Two cases of postoperative recurrence of gastric GIST treated by imatinib

We report two cases of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor imatinib mesylate (IM), and discuss some important items. Case 1: This 63-year-old Japanese man received a partial gastrectomy for leiomyosarcoma in 1993. Partial hepatectomy and proximal gastrectomy were performed for liver metastasis and local recurrence in 2001. However, 5 months after surgery, a CT scan showed multiple tumors in the liver, lung and thyroid. The patient was treated with 300 mg of IM once daily with transient grade 2 neutropenia and intestinal bleeding. Though the response to treatment was SD-PR initially, a CT scan 15 months after initial treatment demonstrated the regrowth of the tumor in his liver. Case 2: A 63-year-old Japanese woman was treated with 200 mg of IM once daily for multiple liver metastases after gastrectomy for GIST with grade 3 neutropenia and edema of legs. The response to treatment was SD, and continued for 12 months. IM is the treatment of choice for unresectable recurrence of GIST. However, some problems remained. Both basic and clinical research is necessary to increase the therapeutic efficacy of IM.     

A case of gastric gastrointestinal stromal tumor operated after low-dose chemotherapy with imatinib mesylate

A 76-year-old man was admitted to our hospital because of tarry motions. Endoscopic findings showed an ulcer on a large submucosal tumor in the stomach. Abodminal CT scan showed a protruding lesion of approximately 13 cm at the lumen of the gastric body. FDG-PET imaging revealed FDG uptake in the gastric body and abdominal cavity. We diagnosed it as GIST with peritoneal dissemination clinically, and treatment with 300 mg of imatinib mesylate was started in December 2006. The main tumor was reduced(reduction rate of 27%)and FDG-PET imaging revealed a decrease in FDG uptake in the main tumor and all disseminated tumors after 5 months of treatment. However, the drug was discontinued for arthritis(grade 3). Partial gastrectomy with sampling peritoneal nodules was performed in June 2007. The present case suggests that low-dose chemotherapy with imatinib mesylate may be useful as a preoperative therapy for a minimal surgery.     

Recurrent gastrointestinal stromal tumor (GIST) of the stomach associated with a novel c-kit mutation after imatinib treatment

A 57-year-old man with gastrointestinal stromal tumor (GIST) of the stomach with peritoneal dissemination underwent gastrectomy. After surgery, he was treated with 400 mg/day of imatinib, without recurrence, for 26 months. At 26 months, the imatinib dose was reduced because of nausea, and 4 months after the dose reduction, recurrence of GIST was detected, for which surgical resection was performed again. The first surgical specimen had a mutation of exon 11 in the c-kit receptor gene. Intriguingly, the second surgical specimen had a novel mutation of exon 17, in addition to the above-mentioned mutation, in the c-kit receptor gene. Based on the result of molecular analysis, the novel mutation of exon 17, induced by longterm chemotherapy, was judged to have been responsible for the recurrence, which perhaps was triggered by the dose reduction of imatinib.     

Effect of angiosonography to monitor response during imatinib treatment in patients with metastatic gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST. EXPERIMENTAL DESIGN: Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor. RESULTS: Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The "nodule(s) within a mass" pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels. CONCLUSIONS: Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.     

A case of gastrointestinal stromal tumor (GIST) successfully treated with resection after a long-term control medication by molecular targeted drugs

We report a case of GIST successfully treated with resection after a long-term control medication by molecular targeted drugs. A 59-year-old man underwent an un-complete resection for multiple abdominal tumors. The patient was treated with imatinib at a dose of 400 mg/day for high risk GIST. Since he had PD 22 months after the treatment, sunitinib was administered at a dose of 50 mg/day. However, abdominal tumor grew, and melena and intra-abdominal hemorrhage were appeared. After 27 months from the first treatment, a resection of tumors was performed to control abdominal hemorrhage. After the operation, abdominal tumor was successfully controlled with the treatment of imatinib.     

A successful case of oral molecularly targeted therapy with imatinib for peritoneal metastasis of a gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are a group of neoplasms arising from mesenchymal stem cells of the gastrointestinal tract. The prognosis of metastatic or recurrent GISTs is poor, because these tumors resist chemotherapy and radiotherapy. We report a patient with recurrent GIST who underwent molecularly targeted therapy with imatinib, a novel oral tyrosine kinase inhibitor. A 50-year-old woman presented with a huge intra-abdominal mass. The patient had a history of gastrectomy for GIST and hepatectomy for its metastases. She also underwent surgery for resection of peritoneal metastases 9 months before. The abdominal mass was 26 × 17 × 12cm in size, as determined by magnetic resonance imaging, and was diagnosed as a peritoneal relapse of GIST. Treatment with 400mg of imatinib daily was started. After 1 week of treatment with imatinib, reduction of the abdominal tumor began to be recognized on palpation. Computed tomographic scanning on day 28 revealed that the tumor had liquefactively regressed and had reduced in size by 66%. The major side effect was leg edema, which was easily manageable with furosemide. The patient has been receiving imatinib treatment in our outpatient clinic, and the tumor regression has continued for 9 months. Imatinib shows promise as a safe and effective drug for the treatment of patients with recurrent GISTs.     

18例直肠间质瘤的诊治分析

目的:直肠间质瘤（Gastrointestinal stromal tumour,GIST）是相对少见的疾病,缺少统一的治疗规范。本研究探讨直肠间质瘤的临床特点、诊断及治疗方法。方法:对中南大学湘雅医院2002年1 月～2009年4 月间收治的18例直肠GIST的临床资料、治疗方法及结果进行回顾性分析。结果:直肠GIST的临床表现无特异性,多表现为血便或大便次数增多。CT或MRI 显示肿块边界清楚,瘤内有出血坏死及无淋巴结肿大。18例标本免疫组化检测CD117 和CD34阳性率均100% 。低危险性和极低危险性共8 例,占44.4% 。全组均经手术治疗,行局部切除12例,直肠前切除术（Dixon）3 例,腹会阴联合切除术（Miles）3 例。术前以伊马替尼新辅助化疗3 例,均达部分缓解（partial response,PR）,然后均行局部切除。随访1～84个月,5 例患者复发转移,其中3 例行伊马替尼治疗,病情稳定。另外2 例未接受伊马替尼治疗,死亡1 例,另1 例反复局部切除后行Miles手术。局部切除组与Miles组的无复发生存时间分别为（75.0 ± 8.4）个月和（26.0 ± 11.1）个月（P=0.023）。 结论:直肠GIST的治疗方法应有别于直肠癌,需要制定个体化的外科治疗方案。对大部分低危险性的患者可通过各种手术路径行局部切除而达到满意效果。伊马替尼新辅助化疗的应用,可使部分直肠GIST患者获得保肛机会。      

A case of imatinib-resistant GIST treated by sunitinib

We report a case of imatinib-resistant GIST, successfully treated by sunitinib. A 62-year-old man with high-grade fever and a huge abdominal tumor was diagnosed with malignant GIST and multiple liver metastases. We performed total gastrectomy combined with distal pancreatectomy, and splenectomy for palliation. Imatinib at a dose of 300mg/day was administered postoperatively, and the liver metastases was well controlled. After nine months, abdominal dissemination increased, and we raised the dose of imatinib to 400mg/day for the progressive state. Subsequently, we had to discontinue imatinib due to its adverse effects. Because the tumors progressed greatly while imatinib was discontinued, we changed to sunitinib. After wards, tumors reduced and his general condition improved remarkably. Although tumors progressed after five months, he was able to obtain good QOL during the administration of sunitinib. Sunitinib is useful for imatinib-resistant GIST, and may be a promising treatment even for patients with poor PS.     

A case of bleeding giant gastrointestinal stromal tumor of the stomach who achieved partial response by chemotherapy

A 80-year-old female was referred to our hospital for hematomesis. An abdominal CT revealed a heterogeneous giant tumor of about 11 cm, rich in vascularity, extending from the gastric fundus, beyond the upper side of the spleen, to the left thoracic diaphragm. Gastroscopy showed a 5 cm submucosal tumor with a visible vessel at the gastric fundus. After biopsy was performed, she was diagnosed with a c-kit-positive gastrointestinal stromal tumor (GIST)of the stomach. Following endoscopic hemostasis for gastric bleeding, imatinib mesilate was administered. The tumor reduced markedly, and vascularity in the tumor was diminished, the visible vessels of the tumor disappeared. For curative resection, total gastrectomy with a distal pancreato -splenectomy and a left diaphgram resection is necessary, but surgery was high-risk for this patient because she was advanced in age. She is now achieving a good partial response without surgery.     

16例巨大型胃肠间质瘤手术治疗分析

目的：通过对巨大型胃肠间质瘤（GIST）的诊断和手术方式进行探索,为临床治疗巨大型 GIST 提供新思路。方法对16例巨大型 GIST 患者一般资料、影像学资料、手术方式、随访指标进行回顾性调查,并进行统计学分析。结果11例服用甲磺酸伊马替尼患者无复发生存期1 a 以上,而5例未服用伊马替尼治疗患者1 a 内复发,中位无复发生存期为33个月。COX 多因素分析显示,肿瘤部位、术中肿瘤有无破裂、是否使用伊马替尼治疗与患者预后有关（P <0.05）,可作为患者预后的独立因素。结论巨大型 GIST 在选择手术时,应遵循术前影像学评估、术前服用甲磺酸伊马替尼治疗缩小肿瘤和手术切除时边缘切净为3大原则,这对于改善患者预后和延长生存期有益。     

Two cases of gastrointestinal stromal tumor (GIST) of the stomach and a consideration of its malignancy potential and treatment strategy - report of two cases

We report two cases of large gastrointestinal stromal tumor (GIST) of the stomach both of which were assessed as highly malignant, but took different clinical courses. Case 1: A 72-year-old male. Case 2: A 63-year-old female. The tumor size of Case 1 was suggestive of high malignancy, but only a partial gastrectomy was selected because it did not show any invasive findings. This patient has been followed up for 3 years post-operatively and no recurrence or metastasis has been noted. Case 2 had liver and lymph node metastases, which was consistent with high malignancy. We performed a total gastrectomy with distal pancreatosplenectomy and segmental liver resection. But after surgery, liver metastasis recurred therefore, imatinib mesylate was administered as adjuvant chemotherapy and since then, the tumor has been diminishing in size. No definitive evidence for adjuvant therapy has been established so far, but we suggest that post-operative adjuvant therapy is effective for high-risk GIST.     

Preoperative imatinib facilitates complete resection of locally advanced primary GIST by a less invasive procedure

Complete resection is the most effective therapy for gastrointestinal stromal tumors (GISTs). Complete resection of locally advanced primary GIST by less invasive procedure is usually difficult at initial diagnosis. Imatinib has been successful in treating locally advanced and metastatic GIST and this report shares the experiences in preoperative use of imatinib for patients with locally advanced primary GISTs. The procedure of treatment and completeness of resection were retrospectively accessed for locally advanced primary GIST. Disease-free survival (DFS) and overall survival (OS) after resection were analyzed. Thirteen patients were treated with imatinib preoperatively. All patients received surgical resection after a median imatinib treatment of 7 months when most tumors shrunk. All patients achieved R0 resection without tumor rupture. Two patients received an en-bloc multivisceral resection for the invasion of surrounding organs and 3 patients underwent Mile’s operation for a low rectal tumor. Eleven patients were disease-free. Median DFS or OS had not been reached, while 1- and 3-year DFS were estimated to be 92.3 and 76.9 %, respectively. 1- and 3-year OS were both estimated to be 100 %. Preoperative use of imatinib is useful in locally advanced primary GIST by downsizing the tumor in most patients and facilitating complete resection through less invasive procedures without tumor rupture.     

Hepatic metastasis from gastric GIST radically resected after imatinib mesylate therapy-a case report

We report a case of hepatic metastasis from gastric gastrointestinal stromal tumor (GIST), which was safely resected with preoperative imatinib therapy. A 60-year-old woman was hospitalized and underwent a treatment for hepatic SOL at another hospital prior to gastric GIST resection. Computed tomography revealed a tumor compressing the right and middle hepatic vein. The tumor volume decreased after an initiation of imatinib therapy aimed at preserving the middle hepatic vein. Although tumor volume was further decreased over the course of twelve months, a new lesion appeared, suggesting a progressive disease. Our findings suggest that a radical resection of gastric GIST to preserve the middle hepatic vein is possible.     

Three cases of giant rectal gastrointestinal stromal tumor

The frequency of rectal gastrointestinal stromal tumor (GIST) is relatively low. We have experienced three cases of giant rectal GIST. Case 1 was treated with sunitinib after imatinib failed by Stevens-Johnson syndrome as neoadjuvant therapy. Case 2 was treated with imatinib as neoadjuvant therapy. These neoadjuvant therapies had no effect on tumor size. All patients underwent an abdominoperineal resection. The mean major axis was 11 .7 cm. Immnohistochemical staining showed that CD34 and KIT were positive. The term of follow-up is short, but no recurrences have been found in all cases. It has been reported that imatinib as neoadjuvant therapy is useful for radical resection in cases of giant rectal GIST. Furthermore, neoadjuvant therapy seems to be one of the treatment options for locally advanced rectal GIST. However, in cases of GIST patients not responding to imatinib, we should perform a surgical resection immediately.     

Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate

BACKGROUND: The aim of the study was to analyze the surgical possibilities of unresectable and/or metastatic GIST CD117(+) patients during imatinib treatment. METHODS: We analyzed the results of surgery in 141 patients treated with imatinib for initially inoperable and/or metastatic GIST CD117(+). Median follow-up time was 12 months (range: 3-26). RESULTS: Surgery was performed as subsequent treatment in 24 patients (Group I, 17%) for resection of residual disease after complete/partial response and lack of further response to imatinib and as salvage therapy in eight patients (Group II, 6%), who progressed on initially successful imatinib therapy. In Group I, the viable GIST cells were not detected histologically in only three resection specimens. The first five patients in Group I did not receive imatinib further and we observed four recurrences. In next 19 patients, continuing imatinib after surgery, we observed only one relapse. In Group II, we continued imatinib therapy after high-risk surgical procedures, but in five patients we observed subsequent progression. CONCLUSIONS: Surgical removal of residual disease during imatinib treatment may allow for complete remission in selected GIST patients after response to therapy, theoretically prolonging durable remission, but it is necessary to continue imatinib for its maintenance.     

Ten Years of Treatment with 400 mg Imatinib per Day in a Case of Advanced Gastrointestinal Stromal Tumor

Imatinib mesylate, as treatment for gastrointestinal stromal tumors (GIST), has dramatically changed the prognosis for survival - not only because it is efficacious, but also because it attracted attention to this malignant disease. GIST is now a well-known disease entity and a paradigm for targeted therapies in malignant diseases. A now 74-year-old patient presented with recurrence of a primary duodenal GIST (initial diagnosis and primary resection in 1998; diameter 10 cm, KIT exon 11 mutation, PM V559D) and liver metastasis after a second surgical resection was performed in 2000. Conventional chemotherapy with adriamycin and ifosfamide failed to control growth of the relapsed tumor and liver metastasis. In July 2001, compassionate use of imatinib was started. Tumor regression was observed at continuous follow-ups (every 2 months for the first 6 months, and 6 months thereafter) and persisted until now. The patient's physical performance has remained in good condition. Side effects consisted of periorbital edema and sudden muscle cramps of toes and fingers, pain of bones and joints, an intentional tremor, a paler color of the skin, as well as a slight anemia. Imatinib is the first orally administered anticancer drug. Our case shows that a sustained response is possible with continuous therapy over a long time, if the drug is well tolerated. This implies a high compliance of the patient and suggests that resistance to imatinib does not have to develop. Exon 11 (point) mutation might not only represent a positive predictor for imatinib response in general, but especially for imatinib response on long-term.     

Imatinib induced severe skin reactions and neutropenia in a patient with gastrointestinal stromal tumor

Background

Imatinib mesylate has been used for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST). The current recommended dose of imatinib is 400 mg/day that is increased to 800 mg/day in cases with disease progression. However, imatinib can be associated with diverse adverse events, which has limited its use. We report a case of severe adverse skin reactions with neutropenic fever during imatinib treatment in a patient with GIST.

Case presentation

A 71-year-old man was admitted with a one month history of epigastric pain and a palpable mass in the right upper quadrant. An abdominal CT scan revealed a 20 × 19 cm intraabdominal mass with tumor invasion into the peritoneum. Needle biopsy was performed and the results showed spindle shaped tumor cells that were positive for c-KIT. The patient was diagnosed with unresectable GIST. Imatinib 400 mg/day was started. The patient tolerated the first eight weeks of treatment. However, about three months later, the patient developed a grade 4 febrile neutropenia and a grade 3 exfoliative skin rash. The patient recovered from this serious adverse events after discontinuation of imatinib with supportive care. However, the skin lesions recurred whenever the patient received imatinib over 100 mg/day. Therefore, imatinib 100 mg/day was maintained. Despite the low dose imatinib, follow up CT showed a marked partial response without grade 3 or 4 toxicities.

Conclusion

The recommended dose of imatinib for the treatment of GIST is 400 mg/day but patients at risk for adverse drug reaction may benefit from lower doses. Individualized treatment is needed for such patients, and we may also try sunitinib as a alternative drug.     

A case of Giant GIST of the stomach successfully treated with imatinib mesylate neoadjuvant therapy and followed postoperatively

Since the advent of imatinib mesylate (IM), its clinical efficacy against gastrointestinal stromal tumor (GIST) has been widely acknowledged, and therapeutic strategies for this disease have undergone great changes. We recently experienced a case of giant GIST of the stomach that was successfully treated with IM neoadjuvant therapy prior to surgical resection, but liver metastasis recurred 1 year and 7 months after the operation. The patient was a 65-year-old male who presented at our department with the chief complaints of dizziness, malaise, and fever in April 2002. An abdominal CT revealed a mass with a maximum diameter of 17 cm, as well as a cystic septate mass, 12 cm in diameter, with a thick capsule in the left lobe of the liver. The patient was diagnosed with GIST of the stomach and liver metastasis. Since radical operation was considered difficult at that point, IM (400 mg/day) was started on May 9. The result of treatment was determined to be PR, and radical operation was considered feasible. On March 18, 2003, total gastrectomy and left hepatic lobectomy/S 6 partial lobectomy were performed in the surgery department of our hospital. The postoperative course was favorable and oral administration of IM was resumed soon after the operation. However, the drug was discontinued for financial reasons and a decreased white blood cell count (grade 3) 2 months after the operation. Recurrence in the liver and abdominal wall was found in October 2004, and oral administration of IM was resumed again. Currently, treatment with IM is ongoing. Case reports on the efficacy of IM neoadjuvant therapy are occasionally found in the literature, but there are few reports on its long-term prognosis. We report this case with a discussion of future therapeutic options.     

Recurrent rectal GIST resected successfully after preoperative chemotherapy with imatinib mesylate

A 60-year-old-man underwent initial resection of a rectal tumor, with a transanal approach, on December 6, 2000. The tumor was diagnosed as a gastrointestinal stromal tumor(GIST) by KIT and CD34 immunohistochemistry. In June 2003, a third recurrence in the rectum was discovered, at the same location as the initial tumor, and he was referred to our hospital. Magnetic resonance imaging (MRI) revealed a tumor 3.0 cm in diameter, compressing the prostate anteriorly. After the oral administration of imatinib mesylate (Gleevec, Glivec) at a dose of 400 mg per day for 3 months, the size of the tumor had decreased to 1.2 cm in diameter. On December 12, 2003, a fourth operation was performed successfully, with a perineal approach, preserving sphincter function. More than 40 months after the fourth operation, neither local recurrence nor distant metastasis was detected. Our strategy of treatment with imatinib allows not only complete excision of the tumor but it also reduces postoperative impediments in patients with recurrent rectal GIST.