Mutations in c-kit Gene Exons 9 and 13 in Gastrointestinal Stromal Tumors among Japanese

Gain-of-function mutation in c-kit proto-oncogene exon 11 has been described in about 20-50% of gastrointestinal stroma tumor (GIST). Recently, additional mutational hot-spots in exon 9 and exon 13 of the c-kit gene have been reported in GISTs without mutations of exon 11, but a subsequent report in a Western population indicated that only a small portion of GISTs (eight of 200 GISTs, 4%) showed mutations in these regions. In this study, we evaluated mutations in exon 9 and exon 13 of the c-kit gene by both polymerase chain reaction-single strand conformation polymorphism analysis and direct sequencing in 48 GISTs in a Japanese population, for which the clinicopatho-logical and immunohistochemical features and mutations in exon 11 had previously been reported. C-kit gene mutation in exon 9, representing insertion of GCC TAT, was identified in only 4 of 48 GISTs (8%), and none of the GISTs had mutations in exon 13. All four GISTs with mutation in exon 9 were high-risk, and the patients died of multiple tumor metastasis. Mutations in exon 9 and exon 13 of the c-kit gene were also rare events in Japanese GISTs and were related to a poor prognosis. These results in Japanese are consistent with those in Western populations, although a preferential occurrence of GISTs with exon 9 mutation in the small intestine, which was suggested in a previous report, was not observed.     

DOG-1在胃肠道间质瘤中的表达及其临床意义

目的研究DOG-1在胃肠道间质瘤(GIST)中的表达及其临床意义。方法应用免疫组织化学方法检测61例GIST中DOG-1的表达,并与CD117标记进行比较观察,分析DOG-1与GIST各临床病理特征的关系。结果CD117和DOG-1在极低度及低度危险性GIST组织中表达率分别为95.2%(20/21)和90.5%(19/21);在中度及高度危险性GIST中CD117和DOG-1阳性表达率分别为100.0%(40/40)和97.5%(39/40)。CD117表达与DOG-1无关;DOG-1表达与GIST发生部位、肿瘤大小、分级和年龄无关;DOG-1阴性与GIST复发及转移显著相关(P<0.01)。结论DOG-1可作为GIST诊断和预后判断的潜在参考指标。     

Long-term Results of Adjuvant Imatinib Treatment for Localized Gastrointestinal Stromal Tumors after Surgery

Objective: Despite the development of two significant classifications for recurrence risk evaluation among patients engaged with gastrointestinal stromal tumor and corresponding treatment criteria, recurrence happens in a number of the patients who were once classified as ineligible for treatment and hence removed from treatment program. As such, the aim of the present study is to increase the number of patients recognized as eligible for treatment, so as to further reduce recurrence rate of this disease. Materials and Methods: A total of 26 patients from Ilam, Kermanshah, Lorestan, Kurdistan, and some parts of Hamedan, entered this study from 2006 until 2016. The western provinces included have similar socioeconomical conditions. Inclusion criteria were operable tumors confirmed radiologically with a gross size larger than 3 centimeters regardless of the mitosis rate in microscopic power fields, tumor location, or presence of peritoneal involvement during the surgery. Imatinib capsules were administered daily at 400 mg for 3 years. The patients were followed up every 3 months by radiology, ultrasonography, biochemical assessment, and clinical examination. Results and Conclusions: The overall survival after 10-years follow up was 100%, while 5-year survival without relapse was 95%. Mean overall survival was 106 months, and only one patient who had limited peritoneal involvement experienced relapse and he is still alive after 2 years. The drug was well tolerated and no significant side effects were observed.     

Gastrointestinal Stromal Tumors: 10-Year Experience in Cancer Center—The Ottawa Hospital (TOH)

(1) Background: The management of gastrointestinal stromal tumors (GIST) has significantly evolved over the last two decades, with the introduction of tyrosine kinase inhibitors (TKI). We aim to report 10 years of experience of GIST management at a regional cancer center in Canada. (2) Methods: We retrospectively analyzed the records of 248 consecutive patients diagnosed with GIST between 2011 and 2021. We describe the clinical and pathological data, management, and outcome, including survival. (3) Results: The most common GIST sites were the stomach 63% (156), followed by the small bowel 29% (73). At diagnosis, 83% (206) of patients had localized disease (stage I–III). According to the modified National Institutes of Health consensus criteria (NIH) for GIST, around 45% (90) had intermediate or high-risk disease. Most patients, 86% (213), underwent curative surgical resection. Forty-nine patients received adjuvant imatinib, while forty-three patients had advanced disease and received at least one line of TKI. With a median follow-up of 47 months, the 5-year recurrence-free survival (RFS) rates for very low and low risk were 100% and 94%, respectively, while those for intermediate and high risk were 84% and 51%, respectively. The 5-year overall survival (OS) rates for very low and low risk were 100% and 94%, while intermediate, high risk, and advanced were 91%, 88%, and 65%, respectively. Using the Kaplan–Meier method, there were statistically significant differences in RFS and OS between NIH risk groups, p < 0.0005. In univariate analysis, ECOG, site, mitosis, secondary malignancy, and size were predictors for OS. High mitosis and large size (>5 cm) were associated with worse RFS. (4) Conclusions: Curative surgical resection remains the gold standard management of GIST. Our results are comparable to the reported literature. Further research is needed to explore histology’s role in risk stratification and initiating adjuvant TKI.     

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。     

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。     

胃肠道间质瘤中Maspin表达及其与p53表达的相关性

目的探讨maspin表达对胃肠道间质瘤（GIST）生物学行为的预测、预后的评估作用,及其与p53表达的相关性。方法选取42例GIST标本,进行maspin和p53免疫组织化学染色,分析maspin表达与p53表达及GIST临床病理参数的关系。结果胃肠道间质瘤中maspin阳性表达率为64.3%（26/42）,与患者性别、年龄及肿瘤部位、组织学类型无显著相关性（P〉0.05）;与肿瘤侵袭危险性及p53表达均呈负相关性（P〈0.05）;39例获得随访的GIST患者中,maspin表达与其生存率无显著相关性（P〉0.05）。结论 maspin和p53联合检测,有助于预测GIST生物学行为及预后判断。     

Adjuvant Therapy of Gastrointestinal Stromal Tumors (GIST)

OPINION STATEMENT: Imatinib was proven to be effective for the adjuvant treatment of localized, surgically excised, gastrointestinal stromal tumors (GIST). Currently, there is proof that it is able to delay relapse and prolong survival. An effect on cure rate of localized GIST is still to be proven, given the shape of relapse-free survival curves, which apparently tend to overlap after 2-3?years from completion of the adjuvant period. Although observation for a longer follow-up is needed, attempts to prolong adjuvant therapy beyond the currently standard 3?years have been made and the results are awaited. However, the impact of more prolonged adjuvant intervals on secondary resistance is unknown, so that standard practice is still 3?years in most institutions. The adjuvant choice should be based on a rather precise identification of the relapse risk of the single patient, reserving treatment to the high-risk subgroups. The choice also should be personalized on the basis of genotype: generally, PDGFRA D842V mutated and wild-type GIST are excluded. Additional results from completed trials on a longer follow-up are awaited to further refine such "precision" decision-making. There are several instances in which part of the "adjuvant" treatment may be administered preoperatively, even on the face of a surgically resectable GIST, to make surgery more limited and/or safer.     

C-kit和PDGFRβ在食管癌组织中的表达及其临床意义

背景与目的：有研究表明STI-571能抑制Bcr—Abl、C-kit、血小板衍生生长因子受体β（Platelet—derived grouth factor receptor—beta,PDGFRβ）的酪氨酸激酶．从而抑制细胞的分化增殖和促进细胞凋亡,本研究旨在检测与STI-571相关的酪氨酸激酶受体在食管癌中的表达情况。方法：应用免疫组化的方法,检测50例食管癌组织、癌旁组织和正常组织中与STI-571相关的酪氨酸激酶受体c—kit和PDGFRβ的表达。结果：c—kit在癌组织、癌旁组织、正常组织中的强表达率较低,分别为4％、4％、12％,表达的差异无统计学意义。PDGFRβ在癌组织、癌旁组织、正常组织中的强表达率分别为68％、28％、28％,表达的差异有统计学意义。应用Logistic回归的方法,发现c—kit或PDGFRl3在癌组织、癌旁组织、正常组织中的强表达率与患者的性别、年龄、肿物的分化程度、肿物的浸润深度、肿物的部位、淋巴结转移情况和分期无相关。结论：食管癌组织中PDGFRβ的强表达率较高,且明显高于癌旁组织和正常组织。食管正常组织中c—kit的强表达率较低,癌组织和癌旁组织中c-kit的强表达率更低。     

Clinico-Pathological Characteristics and Mutational Analysis of Gastrointestinal Stromal Tumors from India: A Single Institution Experience

Background: Gastrointestinal stromal tumor (GIST) is the most common type of mesenchymal neoplasm of gastrointestinal tract. The incidence of GIST in India is not known and its treatment strategy in our country is largely derived from studies in other global populations. Some of the most important features of this type of cancer include its size, site of origin, mitotic index, histology and Immunohistochemistry. In this report we have studied these parameters in the Indian GIST patients presenting at our center. Additionally, we have also studied the mutational spectrum of these GISTs by next generation sequencing. Methods: Thirty one Indian patients of GIST were enrolled in this study and information regarding age, gender, tumor location and size was collected from their records. Immunohistochemistry studies were performed by the pathologist. Mutational analysis of these samples was performed by next generation sequencing. Results and Discussion: The most common site of GIST occurrence in our study was stomach. The tumor size for all 31 patients ranged between 0.6 cms to 20 cms. A spindle-cell pattern was present in 24 out of 31 of the cases. 29 out of 31 subjects were positive for CD117 expression. C-KIT was the most highly mutated gene indentified in our patients. Apart from these findings we observed many similarities as well as dissimilarities between the results of our study and literature published previously. Conclusions: The dissimilarities in the results of our study and published literature could be attributed to the genetic or ethnic differences that exist between the Indian population and other global populations. The results of our study warrant a need to conduct studies of GIST in a much larger population of India. Such large scale studies may also help in better treatment and/or prevention of GIST in developing countries like India.     

Key Issues in the Clinical Management of Gastrointestinal Stromal Tumors: An Expert Discussion

After the revelation of kinase targeting with orally available small molecules, the use of imatinib in chronic myelogenous leukemia and in gastrointestinal stromal tumor (GIST) has now become commonplace and just two of many examples of the use of kinase inhibitors in cancer. In this article, we discuss important practice points that may impact upon questions of therapy of primary and metastatic GIST, with the hope that the questions addressed in this rare solid tumor can serve as examples of what can be achieved with kinase-directed therapies in other cancers. We present cases that highlight some of the key issues in GIST management and afterward discuss both points of consensus and controversial issues in what is now recognized as one of the most common forms of sarcoma.

Implications for Practice:

The treatment of gastrointestinal stromal tumor (GIST) has become sophisticated with the availability of three approved agents in many countries and 15 years of experience with primary and metastatic disease. Important lessons from tyrosine-kinase inhibitors in GIST can be gleaned from this experience and will impact implementation of similar agents for other cancers.     

Circulating cKIT and PDGFRA DNA indicates disease activity in Gastrointestinal Stromal Tumor (GIST)

This prospective trial aimed to investigate whether tumor-specific cKIT and PDGFRA mutations can be detected and quantified in circulating tumor (ct)DNA in patients with active GIST, and whether detection indicates disease activity. We included 25 patients with active disease and cKIT or PDGFRA mutations detected in tissue. Mutant ctDNA was detected in the peripheral blood plasma using allele-specific ligation (L-)PCR and droplet digital (d)PCR. CtDNA harboring tumor-specific cKIT or PDGFRA mutations was detected at least once in 16 out of 25 patients using L-PCR (64%) and in 20 out of 25 patients with dPCR (80%). Using dPCR, the absolute numbers of ctDNA fragments (DNA copies/ml) and the mutant allele frequency (MAF; in percent of wild-type control) strongly correlated with tumor size expressed as RECIST1.1 sum of diameter (SOD) in mm (ρ = 0.3719 and 0.408, respectively, p < 0.0001) and response status (ρ = 0.3939 and 0.392, respectively, p < 0.0001 and p < 0.001). Specificity of dPCR for detection of progression was 79.2% with a sensitivity of 55.2% and dPCR discriminated CR from active disease with a specificity of 96% and s sensitivity of 44.7%. With L-PCR, correlations of MAF with tumor size and response status were less prominent. Serial ctDNA measurement reflected individual disease courses over time. Targeted panel sequencing of four patients detected additional driver mutations in all cases and secondary resistance mutations in two cases. Thus, ctDNA indicates disease activity in patients with GIST and should be incorporated as companion biomarker in future prospective trials.     

Cyclooxygenase-2 Expression in Gastrointestinal Stromal Tumours

Background: While it is well known that cyclooxygenase-2 (COX-2) expression is increased in colorectal adenoma and carcinoma, there is only limited information on its status in stromal tumours. Methods: Immunohistochemical COX-2 staining was performed on a total of 42 confirmed gastrointestinal stromal tumours (GISTs) in the Pathology Department of Gaziantep University and the findings were compared with various other parameters. Results: We found a statistically significant correlation between the tumor mitosis and COX-2 expression in GISTs. However, there was no relationship between COX-2 expression and death rate, presence of metastasis, tumour size, risk staging, usage of tyrosine kinase inhibitors, and complete resection rate. Conclusions: In the light of these findings, the usage of COX-2 inhibitors with or without tyrosine kinase inhibitors in GIST patients may be helpful in the adjuvant setting to prevent or delay recurrence. Moreover, we need more studies to define the status of COX-2 inhibitors in GISTs.     

Laparoscopic Versus Open Resection for Gastrointestinal Stromal Tumors (GISTs)

Purpose

Primary gastrointestinal stromal tumors (GISTs) are typically treated with open resection. There is growing interest in laparoscopic GIST resection; however, data is limited. We report our experience with GIST resections using both open and laparoscopic techniques.

Materials and Methods

Twenty-nine GIST patients underwent definitive intent resection at the University of Missouri from 1990 to 2010. Patients who underwent laparoscopic resection (n?=?7) were matched on the basis of tumor size, age, tumor location, and National Comprehensive Cancer Network (NCCN) risk stratification with seven patients who underwent open resection. The two groups were compared with respect to age, gender, BMI, tumor size, tumor site, mitotic rate, surgical margins, NCCN risk stratification, estimated blood loss, hospital stay, surgical complications, disease recurrence, and overall survival.

Results

The cohorts did not differ with respect to age, gender, BMI, tumor location, tumor size, or positive margins (p?>?0.05). Patients who underwent open resection had more NCCN high-risk patients, but the difference was not statistically significant (p?=?0.08). There was significantly less estimated blood loss (median 15 vs. 150 mL, p?<?0.05) and significantly shorter hospital stay (median 4 vs. 7 days, p?<?0.05) for the laparoscopy group. There were no recurrences in the laparoscopy group, but there was one in the open group with a median follow-up of 55 and 63 months, respectively (p?>?0.05). Five-year disease-free survival was 100 % for the laparoscopic group and 83 % for the open resection group.

Conclusions

Laparoscopic resection for appropriately selected GISTs is feasible and associated with significantly less blood loss and shorter hospitalizations compared to open resection. Further studies are needed to better define its role for GIST.