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- Andersson, Johanna, 1974
(författare)
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Gastrointestinal stromal tumors. Pathogenetic mechanisms, phenotypic characterization and prognosis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gastrointestinal stromal tumor (GIST), the most common non-epithelial neoplasm of the gastrointestinal tract, has historically been problematic both conceptually and clinically. Recently, GIST has been shown to share phenotypic features with the interstitial cells of Cajal (ICC), including the almost uniform expression of the tyrosine kinase receptor KIT. GIST have frequently been found to have activating mutations of the KIT gene or more rarely the platelet derived growth factor receptor alpha (PDGFRA) gene; these apparently play a key role in GIST s pathogenesis. The occurrence of GIST lacking KIT and PDGFRA mutations indicates, however, that alternative pathogenetic mechanisms exist. Clinical studies regarding the correlation of mutations with disease outcome in GIST have been contradictory. Mutation analysis of the KIT gene in 14 GIST revealed exon 11 mutations in 9 tumors. Mutations were detected in benign as well as malignant GIST. Cytogenetic and SKY analyses revealed several recurrent structural and numerical abnormalities; losses of 1p, 14 and 22 being the most common. No correlation was found between biologic behavior, KIT mutation status and chromosome aberrations. All tumors preferentially expressed the shorter, tumorigenic, splice variant of exon 9 of the KIT gene.Imatinib mesylate, a new designer drug, selectively inhibits type III receptor tyrosine kinases and has a dramatic, anti-tumor effect on GIST. In a center-based study of 17 patients with GIST, we studied the relationship between KIT exon 11 mutation status and treatment response. Imatinib was especially effective in tumors with exon 11 mutations - KIT exon 11 mutations were detected in 8 of 9 patients with partial response, whereas no mutations were detected in 3 patients with stable or progressive disease.Earlier studies of receptor tyrosine kinase mutations indicate that different types of mutations are associated with distinctive phenotypes and potentially clinical behavior in GIST. In a large, retrospective, population-based series of GIST from the pre-imatinib mesylate era, we examined whether mutation type correlated with phenotype and clinical course. KIT exon 11 mutations were detected in GIST from 117 of 233 patients (69 deletions, 27 missense mutations and 21 duplications). The deletion subgroup had a significantly decreased disease-free survival. KIT exon 11 deletions were found to be an independent adverse prognostic factor with respect to disease-free survival. GIST have been reported to occasionally occur in patients with neurofibromatosis type I (NF1). NF1 is the most common autosomal dominant inherited disorder, with an incidence of 1/3-4000 individuals. The clinical spectrum of NF1 is extremely wide and includes organic as well as mental manifestations. We analyzed GIST arising in 15 NF1 patients and found that this subset of GIST has a unique phenotype, including an almost uniformly benign appearance histologically, a propensity for multicentricity, association with ICC hyperplasia, predominant location in the small intestine, and a spindle cell morphology as well as benign or very low grade malignant behavior. The NF1-associated GIST also have a unique genotype in that they lack KIT and PDGFRA mutations, indicating that different pathogenetic mechanisms are involved in their evolution.In summary, we have shown that the role of KIT mutations in the biological behavior of GIST is more complex than previously recognized and that the type of mutation influences clinical behavior as well as response to imatinib treatment. NF1-associated GIST are a pheno- and genotypically unique subset of GIST that lack activating mutations in the KIT and PDGFRA genes.
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| 2. |
- Andersson, Johanna, 1974, et al.
(författare)
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Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis
- 2006
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 130:6, s. 1573-81
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. METHODS: Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. RESULTS: KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST
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| 3. |
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| 4. |
- Bümming, Per, 1965, et al.
(författare)
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Population-based study of the diagnosis and treatment of gastrointestinal stromal tumours
- 2006
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 93:7, s. 836-43
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of this retrospective population-based study, which was conducted before the introduction of imatinib, was to evaluate the role of surgery in patients with gastrointestinal stromal tumours (GISTs) and clarify which subgroups might benefit from adjuvant treatment. METHODS: Two hundred and fifty-nine patients with clinically detected GISTs were studied. Univariate and multivariate analyses were performed to identify predictors for recurrent disease and survival. RESULTS: Thirty of 48 patients with high-risk GISTs and all of those with overtly malignant tumours developed recurrent tumour after complete (R0) resection. Thirty-four of 38 first recurrences occurred within 36 months of surgery. No recurrence was observed after 72 months. R0 resection, achieved in 48 (80 per cent) of 60 patients with high-risk tumours, was significantly associated with a decreased risk of death from tumour recurrence (P = 0.008). CONCLUSION: Completeness of surgical resection is an independent prognostic factor in patients with high-risk GISTs. A period of adjuvant treatment with imatinib is recommended in patients with high-risk or overtly malignant GISTs who have undergone R0 resection and have a tumour-free interval of less than 6 years.
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| 5. |
- Hilman, S, et al.
(författare)
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Gastrointestinal stromal tumour with a KIT exon 11 mutation presenting as a paratesticular mass.
- 2009
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Ingår i: The British journal of radiology. - : British Institute of Radiology. - 1748-880X .- 0007-1285. ; 82:977
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumours (GISTs) are sarcomas arising in the gastrointestinal tract. They are characterised by a gain in function mutation of the KIT oncogene and the majority express the receptor tyrosine kinase KIT, which can be detected by the immunohistochemical stain CD117. Patients with a GIST present with symptoms such as abdominal pain or gastrointestinal bleeding, or may be asymptomatic. We describe the clinical history and pathological features of a patient with a GIST who presented with a paratesticular mass which, to our knowledge, has never previously been reported. With the development of new drugs to treat GISTs, the knowledge of the type of mutations may in the future prove helpful in determining optimal treatment strategies and prognosis.
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| 6. |
- Nilsson, Bengt E, 1949, et al.
(författare)
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Adjuvant imatinib treatment improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumours (GIST)
- 2007
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 96:11, s. 1656-8
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Tidskriftsartikel (refereegranskat)abstract
- Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies.
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