Innovations in Therapy

Clinical Trial Design

Advocated and led the implementation of new ways of designing clinical trials involving Bayesian statistical approaches that allow use of previous data rather than “blinding” all data, thereby speeding up clinical research.

Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5(1):27-36.

Developed a response-adaptive randomization design to assign lung cancer patients to effective treatments based on the patient’s biomarker profile.

Zhou X, Liu S, Kim ES, Herbst RS, Lee JJ. Bayesian adaptive design for targeted therapy development in lung cancer – a step toward personalized medicine. Clin Trials. 2008; 5:181-193.

Chemotherapy

Created the nation’s largest bone marrow and stem cell transplantation program, enabling treatment of about 600 patients with high-dose chemotherapy annually.

Pioneered the use of reduced, less-toxic doses of chemotherapy for bone marrow stem cell transplantation, resulting in lower mortality rates and the ability to perform transplant procedures in older patients, now a widely accepted standard of therapy.

Champlin R, Khouri I, Shimoni A, Gajewski J, Kornblau S, Molldrem J, Ueno N, Giralt S, Anderlini P. Harnessing graft-versus-malignancy: non-myeloablative preparative regimens for allogeneic haematopoietic transplantation, an evolving strategy for adoptive immunotherapy. Br J Haematol. 2000;111(1):18-29.

Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, O’Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Kørbling M, Keating M, Kantarjian H, Champlin R. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997;89(12):4531-4536.

Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O’Brien S, Giralt S, Ippoliti C, von Wolff B, Gajewski J, Donato M, Claxton D, Ueno N, Andersson B, Gee A, Champlin R. Transplant lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor cell transplantation as treatment for lymphoid malignancies. J Clin Oncol. 1998;16(8):2817-2824.

Pioneered the use of neoadjuvant chemotherapy given before surgery to shrink tumors of the breast, pancreas, lung and other organs, allowing them to be surgically removed with less damage to surrounding normal tissues.

Hortobagyi GN, Spanos W, Montague ED, Buzdar AU, Yap HY, Blumenschein GR. Treatment of locoregionally advanced breast cancer with surgery, radiotherapy and combination chemoimmunotherapy. Int J Radiat Oncol Biol Phys. 1983;9(5):643-650.

Hortobagyi GN, Blumenschein GR, Spanos W, Montague ED, Buzdar AU, Yap HY. Multimodal treatment of locoregionally advanced breast cancer. Cancer. 1983;51(5):763-768.

Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB, Lee JS, Dhingra H, De Caro L, Chasen M, McGavran M, Atkinson EN, Hong WK. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86(9):673-680.

Spitz FR, Abbruzzese JL, Lee JE, Pisters PW, Lowy AM, Fenoglio CJ, Cleary KR, Janjan NA, Goswitz MS, Rich TA, Evans DB. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15(3):928-937.

Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, Rich TA, Raijman I, Wolff RA, Lenzi R, Lee JE, Evans DB. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol. 1998;16(12):3843-3850.

Discovered the first successful chemotherapy (vincristine) for children with inoperable Wilms’ tumor, a kidney cancer.

Sullivan MP, Sutow WW, Cangir A, Taylor G. Vincristine sulfate in management of Wilms’ tumor. Replacement of preoperative irradiation by chemotherapy. JAMA. 1967;202(5):381-384.

Proposed the concept of combination chemotherapy for lymphoma and conducted the first clinical trials of CHOP (cyclophosphamide, adriamycin, vincristine and prednisone); efficacy later confirmed in multi-center trials conducted by the Southwest Oncology Group.

Gottlieb JA, Gutterman JU, McCredie KB, Rodriguez V, Frei E 3rd. Chemotherapy of malignant lymphoma with adriamycin. Cancer Research. 1973 Nov;33(11):3024-8.

McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, Lane M, Gamble JF, Jones SE, Grozea PN, Gutterman J, Coltman C, Moon TE. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976 Oct;38(4):1484-93.

Demonstrated the efficacy of paclitaxel (Taxol) against breast cancer, now standard treatment.

Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN. Phase II trial of Taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst. 1991;83:1797-1805.

Demonstrated in early studies the efficacy of doxorubicin (Adriamycin) in combination with other drugs for the treatment of lymphoma, breast cancer, sarcomas and other solid tumors.

Gottlieb JA, Gutterman JU, McCredie KB, Rodriguez V, Frei E III. Chemotherapy of malignant lymphoma with Adriamycin. Cancer Res. 1973;33(11):3024-3028.

Gottlieb JA, Baker LH, Quagliana JM, Luce JK, Whitecar JP, Sinkovics JG, Rivkin SE, Brownlee R, Frei E. Chemotherapy of sarcomas with a combination of Adriamycin and dimethyl triazeno imidazole carboxamide. Cancer. 1972;30(6):1632-1638.

Led the clinical trial documenting the efficacy of temozolomide for glioblastoma, an often fatal brain tumor, leading to FDA approval.

Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O’Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol. 1999;17(9):2762-2771.

Designed, synthesized and evaluated in brain tumor patients Berubicin (RTA774), the first blood-brain barrier-penetrating agent that is highly apoptotic.

Fokt I, Conrad C, Madden T, Yung AW, Lang FF, Thapar N, Priebe W. The discovery and development of blood-brain barrier (BBB) penetrating anthracyclines for the treatment of brain tumors. Proceedings of AACR-NCI-EORTC International Conference, Philadelphia, PA. A199, page 106, 2005.

Priebe W, Madden T, Fokt I, Johansen M, Conrad C. Modular design of DNa binding agents capable of penetrating blood-brain barrier and targeting brain tumors. American Association for Cancer Research-American Chemical Society Joint Conference - Chemistry in Cancer Research: A Vital Partnership, Sand Diego, CA 2/4-2/8/2007.

Pioneered preclinical research on the mechanisms of anticancer effects of the spice curcumin, leading to current clinical trials of high-dose treatment for a variety of cancers.

Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies [review]. Anticancer Res. 2003;23(1A):363-398.

Demonstrated the efficacy of clofarabine, developed by M. D. Anderson researchers, against pediatric leukemia, adult myelodysplastic syndrome and adult acute leukemia, leading to FDA approval.

Kantarjian HM, Gandhi V, Kozuch P, Faderl S, Giles F, Cortes J, O’Brien S, Ibrahim N, Khuri F, Du M, Rios MB, Jeha S, McLaughlin P, pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21(6):1167-1173.

Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, Giles F, Faderl S, O’Brien S, Jeha S, Davis J, Shaked Z, Craig A, Keating M, Plunkett W, Freireich EJ. Phase II clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102(7):2379-2386.

Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103(3):784-789.

Faderl S, Gandhi V, O’Brien S, Bonate P, Cortes J, Estey E, Beran M, Wierda W, Garcia-Manero G, Ferrajoli A, Estrov Z, Giles FJ, Du M, Kwari M, Keating M, Plunkett W, Kantarjian H. Results of a phase I-II study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood. 2005;105(3):940-947.

Jeha S, Kantarjian H. Clofarabine for the treatment of acute lymphoblastic leukemia. Expert Rev Anticancer Ther. 2007;7(2):113-118.

Developed and secured FDA approval of Busulfex, an intravenous form of busulfan that is now a standard chemotherapy agent used in bone marrow transplantation for leukemia.

Andersson BS, Gajewski J, Donato M, Giralt S, Gian V, Wingard J, Tarantolo S, Fernandez H, Hu WW, Blume K, Kashyap A, Forman SJ, Champlin RE. Allogeneic stem cell transplantation (BMT) for AML and MDS following IV busulfan and cyclophosphamide (IV BuCY). Bone Marrow Transplant. 2000;25(suppl 2):S35-S38.

Designed, synthesized, formulated in liposomes and patented Annaymcin, a drug highly active against multidrug-resistant tumors; currently in phase I/phase II clinical trials for patients with acute lymphocytic leukemia.

Priebe W, Perez-Soler R. Design tumor targeting of anthracyclines able to overcome multidrug resistance: a double-advantage approach. Pharmac Ther 60: 215-34, 1993.

Perez-Soler R, Ling Y-H, Zou Y, Priebe W. Cellular pharmacology of the partially non-cross- resistant anthracycline Annamycin entrapped in liposomes in KB and KB-V1 cells. Cancer Chemother Pharmacol 34:P 109-18, 1994

Consoli U, Priebe W, Ling Y-H, Mahadevia R, Griffin M, Zhao S, Perez-Soler R, Andreeff M. The novel anthracycline Annamycin is not affected by P-glycoprotein-related multidrug resistance: comparison with idarubicin and doxorubicin in HL-60 leukemia cell lines. Blood 88: 633-44, 1996.

Pioneered gemcitabine chemotherapy for pancreatic cancer, currently the standard therapy.

Abbruzzese JL, Grunewald R, Weeks EA, Gravel D, Adams T, Nowak B, Mineishi S, Tarassoff P, Satterlee W, Raber MN, Plunkett W. A phase I clinical, plasma and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991;9(3):491-498.

Demonstrated the efficacy of paclitaxel (Taxol) for non-small cell lung cancer.

Murphy WK, Fossella FV, Winn RJ, Shin DM, Hynes HE, Gross HM, Davilla E, Leimert J, Dhingra H, Raber MN, Krakoff IH, Hong WK. Phase II study of taxol in patients with untreated advanced non-small cell lung cancer. J Natl Cancer Inst. 1993;85(5):384-388.

Led the pivotal trial demonstrating the efficacy of rituximab in treating indolent B-cell non-Hodgkin’s lymphomas resistant to other chemotherapy regimens, which led to FDA approval of this monoclonal antibody.

McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R., Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler L., White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphomas: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16(8):2825-2833.

Developed the three-drug FND regimen that incorporated the nucleoside analog fludarabine into a highly effective regimen for patients with indolent lymphoma.

McLaughlin P, Hagemeister FB, Romaguera JE, Sarris AH, Pate O, Younes A, Swan F, Keating M, Cabanillas F. Fludarabine, mitoxantrone and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol. 1996;14(4):1262-1268.

Combination Therapies

Led a clinical trial demonstrating the superiority of chemoradiation over radiation alone for advanced cervical cancer, changing the standard of care.

Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340(15):1137-1143.

Demonstrated that trastuzumab (Herceptin), given with chemotherapy, reduces recurrence of breast cancer after tumor excision and radiation therapy.

Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathological complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer, paclitaxel and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005;23(16):3676-3685.

Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, Sahin AA, Esteva F, Symmans WF, Ewer MS, Buchholz TA, Hortobagyi GN. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13(1):228-233.

Pioneered a combined-modality triple treatment strategy for the successful management of locally advanced inflammatory breast cancers, now the standard of care.

Yang CH, Cristofanilli M. Systemic treatments for inflammatory breast cancer. Breast Disease. 2006;22(1):55-65.

Introduced doxorubicin (Adriamycin) in a three-drug combination for the treatment of advanced breast cancer, now the standard of care in much of the world.

Gutterman JU, Cardenas JO, Blumenschein GR, Hortobagyi G, Burgess MA, Livingston RB, Mavligit GM, Freireich EJ, Gottlieb JA, Hersh EM. Chemoimmunotherapy of advanced breast cancer: prolongation of remission and survival with BCG. British Medical Journal. 1976;2(6046):1222-1225.

Introduced doxorubicin (Adriamycin) in combination with other agents in adjuvant chemotherapy to reduce the risk of breast cancer recurrence; this is currently the accepted standard therapy.

Buzdar AU, Gutterman JU, Blumenschein GR, Hortobagyi GN, Tashima CK, Smith TL, Hersh EM, Freireich EJ, Gehan EA. Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer. Cancer. 1978;41(3):1064-1075.

Buzdar AU, Blumenschein GR, Gutterman JU, Tashima CK, Hortobagyi GN, Smith TL, Campos LT, Wheeler WL, Hersh EM, Freireich EJ, Gehan EA. Postoperative adjuvant chemotherapy with 5-fluorouracil, doxorubicin, cyclophosphamide and BCG: a follow-up report. JAMA. 1979;242(14):1509-1513.

Showed that adding pamidronate, a bone growth promoter, to chemotherapy or hormone therapy reduces skeletal complications from breast cancer; this is currently the standard of care.

Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD; for Protocol 19 Aredia Breast Cancer Study Group. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone lesions. N Engl J Med. 1996;335(24):1785-1791.

Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, Wheeler H, Simeone JF, Seaman JJ, Knight RD, Heffernan M, Mellars K, Reitsma DJ; for Protocol 19 Aredia Breast Cancer Study Group. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol. 1998;16(6):2038-2044.

Theriault RL, Lipton A, Hortobagyi GN, Leff R, Glück S, Stewart JF, Costello S, Kennedy I, Simeone J, Seaman JJ, Knight RD, Mellars K, Heffernan M, Reitsma DJ; for Protocol 18 Aredia Breast Cancer Study Group. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol. 1999;17(3):846-854.

Combined chemotherapy with bone-targeting radionuclides for the treatment of hormone-refractory prostate cancer; patients showed prolonged survival after this treatment compared with chemotherapy alone.

Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, Daliani D, Papandreou CN, Smith TL, Kim J, Podoloff DA, Logothetis CJ. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet. 2001;357(9253):336-341. Erratum in: Lancet. 2001;357(9263):1210.

Demonstrated that adding rituximab to chemotherapy improves response to chemotherapy for patients with chronic lymphocytic leukemia and lymphoma, now a standard therapy.

Keating MJ, O’Brien S, Lerner S, Wierda W, Kantarjian H. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) improves complete response (CR), remission duration and survival as initial therapy of chronic lymphocytic leukemia (CLL). J Clin Oncol. 2004;22(14S):6565.

Demonstrated the efficacy of fludarabine and alemtuzumab in chronic lymphocytic leukemia, leading to FDA approval.

Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989;74(1):19-25.

Discovered that the anti-EGF receptor antibody cetuximab (Erbitux) plus radiation therapy had synergistic effects against head-and-neck cancer in a preclinical model; this discovery led to a successful clinical trial and FDA approval of this combination therapy.

Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang K, Mendelsohn J, Fan Z. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res. 2000;6(2):701-708.

Nasu S, Ang KK, Fan Z, Milas L. C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys. 2001;51(2):474-477.

Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK, Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350-7356.

Led an international study that demonstrated improved survival in patients with stage II papillary or follicular thyroid cancer treated with total thyroidectomy, adjuvant radioactive iodine and thyroid hormone suppression therapy.

Jonklaas J, Sarlis NJ, Litofsky D, Ain KB, Bigos ST, Brierley JD, Cooper DS, Haugen BR, Ladenson PW, Magner J, Robbins J, Ross DS, Skarulis M, Maxon HR, Sherman SI. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid. 2006 Dec;16(12):1229-1242.

Developed a novel method of enhancing the efficacy of radiation treatments for head and neck cancer by combining radiation with an antibody (C225) that targets an important receptor in tumor cells.

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D,Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New Engl J Med. 2006;354(6):567-578.

Demonstrated that chemotherapy given concurrently with radiation for cervical cancer is superior to the historical standard of using radiation alone.

Eifel PJ, Winter K, Morris M, Levenback C, Grigsby PW, Cooper J, Rotman M, Gershenson D, Mutch DG. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol. 2004;22(5):872-880.

New Targeted Therapies

Led a multi-institutional trial demonstrating the efficacy of imatinib mesylate (Gleevec) for producing long-term complete remissions in chronic myelocytic leukemia, leading to FDA approval. This was the first highly successful drug proving the concept of targeted therapy.

Kantarjian H, Talpaz M, O’Brien S, Smith TL, Giles F, Faderl S, Thomas DA, Garcia-Manero G, Issa JP, Andreeff M, Kornblau S, Koller C, Beran M, Keating M, Rios MB, Shan J, Resta D, Capdeville R, Hayes K, Albitar M, Freireich E, Cortes J. Imatinib mesylate for Philadelphia-chromosome-positive, chronic-phase myeloid leukemia after failure of Interferon-α: Follow-up results. Clin Can Res 8:2177-2187, 2002.

Kantarjian H, Cortes J, O’Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Jeha S, Rios MB, Letvak L, Bochinski K, Arlinghaus R, Talpaz M. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood 101:97-100, 2003.

Kantarjian H, Talpaz M, O’Brien S, Giles F, Garcia-Manero G, Faderl S, Thomas D, Shan J, Rios MB, Cortes J. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101:473-475, 2003.

Kantarjian H, Talpaz M, O’Brien S, Garcia-Manero G, Verstovsek S, Giles F, Rios MB, Shan J, Letvak L, Thomas D, Faderl S, Ferrajoli A, Cortes J. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873-8, 2004.

Demonstrated the effectiveness of two new drugs, dasatinib and nilotinib, in Gleevec-resistant chronic myelocytic leukemia, leading to FDA approval.

Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542-2551.

Demonstrated that decitabine acts in leukemia and myelodysplastic syndrome by preventing cancer cells from turning off the expression of critical suppres- sor genes, leading to FDA approval.

Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, Bayar E, Lyons J, Rosenfeld CS, Cortes J, Kantarjian HM. Phase I study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103(5):1635-1640.

Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK, Gharybian V, Luna R, Rashid A, Shen L, Estecio MR, Kantarjian HM, Garcia-Manero G, Issa JP. DNA methylation changes after 5-aza-2’-deoxycytidine therapy in patients with leukemia. Cancer Res. 2006;66(10):5495-5503.

Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O’Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109(1):52-57.

Performed pivotal trial of lenalidomide plus dexamethasone for relapsed multiple myeloma patients, leading to FDA approval of lenalidomide.

Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD, for the Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. New Engl J Med. 2007;357(21):2133-2142.

Immunologic Therapies

Conducted the first series of clinical trials showing the efficacy of interferon, leading to FDA approval for its use in treating two types of leukemia; first administration of synthetically produced recombinant interferon.

Kurzrock R, Rosenblum MG, Sherwin SA, Rios A, Talpaz M, Quesada JR, Gutterman JU. Pharmacokinetics, single-dose tolerance and biological activity of recombinant gamma-interferon in cancer patients. Cancer Res. 1985;45(6):2866-2872.

Gutterman JU, Fine S, Quesada J, Horning SJ, Levine JF, Alexanian R, Bernhardt L, Kramer M, Spiegel H, Colburn W, Trown P, Merigan T, Dziewanowski Z. Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance and biologic effects in cancer patients. Ann Intern Med. 1982;96(5):549-556.

Gutterman JU, Blumenschein GR, Alexanian R, Yap HY, Buzdar AU, Cabanillas F, Hortobagyi GN, Hersh EM, Rasmussen SL, Harmon M, Kramer M, Pestka S. Leukocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma and malignant lymphoma. Ann Intern Med. 1980;93(3):399-406.

Currently conducting advanced clinical trials of several promising vaccines against leukemia, melanoma and other cancers, using novel technologies that involve synthetic peptides, viruses and stimulants of immune function.

Molldrem J, Lee P, Wang C, Felio K, Kantarjian H, Champlin R, Davis M. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 6(9):018-23, 2000.

Rusakiewicz S, Kant S, Lizee G, Rabinovich B, Wieder E, Lu S, Hwu P, Molldrem J: CD8T cells with high avidity TCR-ab specifici for serine protease self-determinants for use in adoptive imunotherapy of human leukemia. J Immunology (178) 48.35, 2007.

Radiation Therapy

Developed the first cobalt-60 radiation therapy unit, paving the way for the high-voltage therapy in worldwide use today.

Grimmett L.G. A 1000-Curie Cobalt-60 Irradiator. Texas Reports on Biology and Medicine, 1950; 8 480-490.

Grimmett L.G., Kerman H.D., Brucer M., Fletcher G.H. and Richardson J.E. Design and Construction of a Multicurie Cobalt Teletherapy Unit. Radiology, Vol. 59, No. 1, Pages 19-29, July, 1952.

Demonstrated in clinical studies that “lumpectomy” followed by radiation therapy for breast cancer can be as effective as radical surgical mastectomy, now standard practice worldwide.

Fletcher GH, Montague ED, Nelson AJ. Combination of conservative surgery and irradiation for cancer of the breast. Am J Roentgenol, 126(2):216-22, 1976.

Fisher B, Montague ED, Redmond C, Barton B, Borland D, Fisher ER, Deutsch M, Schwarz G, Margolese R, Donegan W, Volk H, Konvolinka C, Gardner B, Cohn I Jr, Lesnick G, Cruz AB, Lawrence W, Nealon T, Butcher H, Lawton R. Comparison of radical mastectomy with alternative treatments for primary breast cancer: a first report of results from a prospective randomized clinical trial. Cancer, 39(6 Suppl):2827-39, 1977.

Montague ED, Gutierrez AE, Barker JL, Tapley ND, Fletcher GH. Conservation surgery and irradiation for the treatment of favorable breast cancer. Cancer, 43(3):1058-61, 1979.

Developed electron pencil-beam algorithms that greatly improved radiation therapy for cancer patients throughout the world.

Hogstrom K.R., Mills M. D. and Almond P.R. Electron beam dose calculations. Physics in Medicine and Biology, 26: 445-459, 1981.

Hogstrom K.R., Mills M.D., Meyer J.A., Palta J.R., Mellenberg D.E., Meoz R.T. and Fields R.S. Dosimetric evaluation of a pencil-beam algorithm for electrons employing a two-dimensional heterogeneity correction. International Journal of Radiation Oncology Biology Physics, 10:561- 569, 1983.

Invented a micro-multileaf collimator to more precisely shape the radiation therapy beam; the technology was approved by the FDA for conformal radiation.

Shiu AS, Kooy HA, Ewton JR, Tung SS, Wong J, Antes K, Maor MH. Comparison of Miniature Multileaf Collimation (MMLC) with Circular Collimation for Stereotactic Treatment. Int J of Radiat Oncol Biol Phys 37:679-688, 1997.

Parker BC, Shiu AS, Maor MH, Lang FF, Liu H, White A, Antolak JA. PTV Margin Determination in Conformal SRT of Intracranial Lesions. JACMP, 3(3): 176-189, 2002.

Shiu AS, Parker B, Ye J, Lii J. An Integrated Treatment Delivery System for CSRS and CSRT and Clinical Applications. JACMP 4(4):261-273, 2003.

Conducted research on image-guided radiation therapy, using CT scanners to guide the design of treatment fields before and during radiation therapy and to compensate, in real time, for respiration-induced changes in tumor position; these refinements are becoming standard practice.

Chang EL, Shiu AS, Lii MF, Rhines LD, Mendel E, Mahajan A, Weinberg JS, Mathews LA, Brown BW, Maor MH, Cox JD. Phase I clinical evaluation of near-simultaneous computed tomographic image-guided stereotactic body radiotherapy for spinal metastases. Int J Radiat Oncol Biol Phys. 2004;59(5):1288-1294.

Shiu AS, Chang EL, Ye JS, Lii M, Rhines LD, Mendel E, Weinberg J, Singh S, Maor MH, Mohan R, Cox JD. Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: an emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys. 2003;57(3):605-613.

Led research proving the efficacy of intensity-modulated radiation therapy, which optimizes radiation dose patterns to conform tightly to the target volume, leading to significant reduction in toxicity to normal tissues for a wide range of cancers.

Garden AS, Morrison WH, Wong PF, Tung SS, Rosenthal DI, Dong L, Mason B, Perkins GH, Ang KK. Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2007;67(2):438-444.

Ozyigit G, Yang T, Chao KSC. Intensity-modulated radiation therapy for head and neck cancer. Current Treatment Options in Oncology. 2004;5(1):3-9.

Hermanto U, Frija EK, Lii MJ, Chang EL, Mahajan A, Woo SY. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: does IMRT increase the integral dose to normal brain? Int J Radiat Oncol Biol Phys. 2007;67(4):1135-1144.

Opened the nation’s largest and most advanced proton therapy facility to provide high-energy proton beam therapy that spares healthy tissue surrounding tumors for multiple types of cancer and to expand research exploring new ways to combine proton therapy with chemotherapy.

First to demonstrate the effectiveness of proton therapy for pediatric osteosarcoma, a tumor previously regarded as radioresistant.

Mahajan A, Woo S, Kornguth DG, Hughes D, Huh W, Chang EL, Herzog CE, Peloski CE. Multimodal treatment of osteosarcoma: radiation in a high-risk cohort. Pediatr Blood Cancer. 2008;50:976-982.

Surgery

Pioneered limb-sparing surgery for bone tumors and other sarcomas first by implanting donor bones and then by using expandable metal prostheses.

Developed nationally utilized clinical methods, including oncoplastic techniques, to meet the evolving breast reconstructive needs for both total and partial mastectomy in patients who will undergo adjuvant radiation therapy.

Kronowitz SJ, Kuerer HM. Advances and surgical decision-making for breast reconstruction. Cancer. 2006;107(5):893-907.

Kronowitz SJ, Feledy JA, Hunt KK, Kuerer HM, Youssef A, Koutz CA, Robb GL. Determining the optimal approach to breast reconstruction after partial mastectomy. Plast Reconstr Surg. 2006;117(1):1-11; discussion 12-14.

Kronowitz SJ, Robb GL, Youssef A, Reece G, Chang SH, Koutz CA, Ng RL, Lipa JE, Miller MJ. Optimizing autologous breast reconstruction in thin patients. Plast Reconstr Surg. 2003;112(7):1768-1778.

Kronowitz SJ, Chang DW, Robb GL, Hunt KK, Ames FC, Ross MI, Singletary SE, Symmans WF, Kroll SS, Kuerer HM. Implications of axillary sentinel lymph node biopsy in immediate autologous breast reconstruction. Plast Reconstr Surg. 2002;109(6):1888-1896.

Conducted the first surgical transplantation of parathyroid glands during thyroidectomy, now standard therapy.

Demonstrated that use of a preoperative medication (combination of a glucocorticoid with diphenhydramine and famotidine) can prevent anaphylactic reactions to dye used for mapping lymph node metastases during breast cancer surgery, leading to a change in medical practice.

Raut CP, Hunt KK, Akins JS, Daley MD, Ross MI, Singletary SE, Marshall GD, Meric-Bernstam F, Babiera G, Feig BW, Ames FC, Kuerer HM. Incidence of anaphylactoid reactions to isosulfan blue dye during breast carcinoma lymphatic mapping in patients treated with preoperative prophylaxis: results of a surgical prospective clinical practice protocol. Cancer. 2005;104(4):692-699.

Raut CP, Daley MD, Hunt KK, Akins J, Ross MI, Singletary SE, Marshall GD, Meric-Bernstam F, Babiera G, Feig BW, Ames FC, Kuerer HM. Anaphylactoid reactions to isosulfan blue dye during breast cancer lymphatic mapping in patients given preoperative prophylaxis. J Clin Oncol. 2004;22(3):567-568.

Pioneered a new skin flap strategy of microvascular pharyngeal reconstruction during extensive head-and-neck surgery that results in markedly improved postoperative speech and swallowing outcomes.

Yu P, Lewin JS, Reece GP, Robb GL. Comparison of clinical and functional outcomes and hospital costs following pharyngoesophageal reconstruction with the anterolateral thigh free flap versus the jejunal flap. Plast Reconstr Surg. 2006;117(3):968-974.

Yu P, Robb GL. Pharyngoesophageal reconstruction with the anterolateral thigh flap: a clinical and functional outcomes study. Plast Reconstr Surg. 2005;116(7):1845-1855.

Established the beneficial role of surgical resection as a treatment strategy for multiple brain metastases; until this definitive work, surgery was not indicated.

Bindal RK, Sawaya R, Leavens ME, Lee JJ. Surgical treatment of multiple brain metastases. J Neurosurg. 1993;79(2):210-216.