Gastrointestinal Stromal Tumors Treatment & Management
- Author: Nancy S Behazin, MD; Chief Editor: BS Anand, MD more...
Imatinib is a selective small molecule inhibitor of a family of structurally similar tyrosine kinase signaling enzymes, including KIT, PDGFRA, and chronic myelogenous leukemia specific BCR-ABL protein. In laboratory studies, imatinib was shown to inhibit proliferation of BCR-ABL leukemic cells and GIST cells with KIT mutations.
Imatinib mesylate is indicated in patients with advanced GISTs. It is indicated as adjuvant therapy post complete surgical resection in patients with tumors that are stratified to be high risk (see Prognosis) and as neoadjuvant therapy, with the goal of tumor shrinkage prior to surgical resection.
Demetri et al in 2002 randomly assigned patients with metastatic or unresectable GIST to either 400 mg or 600 mg of imatinib. Imatinib induced an objective response in more than half of the patients. The early favorable results of this study led the FDA to approve imatinib for the treatment of KIT-positive unresectable or metastatic GIST in February 2002.
DeMatteo et al in 2009, in a randomized, double-blind, placebo-controlled study showed adjuvant imatinib therapy to be safe and to improve recurrence-free survival compared with placebo after resection of a gastrointestinal tumor.
Joensuu et al in 2012, in a randomized, placebo-controlled trial showed that patients assigned to 36 months of imatinib had longer recurrence-free survival compared with those assigned to 12 months of treatment (hazard ratio, 0.46; 95% confidence interval, 0.32-0.65; P < .001; 5-year recurrence-free survival, 65.6% vs 47.9%, respectively). In some patients, imatinib fails immediately after initiation (primary resistance). Some patients initially show response to imatinib but later develop progressive disease (secondary resistance).
Imatinib resistance may be managed by increasing the dose to 800 mg per day or switching directly to sunitinib.
Sunitinib is another tyrosine kinase receptor inhibitor that is less specific than imatinib. Sunitinib inhibits KIT and PDGFR as well as vascular endothelial growth factor receptors (VEGFR1-3), Fms-related tyrosine kinase 3, colony-stimulating factor (CSF), and RET. Thus, sunitinib has both antiangiogenic and anti-tumor potential.
Demetri et al in 2006 conducted a phase III double-blind study evaluating sunitinib versus placebo in patients with advanced GIST who were intolerant or refractory to imatinib. The time to disease progression was four times longer in those receiving sunitinib (27.3 vs 6.4 weeks for placebo; P < .0001). Progression-free survival and overall survival were better for patients treated with sunitinib.
In January 2006, the FDA approved sunitinib as a second-line agent for patients with advanced GIST.
George et al in 2009 evaluated the safety and efficacy of sunitinib in patients with advanced GIST after imatinib failure. Results suggested that continuous daily dosing of sunitinib was an effective alternative with acceptable safety for patients with imatinib resistant GIST.
Regorafenib (Stivarga) received FDA approval for locally advanced, unresectable GISTs that no longer respond to imatinib or sunitinib. The pivotal phase III GRID trial of 199 patients with metastatic or unresectable GIST showed that regorafenib plus best supportive care (BSC) significantly improved progression-free survival (PFS) compared to placebo plus BSC. Patients were treated with BSC and randomized in a 2:1 ratio to either regorafenib (160 mg daily for 3 weeks followed by a 1-week break) or placebo. Median PFS was 4.8 months for regorafenib and 0.9 months for placebo.[33, 34]
Investigational agents for patients with progressive disease despite imatinib and sunitinib use include the second-generation tyrosine kinase inhibitors: sorafenib, dasatinib, and nilotinib.
The management of GISTs requires the participation of a multidisciplinary team. The team should include a surgeon, gastroenterologist, and medical oncologist.
Surgery is the definitive therapy for patients with GISTs. Radical and complete surgical extirpation offers the only chance for cure. Surgery is also indicated in symptomatic patients with locally advanced or metastatic disease. Debulking large lesions is helpful when adjuvant therapy with imatinib mesylate is contemplated.
In 2003, Wu et al published their experience with 57 patients who underwent surgical treatment of GISTs from 1995-2002. Twenty-eight patients (49%) underwent surgery with curative intent. The remainder were referred to the authors with metastatic disease after undergoing operative treatment at other institutions. In the curative-intent group, resections with completely negative margins were accomplished in 22 patients (79%). In 3 of the patients with complete resections, metastatic disease was totally resected along with the primary tumor. An additional 2 patients had subsequent complete resection after favorable clinical responses to imatinib mesylate therapy. CD117 staining was positive in 96% of the resected specimens. In total, 34 patients were diagnosed with metastatic disease during the initial evaluation and treatment or at some point during follow-up. The most common sites of metastatic disease were the liver (71%) and peritoneum (53%).
The authors monitored the entire cohort for a median duration of 18 months. Twenty-three patients (40%) remained alive and free of disease. An additional 22 patients (39%) are alive with disease. Of the remainder, 7 are known to have died and 5 have been lost to follow-up. Treatment with imatinib effected disease stabilization or regression in 22 (85%) of the 26 treated, with a median duration of response of 19 months.
The authors concluded that complete resection with negative margins is still the only potentially curative treatment of GISTs. Furthermore, imatinib therapy for metastatic disease is associated with good clinical response rates, but the true therapeutic efficacy of this drug will not be known until prospective trials are completed.
In 2003, Besana-Ciani et al reported on 19 patients with GISTs who underwent surgical resection. They were able to achieve complete resection in 78.9% of patients in this series. The mean tumor size was 8.4 cm. These patients received long-term follow-up. Using the Fletcher et al histologic classification, tumors were divided into 2 groups. Tumors classified as very low, low, and intermediate risk comprised one group. The second consisted of tumors classified as high risk. The 5-year survival rates were 63% in the former group and 34% in the latter group. As might be expected, complete resection was also a significant predictor of superior survival compared with incomplete resection. These authors also concluded that radical complete resection offers the only chance for long-term survival in patients with GISTs.
Laparoscopic resection has improved and is a more frequently considered option for patients with a GIST. Chen et al studied 58 patients diagnosed with GISTs from 2005-2010. Of these, 16 underwent laparoscopic surgery and 42 underwent open surgery. It was concluded that laparoscopic surgery was technically possible for GISTs no larger than 5 cm located at the stomach and small bowel. The patients benefited from fewer days until resuming a normal diet, shorter postoperative hospital stays, and less analgesia use. The patients experienced the same short-term oncology result as the patients who underwent open surgery.
In 2012, El-Gendi et al reported on 12 patients who underwent limited duodenal resection for primary nonmetastatic duodenal GIST since 2002. The authors concluded that limited resection is a reliable option for disease-free survival depending on tumor size, adjacent organ involvement, and location.
Preoperative imatinib should be considered if surgical morbidity would be improved by cytoreducing the size of the tumor.
Postoperative imatinib has been shown to increase recurrence-free survival after complete resection of localized GIST. In 2012, Joensuu et al showed that compared with 12 months of adjuvant imatinib, 36 months of imatinib improved recurrence free survival and overall survival of GIST patients with a high risk of GIST recurrence.
The management of GISTs requires the participation of a multidisciplinary team. The team should include a surgeon, gastroenterologist, and medical oncologist.
Cheung MC, Zhuge Y, Yang R, Koniaris LG. Disappearance of racial disparities in gastrointestinal stromal tumor outcomes. J Am Coll Surg. 2009 Jul. 209(1):7-16. [Medline].
Tran T, Davila JA, El-Serag HB. The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to 2000. Am J Gastroenterol. 2005 Jan. 100(1):162-8. [Medline].
Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol. 2006 Apr. 30(4):477-89. [Medline].
Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005 Feb 15. 103(4):821-9. [Medline].
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003 Dec 1. 21(23):4342-9. [Medline].
Ghanem N, Altehoefer C, Furtwangler A, et al. Computed tomography in gastrointestinal stromal tumors. Eur Radiol. 2003 Jul. 13(7):1669-78. [Medline].
Zhou HY, Zhang XM, Zeng NL, Jian SH, Tang W. Use of conventional MR imaging and diffusion-weighted imaging for evaluating the risk grade of gastrointestinal stromal tumors. J Magn Reson Imaging. 2012 Dec. 36(6):1395-401. [Medline].
Tateishi U, Hasegawa T, Satake M, Moriyama N. Gastrointestinal stromal tumor. Correlation of computed tomography findings with tumor grade and mortality. J Comput Assist Tomogr. 2003 Sep-Oct. 27(5):792-8. [Medline].
Shojaku H, Futatsuya R, Seto H, Tajika S, Matsunou H. Malignant gastrointestinal stromal tumor of the small intestine: radiologic-pathologic correlation. Radiat Med. 1997 May-Jun. 15(3):189-92. [Medline].
Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998 May. 152(5):1259-69. [Medline]. [Full Text].
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998 Jan 23. 279(5350):577-80. [Medline].
Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005 Jan. 29(1):52-68. [Medline].
Yamashita F, Sasatomi E, Kiyama M, et al. Radiographic observation of a case of gastrointestinal stromal tumor in stomach. Kurume Med J. 2001. 48(3):233-6. [Medline].
Stroobants S, Goeminne J, Seegers M, et al. 18FDG-Positron emission tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate (Glivec). Eur J Cancer. 2003 Sep. 39(14):2012-20. [Medline].
Pidhorecky I, Cheney RT, Kraybill WG, Gibbs JF. Gastrointestinal stromal tumors: current diagnosis, biologic behavior, and management. Ann Surg Oncol. 2000 Oct. 7(9):705-12. [Medline].
Chak A, Canto MI, Rosch T, et al. Endosonographic differentiation of benign and malignant stromal cell tumors. Gastrointest Endosc. 1997 Jun. 45(6):468-73. [Medline].
Belloni M, De Fiori E, Mazzarol G, Curti A, Crosta C. Endoscopic ultrasound and Computed Tomography in gastric stromal tumours. Radiol Med. 2002 Jan-Feb. 103(1-2):65-73. [Medline].
Gordon BM, Herlong J, Uflacker R, Gordon L. Recurrent lower gastrointestinal hemorrhage: ileal neoplasm diagnosed by scintigraphy with Tc 99m red blood cells and angiography. South Med J. 1996 Dec. 89(12):1204-7. [Medline].
Au VW, Peh WC. Clinics in diagnostic imaging (16). Lower gastrointestinal bleeding caused by ileal tumour. Singapore Med J. 1996 Aug. 37(4):434-7. [Medline].
Nakagawa M, Akasaka Y, Kanai T, et al. Extragastrointestinal stromal tumor of the greater omentum: case report and review of the literature. Hepatogastroenterology. 2003 May-Jun. 50(51):691-5. [Medline].
Suzuki K, Kaneko G, Kubota K, et al. Malignant tumor, of the gastrointestinal stromal tumor type, in the greater omentum. J Gastroenterol. 2003. 38(10):985-8. [Medline].
Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002 May. 33(5):459-65. [Medline].
Koh Y, Lee HE, Oh DY, et al. The lack of CD34 expression in gastrointestinal stromal tumors is related to cystic degeneration following imatinib use. Jpn J Clin Oncol. 2012 Nov. 42(11):1020-7. [Medline].
Woodall CE 3rd, Brock GN, Fan J, et al. An evaluation of 2537 gastrointestinal stromal tumors for a proposed clinical staging system. Arch Surg. 2009 Jul. 144(7):670-8. [Medline].
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15. 347(7):472-80. [Medline].
Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009 Mar 28. 373(9669):1097-104. [Medline].
Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012 Mar 28. 307(12):1265-72. [Medline].
Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010 Apr. 8 Suppl 2:S1-41; quiz S42-4. [Medline].
Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14. 368(9544):1329-38. [Medline].
George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer. 2009 Jul. 45(11):1959-68. [Medline].
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26. 381(9863):295-302. [Medline].
Chustecka Z. Regorafenib Approved for Gastrointestinal Stromal Tumors. Available at http://www.medscape.com/viewarticle/779854. Accessed: March 5, 2013.
Wu PC, Langerman A, Ryan CW, Hart J, Swiger S, Posner MC. Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era. Surgery. 2003 Oct. 134(4):656-65; discussion 665-6. [Medline].
Besana-Ciani I, Boni L, Dionigi G, Benevento A, Dionigi R. Outcome and long term results of surgical resection for gastrointestinal stromal tumors (GIST). Scand J Surg. 2003. 92(3):195-9. [Medline].
Chen YH, Liu KH, Yeh CN, et al. Laparoscopic resection of gastrointestinal stromal tumors: safe, efficient, and comparable oncologic outcomes. J Laparoendosc Adv Surg Tech A. 2012 Oct. 22(8):758-63. [Medline].
El-Gendi A, El-Gendi S, El-Gendi M. Feasibility and oncological outcomes of limited duodenal resection in patients with primary nonmetastatic duodenal GIST. J Gastrointest Surg. 2012 Dec. 16(12):2197-202. [Medline].
Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996 May. 2(5):561-6. [Medline].
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001 Apr 5. 344(14):1031-7. [Medline].
Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996 Jan 1. 56(1):100-4. [Medline].
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000 Aug 1. 96(3):925-32. [Medline].
Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001 Aug 16. 20(36):5054-8. [Medline].
Blanke CD, von Mehren M, Joensuu H, et al. Presented at: American Society of Clinical Oncology 37th Annual Meeting. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI571, in patients with unresectable or metastatic gastrointestinal stromal tumors expressing C-KIT. San Francisco, Calif; 2001. Vol 20: abst 2.
van Oosterom AT, Judson IR, Verweij J, et al. Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2002 Sep. 38 Suppl 5:S83-7. [Medline].
Rink L, Skorobogatko Y, Kossenkov AV, et al. Gene expression signatures and response to imatinib mesylate in gastrointestinal stromal tumor. Mol Cancer Ther. 2009 Aug. 8(8):2172-82. [Medline]. [Full Text].
Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002 May. 33(5):466-77. [Medline].
Crosby JA, Catton CN, Davis A, et al. Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database. Ann Surg Oncol. 2001 Jan-Feb. 8(1):50-9. [Medline].
Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc. 1999 Jun. 74(6):543-52. [Medline].
Conlon KC, Casper ES, Brennan MF. Primary gastrointestinal sarcomas: analysis of prognostic variables. Ann Surg Oncol. 1995 Jan. 2(1):26-31. [Medline].
Dougherty MJ, Compton C, Talbert M, Wood WC. Sarcomas of the gastrointestinal tract. Separation into favorable and unfavorable prognostic groups by mitotic count. Ann Surg. 1991 Nov. 214(5):569-74. [Medline].
Adams VR, Leggas M. Sunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors. Clin Ther. 2007 Jul. 29(7):1338-53. [Medline].
Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008 Oct. 47(10):853-9. [Medline]. [Full Text].
Al-Batran SE, Hartmann JT, Heidel F, et al. Focal progression in patients with gastrointestinal stromal tumors after initial response to imatinib mesylate: a three-center-based study of 38 patients. Gastric Cancer. 2007. 10(3):145-52. [Medline].
Alam I, Kheradmand F, Alam S, Jamil A, Wilson I, Hurley M. Laparoscopic management of acutely presenting gastrointestinal stromal tumors: a study of 9 cases and review of literature. J Laparoendosc Adv Surg Tech A. 2007 Oct. 17(5):626-33. [Medline].
An JY, Choi MG, Noh JH, et al. Gastric GIST: a single institutional retrospective experience with surgical treatment for primary disease. Eur J Surg Oncol. 2007 Oct. 33(8):1030-5. [Medline].
Antman K, Crowley J, Balcerzak SP, et al. An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol. 1993 Jul. 11(7):1276-85. [Medline].
Asakawa M, Sakamoto Y, Kajiwara T, et al. Simple segmental resection of the second portion of the duodenum for the treatment of gastrointestinal stromal tumors. Langenbecks Arch Surg. 2008 Jul. 393(4):605-9. [Medline].
Badalamenti G, Rodolico V, Fulfaro F, et al. Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. Ann Oncol. 2007 Jun. 18 Suppl 6:vi136-40. [Medline].
Berthet B, Sugarbaker TA, Chang D, Sugarbaker PH. Quantitative methodologies for selection of patients with recurrent abdominopelvic sarcoma for treatment. Eur J Cancer. 1999 Mar. 35(3):413-9. [Medline].
Blum MG, Bilimoria KY, Wayne JD, de Hoyos AL, Talamonti MS, Adley B. Surgical considerations for the management and resection of esophageal gastrointestinal stromal tumors. Ann Thorac Surg. 2007 Nov. 84(5):1717-23. [Medline].
Brodsky SV, Gimenez C, Ghosh C, Melamed M, Ramaswamy G. Estrogen and progesterone receptors expression in gastrointestinal stromal tumors and intramural gastrointestinal leiomyomas. Int J Gastrointest Cancer. 2006. 37(4):129-32. [Medline].
Bümming P, Nilsson O, Ahlman H, et al. Gastrointestinal stromal tumors regularly express synaptic vesicle proteins: evidence of a neuroendocrine phenotype. Endocr Relat Cancer. 2007 Sep. 14(3):853-63. [Medline].
Catena F, Di Battista M, Fusaroli P, et al. Laparoscopic treatment of gastric GIST: report of 21 cases and literature's review. J Gastrointest Surg. 2008 Mar. 12(3):561-8. [Medline].
Chustecka Z. Surgery Is Beneficial Even When GIST Responds to Imatinib. Medscape Medical News. January 23, 2013. Available at http://www.medscape.com/viewarticle/778033. Accessed: February 5, 2013.
Corless CL, Heinrich MC. Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008. 3:557-86. [Medline].
Desai J, Shankar S, Heinrich MC, et al. Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res. 2007 Sep 15. 13(18 Pt 1):5398-405. [Medline].
Dong C, Jun-Hui C, Xiao-Jun Y, et al. Gastrointestinal stromal tumors of the rectum: Clinical, pathologic, immunohistochemical characteristics and prognostic analysis. Scand J Gastroenterol. 2007 Oct. 42(10):1221-9. [Medline].
Eilber FC, Rosen G, Forscher C, Nelson SD, Dorey F, Eilber FR. Recurrent gastrointestinal stromal sarcomas. Surg Oncol. 2000 Aug. 9(2):71-5. [Medline].
Elias A, Ryan L, Sulkes A, Collins J, Aisner J, Antman KH. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989 Sep. 7(9):1208-16. [Medline].
Espinosa I, Lee CH, Kim MK, Rouse BT, Subramanian S, Montgomery K. A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol. 2008 Feb. 32(2):210-8. [Medline].
Fernandez A, Sanguino A, Peng Z, et al. An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest. 2007 Dec. 117(12):4044-54. [Medline]. [Full Text].
Fontana MG, Rossi E, Bassotti G, et al. Gastrointestinal stromal tumors: usefulness of immunohistochemistry, flow cytometry and fluorescence in situ hybridization. J Gastroenterol Hepatol. 2007 Nov. 22(11):1754-9. [Medline].
Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005 Dec. 41(18):2868-72. [Medline].
Graham J, Debiec-Rychter M, Corless CL, Reid R, Davidson R, White JD. Imatinib in the management of multiple gastrointestinal stromal tumors associated with a germline KIT K642E mutation. Arch Pathol Lab Med. 2007 Sep. 131(9):1393-6. [Medline].
Gutierrez JC, De Oliveira LO, Perez EA, Rocha-Lima C, Livingstone AS, Koniaris LG. Optimizing diagnosis, staging, and management of gastrointestinal stromal tumors. J Am Coll Surg. 2007 Sep. 205(3):479-91 (Quiz 524). [Medline].
Hassan I, You YN, Shyyan R, et al. Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis. Ann Surg Oncol. 2008 Jan. 15(1):52-9. [Medline].
Holdsworth CH, Badawi RD, Manola JB, et al. CT and PET: early prognostic indicators of response to imatinib mesylate in patients with gastrointestinal stromal tumor. AJR Am J Roentgenol. 2007 Dec. 189(6):W324-30. [Medline].
Issakov J, Jiveliouk I, Nachmany I, Klausner J, Merimsky O. A histopathological review of gastrointestinal related mesenchymal tumors: the hidden GIST. Isr Med Assoc J. 2007 Nov. 9(11):810-2. [Medline].
Janeway KA, Liegl B, Harlow A, et al. Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Res. 2007 Oct 1. 67(19):9084-8. [Medline].
Jeon SW, Park YD, Chung YJ, et al. Gastrointestinal stromal tumors of the stomach: endosonographic differentiation in relation to histological risk. J Gastroenterol Hepatol. 2007 Dec. 22(12):2069-75. [Medline].
Kee D, Zalcberg JR. Current and emerging strategies for the management of imatinib-refractory advanced gastrointestinal stromal tumors. Ther Adv Med Oncol. 2012 Sep. 4(5):255-70. [Medline]. [Full Text].
Kim KM, Kang DW, Moon WS, Park JB, Park CK, Sohn JH. PKCtheta expression in gastrointestinal stromal tumor. Mod Pathol. 2006 Nov. 19(11):1480-6. [Medline].
Kobayashi K, Szklaruk J, Trent JC, et al. Hepatic arterial embolization and chemoembolization for imatinib-resistant gastrointestinal stromal tumors. Am J Clin Oncol. 2009 Dec. 32(6):574-81. [Medline].
McAuliffe JC, Lazar AJ, Yang D, et al. Association of intratumoral vascular endothelial growth factor expression and clinical outcome for patients with gastrointestinal stromal tumors treated with imatinib mesylate. Clin Cancer Res. 2007 Nov 15. 13(22 Pt 1):6727-34. [Medline].
McWhinney SR, Pasini B, Stratakis CA. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med. 2007 Sep 6. 357(10):1054-6. [Medline].
Meara RS, Cangiarella J, Simsir A, Horton D, Eltoum I, Chhieng DC. Prediction of aggressiveness of gastrointestinal stromal tumours based on immunostaining with bcl-2, Ki-67 and p53. Cytopathology. 2007 Oct. 18(5):283-9. [Medline].
Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006 May. 23(2):70-83. [Medline].
Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006 Oct. 130(10):1466-78. [Medline].
Nakajima K, Yasumasa K, Endo S, et al. A versatile dual-channel carbon dioxide (CO2) insufflator for various CO2)applications. The prototype. Surg Endosc. 2006 Feb. 20(2):334-8. [Medline].
Nilsson B, Sjolund K, Kindblom LG, et al. Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST). Br J Cancer. 2007 Jun 4. 96(11):1656-8. [Medline]. [Full Text].
Nishimura J, Nakajima K, Omori T, et al. Surgical strategy for gastric gastrointestinal stromal tumors: laparoscopic vs. open resection. Surg Endosc. 2007 Jun. 21(6):875-8. [Medline].
Rubio J, Marcos-Gragera R, Ortiz MR, et al. Population-based incidenceand survival of gastrointestinal stromal tumors (GIST) in Girona, Spain. Eur J Cancer. 2007. 43:144-148.
Rutkowski P, Debiec-Rychter M, Nowecki ZI, et al. Different factors are responsible for predicting relapses after primary tumors resection and for imatinib treatment outcomes in gastrointestinal stromal tumors. Med Sci Monit. 2007 Nov. 13(11):CR515-522. [Medline].
Sepe PS, Brugge WR. A guide for the diagnosis and management of gastrointestinal stromal cell tumors. Nat Rev Gastroenterol Hepatol. 2009 Jun. 6(6):363-71. [Medline].
Sevinc A, Camci C, Yilmaz M, Buyukhatipoglu H. The diagnosis of C-kit negative GIST by PDGFRA staining: clinical, pathological, and nuclear medicine perspective. Onkologie. 2007 Dec. 30(12):645-8. [Medline].
Steigen SE, Straume B, Turbin D, et al. Clinicopathologic factors and nuclear morphometry as independent prognosticators in KIT-positive gastrointestinal stromal tumors. J Histochem Cytochem. 2008 Feb. 56(2):139-45. [Medline]. [Full Text].
Takahashi T, Nakajima K, Nishitani A, et al. An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors. Int J Clin Oncol. 2007 Oct. 12(5):369-74. [Medline].
Trent JC, Lazar AJ, Zhang W. Molecular approaches to resolve diagnostic dilemmas: the case of gastrointestinal stromal tumor and leiomyosarcoma. Future Oncol. 2007 Dec. 3(6):629-37. [Medline].
Tryggvason G, Gislason HG, Magnusson MK, Jonasson JG. Gastrointestinal stromal tumors in Iceland, 1990-2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005 Nov 1. 117(2):289-93. [Medline].
Tsukuda K, Hirai R, Miyake T, et al. The outcome of gastrointestinal stromal tumors (GISTs) after a surgical resection in our institute. Surg Today. 2007. 37(11):953-7. [Medline].