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Gastrointestinal Stromal Tumours (gastrointestinal + stromal_tumour)
Selected AbstractsFINE NEEDLE ASPIRATION IN ASSESSMENT OF PRIMARY AND METASTATIC GASTROINTESTINAL STROMAL TUMOURSPATHOLOGY INTERNATIONAL, Issue 12 2001Robson DJ No abstract is available for this article. [source] Gastrointestinal stromal tumour (GIST) masquerading as linitis plasticaHISTOPATHOLOGY, Issue 1 2004J M D Wheeler No abstract is available for this article. [source] Surgery for gastrointestinal stromal tumour in the post-imatinib eraANZ JOURNAL OF SURGERY, Issue 3 2005Susan J. Neuhaus Gastrointestinal stromal tumour (GIST) is a rare tumour. Historically, surgery has been the only effective treatment. The prognosis of patients with gastrointestinal stromal tumour is poor. Even after apparently ,curative' surgical resection more than 50% of patients relapse. The development of an effective novel targeted therapy against GIST (imatinib mesylate) is a success story of molecular biology that has dramatically altered the management of patients with these tumours. However, as follow up of patients who have initially responded to imatinib has increased, it has become evident that such hopes of cure were premature because responses to imatinib are of limited duration. Unresolved issues include the role of imatinib as an induction (neo-adjuvant) therapy prior to surgery, or as adjuvant treatment after surgery, the role of surgery in patients with a differential or partial response and the role of surgery in patients with isolated metastatic disease. In the present paper the biology and natural history of GIST are reviewed, and the complexities of surgical management that exist in the context of an effective, but not curative, biological therapy, are addressed. [source] Gastrointestinal stromal tumour (GIST) arising in a colonic duplication cyst: case reportCOLORECTAL DISEASE, Issue 10 2010A. S. Van Rompuy No abstract is available for this article. [source] Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumoursHISTOPATHOLOGY, Issue 3 2008J Lasota Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13,17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors. [source] The epidemiologic, health-related quality of life, and economic burden of gastrointestinal stromal tumoursJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2007P. Reddy PharmD Summary Background and objectives:, Gastrointestinal stromal tumours (GIST) are uncommon tumours believed to arise from interstitial cells of Cajal or their precursors in the gastrointestinal (GI) tract, accounting for a small percentage of GI neoplasms and sarcomas. Given the recent recognition of GIST as a distinct cancer, as well as new treatment options available today, a review of the epidemiologic, health-related quality of life (HRQL), and economic burden of GIST is timely from a payer, provider and patient perspective and may provide guidance for treatment decision making and reimbursement. Methods:, A systematic literature review of PubMed and five scientific meeting databases, was conducted to identify published studies and abstracts describing the epidemiologic, HRQL and economic impact of GIST. Publications deemed worthy of further review, based on the information available in the abstract, were retrieved in full text. Results and discussion:, Thirty-four publications met the review criteria: 29 provided data on GIST epidemiology, one provided cost data, three reported HRQL outcomes, and one reported cost and HRQL outcomes. The annual incidence of GIST (cases per million) ranged from 6·8 in the USA to 14·5 in Sweden, with an estimated 5-year survival rate of 45,64%. On the Functional Illness of Chronic Therapy-fatigue instrument, GIST patients scored 40·0 compared with 37·6 in anaemic cancer patients (0 = worst; 52 = least fatigue). Total costs over 10 years for managing GIST patients with molecularly targeted treatment was estimated at £47 521,£56 146 per patient compared with £4047,£4230 per patient with best supportive care. Conclusions:, The incidence of GIST appears to be similar by country; the lower estimate in one country could be explained by differences in method of case ascertainment. Data suggest that the HRQL burden of GIST is similar to that with other cancers although this requires further exploration. The value of new therapies in GIST needs to consider not only cost but also anticipated benefits and the unmet medical need in this condition. [source] Gastrointestinal stromal tumours: A clinico-radiologic review from a single centre in South IndiaJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 6 2009A Singh Summary Gastrointestinal stromal tumours (GISTs) are rare tumours but are the commonest mesenchymal neoplasms in the gastrointestinal tract. To our knowledge, there is no large case series in Asian countries in which a clinico-radiological descriptive analysis of these tumours has been carried out. In this retrospective study, we analysed our experience of 70 patients with histopathologically proven GISTs, who were presurgically investigated by using CT, and describe the demography, anatomical distribution, imaging features and clinical course of the GIST. We found an unusually large predominance of males in our study, stomach and small bowel appeared to have been involved similarly and small bowel tumours had a higher rate of metastases. We also highlight some unusual CT features of these tumours that we encountered during the study, such as the presence of metastatic lymphadenopathy and satellite nodules, relapse in appendices epiploicae of the bowel, metachronous liposarcoma, adrenal and lung metastases, multiplicity of lesions and aneurysmal dilatation of the bowel. Two of our patients also had multiple neurofibromas, whose association with GIST has been seen in earlier reports. To the best of our knowledge, this article presents one of the largest series of articles on GISTs, to date, in Asian countries. We conclude with a differential diagnosis of GIST, with salient features distinguishing each entity. [source] Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GISTs) with KIT exon 11 deletions,THE JOURNAL OF PATHOLOGY, Issue 2 2008F Haller Abstract Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Gastrointestinal stromal tumours (Br J Surg 2003; 90: 1178- 1186)BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 1 2004S. J. Neuhaus No abstract is available for this article. [source] Giant gastrointestinal stromal tumour of the oesophagus presenting with atypic symptomANZ JOURNAL OF SURGERY, Issue 4 2010Rasih Yilmaz No abstract is available for this article. [source] Surgery for gastrointestinal stromal tumour in the post-imatinib eraANZ JOURNAL OF SURGERY, Issue 3 2005Susan J. Neuhaus Gastrointestinal stromal tumour (GIST) is a rare tumour. Historically, surgery has been the only effective treatment. The prognosis of patients with gastrointestinal stromal tumour is poor. Even after apparently ,curative' surgical resection more than 50% of patients relapse. The development of an effective novel targeted therapy against GIST (imatinib mesylate) is a success story of molecular biology that has dramatically altered the management of patients with these tumours. However, as follow up of patients who have initially responded to imatinib has increased, it has become evident that such hopes of cure were premature because responses to imatinib are of limited duration. Unresolved issues include the role of imatinib as an induction (neo-adjuvant) therapy prior to surgery, or as adjuvant treatment after surgery, the role of surgery in patients with a differential or partial response and the role of surgery in patients with isolated metastatic disease. In the present paper the biology and natural history of GIST are reviewed, and the complexities of surgical management that exist in the context of an effective, but not curative, biological therapy, are addressed. [source] Management of imatinib-related exacerbation of psoriasis in a patient with a gastrointestinal stromal tumourAUSTRALASIAN JOURNAL OF DERMATOLOGY, Issue 1 2009Haiying Cheng SUMMARY A 62-year-old woman with a pre-existing psoriasis was treated with oral imatinib (400 mg/day) for a metastatic gastrointestinal stromal tumour. Within 4 weeks of starting therapy, she developed a guttate psoriasis flare. The eruption markedly improved within 2 weeks following cessation of imatinib. However, it recurred when imatinib was recommenced. She has been able to continue on imatinib (400 mg/day) with low-dose oral methotrexate (12.5 mg/week) controlling the psoriasis. [source] Cutaneous metastasis from gastric glomus tumourCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 8 2009A. P. J. J. Bray Summary A 58-year-old man presented with a 4-month history of a rapidly enlarging asymptomatic tumour on the scalp vertex. Six years earlier, the patient had undergone subtotal gastrectomy for a presumed gastrointestinal stromal tumour (GIST). The tumour extended to the peritoneal surfaces, and foci of vascular invasion were also seen. No adjuvant treatment was given. Owing to diagnostic difficulties with the scalp tumour, a comparison was made with the previous gastric neoplasm. Both had features consistent with glomus tumour, which suggested a revised diagnosis of primary malignant gastric glomus tumour with subsequent cutaneous metastasis to the scalp some years later. This case highlights the features of glomus tumours and is a reminder that although rare, glomus tumours can be malignant and have the potential to metastasize. To our knowledge, this is the only reported case of a primary gastric glomus tumour with secondary metastasis to the skin. [source] Generalized granuloma annulare associated with gastrointestinal stromal tumour: case report and review of clinical features and managementCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 4 2008M. L. S. Chiu Summary The paraneoplastic variant of granuloma annulare (GA) is a rare cutaneous manifestation of underlying malignancy that is most commonly associated with systemic lymphoma. We report an interesting case of a patient with gastrointestinal stornal tumour (GIST) of the stomach presenting with extensive generalized GA. GIST was diagnosed 2 months after the diagnosis of GA. Resolution of the GA was seen 1 month after surgical excision of GIST. The close correlation of the clinical courses of these two rare diseases suggests that their coexistence was more than a coincidental finding. This case highlights the importance of excluding paraneoplastic GA, especially in cases where the skin manifestations are extensive and resistant to treatment. [source] Hypoglycaemia in a patient with a gastrointestinal stromal tumourCLINICAL ENDOCRINOLOGY, Issue 3 2003M. M. J. Beckers No abstract is available for this article. [source] Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumoursHISTOPATHOLOGY, Issue 3 2008J Lasota Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13,17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors. [source] The role of genetic testing in soft tissue sarcomaHISTOPATHOLOGY, Issue 1 2006C R Antonescu Soft tissue tumours represent a heterogeneous group of mesenchymal lesions and their classification continues to evolve as a result of incorporating advances in cytogenetic and molecular techniques. In the last decade traditional diagnostic approaches were supplemented with a significant number of reliable molecular diagnostic tools, detecting tumour type-specific genetic alterations. In addition, the successful application of some of these techniques to formalin-fixed paraffin-embedded tissue made it possible to subject a broader range of clinical material to molecular analysis. Thus, molecular genetics has already become an integral part of the work-up in some tumours, such as paediatric small blue round cell tumours, which demonstrate characteristic translocations. Several lines of evidence suggest that sarcomas can be divided into two major genetic groups: (i) sarcomas with specific genetic alterations and usually simple karyotypes, such as reciprocal chromosomal translocations (e.g. FUS-DDIT3 in myxoid liposarcoma) and specific oncogenic mutations (e.g. KIT mutation in gastrointestinal stromal tumours); and (i) sarcomas with non-specific genetic alterations and complex unbalanced karyotypes. Some of these genetic abnormalities, including chromosomal numerical changes, translocations, gene amplifications or large deletions can be apparent at the cytogenetic level (karyotyping, fluoresence in situ hybridization), while others, such as small deletions, insertions or point mutations, require molecular genetic techniques (polymerase chain reaction and sequence analysis). This review focuses on the applicability of genetic testing in the diagnosis and prognosis of soft tissue sarcomas, and gives a realistic appraisal of the ancillary role of molecular techniques, including its advantages and limitations. [source] Intra-abdominal spindle cell lesions: a review and practical aids to diagnosisHISTOPATHOLOGY, Issue 5 2001A Al-Nafussi Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis Intra-abdominal spindle cell lesions are uncommon and often present a diagnostic challenge. An important group of such lesions are the gastrointestinal stromal tumours. Other intra-abdominal spindle cell lesions include fibromatosis, various sarcomas,in particular, leiomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumour,and, in women, endometrial stromal sarcoma. Less common lesions are inflammatory myofibroblastic tumours, the mesenteric spindle cell reactive lesions, retroperitoneal fibrosis, and solitary fibrous tumour. A variety of intra-abdominal tumours of nonmesenchymal origin may have a spindle cell/sarcomatoid morphology; these include sarcomatoid carcinoma, malignant melanoma and, in women, sarcomatoid granulosa cell tumour. Finally, metastatic sarcomas from pelvic or extra-abdominal organs need also be considered. A set of practical aids to the diagnosis of intra-abdominal spindle cell lesions is presented to assist pathologists dealing with such lesions, particularly with regards to the consideration of differential diagnoses. [source] Aggressive surgical resection for the management of hepatic metastases from gastrointestinal stromal tumours: a single centre experienceHPB, Issue 1 2007D. Gomez Abstract Background: The outcome of surgical intervention for hepatic metastases from gastrointestinal stromal tumours (GIST) is still uncertain. This study evaluated the outcome of patients following aggressive surgical resection and Imatinib mesylate therapy (IM). Patients and methods: This was a retrospective analysis of patients managed with hepatic metastases from GIST over a 13-year period (January 1993 to December 2005). Results: Twelve patients were identified with a median age at diagnosis of 62 (32,78) years. The primary sites of GIST were stomach (n= 5), jejunum (n= 4), sigmoid (n= 1), peritoneum (n= 1) and pancreas (n= 1). Eleven patients underwent surgical resection with curative intent and one patient had cytoreductive surgery. Following surgery with curative intent (n= 11), the overall 2- and 5-year survival rates were both 91%, whereas the 2- and 5-year disease-free rates following primary hepatic resection were 30% and 10%, respectively. The median disease-free period was 17 (3,72) months. Eight patients had recurrent disease and were managed with further surgery (n= 3), radiofrequency ablation (RFA) (n= 2) and IM (n= 8). Overall, there are four patients who are currently disease-free: two patients following initial hepatic resection and two patients following further treatment for recurrent disease. There was no significant association in clinicopathological characteristics between patients with recurrent disease within 2 years and patients who were disease-free for 2 years or more. Overall morbidity was 50% (n= 6), with one postoperative death. The follow-up period was 43 (3,72) months. Conclusion: Surgical resection for hepatic GIST metastases may improve survival in selected patients. Recurrent disease can be managed with surgery, RFA and IM. [source] The epidemiologic, health-related quality of life, and economic burden of gastrointestinal stromal tumoursJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2007P. Reddy PharmD Summary Background and objectives:, Gastrointestinal stromal tumours (GIST) are uncommon tumours believed to arise from interstitial cells of Cajal or their precursors in the gastrointestinal (GI) tract, accounting for a small percentage of GI neoplasms and sarcomas. Given the recent recognition of GIST as a distinct cancer, as well as new treatment options available today, a review of the epidemiologic, health-related quality of life (HRQL), and economic burden of GIST is timely from a payer, provider and patient perspective and may provide guidance for treatment decision making and reimbursement. Methods:, A systematic literature review of PubMed and five scientific meeting databases, was conducted to identify published studies and abstracts describing the epidemiologic, HRQL and economic impact of GIST. Publications deemed worthy of further review, based on the information available in the abstract, were retrieved in full text. Results and discussion:, Thirty-four publications met the review criteria: 29 provided data on GIST epidemiology, one provided cost data, three reported HRQL outcomes, and one reported cost and HRQL outcomes. The annual incidence of GIST (cases per million) ranged from 6·8 in the USA to 14·5 in Sweden, with an estimated 5-year survival rate of 45,64%. On the Functional Illness of Chronic Therapy-fatigue instrument, GIST patients scored 40·0 compared with 37·6 in anaemic cancer patients (0 = worst; 52 = least fatigue). Total costs over 10 years for managing GIST patients with molecularly targeted treatment was estimated at £47 521,£56 146 per patient compared with £4047,£4230 per patient with best supportive care. Conclusions:, The incidence of GIST appears to be similar by country; the lower estimate in one country could be explained by differences in method of case ascertainment. Data suggest that the HRQL burden of GIST is similar to that with other cancers although this requires further exploration. The value of new therapies in GIST needs to consider not only cost but also anticipated benefits and the unmet medical need in this condition. [source] Oncogenic and ligand-dependent activation of KIT/PDGFRA in surgical samples of imatinib-treated gastrointestinal stromal tumours (GISTs),THE JOURNAL OF PATHOLOGY, Issue 1 2009T Negri Abstract As the range of receptor tyrosine kinase (RTK) inhibitors widens, a detailed understanding of the activating mechanisms of KIT/platelet-derived growth factor receptor (PDGFR)A and the related downstream pathways involved in the development and maintenance of GISTs is becoming increasingly important. We analysed areas with different histological response ratios in surgical specimens taken from imatinib-treated and untreated GIST patients in order to investigate KIT and PDGFRA expression/activation, the presence of their cognate ligands and the activation of downstream signalling, by means of biochemistry, immunohistochemistry and flow cytometry. All of the cases showed KIT and PDGFRA co-expression. In addition to the oncogenic activation of mutated receptors, activation of wild-type KIT and wild-type PDGFRA, sustained by heterodimerization and an autocrine,paracrine loop, was demonstrated by the presence of their specific ligands, stem cell factor (SCF) and PDGFA. To confirm RTK activation further, all of the samples (including those with the highest regression ratios) were investigated for downstream effectors, and all proved to have activated downstream signalling. The results show that after the mutated receptors are switched off, heterologous wild-type receptors become important in imatinib-treated GISTs as a means of maintaining signalling activation. Taken together, our findings suggest that drugs targeting wild-type receptors should be tested in imatinib-treated GIST patients. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GISTs) with KIT exon 11 deletions,THE JOURNAL OF PATHOLOGY, Issue 2 2008F Haller Abstract Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Absence of c- kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patientsTHE JOURNAL OF PATHOLOGY, Issue 1 2004Kazuo Kinoshita Abstract Most sporadic gastrointestinal stromal tumours (GISTs) have somatic c- kit gene mutations that are considered to be causal. Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and NF1 patients have an increased risk of developing GISTs. Since most neoplasms are considered to develop as a result of the combination of several gene mutations, these findings suggest that GISTs from NF1 patients might have somatic c- kit gene mutations and that sporadic GISTs from non-NF1 patients might have somatic NF1 gene mutations. The present study analysed 29 GISTs from seven NF1 patients for c- kit gene mutations and ten sporadic GISTs from ten non-NF1 patients for NF1 mutations. Exons 9, 11, 13, and 17 of the c- kit gene were amplified and directly sequenced after the extraction of genomic DNA from wax-embedded tissues from 26 GISTs from five NF1 patients. The whole coding region of the c- kit cDNA and the whole coding region of the NF1 cDNA were amplified and directly sequenced after RNA extraction and cDNA synthesis in three fresh GIST tissues from two NF1 patients and ten fresh GIST tissues from ten non-NF1 patients. Of the ten sporadic GISTs, eight had heterozygous mutations at exon 11, and one at exon 9, of c- kit. Heterozygous NF1 gene mutations were detected in GISTs from the two NF1 patients from whom fresh tissues were available. None of the 29 GISTs derived from NF1 patients had detectable c- kit gene mutations and none of the ten GISTs derived from non-NF1 patients had detectable NF1 mutations. These results suggest that the pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients. Copyright © 2004 John Wiley & Sons, Ltd. [source] Population pharmacokinetics of imatinib and the role of ,1 -acid glycoproteinBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2006N. Widmer Aims The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma ,1 -acid glycoprotein concentrations. Methods A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. Results A one-compartment model with first-order absorption appropriately described the data, giving a mean (± SEM) oral clearance of 14.3 l h,1 (± 1.0) and a volume of distribution of 347 l (± 62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma ,1 -acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. Conclusion Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating ,1 -acid glycoprotein concentrations or free imatinib concentrations. [source] A case of cutaneous leiomyosarcoma with overexpression of KIT: do CD117 (KIT)-positive primary gastrointestinal stromal tumours of the skin exist?BRITISH JOURNAL OF DERMATOLOGY, Issue 5 2006M. Horie No abstract is available for this article. [source] SDHC mutation in an elderly patient without familial antecedentsCLINICAL ENDOCRINOLOGY, Issue 6 2008Elena López-Jiménez Summary Head and neck paragangliomas are usually asymptomatic and benign tumours arising mainly from the carotid body and the vagal, tympanic or jugular glomus. The majority of patients develop sporadic masses, and around 30% of cases harbour germline mutations in one of the succinate dehydrogenase genes: SDHB, SDHC or SDHD. In these hereditary cases, the presence of familial antecedents of the disease, multiplicity/bilaterality, young age at onset, and more recently, presence of gastrointestinal stromal tumours, are main factors to be considered. Here we describe a new mutation (c.256,257insTTT) affecting the SDHC gene in a 60-year-old-patient with a single head and neck paraganglioma, and without familial antecedents of the disease. In silico splice site analysis showed that this variant created a cryptic splice acceptor site and loss of heterozygosity (LOH) supported the pathogenic role of the mutation. Control population analyses did not detect this variant but revealed a novel SDHC polymorphism that exhibited a frequency of 0·3% (3/1020). This latter finding highlights the importance of assessing the clinical relevance of variants of unknown significance by means of analysing sufficient controls. Despite having found a germline mutation in an older, apparently sporadic patient, we consider that the high costs of analysing all susceptibility genes related to the disease support the recommendation of screening for mutations only in patients fulfilling the above criteria. [source] | ||||||||||||||||||||||||||||