LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.     

巢蛋白(Nestin)在胃肠道间质瘤组织中的表达及其临床意义

目的　通过检测胃肠道间质瘤 (GIST )组织中巢蛋白 (nestin)的表达 ,探讨nestin在GIST的诊断、鉴别诊断及起源中的意义。方法　应用免疫组织化学技术EnVision微波二步法 ,检测 94例GIST (良性 44例 ,恶性 5 0例 )组织中nestin蛋白的表达 ,并与平滑肌瘤和平滑肌肉瘤进行对照研究。结果　GIST组织中nestin的阳性表达率为 95 .7% ( 90 /94) ,良、恶性组nestin的阳性率分别为 97.7% ( 4 3 /4 4)、94.0 % ( 4 7/5 0 )。 2组的表达水平无显著性差异 (P >0 .0 5 )。平滑肌瘤和平滑肌肉瘤nestin表达均阴性。结论　Nestin作为胃肠道间质瘤的 1种特异而敏感的新标志物 ,对GIST的诊断及鉴别诊断有重要意义 ,但不能作为GIST分化程度的指标 ,同时提示GIST可能起源于向卡哈尔细胞 (ICC )表型分化的干细胞。     

Hand-assisted laparoscopic surgery for a large gastrointestinal stromal tumor of the stomach

We report two cases of large gastrointestinal stromal tumor (GIST) of the stomach that were successfully treated by hand-assisted laparoscopic surgery (HALS). Two patients, a 56-year-old woman and a 60-year-old man, were admitted to our department for the treatment of a large submucosal tumor of the stomach. After gastrointestinal endoscopy, ultrasonography, computed tomography, and magnetic resonance imaging, we suspected that the masses, measuring 7.0 cm and 8.0 cm in diameter, respectively, were GISTs in the stomach. However, preoperatively, we could not rule out the possibility of malignant neoplasms, because they had been bleeding or gradually growing. Hand-assisted laparoscopic wedge resection was safely performed for the diagnosis and treatment of the submucosal tumor of the stomach. The immunohistochemical diagnosis in both patients was GIST of the stomach with intermediate-grade malignancy. HALS may be a good indication for large GISTs of the stomach that are difficult to diagnose preoperatively, whether they are malignant or benign, because it is safe and minimally invasive, promoting rapid recovery.     

甲磺酸伊马替尼治疗国人胃肠间质瘤的临床研究

 目的 观察和评价甲磺酸伊马替尼（Imatinib mesylate）治疗国人胃肠间质瘤（GIST）的有效性和安全性。方法 2002年8月至2004年12月，在本院通过病理形态学及免疫组化确诊的GIST共52例，其中36例应用伊马替尼治疗，用法为伊马替尼400mg，口服，1／日。参照WHO实体瘤客观疗效标准观察和判定疗效，NCI-CTC2．0版抗癌药的毒性标准观察和判定毒性。结果 伊马替尼治疗的36例患者中，包括新辅助治疗和姑息治疗在内可以评价疗效的有28例，用药后获得部分缓解为14例（50％），疾病稳定10例（35．7％），疾病进展4例（14．3％）；即有效率（RR）为50％，疾病控制率（DCR）达到85．7％。36例均可进行毒性评价，除了1例因胃部GIST合并脾脏B细胞型非霍奇金淋巴瘤，姑息切除术后口服格列卫同时进行CHOP方案化疗，结果 发生了Ⅲ级骨髓抑制外，其他35例中毒副反应均为Ⅰ～Ⅱ级，而且大多数毒性可以控制或恢复正常。结论 与国外文献报道一致，甲磺酸伊马替尼治疗国人GIST安全高效，耐受性好。     

Reducing uncertainty in health-care resource allocation

A key task for health policymakers is to optimise the outcome of health care interventions. The pricing of a new generation of cancer drugs, in combination with limited health care resources, has highlighted the need for improved methodology to estimate outcomes of different treatment options. Here we introduce new general methodology, which for the first time employs continuous hazard functions for analysis of survival data. Access to continuous hazard functions allows more precise estimations of survival outcomes for different treatment options. We illustrate the methodology by calculating outcomes for adjuvant treatment of gastrointestinal stromal tumours with imatinib mesylate, which selectively inhibits the activity of a cancer-causing enzyme and is a hallmark representative for the new generation of cancer drugs. The calculations reveal that optimal drug pricing can generate all win situations that improve drug availability to patients, make the most of public expenditure on drugs and increase pharmaceutical company gross profits. The use of continuous hazard functions for analysis of survival data may reduce uncertainty in health care resource allocation, and the methodology can be used for drug price negotiations and to investigate health care intervention thresholds. Health policy makers, pharmaceutical industry, reimbursement authorities and insurance companies, as well as clinicians and patient organisations, should find the methodology useful.     

Dose-escalation study of a second-generation non-ansamycin HSP90 inhibitor,onalespib (AT13387), in combination with imatinib in patients with metastatic gastrointestinal stromal tumour

BackgroundGastrointestinal stromal tumours (GIST) treated with the tyrosine kinase inhibitor (TKI) imatinib can become resistant when additional mutations in the receptor tyrosine kinases KIT or PDGFRA block imatinib activity. Mutated KIT requires the molecular chaperone heat-shock protein 90 (HSP90) to maintain stability and activity. Onalespib (AT13387) is a potent non-ansamycin HSP90 inhibitor. We hypothesised that the combination of onalespib and imatinib may be safe and effective in managing TKI-resistant GIST.Patients and methodsIn this dose-escalation study, we evaluated the safety and efficacy of combination once-weekly intravenous onalespib for 3 weeks and daily oral imatinib in 28-d cycles. Twenty-six patients with TKI-resistant GIST were enrolled into four sequential dose cohorts of onalespib (dose range, 150–220 mg/m²) and imatinib 400 mg. The relationship between tumour mutational status (KIT/PDGFRA) and efficacy of treatment was explored.ResultsCommon onalespib-related adverse events were diarrhoea (58%), nausea (50%), injection site events (46%), vomiting (39%), fatigue (27%), and muscle spasms (23%). Overall, 81% of patients reported more than one onalespib-related gastrointestinal disorder. Nine patients (35%) had a best response of stable disease, including two patients who had KIT mutations known to be associated with resistance to imatinib and sunitinib. Disease control at 4 months was achieved in five patients (19%), and median progression-free survival was 112 d (95% confidence interval 43–165). One patient with PDGFRA-mutant GIST had a partial response for more than 376 d.ConclusionThe combination of onalespib plus imatinib was well tolerated but exhibited limited antitumour activity as dosed in this TKI-resistant GIST patient population.Trial registration ID: clinicaltrials.gov: NCT01294202     

Sunitinib malate for the treatment of solid tumours: a review of current clinical data

Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth, and mutated or overexpressed RTKs have been implicated in various human cancers. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA for the treatment of advanced renal cell carcinoma and of gastrointestinal stromal tumours after disease progression on or intolerance to imatinib mesilate therapy. Sunitinib has also demonstrated promising clinical activity in the treatment of other advanced solid tumours. The present review provides an updated summary of emerging clinical experience with this promising new anticancer agent.     

Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants

BACKGROUND AND AIMS: Resistance is a major challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). We investigated the mechanisms of resistance in patients with progressive GISTs with primary KIT mutations and the efficacy of the kinase inhibitor PKC412 for the inhibition of imatinib-resistant mutants. METHODS: We performed a cytogenetic analysis and screened for mutations of the KIT and PDGFRA kinase domains in 26 resistant GISTs. KIT autophosphorylation status was assessed by Western immunoblotting. Imatinib-resistant GIST cells and Ba/F3 cells expressing these mutant proteins were tested for sensitivity to imatinib and PKC412. RESULTS: Six distinct secondary mutations in KIT were detected in 12 progressive tumors, with V654A and T670I found to be recurrent. One progressive tumor showed acquired PDGFRA -D842V mutation. Amplification of KIT or KIT / PDGFRA was found in 2 patients. Eight of 10 progressive tumors available for analysis showed phosphorylated KIT. Two remaining progressive tumors lost KIT protein expression. GIST cells carrying KIT -del557-558/T670I or KIT -InsAY502-503/V654A mutations were resistant to imatinib, while PKC412 significantly inhibited autophosporylation of these mutants. Resistance to imatinib and sensitivity to PKC412 of KIT -T670I and PDGFRA -D842V mutants was confirmed using Ba/F3 cells. CONCLUSIONS: This study shows the high frequency of KIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of KIT / PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant KIT -T670I and KIT -V654A and of PDGFRA -D842V mutants to PKC412.     

Contribution of DOG1 expression to the diagnosis of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, and the majority contain KIT or PDGFRA-activating mutations. However, up to 10% of GISTs are c-kit-negative. Antibodies with increased sensitivity and specificity for the detection of c-kit-negative GIST cases may be of value, especially because some of these cases may also benefit from tyrosine kinase inhibitor therapy.