Imatinib mesylate in clinically suspected gastric stromal tumors

Gastrointestinal stromal tumors （GISTs） occur most frequently in the stomach.Diagnosis of gastric GIST is not always clear before surgery.Flexible endoscopy may suggest the nature of the lesion （a bulky tumor with preserved mucosa）; however,biopsy is rarely diagnostic.Therefore,diagnostic medication with safe drugs may provide a feasible way under such conditions after an informed consent is obtained.Based on the excellent efficacy of imatinib mesylate （IM） in the treatment of GIST,we successfully applied it in the diagnostic medication of two patients with clinically suspected gastric stromal tumors.In conclusion,the diagnostic medication with IM can be an alternative option for patients with suspected GIST that can not be confirmed pathologically.

Pathologic complete response confirmed by surgical resection for liver metastases of gastrointestinal stromal tumor after treatment with imatinib mesylate

A 39-year-old male underwent distal gastrectomy for a high grade gastrointestinal stromal tumor(GIST) . Computed tomography(CT) and magnetic resonance imaging(MRI) 107 mo after the operation,revealed a cystic mass(14 cm in diameter) and a solid mass(9 cm in diameter) in the right and left lobes of the liver,respectively. A biopsy specimen of the solid mass showed a liver metastasis of GIST. The patient received imatinib mesylate(IM) treatment,400 mg/day orally. Following the IM treatment for a period of 35 mo,the patient underwent partial hepatectomy(S4 + S5) . The effect of IM on the metastatic lesions was interpreted as pathologic complete response(CR) . Pathologically verified cases showing therapeutic efficacy of IM have been rarely reported.

Evaluation of imatinib mesylate(Gleevec) on KAI1/CD82 gene expression in breast cancer MCF-7 cells using quantitative real-time PCR

Objective: To evaluate the effect of imatinib mesylate on cell viability, anti cancer effect through modulation of KAI1/CD82 gene expression in breast cancer MCF-7 cell line.Methods: The effects of imatinib mesylate on cell viability in MCF-7 cell line were assessed using MTT assay and IC_(50) value was determined. GAPDH and KAI1/CD82 were selected as reference and target genes, respectively. Quantitative real time PCR technique was applied for investigation of KAI1/CD82 gene expression in human breast cancer MCF-7 cells. Subsequently, the quantity of KAI1 compared to GAPDH gene expressions were analyzed using the formula; 2^(-DDCt).Results: Imatinib was showed to have a dose-dependent inhibitory effect on the viability of MCF-7 cells. CD82/GAPDH gene expression ratios were 1.322 ± 0.030(P > 0.05),2.052 ± 0.200(P < 0.05), 2.151 ± 0.270(P < 0.05) for 10, 20 and 40 mmol/L of imatinib concentrations.Conclusions: Based on the present data, imatinib mesylate might modulate metastasis by up-regulating KAI1/CD82 gene expression in human breast MCF-7 cancer cell line.

Advanced gastrointestinal stromal tumor patients with complete response after treatment with imatinib mesylate

瞄准：大多数胃肠的基质肿瘤(大意) 快车组成地激活工具包激酶或导出血小板的生长因素受体高山的变异的 isoforms 哈(PDGFRA ) ，它是为 imatinib mesylate (Glivec ) 的潜在的治疗学的目标。部分反应发生在与 Glivec 对待的几乎三分之二个大意病人。然而，在 Glivec 治疗以后的完全的反应(CR ) 偶发地被报导。这里，我们在 Glivec 治疗以后与 CR 说明了先进大意病人。方法：在 2001 年 1 月和 2005 年 6 月之间， 42 个先进大意病人与 Glivec 被对待。病人们被管理在 100-mg 囊的 Glivec 的 400 mg，每天与食物口头上地拿。到 Glivec 的肿瘤的反应此后在一个月，三个月，和每三个月以后被评估或每当医药需要被显示时。病人的每个肿瘤为工具包或 PDGFRA 的变化被调查。结果：与 Glivec 对待的 42 个先进大意病人的中部的后续时间是 16.9 个月(范围， 1.0-47.0 月) 。总的来说，有的 3 个病人完成反应 CR (7.1%) ， 26 部分反应(67.8%) ， 5 静止疾病(11.9%) ，和 3 进步疾病(11.9%) 。为三个病人的 Glivec 管理的中部的持续时间是 36 个月(范围， 23-36 月) 。在 Glivec 治疗以后的 CR 的中部的时间是 20 个月(范围， 9-26 月) 。11 上的 c 工具包前的删除和插入变化和 9 上的 c 工具包前的插入变化分别地在二种情况和一个案例中被发现。结论：完全的反应(CR ) 能在与 Glivec 对待的选择先进大意病人被完成。在 Glivec 治疗以后的 CR 的中部的时间是 20 个月。11 上的工具包前的删除和插入变化和 9 上的工具包前的插入变化在这些选择盒子中贡献基因特征。

抗癌药Imatinib Mesylate的多晶型结构与稳定性

本文对抗癌药物甲磺酸伊马替尼的多晶型与稳定性进行了分析与研究.通过X射线粉末衍射仪(XRD)测定了伊马替尼的晶型,并测定了在不同湿度下的稳定性,用X射线衍射原位高温附件(in situ high temperature)测定了伊马替尼的热稳定性.结果表明,该批次伊马替尼为α晶型,在从室温至200℃的加热过程中晶体结构稳定,在RH 75%的湿度条件下,结构也比较稳定,但在RH 92.5%的高湿度时,晶体结构逐渐向无定形转化.

Development of multiple myeloma in a patient with gastrointestinal stromal tumor treated with imatinib mesylate:a case report

Gastrointestinal stromal tumors (GISTs) are rare tumors, which represent approximately 1% of the neoplasms of the gastrointestinal tract. These tumors rarely give extra-abdominal metastases. However, their clinical outcome is potentially adverse. In some rare cases, co- existance of GISTs with other malignancies has been reported. Here we present a case of a 74-year old male with GIST, which was managed by surgical resection. Fourteen months later, the patient presented with liver metastases and imatinib mesylated was administered. During treatment, the patient reported skeletal pain and plane X-rays revealed osteolytic bone lesions. Further investigation revealed the presence of multiple myeloma. To the best of our knowledge, this is the first report of the co-existence of multiple myeloma (MM) with GIST.

Assessment of gastrointestinal stromal tumors with computed tomography following treatment with imatinib mesylate

AIM: To evaluate and characterize the patterns of disease progression of metastatic or unresectable gastrointestinal stromal tumor (GIST) treated with imatinib mesylate, and to determine the prognostic significance associated with disease progression. METHODS: Clinical data and computed tomography (CT) images were retrospectively reviewed in 17 GIST patients who were treated with imatinib mesylate from October 2002 to October 2006. Apart from using size measurement for evaluation of tumor response [Response Evaluation Criteria in Solid Tumors (RECIST) criteria], patterns of CT changes during treatment were evaluated and correlated with clinical data. RESULTS: There were eight non-responders and nine responders. Five patterns of CT change during treatment were found: focal progression (FP), generalized progression (GP), generalized cystic change (GC), new cystic lesion (NC) and new solid lesion (NS). At the end of study, all non-responders showed GP, whereas responders showed cystic change (GC and NC) and response according to RECIST criteria. Overall survival was significantly better in patients with cystic change or response within the RECIST criteria compared with GP patients (P = 0.0271). CONCLUSION: Various patterns of CT change in patients with GIST who responded to imatinib mesylate were demonstrated, and might determine the prognosis of the disease. A combination of RECIST criteria and pattern of CT change are proposed for response evaluation in GIST.

Gastrointestinal stromal tumors and second primary malignancies before and after the introduction of imatinib mesylate

Gastrointestinal stromal tumor （GIST） is the most common mesenchymal malignancy of the gastrointestinal tract.GISTs may coexist with different types of cancer,either synchronous or metachronous （1）.Most GISTs develop in a sporadic fashion,but familial occurrence,such as neurofibromatosis and Carney-triad,has also been reported （2）.The overall frequency of second tumors in different series varied from 4.5% to 33%.The most frequent types of GIST-associated cancers were gastrointestinal carcinomas （47%）,lymphoma/leukemia （7%）,carcinomas of prostate （9%）,breast （7%）,kidney （6%）,lung （5%）,female genital tract （5%）,carcinoid tumors （3%）,soft tissue and bone sarcomas （3%）,malignant melanoma （2%） and seminoma （1%） （1,3-5）.

Bilateral Masculine Mastoplasia Associated with Imatinib Mesylate:A Case Report and Literature Review

1 CASE REPORT In June 2009, a 29-year-old Chinese male was diagnosed as having Philadelphia chromosome-positive chronic myeloid leukemia （chronic phase）; other than a high white blood cell count in peripheral blood （WBC, 254.00×10^9/L） and splenomegaly, the patient exhibited no abnormal physical signs in mammary glands. He was given hydroxyurea for several days before he received treatment with 400 mg of imatinib mesylate daily.

Effect of PDGF-Rb antagonist imatinib on endometrial injury repairing in mouse model

Objective: To study the effects of PDGF-Rb antagonists imatinib on endometrial injury repairing in the mouse model. Methods: The cultured MSCs cells from male mice were marked with Brd U in vitro, and then transplanted to the female mice which suffered from radiation injury through tail vein, PDGF-Rb antagonists imatinib was injected through abdominal cavity. Four groups were arranged, which were radiation transplantation group, normal control group, imatinib intervention group and radiation control group. Brd U incorporation, SRY expression and MVD status were detected in uterus of mice. Results: SRY gene was negative expressed in normal control group and radiation control group. SRY gene presented positive in radiation transplantation group and imatinib intervention group; Brd U incorporation showed negative in radiation control group and normal control group which died in the early stage in mice; the incorporation of Brd U was higher in radiation transplantation group compared with imatinib intervention group; CD34 was positive on the uterus of all the four groups,which showed highest in radiation control group and lowest in radiation control group; The MVD in imatinib intervention group was lower than radiation control group; the difference of MVD was significantly compared with normal control group(P<0.05). Conclusions: PDGF-Rb antagonists imatinib could inhibit the repairing function of MSCs in the endometrial lesions in mice.

Long-term survival of a case with multiple liver metastases from duodenal gastrointestinal stromal tumor drastically reduced by the treatment with imatinib and hepatectomy

工具包受体酷氨酸激酶的组成的激活是在胃肠的基质肿瘤(大意) 的致病的一个关键因素。但是几乎没有 imatinib mesylate (IM ) 和外科疗法的联合是否能与 unresectable 在情况中延长幸存的很少信息多重肝转移。我们报导酷氨酸激酶禁止者 IM 和外科疗法对待的大意的手术后的复发的一个案例。对处理的起始的完全的反应(CR ) 为 18 瞬间继续，但是单个肝转移在 IM 处理期间在左肝的脑叶显示出生长。在再发性瘤的部分切除术以后，手术后的路线是平静的，没有复发，病人为 24 瞬间幸存。当前， imatinib 是为 non-resectable 大意的首要的治疗，但是单个代理人治疗经常导致肿瘤抵抗。就算到 imatinib 的忍耐发生， imatinib 和外科疗法的联合能在这里报导了的一些情况中延长幸存。然而，周期性的大意的很多案例上的进一步的研究是必要的评估治疗与外科相结合的 IM 的有效性。

Imatinib-induced fatal acute liver failure

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d. Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor Ⅴ. Five days after admission, grade Ⅱ encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.

MDR1 Haplotypes and G2677T/A Polymorphism Predict Imatinib Response in Tunisian Patients with Chronic Myeloid Leukemia

Background: The role of human multidrug resistance gene (MDR1) SNPs in the interindividual variability of imatinib mesylate (IM) response has received considerable attention. We aimed to study the association between SNPs of the MDR1 gene (C1236T, G2677T/A, C3435T) and IM response in chronic myeloid leukemia (CML) patients. Method: A retrospective case-control study was conducted on 48 patients with CML undergoing IM therapy. All patients were genotyped using PCR-RFLP method. Results: The genotype and allele frequencies of C1236T and C3435T were not significantly different between CML patients responders and non-responders to IM (p > 0.05). The frequencies of 2677T allele and 2677TT genotype were significantly increased in CML patients IM responders which as compared with IM non-responders (50% vs 26.9%, p = 0.013 and 27.3% vs 3.8%, p = 0.029 respectively). Whereas the 2677AA genotype and CAC haplotype were found only in CML patients IM non-responders (15.4%). Conclusion: Pretreatment genotyping of G2677A/T appears to be useful for predicting IM resistance, which may allow the best choice of drug treatment for CML patients.

Sudden extramedullary and extranodal Philadelphia-positive anaplastic large-cell lymphoma transformation during imatinib treatment for CML:A case report

BACKGROUND Chronic myeloid leukemia(CML)is a malignant hematologic malignancy that can progress to blast phase with a myeloid or lymphoid phenotype.Some patients with CML can also progress to blast crisis phase;however,the transformation of CML into Philadelphia-positive lymphoma is extremely rare.CASE SUMMARY We present a patient with CML who experienced a sudden transformation to anaplastic large-cell lymphoma(ALCL)after 7 mo of treatment with imatinib,during which she had achieved partial cytogenetic response as well as early molecular response.The patient noticed a mass in her left shoulder,the biopsy data of which were consistent with ALCL;moreover,her lymphoma cells exhibited BCR-ABL gene fusion.The patient was diagnosed with Philadelphia-positive ALCL that progressed from CML,and was thus treated with the second generation tyrosine kinase inhibitor nilotinib.Six months later,the mass had totally disappeared and the BCR-ABL fusion gene was undetectable in the peripheral blood.To our knowledge,this is the first patient known to have developed Philadelphia-positive ALCL transformed from CML.CONCLUSION Unexplained lymphadenopathy or an extramedullary mass in a patient with CML may warrant a biopsy and testing for BCR-ABL fusion.

甲磺酸伊马替尼联合VDLD方案诱导治疗儿童急性淋巴细胞白血病的临床疗效

目的 探讨甲磺酸伊马替尼联合长春地辛+地塞米松+培门冬酶+去甲氧柔红霉素(VDLD)方案诱导治疗儿童急性淋巴细胞白血病的临床疗效。方法 根据化疗方案的不同将104例急性淋巴细胞白血病患儿分为对照组(n=52)和观察组(n=52),对照组患儿给予VDLD方案治疗,观察组患儿给予甲磺酸伊马替尼联合VDLD方案治疗。比较两组患儿的临床疗效、肿瘤标志物[血管内皮细胞生长因子(VEGF)、血管内皮细胞生长因子受体(VEGFR)、碱性成纤维细胞生长因子(bFGF)]水平、不良反应发生情况及预后情况。结果 观察组患儿的治疗总有效率和5年生存率均高于对照组,5年复发率低于对照组,差异均有统计学意义(P﹤0.05)。治疗后,两组患儿VEGF、VEFGR、bFGF水平均低于本组治疗前,观察组患儿VEGF、VEFGR、bFGF水平均低于对照组,差异均有统计学意义(P﹤0.05)。两组患儿的不良反应总发生率比较,差异无统计学意义(P﹥0.05)。结论 甲磺酸伊马替尼联合VDLD方案诱导治疗儿童急性淋巴细胞白血病,能够提高临床疗效,降低复发率,且不会增加不良反应,安全性较高。

甲磺酸伊马替尼有关物质的合成

为了控制甲磺酸伊马替尼在生产过程中的质量,分别制备了甲磺酸伊马替尼的5个有关物质:以对氯甲基苯甲酸为起始原料,改进合成方法合成4-(氯甲基)-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质A),收率为91.4%。以有关物质A为起始原料,设计了新的合成路线得到4-[[[4-[(4-甲基哌嗪-1-基)甲基]-苯甲酰基]-基-哌嗪-1-基]-甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质B),收率为77.5%。4-[(4-甲基-1-氧化哌嗪-1-基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质C)、4-[(4-甲基-4-氧化哌嗪-1-基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质D)和4-[(4-甲基-1,4-二氧化哌嗪-1-基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质E)结构相似,本研究设计了新的合成方法,其收率分别为85.5%、78.2%和82.5%,并通过MS和NMR对上述五个有关物质结构进行了表征。

Hepatitis B virus reactivation in a chronic myeloid leukemia patient treated with imatinib mesylate

Imatinib mesylate is a molecular targeted agent for treating chronic myeloid leukemia （CML） and gastrointestinal stromal tumor. Although imatinib mesylate is not regarded as an immunosuppressive agent, few studies have also shown that it may impair immune response. In this report, we present a case of transient hepatitis B virus （HBV） reactivation during imatinib mesylate treatment for CML.

Intra-abdominal desmoid tumors mimicking gastrointestinal stromal tumors——8 cases: A case report

BACKGROUND Intra-abdominal desmoid tumors(DTs) can mimic recurrence or progression of gastrointestinal stromal tumors(GISTs). Differential diagnosis is important to avoid unnecessary or inappropriate treatment.CASE SUMMARY All 8 patients experienced surgical resection of GIST, and median time to diagnosis of DT was 1.8 years after surgical resection. All sites of DT were in the peritoneum around the surgical sites of GIST. The following clinical suspicion coupled with radiological findings contributed to the suspicion of intraabdominal DTs:(1) Occurrence of a new single lesion in the peritoneum around the surgical sites of GIST;(2) uncontrolled lesion with imatinib while other lesions being controlled with imatinib;(3) well-defined ovoid shaped lesion with delayed or mild enhancement and absence of necrosis, hemorrhage, and cystic change on computed tomography; and(4) a lesion showing mild or no hypermetabolic activity on 18 fluorodeoxyglucose-positron emission tomography,contrary to initially hyperactive lesion of GIST. All DTs were surgically removed except for one unresectable DT and only one DT recurred at another site of peritoneum, which was also surgically removed.CONCLUSION Intra-abdominal DT should be a differential diagnosis for a new single lesion in patients with GIST.

Primary Extra-Gastrointestinal Stromal Tumor (GIST) arising from mesentery of small bowel and presenting as abdominal mass: A rare entity

Introduction: Majority of mesenchymal tumors of gastrointestinal tract are Gastrointestinal Stromal Tumor (GIST). It is, however, a rare tumor, accounting for less than 1% of primary gastrointestinal (GI) neoplasms. Though, these tumors are refractory to conventional chemotherapy or radiotherapy but show a good response to targeted adjuvant chemotherapy with tyrosine kinase inhibitors following surgical resection. Case Report: we report here a case of primary Extra-GIST tumor arising from mesentry of small bowel near duodeno-jejunal junction in a 69 years old male patient. The patient presented with a palpable mass in upper abdomen for past 15 days. On examination, a non-tender mobile lump of size around 17 × 10 cm, with bosselated surface and firm in consistency was palpable involving epigastric, left hypochondrium and umbilical region. Contrast enhanced computed tomography of abdomen revealed a heterogenous mesentric mass. On surgical intervention a mass was found involving mesentery near dudenojejunal junction without involvement of gastrointestinal tract. Complete surgical resection of the tumor was done and adjuvant chemotherapy with Imatinib mesylate was started as HPE revealing GIST with mitotic index of >10/50 HPF and 17 × 10 cm size placed the patient in high risk category. Patient was discharged on 12th of post-operative day with advice of regular follow-up. Conclusion: GIST occurrence is not restricted to bowel but can involve unusual sites also. The mainstay of treatment remains surgical resection with adequate margin. In cases where tumour has malignant potential (high mitotic figures on histopathology) adjuvent treatment with tyrosine kinase may prevent or delay relapse.

IL-5介导甲磺酸伊马替尼诱发的红皮病型药疹一例并文献复习

报道一例胃间质瘤患者服用甲磺酸伊马替尼7个月后全身泛发红斑脱屑、眶周水肿、指甲甲板增厚色沉等红皮病样表现,给予环孢素口服,2周后皮损好转,检测其治疗前后12项免疫因子发现IL-1β、IL-5及IFN-γ显著下降,其中IL-5从治疗前1811 pg/mL降至36.22 pg/mL,表明IL-5在甲磺酸伊马替尼诱发不良反应中发挥重要作用,提示靶向IL-5的生物制剂可能是治疗该病的潜在药物。