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.

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

AIM： Most gastrointestinal stromal tumors （GISTs） express constitutively activated mutant isoforms of kit kinase or platelet-derived growth factor receptor alpha （PDGFRA）, which are potential therapeutic targets for imatinib mesylate （Glivec）. Partial response occurred in almost two thirds of GIST patients treated with Glivec. However, complete response （CR） after Glivec therapy was sporadically reported. Here we illustrated advanced GIST patients with CR after Glivec treatment. METHODS： Between January 2001 and June 2005, 42 advanced GIST patients were treated with Glivec. Patients were administered 400 mg of Glivec in 100-mg capsules, taken orally daily with food. The response of the tumor to Glivec was evaluated after one month, three months, and every three months thereafter or whenever medical need was indicated. Each tumor of patients was investigated for mutations of kit or PDGFRA. RESULTS： The median follow-up time of the 42 ad-vanced GIST patients treated with Glivec was 16.9 months （range, 1.0- 47.0 months）. Overall, 3 patients had complete response CR （7.1%）, 26 partial response （67.8%）, 5 stationary disease （11.9%）, and 3 progressive disease （11.9%）. The median duration of Glivec administration for the three patients was 36 months （range, 23-36 months）. The median time to CR after Glivec treatment was 20 months （range, 9-26 months）. Deletion and insertion mutations of c-kit exon 11 and insertion mutation of c-kit exon 9 were found in two cases and one case, respectively. CONCLUSION： Complete response （CR） can be achieved in selected advanced GIST patients treated with Glivec. The median time to CR after Glivec treatment was 20 months. Deletion and insertion mutations of kit exon 11 and insertion mutation of kit exon 9 contribute to the genetic features in these selected cases.

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.

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.

Use of a pH-responsive imatinib mesylate sustained-release hydrogel for the treatment of tendon adhesion by inhibiting PDGFRβ/CLDN1 pathway

Adhesion after tendon injury,which can result in limb movement disorders,is a common clinical complication;however,effective treatment methods are lacking.Hyaluronic acid hydrogels are a new biomedical material used to prevent tendon adhesion owing to their good biocompatibility.In addition,potential drugs that inhibit adhesion formation have gradually been discovered.The anti-adhesion effects of a combination of loaded drugs into hydrogels have become an emerging trend.However,current drug delivery systems usually lack specific regulation of drug release,and the effectiveness of drugs for treating tendon adhesions is mostly flawed.In this study,we identified a new drug,imatinib mesylate(IM),that prevents tendon adhesion and explored its related molecular pathways.In addition,we designed a pH-responsive sustained-release hydrogel for delivery.Using the metal-organic framework ZIF-8 as a drug carrier,we achieved controlled drug release to increase the effective drug dose at the peak of adhesion formation to achieve better therapeutic effects.The results showed that IM blocked the formation of peritendon adhesions by inhibiting the PDGFRβ/ERK/STAT3/CLDN1 pathway.Furthermore,the hydrogel with ZIF-8 exhibited better physical properties and drug release curves than the hydrogel loaded only with drugs,showing better prevention and treatment effects on tendon adhesion.

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.

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

Constitutive activation of KIT receptor tyrosine kinase is a critical factor in the pathogenesis of gastrointestinal stromal tumors （GISTs）. But there is little information on whether combination of imatinib mesylate （IM） and surgical treatment can prolong survival in the cases with unresectable multiple liver metastases. We report a case of postoperative recurrence of GIST treated by the tyrosine kinase inhibitor IN and surgical treatment. The initial complete response （CR） to treatment continued for 18 mo, but single liver metastasis showed regrowth in the left hepatic lobe during IN treatment. After partial resection of the recurrent tumor, postoperative course was uneventful and the patient has survived without recurrence for 24 too. Currently, imatinib is the first- line therapy for non-resectable GISTs, but a single agent therapy often leads to tumor resistance. Even if tolerance to imatinib occurs, a combination of imatinib and surgical treatment can prolong survival in some cases as reported here. However, further studies on a large number of cases of recurrent GIST are necessary to evaluate the effectiveness of IN treatment combined with surgery.

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.

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.

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

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 Cajal.GISTs can arise anywhere in the GI tract,but most commonly originate from the stomach and small intestine.The 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 response.Clinical 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 enlarged.Imaging plays a critical role in the diagnosis and management of these tumors with multiphasic computed tomography serving as the imaging modality of choice.Magnetic 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 recurrence.Surgical 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 GISTs.This review article highlights the clinical presentation,pathology and molecular cytogenetics,imaging features,and current management of GISTs.

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.

Modern treatment of gastric gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.

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

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, 2014.RESULTS: 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 died.CONCLUSION: Studies on EGISTs have only been published in the last decade. The lack of studies with large patient cohorts and long-term follow-up limits evidence-based commentary. In theory, each case should be assessed individually and further genetic and immunohistochemical studies are needed.

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

BACKGROUND Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.As 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 literature.CASE SUMMARY Here,we describe 2 cases of gastric GIST occurring during the follow-up of RTRs.We also review the existing literature concerning GIST occurrence in transplant patients.In total and in association with our 2 cases,16 patients have been reported.The median age was 59.5 years and 69%were male.With a median tumor size of 45 mm,no patient displayed metastatic dissemination at diagnosis.Time from transplantation to diagnosis was highly variable between 5 mo and 21 years.Histopathological data mostly revealed high risk of progression(43%).Death increased to 29%during follow-up.Surgical 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.

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

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.

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

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.