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Genetic Polymorphisms Contribute to the Individual Variations of imatinib mesylate Plasma Levels and Adverse Reactions in Chinese GIST Patients

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Genetic Polymorphisms Contribute to the Individual Variation...

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

石河子大学2017年“一带一路”核心区创新驱动发展博士...

作者： Jing Liu Zhiyu Chen Hanmei Chen Yingyong Hou Weiqi Lu Junyi He Hanxing Tong Yuhong Zhou Weimin Cai Department of Clinical Pharmacy School of Pharmacy Fudan University Department of Medical Oncology Shanghai Cancer Center Fudan University Department of Pathology Zhongshan Hospital Fudan University Department of General Surgery Zhongshan Hospital Fudan University Department of Medical Oncology Zhongshan Hospital Fudan University

imatinib mesylate（IM） has dramatically improved the outcomes of gastrointestinal stromal tumor（GIST） patients. However, the clinical responses of IM may considerably vary among single individuals. This study aimed to investigate the influences of genetic polymorphisms of drug-metabolizing enzyme（CYP3A4）, transporters（ABCB1, ABCG2）, and nuclear receptor（Pregnane X Receptor（PXR, encoded by NR1I2）） on IM plasma levels and related adverse reactions in Chinese GIST patients. A total of 68 Chinese GIST patients who have received IM 300–600 mg/day were genotyped for six single nucleotide polymorphisms（SNPs）（CYP3A4 rs2242480;ABCB1 rs1045642;ABCG2 rs2231137;NRI12 rs3814055, rs6785049, rs2276706）, and the steady-state IM trough plasma concentrations were measured by a validated HPLC method. There were statistically significant variances in the steady-state IM trough plasma concentrations（from 272.22 to 4365.96 ng/m L）. Subjects of GG in rs2242480, T allele carriers in rs1045642 and CC in rs3814055 had significantly higher steady-state IM dose-adjusted trough plasma concentrations. Subjects of CC in rs3814055 had significantly higher incidence rate of edema. The genetic polymorphisms of rs2242480, rs1045642, rs3814055 were significantly associated with IM plasma levels, and the genetic variations of rs3814055 were significantly associated with the incidence rate of edema in Chinese GIST patients. The current results may serve as valuable fundamental knowledge for IM therapy in Chinese GIST patients.

关键词： imatinib mesylate gastrointestinal stromal tumor genetic polymorphisms plasma levels adverse reactions Chinese

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World Journal of Clinical Cases 2022年第28期10卷 10339-10345页

作者： Qiong Wu Yong Kang Jing Xu Wen-Can Ye Zhen-Jiang Li Wen-Feng He Yuan Song Qing-Ming Wang Ai-Ping Tang Ting Zhou Department of Clinical Laboratory The Second Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina Department of Hematology The Second Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina Department of Hematology Pingxiang People's hospitalPingxiang 337000Jiangxi ProvinceChina Department of Hematology The First Affiliated Hospital of Gannan Medical UniversityGanzhou 341001Jiangxi ProvinceChina Key laboratory of Molecular Medicine of Jiangxi The Second Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina Department of Pathology The Second Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina

BACKGROUND Chronic myeloid leukemia(CML)is a malignant hematologic malignancy that can progress to blast phase with a myeloid or lymphoid *** patients with CML can also progress to blast crisis phase;however,the transformation of CML into Philadelphia-positive lymphoma is extremely *** 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 *** 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 *** patient was diagnosed with Philadelphia-positive ALCL that progressed from CML,and was thus treated with the second generation tyrosine kinase inhibitor *** months later,the mass had totally disappeared and the BCR-ABL fusion gene was undetectable in the peripheral *** our knowledge,this is the first patient known to have developed Philadelphia-positive ALCL transformed from *** Unexplained lymphadenopathy or an extramedullary mass in a patient with CML may warrant a biopsy and testing for BCR-ABL fusion.

关键词： Chronic myeloid leukemia BCR-ABL fusion gene imatinib mesylate Anaplastic large-cell lymphoma Philadelphia-positive Nilotinib Case report

Gastrointestinal tumors in transplantation: Two case reports and review of literature

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World Journal of Gastroenterology 2022年第34期28卷 5076-5085页

作者： Romain Stammler Dany Anglicheau Bruno Landi Tchao Meatchi Emilia Ragot Eric Thervet Helene Lazareth Department of Nephrology Georges Pompidou European HospitalParis 75015France Department of Renal Transplantation Necker-Enfants Malades InstituteFrench National Institutes of Health and Medical Research U1151Paris 75015France Universite Paris Cite Assistance Publique des Hôpitaux de ParisParis 75001France Department of Gastroenterology and Digestive Oncology Georges Pompidou European HospitalParis 75015France Department of Pathology Georges Pompidou European HospitalParis 75015France Department of Digestive Surgery Georges Pompidou European HospitalParis 75015France

BACKGROUND Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal *** most of them harbor a KIT mutation(75%),selective kinase inhibitors are the therapeutic option and show a sustained objective response among patients with metastatic or unresectable GISTs.A wellknown higher risk of neoplasm has been described among renal transplant recipients(RTRs).Nevertheless,only few cases of GIST onset among transplant patients have been reported in the *** SUMMARY Here,we describe 2 cases of gastric GIST occurring during the follow-up of *** also review the existing literature concerning GIST occurrence in transplant *** total and in association with our 2 cases,16 patients have been *** median age was 59.5 years and 69%were *** a median tumor size of 45 mm,no patient displayed metastatic dissemination at *** from transplantation to diagnosis was highly variable between 5 mo and 21 *** data mostly revealed high risk of progression(43%).Death increased to 29%during *** treatment was systematically performed when the tumor was operable(94%).The use of adjuvant therapy was uncommon(19%).CONCLUSION GISTs represent rare but potentially severe malignant complication among transplant patients.

关键词： Gastrointestinal stromal tumors imatinib mesylate Transplantation Kidney transplantation Proto-oncogene protein c-KIT Case report

FIPIL1-PDGFRα alone or with other genetic abnormalities reveals disease progression in chronic eosinophilic leukemia but good response to imatinib

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Chinese Medical Journal 2008年第10期121卷 867-873页

作者： WANG Lin-na PAN Qin FU Jian-fei SHI Jing-yi JIN Jie LI Jun-ming HU Jion ZHAO Wei-li CHEN Zhu CHEN Sai-juan State Key Laboratory of Medical Genomics Shanghai institute of Hematology Shanghai Ruijin Hospital Shanghai Jiao TongUniversity School Of Medicine Shanghai 200025 China Zhejiang Institute of Hematology First Affiliated HospitalZhejiang University School of Medicine Hangzhou Zhejiang 310003 China

Background The FIP1L1-PDGFRa fusion gene plays an important role in the pathogenesis of chronic eosinophilic leukemia （CEL） and is a direct therapeutic target of the tyrosine kinase inhibitor imatinib mesylate. Methods In 24 hypereosinophilic syndromes （HES） patients, using reverse transcriptase-polymerase chain reaction （RT-PCR）, nested PCR and sequence analysis, we investigated the frequency of FIPIL1-PDGFRa and other abnormalities of tyrosine kinase family genes like PDGFRa, PDGFRβ, C-KIT, FGFR1, ABL and FLT3 as well as gene mutation ＂hotspots＂, like MPL515 and JAK2V617F, frequently involved in myeloproliferative diseases. Fluorescence in situ hybridization was used to confirm the 4q 12 deletion. Results The FIP1L1-PDGFRa fusion transcript was found in 8 （33%） of 24 patients with HES, corresponding to the chromosome 4q12 deletion identified by FISH. The FIP1L 1-PDGFRα-associated patients diagnosed with CEL, frequently had hepatosplenomegaly, eosinophil-related tissue damage, anemia, thrombocytopenia, myelofibrosis and a short overall survival time. Nevertheless, imatinib mesylate induced rapid and complete hematological responses in treated FIP1L1-PDGFRa cases, followed by molecular remission and reversal of myelofibrosis. FIP1L1-PDGFRa fusion could co-exist with other mutations of tyrosine kinase family genes, like FLT3 or PDGFRβ. We also demonstrated that the SNPs of PDGFRβ were associated with selective splicing of exon 19 in case 20. Conclusions Correlating the CEL genotype with phenotype, FIP1L1-PDGFRa emerges as a relatively homogeneous clinicobiological entity that co-exists with other abnormalities of tyrosine kinase family genes. It reflects the disease progression and there is a good response to imatinib. Detection of the FIP1L 1-PDGFFla fusion gene is valid for both CEL diagnosis and therapy surveillance.

关键词： chronic eosinophilic leukemia FIP1L1-PDGFRa tyrosine kinase imatinib mesylate myeloproliferative disease

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

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Journal of Biosciences and Medicines 2022年第9期10卷 118-131页

作者： Mariam Ammar Sonia Ktari Moez Medhaffar Hanen Ghozzi Moez Elloumi Adnen Hammami Khaled Zeghal Lobna Ben Mahmoud Department of Pharmacology Faculty of Medicine University of Sfax Sfax Tunisia Faculty of Sciences of Sfax University of Sfax Sfax Tunisia Department of Bacteriology Faculty of Medicine University of Sfax Sfax Tunisia Department of Clinical Hematology Hedi Chaker Hospital University of Sfax Sfax Tunisia

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.

关键词： Chronic Myeloid Leukemia imatinib mesylate P-Glycoprotein Multi Drug Resistance G2677T/A Haplotype

STI571 combined with vincristine greatly suppressed the tumor formation of multidrug-resistant K562 cells in a human-nude mice xenograft model

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Chinese Medical Journal 2006年第11期119卷 911-918页

作者： GA0 Lei CHEN Li FEI Xin-hong QIU Hui-ying ZH0U Hong WANG Jian-min Department of Hematology Changhai Hospital Second Military Medical University Shanghai 200433 China

Background The development of the targeted signal transduction inhibitor STI571 has prompted us to treat chronic myeloid leukemia in different ways. Since STI571 may reverse multidrug-resistance of K562/MDR cells in vitro, we studied the effect of STI571 on multidrug-resistant K562 cells in vivo. Methods Multidrug-resistant human leukemia cell line K562-n/VCR expresses both bcr/abl fusion gene and multi-drug resistance （mdrl） gene. It is a vincristine resistant cell line subcloned from the vincristine （VCR） sensitive cell line K562-n induced by vincristine in vitro. K562-n and K562-n/VCR cells were inoculated subcutaneously into both sides of nude mice breast （5×10^6 cells/each） to establish a human leukemia xenograft model. The incidence and volume of tumor were observed. In the tumor-bearing nude mice, anti-tumor drugs vincristine, daunorubicin （DNR）, STI571, and STI571 plus VCR for the treatment of mdrl and bcr/abl double positive leukemia were studied respectively. Results The tumor incidence was 100% in the nude mice inoculated with either K562-n or K562-n/VCR. The transcription of the mdrl gene and expression of P-gp were negative in K562-n cells but positive in K562-n/VCR cells. The intracellular accumulation of DNR in K562-n cells was higher than that in K562-n/VCR cells （P〈0.05） The tumor incidence of K562-n/VCR cells in nude mice was much higher than that of K562-n cells in chemotherapy groups, and the mean volume of the tumors was also larger （P〈0.05）. STI571 combined with VCR significantly suppressed the proliferation of K562-n/VCR cells. Conclusions The MDR characteristics of K562-n/VCR in vivo were the same as in vitro. STI571 had a significant tumor-suppressing effect on VCR-sensitive leukemia ceils and a moderate effect on MDR leukemia cells. VCR combined with STI571 had an excellent tumor-suppressing effect on both K562-n/VCR and K562-n in the human-nude mice xenograft model.

关键词： K562 cells leukemia multidrug-resistance imatinib mesylate xenograft model antitumor assays

Current update on molecular cytogenetics, diagnosis and management of gastrointestinal stromal tumors

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World Journal of Gastroenterology 2021年第41期27卷 7125-7133页

作者： Mindy X Wang Catherine Devine Nicole Segaran Dhakshinamoorthy Ganeshan Department of Diagnostic Imaging University of Texas MD Anderson Cancer CenterHoustonTX 77030United States Department of Radiology Mayo Clinic ArizonaPhoenixAZ 85259United States

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal(GI)tract and are thought to arise from precursors of the interstitial cells of *** can arise anywhere in the GI tract,but most commonly originate from the stomach and small *** majority of GISTs occur as a result of activating mutations in two receptor protein tyrosine kinases:KIT and/or platelet-derived growth factor receptor-α.Mutational analyses allow for predicting patient prognosis and treatment *** presentations can vary from no symptoms,typical in the case of small incidentally found tumors,to GI bleeding,abdominal discomfort,and ulcer-related symptoms when the tumor is *** plays a critical role in the diagnosis and management of these tumors with multiphasic computed tomography serving as the imaging modality of *** resonance imaging and positron emission tomography-computed tomography can serve as imaging adjuncts in lesion characterization,especially with liver metastases,and subsequent staging and assessment for treatment response or *** resection is the preferred management for small GISTs,while tyrosine kinase inhibitors−imatinib mesylate and sunitinib malate−serve as crucial molecular-targeted therapies for locally advanced and metastatic *** review article highlights the clinical presentation,pathology and molecular cytogenetics,imaging features,and current management of GISTs.

关键词： Gastrointestinal stromal tumors Cytogenetics Diagnostic imaging Computed tomography Magnetic resonance imaging imatinib mesylate

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c-Abl基因在小鼠消化道稳态中的作用

c-Abl基因在小鼠消化道稳态中的作用

作者：包丹丹上海交通大学

学位级别：硕士

甲磺酸伊马替尼(imatinib mesylate，STI571或Gleevec)是临床上常用的一种治疗慢性粒细胞白血病的药物，它还可以用于治疗其它一些癌症，如胃肠道间质瘤、结肠直肠癌、人上皮乳腺癌等。它主要的靶基因是c-Abl、c-Kit和血小板生长因子受... 详细信息

甲磺酸伊马替尼(imatinib mesylate，STI571或Gleevec)是临床上常用的一种治疗慢性粒细胞白血病的药物，它还可以用于治疗其它一些癌症，如胃肠道间质瘤、结肠直肠癌、人上皮乳腺癌等。它主要的靶基因是c-Abl、c-Kit和血小板生长因子受体(PDGFR)基因。本文对正常小鼠腹腔注射imatinib mesylate进行研究，发现小鼠的食管、胃和大肠的肌肉层发生病理学改变，从而揭示了这种药物的一种不良影响。c-Abl的小鼠消化道尤其是肌肉层部位也出现相似的表型缺陷，这说明imatinibmesylate通过影响c-Abl从而影响消化道稳态。另外，我们发现c-Abl小鼠在年老时有巨食管和直肠脱垂的表型，于是我们又研究衰老相关基因p16缺失后对c-Abl小鼠表型的影响，结果发现p16的缺失挽救了c-Abl小鼠的出生后的高死亡率和生殖缺陷，但对直肠脱垂只有微小的影响，对巨食管表型没有影响，这说明p16介导的衰老过程几乎和巨食管与直肠脱垂无关。我们还发现c-Abl小鼠中血纤维蛋白溶酶原系统被抑制，因此我们推断巨食管的发病机理可能与血纤维蛋白溶酶原系统有关。以上结果表明c-Abl小鼠为研究巨食管和直肠脱垂发病机理提供了一种有力的模型，临床上病人使用imatinib mesylate后可能会引起肠胃问题，这点应该引起重视。

关键词： c-Abl imatinib mesylate 巨食管直肠脱垂消化道

Pancreatic extragastrointestinal stromal tumor:A case report and comprehensive literature review

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World Journal of Gastrointestinal Surgery 2014年第9期6卷 175-182页

作者： Sami Akbulut Rdvan Yavuz Emrah Otan Sinan Hatipoglu Department of Surgery Diyarbakir Education and Research HospitalUckuyular Mevki Department of Surgery and Liver Transplant Institute Inonu University Faculty of MedicineTurgut Ozal Medical Center Department of Surgery Inonu University Faculty of Medicine Department of Surgery Adiyaman University Faculty of Medicine

AIM: To provide an overview of the literature on pan-creatic extragastrointestinal stromal tumors(EGISTs).METHODS: We report a case of pancreatic EGIST and review published studies on pancreatic EGIST ac-cessed via the PubMed, MEDlInE, Google Scholar, and Google databases. The keywords used were "pancreas and GIST", "pancreas and extra GIST", "pancreas and gastrointestinal stromal tumor", and "pancreas and ex-tragastrointestinal stromal tumor". literature reviews and/or duplicate studies were excluded. The search included articles published in the English language be-tween January 1, 2000 and May 15, ***: From our literature survey, 30 manuscripts on pancreatic EGISTs were considered, of which 27met the search criteria and three were excluded. The studies involved 30 patients(15 men, 15 women) with a mean age of 55.3 ± 14.3 years(range 30-84 years). The mean age of the male patients was 50.8 ± 13.7 years(range 30-84 years); that of the female patients was 59.9 ± 13.3 years(range 38-81 years). Tumor dimensions were obtained for 28 cases(mean 114.4 ± 78.6 mm; range 20-350 mm). Tumors were diagnosed incidentally in 23.3% of patients; abdominal discomfort and weight loss were the major complaints in symp-tomatic patients. Risk of aggressive behavior according to Fletcher criteria was determined in 25 of 30 patients(68%: high risk, 28%: intermediate risk, 4%: low risk). Histopathological examination revealed the presence of spindle cells in 96.1% of cases; CD117 and CD34 were present immunohistochemically in 96.6% and 84% of patients, respectively. The most common surgical pro-cedures were distal pancreatectomy with splenectomy(n = 9) and pancreaticoduodenectomy(n = 7). The to-tal follow-up period for the 28 patients ranged from 3-66 mo, during which locoregional or distant metastases were diagnosed in six patients and two patients ***: Studies on EGISTs have only been published in the last decade. The lack of studies with large patient cohorts and l

关键词： Gastrointestinal stromal tumor Extra-gastrointestinal stromal tumor Pancreas imatinib mesylate CD117