Long-term survival after excision of a giant esophageal gastrointestinal stromal tumor with imatinib mesylate resistance: report of a case

A 69-year-old woman underwent 4 months of imatinib mesylate chemotherapy for a diagnosed gastrointestinal stromal tumor of the esophagus. This treatment was suspended because of its side effects and because radiological examinations showed that the tumor had not changed or had even increased slightly in size. Thus, we performed esophagectomy via left thoracotomy and removed a tumor that measured 18 × 17 × 10 cm. Immunohistochemical examination revealed positive reactions for c-kit and CD34, suggestive of a high-risk malignancy. The patient was discharged from hospital on postoperative day 30, and has remained well with no sign of tumor recurrence for more than 5 years, without adjuvant chemotherapy.     

Complete Remission of Recurrent Gastrointestinal Stromal Tumors After Treatment with Imatinib: Report of a Case

A 49-year-old man underwent partial resection of the jejunum for an abdominal tumor, which was histologically confirmed to be a gastrointestinal stromal tumor (GIST). Immunohistochemistry revealed that the tumor cells were positive for c-kit, p52, and MIB-1. He underwent resection of a total of 83 recurrent tumors over the next 36 months. A computed tomography (CT) scan done a few months later showed multiple tumor recurrences. The patient was started on imatinib mesylate 400 mg/day, and 3 months later, a CT image showed an increase in tumor size but a decrease in tumor density. Subsequent CT scans showed a marked decrease in tumor size 3 months later and no evidence of tumor recurrence 9 and 12 months after the commencement of imatinib treatment. The patient remains in complete remission 31 months after the start of treatment.     

Predicting the Antitumor Effects of STI571 by Analysis of c-kit Gene Mutations in Gastrointestinal Stromal Tumors of the Stomach: Report of a Case

We report a case of a large gastrointestinal stromal tumor (GIST), greater than 5 cm in diameter, in the stomach. Microscopically, high levels of mitosis were observed, indicative of a high-grade malignancy. We analyzed the c-kit gene mutations by a replication competent retrovirus assay and DNA sequencing, which revealed a c-kit mutation in exon 11. Liver metastases were detected 7 months after surgery. Patients with an exon 11 mutation of the c-kit gene are reported to have a high response to STI571 (imatinib mesylate, Glivec). Accordingly, a 1-month course of STI571 treatment clearly changed the characterization of the metastatic tumors radiographically. Thus, it may be important to analyze c-kit gene mutations in patients presenting with GISTs to predict the effectiveness of STI571 in suppressing GISTs, especially tumors thought to have malignant potential.     

Successful resection of a gastrointestinal stromal tumor in the pelvis with imatinib mesylate as neoadjuvant therapy

We report a case of marginally resectable gastrointestinal stromal tumor (GIST) in the pelvis treated with neoadjuvant intent before subsequent successful surgical resection. A 46-year old man presented with urinary frequency and rectal discomfort with tenesmus. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 12 cm diameter mass between the bladder and rectum and the margin of the tumor and prostate was unclear. No metastases were evident. Trans-rectal needle core biopsy confirmed c-kit positive GIST. Because of the locally advanced nature of the tumor,immediate surgical resection would have required total pelvic exenteration with eternal colostomy and urinary diversion. Therefore,the patient was treated with imatinib mesylate 400 mg daily in anticipation of adequate tumor size reduction to enable a more simplified surgical approach. After 3 months of imatinib therapy,MRI demonstrated a reduction in tumor size of 60%. Consequently,a complete surgical resection including the bladder,prostate and part of the sigmoid colon with temporary ileostomy and ileal conduit was performed. Pathological findings of the resected specimen showed widespread degeneration with cystic changes,necrosis, and hypocellularlity,as well as nodules of residual viable c-kit positive tumor cells. The patient has been treated with imatinib mesylate for 39 months following the operation without tumor recurrence.     

Advanced-stage gastrointestinal stromal tumor treated with imatinib in a 12-year-old girl with a unique mutation of PDGFRA

A 12-year-old girl presented with a large abdominal tumor. At surgery, a huge pedunculated extraluminal tumor was found arising from the greater curvature of the stomach and invading the surrounding structures, and there were also a submucosal tumor measuring 5 × 4 × 4 cm and multiple intramural nodules beside the main tumor. These lesions, which were removed with 1.0-cm surgical margins, were immunohistochemically positive for c-kit (CD117) and CD34. A diagnosis of gastrointestinal stromal tumor (GIST) was made. The huge size of the tumor (3.6 kg in weight and 36 × 25 × 25 cm in diameter), the invasion of the surrounding structures, and the increased mitotic figures indicated the GIST had malignant potential. Sequence analysis of the polymerase chain reaction product of RNAs from the tumor cells revealed a novel platelet-derived growth factor receptor α (PDGFRA) mutation, which would exhibit biologic consequences similar to those of the c-kit mutation. The patient underwent a 3-month course of imatinib mesylate as adjuvant chemotherapy because of the possible risk for tumor recurrence. She is now doing well without any evidence of recurrence or metastasis 25 months after the surgery. Only 9 cases of GIST have been reported in children, and a review of those cases revealed GISTs in children would be associated with a better prognosis than in adults and that one third of pediatric GISTs presented with intestinal obstruction in the newborn period.     

A gastrointestinal stromal tumor of the third portion of the duodenum treated by wedge resection: A case report

A 65-year old woman was admitted to our hospital with abdominal pain. Computed tomography showed a tumor measuring about 3 cm in diameter with no metastatic lesion or signs of local infiltration. Gastroduodenal endoscopy revealed the presence of a submucosal tumor in the third portion of the duodenum and biopsy revealed tumor cells stained positive for c-kit. These findings were consistent with gastrointestinal stromal tumors (GISTs) and we performed a wedge resection of the duodenum, sparing the pancreas. The postoperative course was uneventful and she was discharged on day 6. Surgical margins were negative. Histology revealed a GIST with a diameter of 3.2 cm and < 5 mitoses/50 high power fields, indicating a low risk of malignancy. Therefore, adjuvant therapy with imatinib was not initiated. Wedge resection with primary closure is a surgical procedure that can be used to treat low malignant potential neoplasms of the duodenum and avoid extensive surgery, with significant morbidity and possible mortality, such as pancreatoduodenectomy.     

Unexpected rapid progression of metastatic adenoid cystic carcinoma during treatment with imatinib mesylate

BACKGROUND: There is a lack of effective treatment for metastatic adenoid cystic carcinoma (ACC), a usually indolent tumor. We studied the efficacy of imatinib mesylate, a potent inhibitor of KIT tyrosine kinase, in patients with KIT-positive metastatic ACC. METHOD: Five patients with lung metastasis were treated in a pilot study with imatinib 400 mg by mouth twice a day. Mutations of c-kit and platelet-derived growth factor receptor (PDGFR)-alpha in tumors from these patients were analyzed. RESULTS: Disease progression was noted in three of five patients during the short treatment periods, ranging from 2 to 3 weeks. Three patients died of disease within 6 months. No detectable mutations were found in c-kit and PDGFR-alpha. CONCLUSION: We observed an unexpected high progression rate of metastatic ACC within short periods during imatinib treatment. Use of imatinib to treat cancers without c-kit or PDGFR-alpha mutation should be approached with caution.     

Secondary resistance of extra-gastrointestinal stromal tumors to imatinib mesylate: report of a case

Extra-gastrointestinal stromal tumors (EGISTs) that do not originate in the digestive tract are rare. We report a case of multiple EGISTs, which was monitored closely by KIT gene mutation analysis and other investigations. The patient was a 52-year-old man in whom multiple tumors in the abdominal cavity were diagnosed as EGISTs. Immunohistochemical analysis revealed positive staining for c-kit; however, no mutations were found in the KIT gene. The tumors decreased in size remarkably following treatment with imatinib mesylate, but after 2 years of this treatment, multiple liver metastases and some regrowth of the abdominal masses were found simultaneously. The liver metastasis and the abdominal masses were excised, and further analysis of the KIT gene revealed the same mutation in exon 11 in the KIT gene in the metastatic tumors. We speculate that the treatment might have triggered development of the imatinib mesylate-resistant clone, which may have existed in the primary lesion as a KIT gene mutant. This report provides valuable insight into the mechanisms of recurrent GISTs after treatment with imatinib mesylate.     

Successful Resection of an Advanced Duodenal Gastrointestinal Stromal Tumor After Down-Staging with Imatinib: Report of a Case

The diagnosis of gastrointestinal stromal tumor (GIST) relies on a combination of the following criteria: anatomic location, typical histopathology, and the presence of CD 117-antigen (the tyrosine kinase receptor, c-kit) or CD 34-antigen. Imatinib mesylate, a specific tyrosine kinase inhibitor, is highly efficient against locally advanced or metastatic GIST. We report a case of unresectable duodenal GIST, which we were able to resect with curative intent after down-staging treatment with a dosage of imatinib 400 mg daily for 8 months. We performed Whipple's procedure combined with en bloc resection of the right kidney and adrenal gland. The patient was recurrence free at his 24-month follow-up examination. Down-staging treatment may be worthwhile in selected patients, but further prospective studies of imatinib in this setting are necessary. We think that imatinib should be continued postoperatively, as the risk of recurrence in these patients may be high.     

Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that are characterized by constitutive overexpression of the tyrosine kinase receptor KIT (CD117). Imatinib mesylate is a selective inhibitor of tyrosine kinase-mediated activity. This study reports a single-institution experience of surgical resection and the use of imatinib in the treatment of GIST. METHODS: A retrospective review from 1995 to 2002 identified 57 patients (M:F, 29:28; median age, 61 years) with GIST who were treated at the University of Chicago. Twenty-eight patients underwent exploratory surgery with curative intent; 29 patients were referred for treatment of metastatic disease after surgery at outside institutions. Twenty-nine patients were treated with oral imatinib for either metastatic disease (n=26 patients) or in the adjuvant setting after complete resection (n=3 patients). RESULTS: Resections were performed in 53 patients, and metastatic disease was identified in 17 patients at the time of exploratory surgery. Immunohistochemical staining for CD117 was positive in 96% of patients. A size larger than 5 cm, a mitotic rate larger than 1/10 high-power field, and tumor necrosis predicted recurrence in patients after resection. The median follow-up period was 18 months (range, 4-81 months). Twenty-three patients (40%) are alive without disease; 22 patients (39%) are alive with disease; 7 patients died, and 5 patients are lost to follow-up. Among the 26 patients with metastatic disease who were treated with imatinib, 5 deaths have occurred, and disease stabilization or tumor regression was observed initially in 22 patients, with a median duration of response of 19 months. CONCLUSIONS: Complete surgical extirpation remains the only curative treatment of GIST. Imatinib-targeted therapy of metastatic disease yields encouraging clinical responses. The true efficacy of imatinib in this setting, as induction therapy or as an adjuvant treatment in patients with GIST, is unknown pending the completion of ongoing prospective trials.     

The functional effects of a c-kit tyrosine inhibitor on guinea-pig and human detrusor

OBJECTIVE: To describe the effect of a specific c-kit receptor inhibitor (imatinib mesylate) on human detrusor strips in vitro and guinea-pig cystometry in vivo, and to show histological data suggesting differences in the distribution of interstitial cells of Cajal (ICC)-like cells in 'normal' and overactive human detrusor, as these cells have been identified as possible mediators of spontaneous activity and excitability in bladder smooth muscle. MATERIALS AND METHODS: Specimens of human detrusor were stained immunohistochemically with a c-kit antibody. Human detrusor strips were mounted in a superfused organ-bath apparatus, and smooth muscle contraction was evoked with carbachol and electrical field stimulation in the presence and absence of imatinib mesylate. Also, guinea-pig urodynamic studies were conducted before and after i.v. administration of imatinib mesylate, and changes in bladder variables and spontaneous activity were recorded. RESULTS: Imatinib mesylate (10(-6)M) inhibited evoked smooth muscle contraction and spontaneous activity in overactive human detrusor, with less effect on normal human tissue. Imatinib mesylate (10(-5)M) improved bladder capacity, compliance, voided volumes, urinary frequency, and reduced contraction thresholds and spontaneous activity during guinea-pig cystometry. c-kit labelling showed significantly more ICC-like cells in overactive human detrusor than in normal specimens. CONCLUSION: c-kit receptor blockers have inhibitory effects on guinea-pig and overactive human detrusor, possibly via c-kit receptors on bladder ICC-like cells. This and the possibility that there are more ICC-like cells in overactive bladder suggest that the c-kit receptor may provide a novel target for treating detrusor overactivity.     

Perisacral gastrointestinal stromal tumor with intracranial metastasis. Case report

A 68-year-old woman presented with an extremely rare intracranial metastasis from a gastrointestinal stromal tumor (GIST) manifesting as left hemiparesis 2 years after resection of a sacral tumor adjacent to the coccygeal bone. Magnetic resonance imaging revealed an intracranial tumor in the right parietal lobe. Craniotomy was performed to completely remove the tumor. Although the tumor was located extra-axially, only internal carotid angiography showed mass staining. Seven months after surgery, the tumor recurred. Repeat craniotomy was performed to remove the recurrent tumor. Immunohistochemical analysis showed that the tumor cells were positive for c-kit and CD34, and the tumors were identified as intracranial metastasis of GIST. Following the second intracranial surgery, the patient developed severe lower back pain caused by metastatic tumor invading the lumbar spine and ureter. To avoid surgical complications and to reduce tumor volume, imatinib mesylate (Gleevec) was administered. The severe pain was relieved, although the tumor was not reduced. In this case, the extra-axial tumor was fed only by the internal carotid artery.     

Leiomyosarcoma originating from the superior mesenteric vein: a case report and review of the literature

We describe a rare case of leiomyosarcoma originating from the superior mesenteric vein with concomitant liver metastases in a 62-year-old woman. She underwent a tumor resection and venous reconstruction, right hemicolectomy, and right hepatic lobectomy. Since the tumor was weakly positive for c-kit, she was treated with imatinib mesylate for the recurrent liver tumors. She has survived for about 3 years after undergoing the surgical procedures.     

Gastrointestinale Stromatumoren

Gastrointestinal stroma tumors (GIST), an abdominal stroma entity, are characterized by a gain-in-function mutation in the c-kit proto-oncogen (CD117). Initial treatment should aim at complete removal of the primary tumor (R0 resection), which almost never develops lymphatic metastases. Distant metastatic spread mainly involves the peritoneal cavity and the liver. In patients with metastatic disease, treatment with the tyrosine kinase inhibitor imatinib mesylate is indicated and very effective. Systemic chemotherapy and external beam radiation must be considered ineffective. Patients requiring multivisceral resection for primary tumor removal quickly develop tumor recurrence and could benefit from preoperative treatment with imatinib. To assess the response to treatment, 18F-FDG positron emission tomography or gadolinium-enhanced magnetic resonance imaging have proven helpful, as the conventional criteria of tumor shrinkage according to WHO standards are rarely met. Primary tumors are classified into four risk categories according to size and mitotic activity. The possible advantages of adjuvant treatment are currently under investigation through international randomized trials. Patients who develop extensive remission of metastatic disease should be evaluated individually for resection of the tumor remnants. Even the resection of single progressive lesions (newly developed mutations) should be considered in carefully selected patients if the remaining tumor can be controlled by continued imatinib treatment.     

胃肠间质瘤治疗进展

胃肠间质瘤（GIST）是胃肠道最常见的间叶来源肿瘤。大部分患者存在c-kit或PDGFRa基因突变。手术根治性切除是治疗胃肠间质瘤的基石,但是术后复发率较高。近年来,以伊马替尼为代表的靶向治疗大大提高了GIST治疗效果。对于手术可以切除的患者,手术切除联合新辅助或辅助治疗改善了高危患者的预后：对于手术不可切除的患者,靶向治疗也有效地抑制、延缓了病情的进展。     

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??Therapeutic drug monitoring of plasma imatinib mesylate for the treatment of gastrointestinal stromal tumor and prognosis XU Ze-kuan, XU Hao. Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
Corresponding author: XU Ze-kuan, E-mail:xuzekuan@njmu.edu.cn
Abstract Imatinib mesylate is a tyrosine kinase inhibitor recommended for treatment in patients with unresectable??metastastic and relapsing GIST as well as patients who have been identified with moderate or high risk of recurrence after receiving complete tumor resection. Imatinib plasma trough concentration??Cmin?? is significantly correlated with better clinical benefit when Cmin >1100μg/L. Therapeutic drug monitoring (TDM) for plasma imatinib is becoming a potential adjuvant therapy for GIST.     

c-kit基因突变对胃肠道间质瘤预后影响的荟萃分析

目的 探讨c-kit基因突变对胃肠道间质瘤(GIST)预后的影响.方法 通过电子检索PubMed、MedLine数据库,对1999年1月至2008年8月有关c-kit基因突变对GIST预后影响相关病例对照研究资料,用RevMan 5.0.15软件进行荟萃分析.结果 共纳入文献16篇,共计患者1751例.其中与细胞病理学相关统计显示c-kit基因野生型与突变型在有丝分裂计数>5/50 HPF(高倍视野)的病例发生率上差异无统计学意义(P=0.710);与术后复发转移发生率相关统计显示,c-kit基因突变型术后复发转移的发生率显著高于野生型者(P=0.010);与伊马替尼疗效相关统计显示,c-kit基因突变型患者伊马替尼治疗缓解率显著高于野生型(P=0.009),而伊马替尼耐药率较低(P=0.000).亚组分析发现,外显子11突变型的患者伊马替尼治疗缓解率显著高于野生型和外显子9突变型者(P均<0.05),而伊马替尼耐药率较低(P均<0.05).c-kit基因二次突变与伊马替尼获得性耐药相关研究发现,二次突变区域集中在外显子13、14和17,部分为混合型突变.结论 c-kit基因突变与GIST术后复发转移的发生有着密切关系,c-kit基因突变可能会影响伊马替尼的疗效,而二次突变的发生可能是GIST产生耐药的主要原因之一.     

延长伊马替尼辅助治疗时间对中高度复发风险胃肠问质瘤的疗效观察

目的评估延长伊马替尼辅助治疗时间对中高度复发风险胃肠间质瘤（GIST）患者无复发生存率与安全性的影响。方法回顾性分析北京大学肿瘤医院消化肿瘤内科自2004年3月至2009年5月接受伊马替尼辅助治疗、且随访时间均在3年以上的101例中高度复发风险GIST患者的临床和随访资料。伊马替尼治疗情况：3例因不良反应服药不足1年后停药;24例服药1年后停药：21例患者服药2年后停药;18例患者服药3年后停药;8例患者服药3年余仍继续治疗中：27例患者服药超过4年。结果中位随访时间60个月（95％CI：57．9～62．1个月）,19例患者出现肿瘤复发,其中5例于辅助治疗过程中出现复发,14例为终止辅助治疗后出现复发。伊马替尼停药至肿瘤复发的中位时间为12．0个月（95％CI：9．6～14．4个月）,再次给予伊马替尼治疗均获得肿瘤控制。53例辅助治疗时间3年或3年以上者5年无复发生存率为93．9％,明显优于不足3年的48例患者（68．0％,P〈0．01）。其中,3年以上者与3年者5年无复发生存率分别为97．1％和86．6％,差异无统计学意义（P〉0．05）。除乏力发生率有所增加外,辅助治疗时间3年以上者总体不良反应发生率并未明显增加（P〉0．05）。结论延长伊马替尼辅助治疗时间超过3年有望进一步延长中高度复发风险GIST术后的无复发生存期,且其不良反应并未显著增多。     

Surgical Outcomes of Patients with Gastrointestinal Stromal Tumors in the Era of Targeted Drug Therapy

Background  The discovery of the c-KIT mutation and the advent of targeted drug therapy with imatinib mesylate have revolutionized the management of gastrointestinal stromal tumors (GISTs). The outcome of patients with surgically treated GISTs treated in the era of targeted drug therapy was assessed and factors associated with adverse outcomes determined. Materials and Methods  Patients with GISTs requiring surgery at a tertiary care center from 2002 to 2007 were reviewed and prognostic factors determined. Results  Forty patients were surgically treated for GISTs. The median age at presentation was 59 years. The stomach (55%) was the main site of primary disease. The median tumor size was 7 cm. Eleven (28%) patients had metastatic disease at presentation. Surgery was undertaken in all patients with curative intent. Multi-organ resection was required in 10 (25%) patients. Imatinib mesylate was administered postoperatively in 68% of cases. Median follow-up was 24 months. There was a 40% recurrence rate with 63% undergoing repeat surgical resection. The peritoneum and liver were the main sites of recurrent disease. The 5-year disease-specific survival and disease-free survival (DFS) were 65% and 35%, respectively. High mitotic rate (P = 0.017) and tumor size greater than 10 cm (P = 0.009) were the only prognostically significant adverse factors of DFS on multivariate analysis, independent of imatinib mesylate treatment. Conclusion  Aggressive surgical treatment and follow-up of GISTs, combined with targeted drug therapy, leads to long-term DFS survival. Tumor recurrence is independently associated with a high tumor mitotic rate and size greater than 10 cm, despite the use of adjuvant targeted drug therapy.