甲磺酸伊马替尼治疗晚期胃肠间质瘤的临床疗效观察

目的：评价甲磺酸伊马替尼治疗晚期胃肠间质瘤的临床疗效和不良反应。方法：2006年10月至20010年10月期间经病理检查确诊的25例晚期胃肠间质瘤患者,使用甲磺酸伊马替尼400mg/日治疗。结果：25例病人均得到随访,完全缓解（CR）0例,部分缓解（PR）13例,疾病稳定（SD）8例,疾病进展（PD）4例,死亡3例。1年存活率100%,2年存活率96%。结论：甲磺酸伊马替尼治疗晚期胃肠间质瘤有较好疗效,能延长患者生命,不良反应轻微,患者能长期耐受。     

microRNA-21抑制剂联合伊马替尼对慢性髓系白血病K562细胞增殖的影响研究

目的:研究microRNA-21抑制剂(miRZip-21)联合伊马替尼对慢性髓系白血病细胞K562的细胞生长及周期的影响。方法:用慢病毒空载体pmiRZip或表达载体pmiRZip-21转染293TN细胞收获慢病毒颗粒miRZip或miRZip-21,分别感染K562细胞,采用Northern杂交检测microRNA-21的表达;然后对K562细胞进行以下不同处理:miRZip感染、miRZip-21感染、伊马替尼处理和miRZip-21感染与伊马替尼处理联合使用,采用MTT法检测后3种处理后细胞生长情况,流式细胞仪检测4种处理后细胞周期运行情况。结果:与miRZip感染比较,miRZip-21感染导致K562细胞中microRNA-21表达降低,细胞周期运行受到阻滞;而与miRZip-21感染或伊马替尼处理比较,miRZip-21感染与伊马替尼处理联合使用导致K562细胞生长速度明显减慢,细胞存活率显著降低(P<0.05或P<0.01),细胞周期运行也受到严重的阻滞。结论:miRZip-21联合伊马替尼能够协同抑制K562细胞生长及细胞周期运行。     

Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy

Background Although imatinib has shown high activity in the majority of patients with advanced gastrointestinal stromal tumors (GIST), it has become clear that secondary resistance appears during chronic therapy. The aim of this study was to retrospectively analyze the safety and prognostic effects of surgical interventions for focal progression during imatinib treatment. Methods Between January 2002 and May 2005, 16 patients who had focal lesions of secondary-resistant GIST to imatinib treatment (male/female, 12 : 4; median age, 62 years) underwent surgical interventions such as resection, radiofrequency ablation, and their combination. Results Postoperative complications, including liver abscess, bile leak, wound infection, and ileus were mostly mild, and the patients recovered with conservative therapy. There was no hospital death. The median time to progression (TTP) of all patients was 5.5 months, and only one patient died of the disease; the others are alive after a median follow up of 12.4 months. Patients with complete resections of resistant lesions (n = 7) showed significantly better median TTP than those with incomplete resections (n = 9; P = 0.014). The impact of curability on focal lesions with secondary resistance was mainly significant in patients with tumors of stomach origin (P = 0.013), and a smaller number (P = 0.014) and smaller size (P = 0.018) of resistant lesions. Overall survival was 100% at 1 year and 75% at 2 years. Conclusion Our study indicates that surgical interventions in patients with GIST resistant to imatinib therapy are efficacious when complete resections are performed, when the lesions are of gastric origin, when the number of lesions is lower, and when the lesions are a smaller size.     

甲磺酸伊马替尼抑制黑素细胞游走的实验研究

目的探讨甲磺酸伊马替尼对人黑素细胞(NHEM)游走的抑制作用。方法培养NHEM,用四甲基偶氮唑蓝(MTT)还原法测定甲磺酸伊马替尼对NHEM生长和分化的影响;使用侵袭小室测定甲磺酸伊马替尼抑制NHEM的游走情况;用蛋白印记法测定甲磺酸伊马替尼抑制c-kit磷酸化情况。结果甲磺酸伊马替尼0.1μmol/L,1.0μmol/L,5.0μmol/L能够抑制由SCF50ng/mL引起的NHEM游走,并能抑制c-kit的磷酸化。结论甲磺酸伊马替尼抑制SCF引起的NHEM游走及抑制c-kit的磷酸化,为其用于防治色素痣治疗后的复发奠定了理论基础。     

Kinase Mutations and Imatinib Mesylate Response for 64 Taiwanese with Advanced GIST: Preliminary Experience from Chang Gung Memorial Hospital

Purpose Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutation of kit or platelet-derived growth factor receptor alpha (PDGFRA), which are therapeutic targets for imatinib. Results of 64 Taiwanese with advanced GIST treated with imatinib were reported. Method and materials Between 2001 and May 2006, a prospective, non-randomized, and a single center trial containing 64 Taiwanese patients with advanced GIST treated with imatinib was conducted. Each tumor was investigated for mutations of kit or PDGFRA. Results The median follow-up time after imatinib administration was 16.1 months. 12 patients (18.8%) had complete response (CR), 24 (37.5%) had a partial response (PR), 12 stationary disease (18.8%), 16 progressive disease (25.0%). The 64 Taiwanese with advanced GIST had an estimated median survival of 48.0 months and 4-year survival rate for 76.1%. Kit mutation was found in 49 of 54 (90.7%) test patients and five of them had no mutation (9.3%). No PDGFRA mutant was identified. In 40 patients harboring kit exon 11 mutations, the CR and PR rates (ORR) were 57.5% , nine patients with tumors containing kit exon 9 mutation had ORR rates of 22.2%, and five patients with no mutation had ORR rates of 60.0% (not significant; P = 0.149). Conclusions Activated mutation of kit constituted 90.7% genetic alteration of Taiwanese with advanced GIST and no PDGFRA mutation was detected. Imatinib induced a sustained objective response in more than half of Taiwan advanced GIST patients. ORR did not differ between patients whose GISTs had no mutation, kit exon 9, and 11 mutations.     

胃肠间质瘤患者中Imatinib血药浓度与治疗疗效的相关性

目的 检测中国晚期胃肠间质瘤(GIST)患者中伊马替尼(Imatinib)血药浓度,并分析血药浓度与治疗疗效的相关性.方法 收集112例接受Imatinib治疗超过28 d的GIST患者的117份血浆样本,用HPLC-MS/MS法检测血浆中Imatinib浓度.分析Imatinib血药浓度与治疗疗效的相关性.结果 高剂量组(600 ms/d)患者的血药浓度较低剂量组(400 mg/d)明显升高(P<0.001).服药时间为1～2年患者的血药浓度(平均值1 268 ng/mL)较服药时间小于1年的患者(平均值1 845 ng/mL)明显降低(P<0.05).随着血药浓度的增加有效率也随之增加,血药浓度低、中及高水平组的有效率分别为50%、67.5%及66.7%.结论 Imatinib血药浓度与服药剂量及服药时间明显相关;Imatinib治疗有效率随着血药浓度的增高呈增加趋势.     

Dermatofibrosarcoma protuberans – An Update

Dermatofibrosarcoma protuberans (DFSP) is a rare fibroblastic skin tumor of intermediate malignancy. Its pathogenesis has not yet been fully clarified. Recent basic genetic research has shown chromosomal translocations, generally termed “ring chromosomes”, in DFSP. These arise from a fusion of chromosome regions 17q22 and 22q13, the gene loci which code the alpha chain of type I collagen. The diagnosis is made histologically. Differentiation from atypical dermatofibroma and dermatomyofibroma, as well as from malignant fibrous histiocytoma, whose prognosis is usually much less favorable, can be improved by immunostaining for CD 34 and Factor XIIIa. The extent of the tumors can be estimated by CT and more precisely with MRI. All these techniques fail to detect the fine tumor fascicles extending into the adjacent connective tissue and fat. Surgery is the therapy of choice for DFSP. The locally infiltrative growth pattern features clinically inapparent extensions which often extend for long distances in a horizontal direction. These tumor extensions are best detected by uninterrupted histological check of all margins, including the base (3‐D‐histology), with paraffin sections. Re‐excision of tumor‐positive areas until tumor‐free margins are obtained (“histographic surgery”) insures a high cure rate (97 %) while preserving normal tissue.     

The analysis of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST) treated in routine practice

IntroductionThe real-world data on adjuvant imatinib therapy in high-risk primary GIST are scarce.MethodsWe have analysed the data of 107 consecutive patients with gastrointestinal stromal tumour (GIST) after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centres in 2013–2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy without any further selection. Median follow-up time was 27 months.ResultsThe most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harboured exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Forty patients (37%) finished 3-year adjuvant imatinib therapy as planned, 48 (45%) still continue therapy, 5 (4.5%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 8 (7.5%) due to other reasons. The disease relapse was detected in 19 patients, of them in 5 cases in exon 9 KIT mutants (45%), and 14 cases in patients with exon 11 KIT mutations (11%) [p < 0.01]. Estimated 4-year relapse-free survival (RFS) rate is 78%.ConclusionsThe early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-driven GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. We found overrepresentation of exon 9 KIT mutants and ruptured tumors in a group of patients with disease relapse.     

Phase I/II Trial of Imatinib and Bevacizumab in Patients With Advanced Melanoma and Other Advanced Cancers

Background.

Vascular endothelial growth factor and platelet-derived growth factor signaling in the tumor microenvironment appear to cooperate in promoting tumor angiogenesis.

Patients and Methods.

We conducted a phase I trial combining bevacizumab (i.v. every 2 weeks) and imatinib (oral daily). Once a recommended phase II dose combination was established, a phase II trial was initiated in patients with metastatic melanoma. A Simon 2-stage design was used with 23 patients required in the first stage and 41 patients in total should the criteria to proceed be met. We required that 50% of the patients be progression-free at 16 weeks. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and power Doppler ultrasonography were performed in patients with metastatic tumors amenable to imaging with these methods at baseline and after 4 weeks.

Results.

A total of 17 patients were accrued to 4 dose and combination levels. Bevacizumab 10 mg/kg every 2 weeks could be safely combined with imatinib 800 mg daily. Common toxicities included fatigue, nausea, vomiting, edema, proteinuria, and anemia, but were not commonly severe. A total of 23 patients with metastatic melanoma (48% with American Joint Commission on Cancer stage M1c; median age, 63 years) were enrolled in the first stage of phase II. The 16-week progression-free survival rate was 35%, leading to termination of phase II after the first stage. In the small subset of patients who remained on study with lesions evaluable by DCE-MRI, significant decreases in tumor vascular permeability were noted, despite early disease progression using the Response Evaluation Criteria In Solid Tumors.

Conclusion.

Bevacizumab and imatinib can be safely combined at the maximum doses used for each agent. We did not observe significant clinical activity with this regimen in melanoma patients.

Implications for Practice:

Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy has proven clinical efficacy as a standalone therapy in renal cell carcinoma and glioblastoma multiforme. Also, enhancement of conventional cytotoxic chemotherapy efficacy has been observed in colorectal, non-small-cell lung, breast, and ovarian cancers. Optimal strategies to cotarget angiogenic cytokines combined with VEGF have not been defined. It was found that bevacizumab could be safely combined with imatinib, which was used as a platelet-derived growth factor receptor inhibitor in our study. High-dose imatinib-related edema was not observed when paired with bevacizumab. This regimen might be suitable for further investigation in other cancers but apparently not in melanoma.