Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib

Bono, Petri; Krause, Andreas; Mehren, Margaret von; Heinrich, Michael C.; Blanke, Charles D.; Dimitrijević, Saša; Demetri, George D.; Joensuu, Heikki

doi:10.1182/blood-2003-10-3443

Cited by 55 publications

(37 citation statements)

References 33 publications

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“…30 This finding of decreased VEGF levels was observed in patients with gastrointestinal stromal tumors who received imatinib. 47 Our observations support those suggested by others that there is a secondary increase in VEGF and other proangiogenic cytokines with imatinib and other small-molecule signal inhibitors. This may be one explanation for the lack of activity of single-agent imatinib in ovarian cancer, a cancer with a known strong angiogenic drive.…”

Section: Discussionsupporting

confidence: 82%

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

Posadas

Kwitkowski²,

Kotz³

et al. 2007

Cancer

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The morphology of the telencephalon displays great diversity among different vertebrate lineages. Particularly the everted telencephalon of ray‐finned fishes shows a noticeably different morphology from the evaginated telencephalon of nonray‐finned fishes and other vertebrates. This makes the comparison between the different parts of the telencephalon of ray‐finned fishes and other vertebrates difficult. Based on neuroanatomical, neurochemical, and connectional data no consensus on the subdivisions of the adult telencephalon of ray‐finned fishes and their relation to nuclei in the telencephalon of other vertebrates has been reached yet. For tetrapods, comparative expression pattern analysis of homologous developmental genes has been a successful approach to clarify homologies between different parts of the telencephalon. In the larval zebrafish, subdivisions of the subpallium have been proposed using conserved developmental gene expression. In this study, we investigate the subdivisions of the adult zebrafish telencephalon by analyzing the expression pattern of conserved molecular marker genes. We identify the boundary between the pallium and subpallium based on the complementary expression of dlx2a, dlx5a in the subpallium and tbr1, neurod in the pallium. Furthermore, combinatorial expression of Isl, nkx2.1b, lhx1b, tbr1, eomesa, emx1, emx2, and emx3 identifies striatal‐like, pallidal‐like, and septal‐like subdivisions within the subpallium. In contrast to previous models, we propose that the striatum and pallidum are stretched along the rostrocaudal axis of the telencephalon. Further, the septal nuclei derive from both the pallium and subpallium. On this basis, we present a new model for the subdivisions of the subpallium in teleost fish. J. Comp. Neurol. 520:633–655, 2012. © 2011 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 82%

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

Posadas

Kwitkowski²,

Kotz³

et al. 2007

Cancer

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“…Decreased imatinib levels under chronic treatment could be due to increased imatinib clearance (20) or to decreased intracellular accumulation of imatinib (21). Another possibility might be a change in the serum level of KIT or KIT ligand as proposed by Bono et al (22). Furthermore, several drugs known to influence the serum level of imatinib are frequently taken by older GIST patients (23).…”

Section: Discussionmentioning

confidence: 99%

Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate

Wardelmann

Merkelbach‐Bruse²,

Pauls³

et al. 2006

Clinical Cancer Research

340

246

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Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor a (PDGFRa) gene. Both PDGFRa and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.

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“…In one study, 107 (2-19 years old) healthy children had serum VEGF levels of 241±147 pg/mL (mean±s.d.). 21 According to Bono et al, 22 serum VEGF levels in healthy adults varied between 28 and 850 pg/mL (median 190, n ¼ 63), and serum Ang2 levels between 825 and 24 500 pg/mL (median 2275, n ¼ 46) (Bono et al, unpublished data). There are no published control values for Ang2 levels in pediatric population.…”

Section: Discussionmentioning

confidence: 99%

Higher angiopoietin-2 and VEGF levels predict shorter EFS and increased non-relapse mortality after pediatric hematopoietic SCT

Porkholm

Bono

Saarinen-Pihkala

et al. 2012

Bone Marrow Transplant

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The roles of angiogenesis and angiogenic factors after allogenic hematopoietic SCT (HSCT) and during acute GVHD (aGVHD) are not known. Studies on pediatric patients are extremely scarce. Levels of angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) were analyzed from blood samples of 67 consecutive patients. The levels were correlated with aGVHD grades, routine laboratory parameters and outcome. Pre-transplant Ang2 values correlated with the occurrence of intestinal aGVHD (P ¼ 0.009), whereas post-transplant measurements correlated with the severity of skin and liver aGVHD (P ¼ 0.03, P ¼ 0.04, respectively). Pre-transplant levels of VEGF were associated with the occurrence of skin aGVHD (P ¼ 0.04), whereas post-transplant levels correlated to the severity of intestinal aGVHD (P ¼ 0.04). High Ang2 levels were associated with shorter EFS (P ¼ 0.039) and increased non-relapse mortality (NRM) (P ¼ 0.009). In conclusion, higher Ang2 levels predict higher NRM and, with coexisting high VEGF, also shorter EFS after pediatric HSCT. Our results suggest that both pre-and post-transplant levels of Ang2 and VEGF seem to correlate to the clinical state of the patient. However, the pathophysiology of this connection needs further studies.

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Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib

Cited by 55 publications

References 33 publications

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

A prospective analysis of imatinib‐induced c‐kit modulation in ovarian cancer

Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate

Higher angiopoietin-2 and VEGF levels predict shorter EFS and increased non-relapse mortality after pediatric hematopoietic SCT

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