Journal of Clinical Oncology, Vol 20, Issue 17
(September), 2002: 3586-3591
© 2002 American Society for Clinical Oncology
Molecular Targeting of Platelet-Derived Growth Factor B by Imatinib Mesylate in a Patient With Metastatic Dermatofibrosarcoma Protuberans
By Brian P. Rubin,
Scott M. Schuetze,
Janet F. Eary,
Thomas H. Norwood,
Sohail Mirza,
Ernest U. Conrad,
James D. Bruckner
From the Departments of Pathology, Medicine, Nuclear Medicine, and Orthopedics, University of Washington Medical Center, Seattle, WA.
The first two authors contributed equally to this article.Address reprint requests to Brian P. Rubin, MD, PhD, Department of Anatomic Pathology, University of Washington Medical Center, Box 356100, 1959 NE Pacific St, Seattle, WA 98195; email: bprubin{at}u.washington.edu
 |
ABSTRACT
|
|---|
PURPOSE: Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate.
PATIENTS AND METHODS: A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation.
RESULTS: The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate.
CONCLUSION: Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.
|
INTRODUCTION
|
|---|
DERMATOFIBROSARCOMA protuberans is an uncommon, low-grade, fibrohistiocytic tumor of intermediate malignant potential.1 It usually occurs in adults, without sex or racial predilection. Lesions tend to arise in the dermis and subcutis of the trunk, groin, or lower extremity, and less commonly in the head and neck. They are extremely infiltrative and thus have a high propensity for local recurrence. There is a small but definite risk of metastasis.2 Rarely, dermatofibrosarcoma protuberans tumors transform into high-grade fibrosarcomas.3 Histologically, they are cellular spindle cell neoplasms with a prominent storiform architectural pattern and infrequent mitotic figures. Immunohistochemically, they uniformly express CD34 antigen.4 Most dermatofibrosarcoma protuberans tumors possess either ring chromosomes or translocations that result in fusion of 17q22 and 22q13, the location of the COL1A1 and PDGFB genes, respectively.5,6 Rarely, the 22q13 region is fused to other regions of the genome besides 17q22, but presumably, the oncogenic mechanism is the same.7
The COL1A1 gene encodes the  1(I) chain of type I collagen, whereas the PDGFB gene encodes the B-chain of platelet-derived growth factor (PDGFB). The chromosomal translocation results in expression of a COL1A1-PDGFB fusion protein that is processed to mature PDGFB and exerts its pathogenic effect through autocrine or paracrine interaction with PDGFB receptor present on the cell surface of dermatofibrosarcoma protuberans.8
Imatinib mesylate (STI-571, Gleevec; Novartis Pharmaceuticals, East Hanover, NJ), a small-molecule adenosine triphosphate analog, selectively inhibits PDGFB, ABL, and KIT kinases, and is effective in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, which have aberrantly activated ABL and KIT kinases, respectively.9-11 Exposure of primary cultures of dermatofibrosarcoma protuberans to imatinib mesylate in vitro has been shown to inhibit cell growth.12 However, xenograft models of dermatofibrosarcoma protuberans treated with imatinib mesylate have not demonstrated tumor regression.13 We report here the first known treatment and response of a patient with metastatic, inoperable dermatofibrosarcoma protuberans using imatinib mesylate.
|
PATIENTS AND METHODS
|
|---|
Patient Selection
A 25-year-old man with a history of dermatofibrosarcoma protuberans of the right thigh that had been treated by wide local resection in June 1995 presented to medical attention in May 2001 with progressive back pain over months, and radicular paresthesias and weakness in his legs over a 3-week period. He was unable to walk because of severe weakness in his psoas and quadriceps muscles. A 21 x 6 x 8-cm, biopsy-confirmed, paravertebral metastatic dermatofibrosarcoma protuberans that extended through the right L1 to L2 neural foramina and along the thecal sac from T12 to L3 was seen on magnetic resonance imaging (MRI) (Fig 1C). The tumor was inoperable because of the large size and location. He was treated with methylprednisolone but experienced only minor improvement in the paresthesias and weakness after 5 days of therapy.
View larger version (160K):
[in this window]
[in a new window]
|
Fig 1. Positron emission tomography scan with elevated FDG uptake before therapy (arrow, A), and background levels 2 weeks later (arrow, B). MRI studies before therapy (C), and 16 days (D) and 4 months (E) after initiation of therapy reveal a reduction in tumor size and loss of enhancement.
|
|
The patient provided informed consent to treatment using 400 mg of imatinib mesylate bid, and steroid therapy was discontinued. The dose of imatinib mesylate was determined on the basis of clinical experience in patients treated for advanced gastrointestinal stromal tumors.10,14 Tolerance to the chemotherapy, toxicity from treatment, and response were assessed at monthly intervals using interval history, physical examination, determination of the complete blood counts, serum chemistries, hepatic function tests, and MRI.
[18F]Fluorodeoxyglucose Positron Emission Tomography
Standard clinical positron emission tomography using [18F]fluorodeoxyglucose (FDG) was performed before treatment with imatinib mesylate and 2 weeks later (Figs 1A and 1B). Images were obtained from a dedicated positron emission tomography scanner and were attenuation corrected.
Immunohistochemistry
Immunohistochemistry was performed with antibodies to CD34 (monoclonal MY10, 1:100, microwave pretreatment; Becton Dickinson, Bedford, MA), and KIT (CD117) (polyclonal, 1:2000, microwave pretreatment; Santa Cruz Biotechnology, Inc, Santa Cruz, CA). Staining was analyzed by detection with DAB (Sigma, St Louis, MO).
Cytogenetics
Cytogenetic analysis was performed according to previously published procedures.15 A fluorescent in situ hybridization study was carried out using a whole chromosome 17 paint probe (Oncor, Gaithersburg, MD, Catalogue no. p5217-DIG) according to procedures described in the manufacturer’s catalogue.
|
RESULTS
|
|---|
The patient experienced substantial reduction in back pain and improvement in strength within 2 weeks of initiating imatinib mesylate therapy and was able to walk out of the hospital. Five weeks later, he had a normal neurologic examination. The clinical improvement in symptoms and strength coincided with a decrease in tumor uptake of FDG. Before therapy with imatinib mesylate the tumor showed a maximum standard uptake value of 3.0 (Fig 1A), and imaging after 2 weeks of treatment showed a maximum standard uptake value similar to muscle background (Fig 1B).
At the time of presentation in May 2001, an MRI scan demonstrated a 21 (craniocaudal) x 6 (transverse) x 8 (anteroposterior) cm right-sided paraspinous soft tissue mass that extended from above the diaphragm to the inferior border of the third lumbar vertebra (Fig 1C). The mass extended through the L1 to L2 neural foramina and severely compressed the spinal cord from L1 through L3. Two weeks after initiating imatinib mesylate therapy, imaging demonstrated regression in the size of the tumor to 20 x 4.3 x 5.3 cm and resolution of compression and enhancement of the thecal sac and spinal cord. One month later, repeat imaging revealed further reduction in the tumor size to 20 x 2.9 x 3.5 cm and no intradural or extradural enhancement (Fig 1D). Before surgical resection, the lesion measured 17 x 2.5 x 2.5 cm, which was a greater than 75% reduction in tumor volume (Fig 1E). Because of the uncertainty of long-term control of dermatofibrosarcoma protuberans using imatinib mesylate and the substantial regression in tumor volume, the mass was resected in two stages. In the first procedure, release of the tumor from the posterior aspect of the spine extending from T8 to L3 and removal of the tumor from the dura was performed. Resection of the entire mass was performed through a thoracolumbar approach 1 week later. The patient’s postoperative recovery was uneventful.
The toxicity of this therapy was minimal and consisted of National Cancer Institute grade 1 leukopenia, neutropenia, and thrombocytopenia; grade 1 nausea and gastritis; and grade 1 elevation of alkaline phosphatase and the transaminases. These mild toxicities are similar to effects seen in patients treated with imatinib mesylate for gastrointestinal stromal tumors.10,14
The patient’s primary thigh mass, which was resected at a community hospital, was obtained for review. The paraffin-embedded blocks had been destroyed; therefore, ancillary studies were not performed. The primary lesion measured 1.6 cm in greatest dimension, and involved the deep dermis and subcutaneous tissue; 2 cm of normal tissue surrounded the lesion. The lesion showed the typical histologic features of dermatofibrosarcoma protuberans and consisted of a cellular, monomorphic proliferation of bland spindle cells with a storiform architectural pattern (Fig 2A). Focally, the lesion exhibited a myxoid stroma, which is occasionally seen in dermatofibrosarcoma protuberans. There was prominent entrapment of fat at the edge of the lesion (Fig 2C). Mitotic figures numbered up to five per 10 high-power fields; there was no necrosis, cytologic atypia, or pleomorphism.
View larger version (154K):
[in this window]
[in a new window]
|
Fig 2. Histologic appearance of primary lesion (A, x400) and paravertebral metastasis (B, x400). Primary lesion showing entrapment of adipose tissue (C, x200). Diffuse CD34 immunoreactivity in metastasis (D, x400). Histologic appearance of resection specimen after imatinib mesylate therapy (E, x200) and showing absence of CD34 staining (blood vessels are positive) (F, x200).
|
|
The core needle biopsy of the paravertebral mass was histologically identical to the primary neoplasm (Fig 2B). Mitotic figures numbered up to four per 10 high-power fields. Immunohistochemically, the neoplastic cells were diffusely and strongly positive for CD34 (Fig 2D) and negative for KIT (CD117).
The resection specimen was a well-circumscribed, bilobed mass, measuring 16.5 cm in greatest dimension, and was adherent to a portion of the vertebral column with attached ribs. The tumor had a fibrous cut surface with focal areas of calcification. Histologically, the lesional tissue consisted of extremely hypocellular fibrovascular tissue with scattered foamy histiocytes (Fig 2E). No viable tumor was identified. Immunohistochemical studies failed to identify any CD34+ cells within the fibrovascular tissue, indicating that the tumor cells had been completely replaced by scar tissue after tumor cell death (Fig 2F).
Multiple structural and numeric clonal aberrations were observed in 12 of 20 cells that were analyzed. The karyotype can be summarized as follows: 49,XY,del(3)(p13), +add(5)(p14),ins(7,?)(p?13,??),+8,+16,add(22)(q13.3). Notably, neither ring chromosomes nor a t(17;22) were identified. Instead, a translocation involving 22q13 (the region of the PDGFB gene) with an unidentified translocation partner was seen. Fluorescent in situ hybridization with a chromosome 17 paint probe revealed that the translocation partner was not chromosome 17, suggesting that PDGFB may have been aberrantly expressed through gene fusion involving an alternative translocation partner or a cryptic t(17;22) translocation.
|
DISCUSSION
|
|---|
Imatinib mesylate selectively inhibits the tyrosine kinase activity of ABL, KIT, and PDGFB tyrosine kinases at a concentration easily achieved with oral administration of the drug.9 Cytogenetic studies of dermatofibrosarcoma protuberans have consistently revealed abnormalities involving the PDGFB locus, indicating that activation of the PDGFB receptor tyrosine kinase pathway is central to the pathogenesis of this lesion. The critical role of the PDGFB receptor and the potential therapeutic effect of disruption of this growth stimulus is supported by in vitro and in vivo experiments using fibroblasts transfected with the COL1A1/PDGFB fusion construct. Because PDGFB receptor activation seems to be vital to tumor cell growth, we reasoned that imatinib mesylate might be effective in the treatment of dermatofibrosarcoma protuberans. This is important because even though dermatofibrosarcoma protuberans rarely metastasizes, it may recur repeatedly, leading to disfiguring surgery.2 Furthermore, although radiation therapy may be of use in the local control of recurrent dermatofibrosarcoma protuberans, chemotherapy has not been helpful in controlling either metastatic or locally recurrent disease.16,17 In addition, fibrosarcomatous dermatofibrosarcoma protuberans, which retains the COL1A1/PDGFB gene fusion, is an aggressive neoplasm, with the capacity for widespread metastasis, often leading to death, and thus also represents a potential target for imatinib mesylate therapy. Our result indicates that inhibition of the PDGFB receptor kinase by imatinib mesylate is a potentially effective therapy in the management of locally recurrent/metastatic dermatofibrosarcoma protuberans, and may be useful in the treatment of fibrosarcomatous dermatofibrosarcoma protuberans.
Our patient presented with unresectable metastatic dermatofibrosarcoma protuberans that responded to bid imatinib mesylate therapy as measured by a reduction of tumor volume of greater than 75%. It is unlikely that a 5-day course of methylprednisolone had a long-lasting effect. The antitumor activity of imatinib mesylate in this case is also supported by the decrement in FDG uptake of the tumor within 2 weeks of therapy. A rapid reduction in FDG uptake has also been seen in gastrointestinal stromal tumors treated with imatinib mesylate. Most important, histologic assessment of the resected tumor mass revealed complete replacement of dermatofibrosarcoma protuberans by hypocellular fibrovascular tissue (scar), consistent with a complete histologic response. This emphasizes the point that anatomic imaging studies may underestimate the response of sarcomas to therapy.18
We chose to treat this patient with 400 mg of imatinib mesylate bid because this was the previously determined maximum-tolerated dose and there were no data available regarding the dose-response relationship for imatinib mesylate and dermatofibrosarcoma protuberans.14 Furthermore, a murine model of transplanted fibroblasts transformed by a COL1A1/PDGFB fusion construct suggested that inhibition of PDGFB receptor phosphorylation is maximal at 5 to 6 hours and returns to pretreatment levels within 16 hours after oral administration of imatinib mesylate.13 A bid to tid administration schedule of imatinib mesylate for treatment of dermatofibrosarcoma protuberans may be more efficacious than a once-a-day schedule.
Imatinib mesylate has already been shown to be effective in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors.10,11,14 This is because the drug targets specific molecular pathways that are known to be central to the pathogenesis of these tumors. The great success that imatinib mesylate has shown in these tumors has led some clinicians to treat other neoplasms that are not susceptible to standard chemotherapy with this drug. We would like to emphasize that use of imatinib mesylate in the treatment of neoplasms in which the pathogenesis is not clearly dependent on activation of a susceptible tyrosine kinase is unlikely to be effective, and at best should be considered investigational.
In this report, imatinib mesylate has been shown to be effective in the treatment of dermatofibrosarcoma protuberans, which owes its pathogenesis to the central role of PDGFB receptor kinase activation through induced expression of the ligand. This report demonstrates that inhibition of the PDGFB receptor with imatinib mesylate can have profound antitumor effects in at least one type of human solid tumor. The dramatic response of dermatofibrosarcoma protuberans in our patient to treatment with imatinib mesylate should help the rational development of larger studies in individuals with inoperable or metastatic dermatofibrosarcoma protuberans, fibrosarcomatous dermatofibrosarcoma protuberans, or other solid tumors dependent on PDGFB receptor activation.
|
REFERENCES
|
|---|
1. Weiss SW, Goldblum JR: Fibrohistiocytic tumors of intermediate malignancy, in Weiss SW, Goldblum JR (eds): Enzinger and Weiss’s Soft Tissue Tumors. St. Louis, MO, Mosby, 2001, pp 491-506
2. McPeak CJ, Cruz T, Nicastri AD: Dermatofibrosarcoma protuberans: An analysis of 86 cases—Five with metastasis. Ann Surg 166: 803-816, 1967[Medline]
3. Mentzel T, Beham A, Katenkamp D, et al: Fibrosarcomatous ("high-grade") dermatofibrosarcoma protuberans: Clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. Am J Surg Pathol 22: 576-587, 1998[CrossRef][Medline]
4. Aiba S, Tabata N, Ishii H, et al: Dermatofibrosarcoma protuberans is a unique fibrohistiocytic tumour expressing CD34. Br J Dermatol 127: 79-84, 1992[CrossRef][Medline]
5. Simon MP, Pedeutour F, Sirvent N, et al: Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet 15: 95-98, 1997[CrossRef][Medline]
6. O’Brien KP, Seroussi E, Dal Cin P, et al: Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas. Genes Chromosomes Cancer 23: 187-193, 1998[CrossRef][Medline]
7. Sonobe H, Furihata M, Iwata J, et al: Dermatofibrosarcoma protuberans harboring t(9;22)(q32;q12.2). Cancer Genet Cytogenet 110: 14-18, 1999[CrossRef][Medline]
8. Shimizu A, O’Brien KP, Sjoblom T, et al: The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 59: 3719-3723, 1999[Abstract/Free Full Text]
9. Buchdunger E, Cioffi CL, Law N, et al: Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295: 139-145, 2000[Abstract/Free Full Text]
10. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344: 1052-1056, 2001[Free Full Text]
11. Mauro MJ, Druker BJ: STI571: Targeting BCR-ABL as therapy for CML. Oncologist 6: 233-238, 2001[Abstract/Free Full Text]
12. Greco A, Fusetti L, Villa R, et al: Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans. Oncogene 17: 1313-1319, 1998[CrossRef][Medline]
13. Sjoblom T, Shimizu A, O’Brien KP, et al: Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res 61: 5778-5783, 2001[Abstract/Free Full Text]
14. van Oostertom AT, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358: 1421-1423, 2001[CrossRef][Medline]
15. O’Malley DP, Opheim KE, Barry TS, et al: Chromosomal changes in a dedifferentiated chondrosarcoma: A case report and review of the literature. Cancer Genet Cytogenet 124: 105-111, 2001[CrossRef][Medline]
16. Suit H, Spiro I, Mankin HJ, et al: Radiation in management of patients with dermatofibrosarcoma protuberans. J Clin Oncol 14: 2365-2369, 1996[Abstract]
17. Rutgers EJ, Kroon BB, Albus-Lutter CE, et al: Dermatofibrosarcoma protuberans: Treatment and prognosis. Eur J Surg Cancer 18: 241-248, 1992
18. Casper ES, Gaynor JJ, Harrison LB, et al: Preoperative and postoperative adjuvant combination chemotherapy for adults with high grade soft tissue sarcoma. Cancer 73: 1644-1651, 1994.[CrossRef][Medline]
Submitted January 4, 2002;
accepted May 28, 2002.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
R. G. Maki, D. R. D'Adamo, M. L. Keohan, M. Saulle, S. M. Schuetze, S. D. Undevia, M. B. Livingston, M. M. Cooney, M. L. Hensley, M. M. Mita, et al.
Phase II Study of Sorafenib in Patients With Metastatic or Recurrent Sarcomas
J. Clin. Oncol.,
July 1, 2009;
27(19):
3133 - 3140.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. George, P. Merriam, R. G. Maki, A. D. Van den Abbeele, J. T. Yap, T. Akhurst, D. C. Harmon, G. Bhuchar, M. M. O'Mara, D. R. D'Adamo, et al.
Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas
J. Clin. Oncol.,
July 1, 2009;
27(19):
3154 - 3160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich, H. Joensuu, G. D. Demetri, C. L. Corless, J. Apperley, J. A. Fletcher, D. Soulieres, S. Dirnhofer, A. Harlow, A. Town, et al.
Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases
Clin. Cancer Res.,
May 1, 2008;
14(9):
2717 - 2725.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Puttini, S. Redaelli, L. Moretti, S. Brussolo, R. H Gunby, L. Mologni, E. Marchesi, L. Cleris, A. Donella-Deana, P. Drueckes, et al.
Characterization of compound 584, an Abl kinase inhibitor with lasting effects
Haematologica,
May 1, 2008;
93(5):
653 - 661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. McArthur
Dermatofibrosarcoma Protuberans: Recent Clinical Progress
Ann. Surg. Oncol.,
October 1, 2007;
14(10):
2876 - 2886.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Maire, S. Fraitag, L. Galmiche, F. Keslair, N. Ebran, M.-J. Terrier-Lacombe, Y. de Prost, and F. Pedeutour
A Clinical, Histologic, and Molecular Study of 9 Cases of Congenital Dermatofibrosarcoma Protuberans
Arch Dermatol,
February 1, 2007;
143(2):
203 - 210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Arteaga
Can Trastuzumab Be Effective Against Tumors With Low HER2/Neu (ErbB2) Receptors?
J. Clin. Oncol.,
August 10, 2006;
24(23):
3722 - 3725.
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Potapova, A. D. Laird, M. A. Nannini, A. Barone, G. Li, K. G. Moss, J. M. Cherrington, and D. B. Mendel
Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248
Mol. Cancer Ther.,
May 1, 2006;
5(5):
1280 - 1289.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. West, B. P. Rubin, M. A. Miller, S. Subramanian, G. Kaygusuz, K. Montgomery, S. Zhu, R. J. Marinelli, A. De Luca, E. Downs-Kelly, et al.
A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells
PNAS,
January 17, 2006;
103(3):
690 - 695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Reardon, M. J. Egorin, J. A. Quinn, J. N. Rich Sr, I. Gururangan, J. J. Vredenburgh, A. Desjardins, S. Sathornsumetee, J. M. Provenzale, J. E. Herndon II, et al.
Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme
J. Clin. Oncol.,
December 20, 2005;
23(36):
9359 - 9368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. K. Dy, A. A. Miller, S. J. Mandrekar, M.-C. Aubry, R. M. Langdon Jr., R. F. Morton, S. E. Schild, J. R. Jett, and A. A. Adjei
A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study
Ann. Onc.,
November 1, 2005;
16(11):
1811 - 1816.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Fiore, R. Miceli, C. Mussi, S. Lo Vullo, L. Mariani, L. Lozza, P. Collini, P. Olmi, P. G. Casali, and A. Gronchi
Dermatofibrosarcoma Protuberans Treated at a Single Institution: A Surgical Disease With a High Cure Rate
J. Clin. Oncol.,
October 20, 2005;
23(30):
7669 - 7675.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. B. Koon, G. J. Bubley, L. Pantanowitz, D. Masiello, B. Smith, K. Crosby, J. Proper, W. Weeden, T. E. Miller, P. Chatis, et al.
Imatinib-Induced Regression of AIDS-Related Kaposi's Sarcoma
J. Clin. Oncol.,
February 10, 2005;
23(5):
982 - 989.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. McArthur, G. D. Demetri, A. van Oosterom, M. C. Heinrich, M. Debiec-Rychter, C. L. Corless, Z. Nikolova, S. Dimitrijevic, and J. A. Fletcher
Molecular and Clinical Analysis of Locally Advanced Dermatofibrosarcoma Protuberans Treated With Imatinib: Imatinib Target Exploration Consortium Study B2225
J. Clin. Oncol.,
February 1, 2005;
23(4):
866 - 873.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Sihto, M. Sarlomo-Rikala, O. Tynninen, M. Tanner, L. C. Andersson, K. Franssila, N. N. Nupponen, and H. Joensuu
KIT and Platelet-Derived Growth Factor Receptor Alpha Tyrosine Kinase Gene Mutations and KIT Amplifications in Human Solid Tumors
J. Clin. Oncol.,
January 1, 2005;
23(1):
49 - 57.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Th. Went, S. Dirnhofer, M. Bundi, M. Mirlacher, P. Schraml, S. Mangialaio, S. Dimitrijevic, J. Kononen, A. Lugli, R. Simon, et al.
Prevalence of KIT Expression in Human Tumors
J. Clin. Oncol.,
November 15, 2004;
22(22):
4514 - 4522.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. H. Shih, C. Dai, X. Hu, M. K. Rosenblum, J. A. Koutcher, and E. C. Holland
Dose-Dependent Effects of Platelet-Derived Growth Factor-B on Glial Tumorigenesis
Cancer Res.,
July 15, 2004;
64(14):
4783 - 4789.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Guilhot
Indications for Imatinib Mesylate Therapy and Clinical Management
Oncologist,
June 1, 2004;
9(3):
271 - 281.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Furuhashi, T. Sjoblom, A. Abramsson, J. Ellingsen, P. Micke, H. Li, E. Bergsten-Folestad, U. Eriksson, R. Heuchel, C. Betsholtz, et al.
Platelet-Derived Growth Factor Production by B16 Melanoma Cells Leads to Increased Pericyte Abundance in Tumors and an Associated Increase in Tumor Growth Rate
Cancer Res.,
April 15, 2004;
64(8):
2725 - 2733.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bono, A. Krause, M. von Mehren, M. C. Heinrich, C. D. Blanke, S. Dimitrijevic, G. D. Demetri, and H. Joensuu
Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib
Blood,
April 15, 2004;
103(8):
2929 - 2935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Peng, C. Dutreix, G. Mehring, M. J. Hayes, M. Ben-Am, M. Seiberling, R. Pokorny, R. Capdeville, and P. Lloyd
Absolute Bioavailability of Imatinib (Glivec(R)) Orally versus Intravenous Infusion
J. Clin. Pharmacol.,
February 1, 2004;
44(2):
158 - 162.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Sawyers
Opportunities and challenges in the development of kinase inhibitor therapy for cancer
Genes & Dev.,
December 15, 2003;
17(24):
2998 - 3010.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich, C. L. Corless, G. D. Demetri, C. D. Blanke, M. von Mehren, H. Joensuu, L. S. McGreevey, C.-J. Chen, A. D. Van den Abbeele, B. J. Druker, et al.
Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor
J. Clin. Oncol.,
December 1, 2003;
21(23):
4342 - 4349.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Linn, R. B. West, J. R. Pollack, S. Zhu, T. Hernandez-Boussard, T. O. Nielsen, B. P. Rubin, R. Patel, J. R. Goldblum, D. Siegmund, et al.
Gene Expression Patterns and Gene Copy Number Changes in Dermatofibrosarcoma Protuberans
Am. J. Pathol.,
December 1, 2003;
163(6):
2383 - 2395.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. E. Johnson, T. Fischer, B. Fischer, D. Dunlop, D. Rischin, S. Silberman, M. O. Kowalski, D. Sayles, S. Dimitrijevic, C. Fletcher, et al.
Phase II Study of Imatinib in Patients with Small Cell Lung Cancer
Clin. Cancer Res.,
December 1, 2003;
9(16):
5880 - 5887.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Tanvetyanon and S. Nand
Overcoming Recurrent Cutaneous Reactions from Imatinib Using Once-Weekly Dosing
Ann. Pharmacother.,
December 1, 2003;
37(12):
1818 - 1820.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Druker
Imatinib As a Paradigm of Targeted Therapies
J. Clin. Oncol.,
December 1, 2003;
21(90230):
239s - 245.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Heinrich and C. L. Corless
In Reply:
J. Clin. Oncol.,
October 15, 2003;
21(20):
3886 - 3887.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Cruz III, B. P. Rubin, D. Wilson, A. Town, A. Schroeder, A. Haley, T. Bainbridge, M. C. Heinrich, and C. L. Corless
Absence of BRAF and NRAS Mutations in Uveal Melanoma
Cancer Res.,
September 15, 2003;
63(18):
5761 - 5766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Pietras, M. Stumm, M. Hubert, E. Buchdunger, K. Rubin, C.-H. Heldin, P. McSheehy, M. Wartmann, and A. Ostman
STI571 Enhances the Therapeutic Index of Epothilone B by a Tumor-selective Increase of Drug Uptake
Clin. Cancer Res.,
September 1, 2003;
9(10):
3779 - 3787.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Weitz, C. R. Antonescu, and M. F. Brennan
Localized Extremity Soft Tissue Sarcoma: Improved Knowledge With Unchanged Survival Over Time
J. Clin. Oncol.,
July 15, 2003;
21(14):
2719 - 2725.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kurzrock, H. M. Kantarjian, B. J. Druker, and M. Talpaz
Philadelphia Chromosome-Positive Leukemias: From Basic Mechanisms to Molecular Therapeutics
Ann Intern Med,
May 20, 2003;
138(10):
819 - 830.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Sausville
Is Another Bcr-Abl Inhibitor Needed for Chronic Myelogenous Leukemia?
Clin. Cancer Res.,
April 1, 2003;
9(4):
1233 - 1234.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Nahta, G. N. Hortobagyi, and F. J. Esteva
Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention
Oncologist,
February 1, 2003;
8(1):
5 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Sawyers
Imatinib GIST Keeps Finding New Indications: Successful Treatment of Dermatofibrosarcoma Protuberans by Targeted Inhibition of the Platelet-Derived Growth Factor Receptor
J. Clin. Oncol.,
September 1, 2002;
20(17):
3568 - 3569.
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
