Response to imatinib rechallenge in a patient with a recurrent gastrointestinal stromal tumor after adjuvant therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Adjuvant imatinib improves recurrence-free survival of patients following resection of primary KIT-positive gastrointestinal stromal tumors. However, it is unknown whether patients who previously received adjuvant imatinib therapy will respond to imatinib rechallenge as treatment for recurrent disease. Here we present the first report documenting the benefits of imatinib rechallenge in a patient previously exposed to imatinib during adjuvant treatment.</p> <p>Case presentation</p> <p>A 51-year-old Asian woman with a wedge-resected primary gastric gastrointestinal stromal tumor at high risk of relapse underwent two years of adjuvant treatment with imatinib. Only 10 months after the completion of adjuvant imatinib treatment, a computed tomography scan revealed gastrointestinal stromal tumor recurrence in this patient, with multiple peritoneal nodules in the upper abdomen being detected. Our patient was rechallenged with imatinib 400 mg/day and had a partial response after one month of treatment. Imatinib rechallenge was well tolerated by our patient; the only adverse events she experienced were grade 1 edema, anemia and fatigue. Our patient maintained a partial response two years and six months after the imatinib rechallenge. However, computed tomography scans three months later showed that our patient had disease progression.</p> <p>Conclusions</p> <p>This case report demonstrates that a patient with a gastrointestinal stromal tumor who had previously received adjuvant imatinib therapy responded to imatinib rechallenge as treatment for her recurrent disease. These results indicate that imatinib sensitivity can be maintained in a patient with previous exposure to adjuvant imatinib therapy.</p

The role of mutational analysis of KIT and PDGFRA in gastrointestinal stromal tumors in a clinical setting

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Most GIST harbor a mutation affecting either the KIT or PDGFRA genes, whereas a small subgroup of tumors is wild type for mutations

Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors

<p>Abstract</p> <p>Background</p> <p>Oncogenic point mutations in <it>KIT </it>or <it>PDGFRA </it>are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.</p> <p>Methods</p> <p>In the present study, somatic mutations in <it>KIT </it>and <it>PDGFRA </it>were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.</p> <p>Results</p> <p>We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in <it>KIT </it>and 11.25% in <it>PDGFRA</it>. Secondary <it>KIT </it>mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with <it>KIT </it>mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.</p> <p>Conclusions</p> <p>In addition to <it>KIT/PDGFRA </it>mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.</p

Abundant Fas expression by gastrointestinal stromal tumours may serve as a therapeutic target for MegaFasL

Although the tyrosine kinase inhibitor imatinib has been shown to be an active agent in patients with gastrointestinal stromal tumours (GIST), complete remissions are almost never seen and most patients finally experience disease progression during their course of treatment. An alternative therapeutic option is to target death receptors such as Fas. We showed that a panel of imatinib-sensitive (GIST882) and imatinib-resistant (GIST48, GIST430 and GIST430K-) cell lines expressed Fas. MegaFasL, a recently developed hexameric form of soluble Fas ligand (FasL), appeared to be an active apoptosis-inducing agent in these cell lines. Moreover, MegaFasL potentiated the apoptotic effects of imatinib. Immunohistochemical evaluations, in 45 primary GISTs, underscored the relevance of the Fas pathway: Fas was expressed in all GISTs and was expressed strongly in 93%, whereas FasL was expressed at moderate and strong levels in 35 and 53% of GISTs, respectively. Fas and FasL expression were positively correlated in these primary GISTs, but there was no association between Fas or FasL expression and primary site, histological subtype, tumour size, mitotic index, risk classification, and KIT mutation status. The abundant immunohistochemical Fas and FasL expression were corroborated by western blot analysis. In conclusion, our data implicate Fas as a potential therapeutic target in GIST

Gastrointestinal stromal tumour of the duodenum in childhood: a rare case report

<p>Abstract</p> <p>Background</p> <p>Gastrointestinal stromal tumours (GISTs) are uncommon primary mesenchymal tumours of the gastrointestinal tract mostly observed in the adults. Duodenal GISTs are relatively rare in adults and it should be regarded as exceptional in childhood. In young patients duodenal GISTs may be a source of potentially lethal haemorrhage and this adds diagnostic and therapeutic dilemmas to the concern about the long-term outcome.</p> <p>Case presentation</p> <p>A 14-year-old boy was referred to our hospital with severe anaemia due to recurrent episodes of upper gastrointestinal haemorrhage. Endoscopy, small bowel series, scintigraphy and video capsule endoscopy previously done elsewhere were negative. Shortly after the admission, the patient underwent emergency surgery for severe recurrence of the bleeding. At surgery, a 4 cm solid mass arising from the wall of the fourth portion of the duodenum was identified. The invasion and the erosion of the duodenal mucosa was confirmed by intra-operative pushed duodenoscopy. The mass was resected by a full-thickness duodenal wall excision with adequate grossly free margins. Immunohistochemical analysis of the specimen revealed to be positive for CD117 (c-KIT protein) consistent with a diagnosis of GIST. The number of mitoses was < 5/50 HPF. Mutational analysis for c-KIT/PDGFRA tyrosine kinase receptor genes resulted in a wildtype pattern. The patient had an uneventful course and he has remained disease-free during two years of follow-up.</p> <p>Conclusion</p> <p>Duodenal GISTs in children are very rare and may present with massive bleeding. Cure can be achieved by complete surgical resection, but even in the low-aggressive tumours the long-term outcome may be unpredictable.</p

Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

KIT is a tyrosine kinase receptor expressed by several tumours, which has for specific ligand the stem cell factor (SCF). KIT is the main oncogene in gastrointestinal stromal tumours (GISTs), and gain-of-function KIT mutations are present in 70% of these tumours. The aim of the study was to measure and investigate the mechanisms of KIT activation in 80 KIT-positive GIST patients. KIT activation was quantified by detecting phosphotyrosine residues in Western blotting. SCF production was determined by reverse transcriptase–PCR, ELISA and/or immunohistochemistry. Primary cultures established from three GISTs were also analysed. The results show that KIT activation was detected in all cases, even in absence of KIT mutations. The fraction of activated KIT was not correlated with the mutational status of GISTs. Membrane and soluble isoforms of SCF mRNA were present in all GISTs analysed. Additionally, SCF was also detected in up to 93% of GISTs, and seen to be present within GIST cells. Likewise, the two SCF mRNA isoforms were found to be expressed in GIST-derived primary cultures. Thus, KIT activation in GISTs may in part result from the presence of SCF within the tumours