice N / Gorman, Mark / Kim, Theodore Y / McMasters, Kelly M / Noyes, R Dirk / Schuchter, Lynn M / Valsecchi, Matias E / Weaver, Donald L / Lyman, Gary H / Anonymous1300731 / Anonymous1310731. ·University of Michigan, Ann Arbor, MI, USA. ·J Clin Oncol · Pubmed #22778321.

ABSTRACT: PURPOSE: The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. METHODS: A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. RESULTS: Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. RECOMMENDATIONS: SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1 to 4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, > 4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, < 1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.

4 Guideline Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. 2012

Wong, Sandra L / Balch, Charles M / Hurley, Patricia / Agarwala, Sanjiv S / Akhurst, Timothy J / Cochran, Alistair / Cormier, Janice N / Gorman, Mark / Kim, Theodore Y / McMasters, Kelly M / Noyes, R Dirk / Schuchter, Lynn M / Valsecchi, Matias E / Weaver, Donald L / Lyman, Gary H / Anonymous11110730 / Anonymous11120730. ·University of Michigan, Ann Arbor, MI, USA. ·Ann Surg Oncol · Pubmed #22766987.

ABSTRACT: PURPOSE: The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. METHODS: A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. RESULTS: Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. RECOMMENDATIONS: SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1-4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, >4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, <1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.

5 Guideline EANM-EORTC general recommendations for sentinel node diagnostics in melanoma. 2009

Chakera, Annette H / Hesse, Birger / Burak, Zeynep / Ballinger, James R / Britten, Allan / Caracò, Corrado / Cochran, Alistair J / Cook, Martin G / Drzewiecki, Krzysztof T / Essner, Richard / Even-Sapir, Einat / Eggermont, Alexander M M / Stopar, Tanja Gmeiner / Ingvar, Christian / Mihm, Martin C / McCarthy, Stanley W / Mozzillo, Nicola / Nieweg, Omgo E / Scolyer, Richard A / Starz, Hans / Thompson, John F / Trifirò, Giuseppe / Viale, Giuseppe / Vidal-Sicart, Sergi / Uren, Roger / Waddington, Wendy / Chiti, Arturo / Spatz, Alain / Testori, Alessandro / Anonymous1200637. ·Department of Plastic Surgery and Burns Unit, Rigshospitalet, Copenhagen, Denmark. annette.hougaard.chakera@live.dk ·Eur J Nucl Med Mol Imaging · Pubmed #19714329.

ABSTRACT: The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to "general consensus" and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.

6 Editorial Identification, clinical significance, and management of very small melanoma metastases in sentinel lymph nodes. 2015

Cochran, Alistair J. ·Departments of Pathology and Laboratory Medicine and Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA, acochran@mednet.ucla.edu. ·Ann Surg Oncol · Pubmed #26014157.

ABSTRACT: -- No abstract --

7 Editorial Sentinel lymph node biopsy for melanoma: a plea to let the data be heard. 2014

Thompson, John F / Faries, Mark B / Cochran, Alistair J. ·Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia, john.thompson@melanoma.org.au. ·Ann Surg Oncol · Pubmed #25103536.

ABSTRACT: -- No abstract --

8 Editorial Should patients being considered for surgical management in melanoma centers have their histology reviewed by specialized pathologists? 2014

Cochran, Alistair J. ·Pathology, Laboratory Medicine and Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA, acochran@mednet.ucla.edu. ·Ann Surg Oncol · Pubmed #24728821.

ABSTRACT: -- No abstract --

9 Editorial A glimpse of future management of melanoma. 2009

Cochran, Alistair J. · ·Arch Dermatol · Pubmed #19841407.

ABSTRACT: -- No abstract --

10 Review Clinically relevant information from sentinel lymph node biopsies of melanoma patients. 2011

Wen, Duan-Ren / Cochran, Alistair J / Huang, Rong-Rong / Itakura, Eijun / Binder, Scott. ·Department of Pathology and Laboratory Medicine and Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. ·J Surg Oncol · Pubmed #21858831.

ABSTRACT: Careful laboratory evaluation of sentinel nodes (SNs) is critical to determine the presence of tumor. This requires evaluation of multiple full-face sections from the SN, using H&E staining and immunohistochemistry. In the future, molecular and genetic approaches may be adjunctive to microscopy. Number of tumor-positive SNs and the amount and location of tumor in SNs correlate with tumor spread to non-sentinel nodes, subsequent recurrences and melanoma death, permitting patient assignment to a risk category.

11 Clinical Trial Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. 2017

Faries, Mark B / Thompson, John F / Cochran, Alistair J / Andtbacka, Robert H / Mozzillo, Nicola / Zager, Jonathan S / Jahkola, Tiina / Bowles, Tawnya L / Testori, Alessandro / Beitsch, Peter D / Hoekstra, Harald J / Moncrieff, Marc / Ingvar, Christian / Wouters, Michel W J M / Sabel, Michael S / Levine, Edward A / Agnese, Doreen / Henderson, Michael / Dummer, Reinhard / Rossi, Carlo R / Neves, Rogerio I / Trocha, Steven D / Wright, Frances / Byrd, David R / Matter, Maurice / Hsueh, Eddy / MacKenzie-Ross, Alastair / Johnson, Douglas B / Terheyden, Patrick / Berger, Adam C / Huston, Tara L / Wayne, Jeffrey D / Smithers, B Mark / Neuman, Heather B / Schneebaum, Schlomo / Gershenwald, Jeffrey E / Ariyan, Charlotte E / Desai, Darius C / Jacobs, Lisa / McMasters, Kelly M / Gesierich, Anja / Hersey, Peter / Bines, Steven D / Kane, John M / Barth, Richard J / McKinnon, Gregory / Farma, Jeffrey M / Schultz, Erwin / Vidal-Sicart, Sergi / Hoefer, Richard A / Lewis, James M / Scheri, Randall / Kelley, Mark C / Nieweg, Omgo E / Noyes, R Dirk / Hoon, Dave S B / Wang, He-Jing / Elashoff, David A / Elashoff, Robert M. ·From the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica (M.B.F., D.S.B.H.), and the Departments of Pathology (A.J.C.), Biomathematics (H.-J.W., D.A.E., R.M.E.), and Medicine (D.A.E.), University of California, Los Angeles - both in California · Melanoma Institute Australia and the University of Sydney, Sydney (J.F.T., O.E.N.), Peter MacCallum Cancer Centre, Melbourne, VIC (M.H.), Princess Alexandra Hospital, Brisbane, QLD (B.M.S.), and Newcastle Melanoma Unit, Waratah, NSW (P.H.) - all in Australia · Huntsman Cancer Institute, Salt Lake City (R.H.A., R.D.N.), and Intermountain Healthcare Cancer Services-Intermountain Medical Center, Murray (T.L.B.) - both in Utah · Istituto Nazionale dei Tumori Napoli, Naples (N.M.), Istituto Europeo di Oncologia, Milan (A.T.), and Istituto Oncologico Veneto-University of Padua, Padua (C.R.R.) - all in Italy · H. Lee Moffitt Cancer Center, Tampa, FL (J.S.Z.) · Helsinki University Hospital, Helsinki (T.J.) · Dallas Surgical Group, Dallas (P.D.B.) · Universitair Medisch Centrum Groningen, Groningen (H.J.H.), and Netherlands Cancer Institute, Amsterdam (M.W.J.M.W.) - both in the Netherlands · Norfolk and Norwich University Hospital, Norwich (M. Moncrieff), and Guy's and St. Thomas' NHS Foundation Trust, London (A.M.-R.) - both in the United Kingdom · Swedish Melanoma Study Group-University Hospital Lund, Lund, Sweden (C.I.) · University of Michigan, Ann Arbor (M.S.S.) · Wake Forest University, Winston-Salem (E.A.L.), and Duke University, Durham (R.S.) - both in North Carolina · Ohio State University, Columbus (D.A.) · University of Zurich, Zurich (R.D.), and Centre Hospitalier Universitaire Vaudois, Lausanne (M. Matter) - both in Switzerland · Penn State Hershey Cancer Institute, Hershey (R.I.N.), Thomas Jefferson University (A.C.B.) and Fox Chase Cancer Center (J.M.F.), Philadelphia, and St. Luke's University Health Network, Bethlehem (D.C.D.) - all in Pennsylvania · Greenville Health System Cancer Center, Greenville, SC (S.D.T.) · Sunnybrook Research Institute, Toronto (F.W.), and Tom Baker Cancer Centre, Calgary, AB (G.M.) - both in Canada · University of Washington, Seattle (D.R.B.) · Saint Louis University, St. Louis (E.H.) · Vanderbilt University (D.B.J., M.C.K.), Nashville, and University of Tennessee, Knoxville (J.M.L.) - both in Tennessee · University Hospital Schleswig-Holstein-Campus Lübeck, Lübeck (P.T.), University Hospital of Würzburg, Würzburg (A.G.), and City Hospital of Nürnberg, Nuremberg (E.S.) - all in Germany · SUNY at Stony Brook Hospital Medical Center, Stony Brook (T.L.H.), Memorial Sloan Kettering Cancer Center, New York (C.E.A.), and Roswell Park Cancer Institute, Buffalo (J.M.K.) - all in New York · Northwestern University Feinberg School of Medicine (J.D.W.) and Rush University Medical Center (S.D.B.), Chicago · University of Wisconsin, Madison (H.B.N.) · Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (S.S.) · M.D. Anderson Medical Center, Houston (J.E.G.) · Johns Hopkins University School of Medicine, Baltimore (L.J.) · University of Louisville, Louisville, KY (K.M.M.) · Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.J.B.) · Hospital Clinic Barcelona, Barcelona (S.V.-S.) · and Sentara CarePlex Hospital, Hampton, VA (R.A.H.). ·N Engl J Med · Pubmed #28591523.

ABSTRACT: BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

12 Clinical Trial Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. 2014

Chodon, Thinle / Comin-Anduix, Begoña / Chmielowski, Bartosz / Koya, Richard C / Wu, Zhongqi / Auerbach, Martin / Ng, Charles / Avramis, Earl / Seja, Elizabeth / Villanueva, Arturo / McCannel, Tara A / Ishiyama, Akira / Czernin, Johannes / Radu, Caius G / Wang, Xiaoyan / Gjertson, David W / Cochran, Alistair J / Cornetta, Kenneth / Wong, Deborah J L / Kaplan-Lefko, Paula / Hamid, Omid / Samlowski, Wolfram / Cohen, Peter A / Daniels, Gregory A / Mukherji, Bijay / Yang, Lili / Zack, Jerome A / Kohn, Donald B / Heath, James R / Glaspy, John A / Witte, Owen N / Baltimore, David / Economou, James S / Ribas, Antoni. ·Authors' Affiliations: Departments of Medicine, Surgery, Pathology and Laboratory Medicine, Microbiology, Immunology and Molecular Genetics, and Molecular and Medical Pharmacology; Jonsson Comprehensive Cancer Center; Department of Ophthalmology, Jules Stein Eye Institute; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research; Howard Hughes Medical Institute, University of California, Los Angeles (UCLA); The Angeles Clinic Research Institute, Los Angeles; Department of Medicine, University of California San Diego (UCSD) Moores Cancer Center, La Jolla; Divisions of Chemistry and Biology, California Institute of Technology, Pasadena, California; Department of Medical and Molecular Genetics, Indiana University, and the Indiana University Viral Production Facility (IU VPF), Indianapolis, Indiana; Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada; Mayo Clinic Scottsdale, Scottsdale, Arizona; Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut; and Center for Immunology, Roswell Park Cancer Institute, Buffalo, New York. ·Clin Cancer Res · Pubmed #24634374.

ABSTRACT: PURPOSE: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. EXPERIMENTAL DESIGN: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. RESULTS: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. CONCLUSION: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.

13 Clinical Trial A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology. 2014

Linden, Kenneth G / Leachman, Sancy A / Zager, Jonathan S / Jakowatz, James G / Viner, Jaye L / McLaren, Christine E / Barr, Ronald J / Carpenter, Philip M / Chen, Wen-Pin / Elmets, Craig A / Tangrea, Joseph A / Lim, Sung-Jig / Cochran, Alistair J / Meyskens, Frank L. ·Department of Dermatology and The Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, 101 The City Drive, Orange, CA 92868. kglinden@uci.edu. ·Cancer Prev Res (Phila) · Pubmed #24614012.

ABSTRACT: On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed.

14 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.).

15 Clinical Trial Multifunctional T-cell analyses to study response and progression in adoptive cell transfer immunotherapy. 2013

Ma, Chao / Cheung, Ann F / Chodon, Thinle / Koya, Richard C / Wu, Zhongqi / Ng, Charles / Avramis, Earl / Cochran, Alistair J / Witte, Owen N / Baltimore, David / Chmielowski, Bartosz / Economou, James S / Comin-Anduix, Begonya / Ribas, Antoni / Heath, James R. ·NanoSystems Biology Cancer Center, Division of Physics, California Institute of Technology, Pasadena, CA 91125, USA. ·Cancer Discov · Pubmed #23519018.

ABSTRACT: SIGNIFICANCE: A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.

16 Clinical Trial CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. 2011

Huang, Rong Rong / Jalil, Jason / Economou, James S / Chmielowski, Bartosz / Koya, Richard C / Mok, Stephen / Sazegar, Hooman / Seja, Elizabeth / Villanueva, Arturo / Gomez-Navarro, Jesus / Glaspy, John A / Cochran, Alistair J / Ribas, Antoni. ·Division of Hematology-Oncology, 11-934 Factor Building, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA. ·Clin Cancer Res · Pubmed #21558401.

ABSTRACT: BACKGROUND: CTLA4 blocking monoclonal antibodies provide durable clinical benefit in a subset of patients with advanced melanoma mediated by intratumoral lymphocytic infiltrates. A key question is defining whether the intratumoral infiltration (ITI) is a differentiating factor between patients with and without tumor responses. METHODS: Paired baseline and postdosing tumor biopsy specimens were prospectively collected from 19 patients with metastatic melanoma, including 3 patients with an objective tumor response, receiving the anti-CTLA4 antibody tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+) cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for cell density by automated imaging capture and further characterized for functional lymphocyte properties by assessing the cell activation markers HLA-DR and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker FOXP3. RESULTS: There was a highly significant increase in ITI by CD8(+) cells in biopsy samples taken after tremelimumab treatment. This included increases between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of clinical tumor response or progression. There was no difference between the absolute number, location, or cell density of infiltrating cells between clinical responders and patients with nonresponding lesions that showed acquired intratumoral infiltrates. There were similar levels of expression of T-cell activation markers (CD45RO, HLA-DR) in both groups and no difference in markers for cell replication (Ki67) or the suppressor cell marker FOXP3. CONCLUSION: CTLA4 blockade induces frequent increases in ITI by T cells despite which only a minority of patients have objective tumor responses.

17 Clinical Trial Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. 2009

Ribas, Antoni / Comin-Anduix, Begoña / Chmielowski, Bartosz / Jalil, Jason / de la Rocha, Pilar / McCannel, Tara A / Ochoa, Maria Teresa / Seja, Elizabeth / Villanueva, Arturo / Oseguera, Denise K / Straatsma, Bradley R / Cochran, Alistair J / Glaspy, John A / Hui, Liu / Marincola, Francesco M / Wang, Ena / Economou, James S / Gomez-Navarro, Jesus. ·Department of Medicine, Division of Hematology/Oncology, University of California at Los Angeles, Los Angeles, California 90095-1782, USA. aribas@mednet.ucla.edu ·Clin Cancer Res · Pubmed #19789309.

ABSTRACT: PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone.

18 Article High response rate to PD-1 blockade in desmoplastic melanomas. 2018

Eroglu, Zeynep / Zaretsky, Jesse M / Hu-Lieskovan, Siwen / Kim, Dae Won / Algazi, Alain / Johnson, Douglas B / Liniker, Elizabeth / Ben Kong, ? / Munhoz, Rodrigo / Rapisuwon, Suthee / Gherardini, Pier Federico / Chmielowski, Bartosz / Wang, Xiaoyan / Shintaku, I Peter / Wei, Cody / Sosman, Jeffrey A / Joseph, Richard W / Postow, Michael A / Carlino, Matteo S / Hwu, Wen-Jen / Scolyer, Richard A / Messina, Jane / Cochran, Alistair J / Long, Georgina V / Ribas, Antoni. ·University of California Los Angeles, Los Angeles, California, USA. · Moffitt Cancer Center and University of South Florida, Tampa, Florida, USA. · The University of Texas-MD Anderson Cancer Center, Houston, Texas, USA. · University of California San Francisco, San Francisco, California, USA. · Vanderbilt Ingram Cancer Center, Nashville, Tennessee, USA. · Melanoma Institute Australia, Sydney, New South Wales, Australia. · Westmead Hospital, Sydney, New South Wales, Australia. · Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Weill Cornell Medical College, New York, New York, USA. · Georgetown Lombardi Cancer Center, Washington DC, USA. · Parker Institute for Cancer Immunotherapy, San Francisco, California, USA. · Mayo Clinic, Jacksonville, Florida, USA. · The University of Sydney, Sydney, New South Wales, Australia. · Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. · Royal North Shore Hospital, Sydney, New South Wales, Australia. ·Nature · Pubmed #29320474.

ABSTRACT: Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

19 Article Impact of Time Between Diagnosis and SLNB on Outcomes in Cutaneous Melanoma. 2017

Nelson, Daniel W / Stern, Stacey / Elashoff, David E / Elashoff, Robert / Thompson, John F / Mozzillo, Nicola / Nieweg, Omgo E / Hoekstra, Harald J / Cochran, Alistair J / Faries, Mark B. ·Division of Surgical Oncology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA. · Department of Biostatistics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA. · Department of Biostatistics, University of California Los Angeles, Los Angeles, CA. · Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. · Istituto Nazionale dei Tumori Napoli, Napoli, Italy. · Division of Surgical Oncology, Groningen University, University Medical Center Groningen, Groningen, The Netherlands. · Department of Pathology, University of California Los Angeles, Los Angeles, CA. · Division of Surgical Oncology, The Angeles Clinic and Research Institute, Los Angeles, CA. Electronic address: mfaries@theangelesclinic.org. ·J Am Coll Surg · Pubmed #28668274.

ABSTRACT: BACKGROUND: Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response. Available data are conflicting about the effect of SLNB delay on patient survival. Our objective was to determine whether delay between initial diagnosis and SLNB affects outcomes in patients with cutaneous melanoma. STUDY DESIGN: We performed query and analysis of a large prospectively maintained database of patients with primary cutaneous melanomas undergoing SLNB. An independent dataset from MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was used for validation. Primary outcomes included disease-free survival and melanoma-specific survival. RESULTS: Early and delayed SLNB were defined as less than 30 and 30 or more days from initial diagnosis, respectively. There were 2,483 patients that met inclusion criteria. Positive sentinel lymph nodes were identified in 17.4% (n = 432). Among all patients, 42% had SLNB 30 or more days after diagnosis and 37% of positive sentinel lymph nodes were at 30 or more days. No differences in sex, anatomic site, or histopathologic features were identified between the 2 groups. There was no difference in melanoma-specific survival or disease-free survival between those undergoing early or delayed SLNB. Examination of MSLT-1 trial data similarly demonstrated no difference in survival outcomes. CONCLUSIONS: This, the largest study on this subject to date, found no adverse impact on long-term clinical outcomes of patients due to delay of SLNB beyond 30 days. The MSLT-1 data confirm this result. Patients can be reassured that if the operation is performed 30 or more days after diagnosis, it will not cause harm.

20 Article Multicenter Selective Lymphadenectomy Trial-I confirms the central role of sentinel node biopsy in contemporary melanoma management: response to 'No survival benefit for patients with melanoma undergoing sentinel lymph node biopsy: critical appraisal of the Multicenter Selective Lymphadenectomy Trial-I final report'. 2015

Faries, M B / Cochran, A J / Elashoff, R M / Thompson, J F. ·Departments of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Blvd, Santa Monica, CA, 90404, U.S.A. mark.faries@jwci.org. ·Br J Dermatol · Pubmed #25776247.

ABSTRACT: Sentinel lymph node (SLN) biopsy has become a standard procedure for many patients with melanoma and is recommended in numerous national and professional melanoma guidelines. The Multicenter Selective Lymphadenectomy Trial (MSLT-1) confirms earlier large database studies and prospective clinical trials in demonstrating the independent and unequalled prognostic value of the SLN. It also demonstrates the ability of biopsy-directed management to provide effective regional disease control with the least possible morbidity. These benefits are not in question and provide ample justification for the procedure, even without evidence of a survival benefit. However, MSLT-1 also provides strong evidence of a substantial reduction in the risk of melanoma death for patients with intermediate thickness melanomas who harbour occult nodal metastases at the time of presentation. Denying appropriately selected patients with melanoma the opportunity to undergo SLN biopsy is no longer reasonable or acceptable.

21 Article Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up. 2014

Gerami, Pedram / Busam, Klaus / Cochran, Alistair / Cook, Martin G / Duncan, Lyn M / Elder, David E / Fullen, Douglas R / Guitart, Joan / LeBoit, Philip E / Mihm, Martin C / Prieto, Victor G / Rabkin, Michael S / Scolyer, Richard A / Xu, Xiaowei / Yun, Sook Jung / Obregon, Roxana / Yazdan, Pedram / Cooper, Chelsea / Weitner, Bing Bing / Rademaker, Alfred / Barnhill, Raymond L. ·*Department of Dermatology †Robert H. Lurie Cancer Center †††Department of Preventive Medicine and the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL ‡Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY §Department of Pathology and Laboratory Medicine, Dermatopathology, UCLA Medical Center, Los Angeles ‡‡Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, CA ¶Pathology Service, Massachusetts General Hospital, Boston, MA #Department of Pathology, University of Pennsylvania, Philadelphia ¶¶Rabkin Dermatopathology Laboratory, P.C., Tarentum, PA Departments of **Pathology ††Dermatology, University of Michigan Medical Center, Ann Arbor, MI §§Department of Pathology, Section of Dermatopathology ∥∥Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX ∥Department of Histopathology, Royal Surrey County Hospital & Division of Clinical Medicine, University of Surrey, Guildford, Surrey, UK ##Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Melanoma Institute Australia and The University of Sydney, NSW, Australia ***Departments of Dermatology, Chonnam National University Medical School, Gwangju, Korea. ·Am J Surg Pathol · Pubmed #24618612.

ABSTRACT: Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors.

22 Article CTLA4 blockade broadens the peripheral T-cell receptor repertoire. 2014

Robert, Lidia / Tsoi, Jennifer / Wang, Xiaoyan / Emerson, Ryan / Homet, Blanca / Chodon, Thinle / Mok, Stephen / Huang, Rong Rong / Cochran, Alistair J / Comin-Anduix, Begoña / Koya, Richard C / Graeber, Thomas G / Robins, Harlan / Ribas, Antoni. ·Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine, Departments of Molecular and Medical Pharmacology, Medicine Statistics core, and Pathology and Laboratory Medicine, Division of Surgical-Oncology, Department of Surgery, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; Fred Hutchinson Cancer Research Center; Adaptive Biotechnologies, Seattle, Washington; and Instituto de Salud Carlos III, Madrid, Spain. ·Clin Cancer Res · Pubmed #24583799.

ABSTRACT: PURPOSE: To evaluate the immunomodulatory effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC). EXPERIMENTAL DESIGN: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab. RESULTS: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders. CONCLUSIONS: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system.

23 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.

24 Article COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors. 2014

Escuin-Ordinas, Helena / Atefi, Mohammad / Fu, Yong / Cass, Ashley / Ng, Charles / Huang, Rong Rong / Yashar, Sharona / Comin-Anduix, Begonya / Avramis, Earl / Cochran, Alistair J / Marais, Richard / Lo, Roger S / Graeber, Thomas G / Herschman, Harvey R / Ribas, Antoni. ·Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA. · Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · The Paterson Institute, Manchester, UK. · Department of Medicine (Division of Dermatology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. · Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: hherschman@mednet.ucla.edu. · Department of Medicine (Division of Hematology-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Surgery (Division of Surgical-Oncology), David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. ·Mol Oncol · Pubmed #24345644.

ABSTRACT: Keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs) develop in 15-30% of patients with BRAF(V600E) metastatic melanoma treated with BRAF inhibitors (BRAFi). These lesions resemble mouse skin tumors induced by the two-stage DMBA/TPA skin carcinogenesis protocol; in this protocol BRAFi accelerates tumor induction. Since prior studies demonstrated cyclooxygenase 2 (COX-2) is necessary for DMBA/TPA tumor induction, we hypothesized that COX-2 inhibition might prevent BRAFi-accelerated skin tumors. Celecoxib, a COX-2 inhibitor, significantly delayed tumor acceleration by the BRAFi inhibitor PLX7420 and decreased tumor number by 90%. Tumor gene expression profiling demonstrated that celecoxib partially reversed the PLX4720-induced gene signature. In PDV cuSCC cells, vemurafenib (a clinically approved BRAFi) increased ERK phosphorylation and soft agar colony formation; both responses were greatly decreased by celecoxib. In clinical trials trametinib, a MEK inhibitor (MEKi) increases BRAFi therapy efficacy in BRAF(V600E) melanomas and reduces BRAFi-induced KA and cuSCC frequency. Trametinib also reduced vemurafenib-induced PDV soft agar colonies, but less efficiently than celecoxib. The trametinb/celecoxib combination was more effective than either inhibitor alone. In conclusion, celecoxib suppressed both BRAFi-accelerated skin tumors and soft-agar colonies, warranting its testing as a chemopreventive agent for non-melanoma skin lesions in patients treated with BRAFi alone or in combination with MEKi.

25 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.

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