Gastrointestinal Stromal Tumors: Review Article

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Gastrointestinal Stromal Tumors:

Review Article

1Fahad AL-Enezi, 2Khaled AL-Khaledy , 3Mahmood Labeeb, 4Amanguno Henny

1Medical oncology department, 2Surgical department, 3Radiology department, 4Histopathology department

INTRODUCTION

Gastrointestinal stromal tumors GISTs, precursors of interstitial cells of cajal, are rare mesenchymal tumors of the gastrointestinal tract that are highly resistant to chemotherapy and radiotherapy.

The incidence of this rare disease is approximately 1.5 per 100,000 persons.1

The recent advances in immunohistochistry and molecular aspects increased the rate of accurate diagnosis.

Imatinib is the standard first line systemic therapy for metastatic cases. Neoadjuvant treatment has been used for locally advanced tumors. Surgical resection is the primary modality for early, localized cases. Post-operatively, those who have high risk profiling will be candidates for adjuvant Imatinib.

Resistance or intolerance will eventually develop in a significant proportion of patients while on Imatinib treatment.

Many alternative therapies have been introduced. Suinitinb is approved as a second line of systemic treatment while many others are still investigational.

This review will present the latest advances in the diagnostic and therapeutic aspects of GIST.

The mechanism of action, side effects, of Imatinib as well as the patterns of resistance to this therapy will be presented.

The radiological features of the primary disease and metastatic will be discussed. This review will address the role imaging modalities in evaluating the response to therapy.

Molecular studies to confirm GIST as well as their potential role in predicting response to therapy are included in this review.

DIAGNOSIS

I. Clinical

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pattern, and size. Small tumors may be asymptomatic and are discovered as an incidental finding.

A palpable abdominal mass with vague pain and discomfort occurring in 50-70% of cases. One third of patients present with gastrointestinal bleeding. Other patients might present with gastrointestinal obstruction, less commonly, patients present with weight loss, nausea, and other non-specific features

GISTs may occur anywhere in the gastrointestinal tract but world-wide, stomach tumors accounting for the majority of cases 50-70 % of cases then small intestine constituting 25 -30 % of cases. Others arise in the colon (10%), esophagus (5%), and omentum (7%).2

II. Histopathology

A. Morphology

GISTs occur in several morphological variants. The tumor cells may be spindle shaped, epitheloid or a mixed cell phenotype.

Cells within the tumor not only have the mesenchymal features but they may exert differentiation into other cell lines including smooth muscle or neural differentiation. Such a differentiation needs careful analysis of immunohistochemistry staining.

B. Immunohistochemistry IHC

1) C-Kit / CD 117 –the receptor for stem cell factor is positive in majority of cells in a GIST appearing in the membrane and cytoplasm as strong and diffuse. Five percent GISTs may be c-Kit / CD 117 negative KIT expression might be found in other soft tissue sarcomas, and epithelial tumors like Non-Hodgkin’s lymphoma, melanoma, and small cell lung carcinoma. It needs to be stressed that immunopositivity for KIT dose not necessarily indicate activation or mutation.3

2) Smooth-muscle actin SMA and desmin will help in distinguishing smooth-muscle sarcomas as leiomyosarcomas from true ultrasructurally ,a subset of GISTs showed a smooth muscle phenotype, which correlated with over expression of genes involved in muscle differentiation and function .4

3) S-100 protein will distinguish neural crest-derived tumors as schwannoma from true GISTs with a neural appearance. Agaram et al found neurosecretory granules (NS-G) to be present in 27% of cases having c-kit 11 genotype and associated with spindle cell morphology. Those with PDGFRA mutations to have

gastric location with epitheloid cell morphology and lacked neurosecretory granules.5

4) CD 34 expressed in two-thirds of cases but not specific for GIST and expressed in many other tumors. 5) Keratin in 1-2 % of GISTs

C. Extragastroinrestinal stromal tumors:

EGIST

EGIST are histologically and immunophenotypically similar to GIST. They occurred in soft tissues of abdominal cavity (omental and mesenteric) or retroperitoneally.

Reith etal, reported an extensive pathological description. Epitheloid variety were shown to have uniform, rounded cells with scant cytoplasm arranged in sheets or singly in a densely collanegized background. Occasionally, they might acquire prominent cytoplasmic vacuoles resulting in signet ring cell formation. Less commenly; they might appear as a degenerative nuclear atypia.

Spindle pattern resembling smooth muscle with short and fusiform morphology with a lightly staining cytoplasm, and short fascicles. Occasionly, they have nuclear palisading.

In their series, they found all cases of EGIST to stain for c-kit in almost all cases. Half of the cases were focally positive for CD34.

EGISTs are usually of large size, the mean size is 12 cm.

They Showed an aggressive course more akin to small intestinal than gastric GISTs. In this regard, the main differentiation point is the absence of skeinoid fibers in these EGIST.6

III. Genotyping / Mutational assessment

Genotyping might establish c-Kit / CD 117 undetectable tumors suspected to be GIST.

This also aids in the diagnosis of GISTs with unusual morphology particularly in younger patients

Genotyping can be predictive for response to therapy based on c-Kit as appreciated that tumors with exon 11 to behave more aggressively than those without it.7

They were reported to be more responsive to treatment.

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This test should be obtained at initial diagnosis or after surgery for all cases except for fully resected low risk tumors.

IV. Imaging

The increasing recognition of GISTs and the prolonged survival have made imaging increasingly important, not only for the tumor diagnosis, but also for monitoring the effects of treatment and detecting tumor progression.

Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), magnetic resonance (MR) imaging, Computed tomogram CT scan and ultrasonography (US) have been used diagnostic and / or monitoring purposes .

MR imaging would be the prinicipal imaging modality for certain cases. The first of them will be those patients in whom CT scan is either contraindicated or their metastatic deposits will be indeterminate. The other indication would be the surgical planning for localized rectal GIST.

Although, FDG PET is highly sensitive in the detection of GISTs.8 & 9 It might miss some of the pre treatment small

lesions. Moreover; it has a worldwide limited access.

Ultrasound is useful in diagnosing liver disease.

Computed tomography (CT) is currently the modality of choice for the purposes of diagnosing and evaluating the treatment responses of GISTs CT scan’s reliability is comparable to FDG PET scan if the enhancement patterns are considered along with the size criteria.

Triphasic CT imaging is the preferable method as a baseline and, whenever possible, for follow-up purposes. This means Performing CT scan in the early and late arterial phases and the portal venous phase.

CT scan findings at initial presentation vary greatly, depending on the size and aggressiveness of the tumor and the time of presentation during the course of the disease.

The findings of primary GISTs are typically large, hyper-vascular, and enhancing masses on contrast-enhanced CT scans and are often heterogeneous. The heterogeneity of these tumors can be attributed to necrosis, hemorrhage, or cystic degeneration at the time of presentation10 & 11

The CT characteristics of metastatic lesions of GISTs are similar to those of primary tumors but often associated with evident vessels within the vicinity of the tumor.

Figure 1. Contrast-enhanced CT scan shows a homogeneous extra-luminal mass arising from the greater curvature of the stomach. This appearance is typical of primary GIST.

Fig. 2 Gastric GIST with multiple hepatic metastases.

RESPONSE EVALUATION

Treatment with imatinib results in decreases in the size of GISTs, but this response typically takes several months before satisfying traditional tumor response criteria. Evaluating the response in terms of size alone criteria through implementing the Response Evaluation Criteria in Solid Tumors (RECIST)12 might be misleading.

At contrast-enhanced CT, a response to imatinib is characterized by rapid transition from a heterogeneously hyper-attenuating pattern to a homogeneously hypoattenuating pattern with resolution of the enhancing tumor nodules and a decrease in tumor vessels.

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The tumor response observed subjectively at CT, which is based on a decrease in or the disappearance of enhancing tumor nodules or tumor vessels or on a decrease in the overall tumor attenuation or size, correlates well with the response observed at FDG PET, which is based on a change in maximum standardized uptake value.13

An objective evaluation of tumor attenuation, measured in Hounsfield units, has been shown to be useful in early quantitative evaluation of tumor response.14 & 15

Short-term follow-up CT, perhaps within 1 month, is recommended.

IMAGING FEATURES OF TUMOR

RECURRENCES:

Traditional criteria for progression include tumor size increase, the development of new lesions at the site of the previous disease, and/or the development of new metastasis.

All of these criteria remain of value in monitoring patients with GISTs. The development of enhancing tumor nodules within a previously treated hypo-attenuating tumor is consistent with GIST recurrence. This is unique feature of progressing GIST regardless of changes in tumor size.16

IMAGING PITFALLS!

Imatinib might cause fluid retention including ascites and visceral edema. The finding of these changes on imaging scans, while on therapy need not to be attributed as merely a sign of recurrence. This is particularly an important point to be considered when the disease is otherwise stable or resolving.

Mild intratumoral hemorrhages might occur in approximately 5% of patients with bulky tumors thus increasing the tumor size. This might suggest disease progression warranting surgical intervention. This needs careful clinical, radiological, and hematological parameters.

The clue would be through careful observation that can reveal the drop in hemoglobin level during the first 4-8 weeks of imatinib treatment.

In addition, this might spuriously increase the tumor attenuation, and so complicating the picture of response evaluation.

Also, tumor progression might erroneously be assumed in the presence of an enlarging mass devoid of new or enlarging enhancing nodules.

Fig. 3 Post therapy Scan showing mesenteric edema.

TREATMENT

Imatinib is approved world-wide as the first line treatment for patients with advanced and metastatic GIST tumors. Recently; it has been approved in neoadjuvant and adjuvant settings. Resistance might develop and selected patients will be elected for another line of therapy.

Imatinib inhibits Bcr-Abl and blocks proliferation and growth of tumor cells expressing these onco-proteins. Imatinib is also a potent inhibitor two cell-surface protein tyrosine kinases, the platelate-derived growth factor receptor PDGF-R and the stem-cell factor receptor c-Kit.

Imatinib is currently approved for the first-line treatment of adult patients with newly diagnosed ph+ CML at all stages and also for patients having metastatatic or unresectable malignant GIST.17

Up to 92 % of GISTs characterized by the expression of the receptor tyrosine kinase C-KIT (CD117). The reminder who are lacking KIT mutations either having activating mutations in the related tyrosine kinase platelet-derived growth factor receptor alpha (PDGFRA) or having no identified kinase mutations. Heinrich et al, reported the mutational status to have an important therapeutic implications. The median event-free survival for patients without detectable KIT or PDGFRA mutations was 82 days and was 200 days for patients with a KIT mutation of exon 9 and was 687 days for those harboring KIT mutation of exon 11.18

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The 5-years survival for completely resected primary tumor reported to be 41-54 % but post-operative recurrence or metastases reported to develop in 40 -90 % of cases.

Demetri et al, assessed the anti tumor response, the safety and tolerabity of Imatinib on 147 patients who were assigned to receive a daily dose of 400 mg or 600 mg. They reported that 53.7% had a partial response and 27.9% had a stable disease. The drug was well tolerated with similar responses and toxicity profiles between the two doses.20

In S0033 trial, a subset of patients with c-Kit negative GIST was treated. Though significant difference in overall survival favoring those with c-Kit positive over c-Kit negative cases, the response rates and progression free survival at two years were similar.21

Imatinib is indicated as first line therapy for metastatic or unresctable GISTs.TheUS-Finland B 222, Phase II Trial, demonstrated an overall clinical benefit rate in terms of objective response and stable disease of 84 % and with a median overall survival of 58 months. The response has been maintained for 2.3 years.

The optimal dose of Imatinib was investigated by two phase III trials.

The EORTC soft tissue and bone sarcoma group in collaboration with the Italian and Australian sarcoma groups’ trial that equally randomized 946 patients to receive Imatinib at 400 mg per day versus 400 mg twice daily did not establish superiority of the higher dose.22

The same outcome was reported by the North American S0033 trial in which 746 patients were randomizing between these two doses.23

Upon further follow-up of these 746 patients in Rankin group were sub-sequently re- assessed aiming to determine the impact of Imatinib on overall survival. Patients who progressed on the lower dose were crossed over to receive the higher dose. The analysis supported the durable survival benefits and continued to demonstrate no significant differences between these two dose levels of Imatinib.24, 25

The meta-analysis conducted by Van Glabbeke, based on 1,640 patients revealed that the adverse prognostic factors to be male gender, patients with poor PS, GIST of bowel origin, baseline low hemoglobin, high neutrophil counts, and patients with either wild type or exon 9 mutations. This meta-analysis confirmed a small advantage in terms of progression-free survival of the high dose for KIT exon 9 mutant cohorts.26

One hundred sixty-five patients with single KIT-positive GISTs that were completely resected were followed by Martin et al in their A GEIS study.

Their patients with a tumor size<6 cm, mitotic count <5 per 50 HPFs, stomach location, or paucicellular have a good profile and so a better disease free-survival.

On the other hand, those tumors having a larger size, high mitotic counts, or high cellularity should be considered as having a high risk of recurrence and should be recommended for sustained systemic therapy such as Imatinib following their complete resection in order to prolong their disease free-survival.27

It is very clear that the tumor-size criteria alone do not accurately reflect tumor response of advanced GISTs to Imatinib.

Casali PG et al28 evaluated the response of 129 patents

with advanced inoperable patient to Imatinib therapy. They reported that responses based on RECIST criteria, the clinical benefits from Imatinib may be underestimated. The patterns of tumor responses were reviewed and could be codified as one of the following:

1 Complete responses

a) Pathologic complete response b) Clinical complete response 2 Partial responses

a) Partial volume response b) Partial tissue response c) Partial functional response 3 Stable diseases

4 Progressive diseases

a) Partial lesion progression b) Partial disease progression c) Complete disease progression

ADJUVANT IMATINIB

DeMatteo et al,29 indicated in ACOSOG Z9001 phase III

trial that adjuvant Imatinib therapy for one year increased recurrence-free survival in patients with completely resected localized gastrointestinal stromal tumors for those having a tumor size of at least 3 cm.

At a median follow-up of 13 months 21 out of 325 patients in the treatment arm but 62 out of 319 patients in the placebo arm developed metastases.

DeMatteo et al,30 updated their results after 4 years of

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Survival Overall Recurrence-free

1 year 99% 94%

2 year 97% 73%

3 year 97% 61%

DeMatteo et al did not consider the mitotic criterion along with the size of these tumors.

High risk patients were defined by ACOSOG Z900 group to be as such:

1) Tumor size >10 cm. 2) Tumor rupture.

3) Presence of <5 peritoneal deposits.

The impact of and the optimal duration for adjuvant treatment need to be defined for high risk patients.

NEOADJUVANT THERAPY

Neoadjuvant Imatinib for about 6-12 months at physician discretion is justified for those with unresectable, large GIST tumors in whom surgery will result in increased rates of morbidity or patients who are inoperable and in whom organ function preservation is of great importance.

The time elapse with preoperative Imatinib should be chosen as short as curative tumor resection or function sparing surgery can be carried out.31

The major advantage for neoadjuvant approach in these circumstances would be is its usefulness in avoiding a major surgery such as Whipple’s procedure.

The starting dose will be 400 mg per day, but a higher dosage might be opted for certain groups of patients like those who are harboring c-Kit exon 9 patients.35

It has been reported that resistance to neoadjuvant therapy might arise in relation to development of secondary mutations of the activation loop KIT.

ADVERSE EFFECTS OF IMATINIB:

The adverse effects of imatinib include fluid retention, diarrhea, nausea, fatigue, muscle cramps, abdominal pain, and rash. Treatment-related fluid overload may manifest as ascites, a pleural effusion, a pericardial effusion, or extensive subcutaneous edema

METASTATIC GISTS

Nilsson etal reported that 44% in their series to have high risk profile (29%) and overtly malignant disease (15%).

Apparently those with overt malignancy were having an increased rate of metastases; tumor related deaths and reduced median survival time.32

Most metastases of GISTs involve the liver and peritoneum by haematogenous spread and peritoneal seeding, respectively. Less commonly, metastases are found in the soft tissue, lungs, and pleura. Unlike gastrointestinal adenocarcinomas, GISTs metastasizing to the lymph nodes are extremely rare.

The development of imatinib resistant clones has been postulated to be responsible for such recurrences.

A recent report from the National Comprehensive Cancer Network suggests that recurrent GISTs should be managed as metastatic disease.35

LOCAL RECURRENCES

The clinical significance and management of local recurrence in an asymptomatic patient are still debatable. However, it is important to identify these recurrences as early as possible so as to perform the local therapies such as ablation and/or local resection.33

Conversely, tumor progression should not be assumed in the presence of an enlarging mass devoid of new or enlarging enhancing nodules.

The median time to recurrence after surgical resection is approximately 2 years.35

RESISTANCE TO IMATINIB

TREATMENT

Two types of resistance to Imatinib have been described. Primary resistance accounts for 12% of cases in whom progressive lack or loss of response to Imatinib occurs within the first 6 months of treatment. This is usually generalized, multifocal and exhibiting wild type kit, exon 9 of KIT, or mutated PDGFRA with a D842V.

Secondary resistance occurs in 50 % where loss of response occurs beyond the first 6 months of Imatinib therapy. This was reported to exist in two patterns as follows:

(I) Partial resistance

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Percutanous radiofrequency ablation was found to be safe and an effective approach for limited progressions.33

(II) Multifocal resistance.

In this case, the patients having a good performance status and the therapeutic options include either increasing the dose of Imatinib or proceeding into the second line of systemic therapy, Sunitinib.

It is very important prior labeling the patient to have disease progression or acquired a kind of resistance to Imatinib; need to be certain about two important issues. The first of them is to ensure that the patient was compliant to therapy.

The other issue was pointed out by Van Den Abbeele et al, who described the occurrence of a flare phenomenon upon termination of Imatinib in some patients who are shown to progress while on treatment. This could be reflected on FDG-PET scan. This misleading phenomenon was attributed to the existence of tumor cell populations for which Imatinib is still effective.34

ALTERNATIVE THERAPIES

The updated NCCN guidelines gave a summary about the latest management for the primary disease and approaches for alternative therapies.35

Sunitinib malate (SU 11248) has been approved as a second line treatment for disease progression, or patient’s intolerance of, Imatinib.

Demetri et al conducted a phase I/II trial in which SU11248 was given to those who progressed while on Imatinib. The phase II regimen chosen was SU11248 fifty mg orally once daily for 4 weeks, followed a 2 period off drug in each 6 weeks cycle SU11248 treatment induced objective response or stable for more than 6 months in 54% of those who progressed on Imatinib with 13% confirmed partial responses. KIT exon mutations had fewer secondary mutations than exon 11 GISTs. These data comprised the basis for phase III trial to define further the activity of SU11248 in patients with Imatinib resistant GISTs.36

Casali et al, demonstrated in their phase III trial found Sunitinib significantly prolonged time to progression TTP and overall survival OS in those whom declared to have failure on Imatinib therapy.37

Van Oosterom et al conducted a phase I/II trial to evaluate the efficacy and feasibility of combining m-TOR inhibitor Everolimus (RAD001) with Imatinib for the treatment of

patients progressed on Imatinib monothertapy. Patients were included upon progression after 4 months of Imatinib, including 2 months of 600 mg per day. Synergism has been shown in-vitro between Everolimus and Imatinib, slowing proliferation and inducing apoptosis in primary GIST cell lines resistant.38

Imatinib and Sunitinib resistant tumors can be treated using more potent kinase inhibitors, such as Nilotinib, which inactivate the mutant kinase protein.

Alternatively, the mutant kinase protein can be targeted by either using HPS 90 inhibitors which result in degradation of activated kit and/or PDGFRA, or by using kit transcriptional receptors, such as Flavopiridol.39

Nimeiri etal,40 found that Sorafenib at 400 mg orally twice

daily yielded disease control in terms of partial response and stable disease at rate of 78% with a median progression -free survival of 13.3 months.

CONCLUSIONS

The increased awareness about GISTs and the development of new diagnostic and therapeutic measures revolutionized the management of patients having GISTs.

Different immunohistochemical properteries have been identified. These are shown in table 2. These might help in differentiating GISTs from other mesenchymal tumors.41

Contrasted CAT scan is the main imaging tool to delineate the extent of disease and can be used to monitor response to various therapeutic modalities. MRI and FDG-PET scan can be used in certain cases.

Table (2) Immunohistochemical Properties of Gastrointestinal Mesenchymal Tumors (41)

Tumor CD117 S-100 ααααα-SMA Type Protein

GIST Positive May be Usually positive negative GIGT Negative Positive Negative GILT Negative Negative Positive GIFT Negative Negative Negative

Abbreviations:-GIST = gastrointestinal stromal tumor, GIGT = gastrointestinal glial tumor,

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Table (3) Therapeutic approaches (42)

Unrespectable or metastatic GIST

First-line therapy Imatinib

Starting Doses - 400 mg / day,

- 800 mg / day (KIT exon 9 patients)

Options on Progression

A) Limited progression 1) Continue Imatinib dose 2) Escalate Imatinib dose 3) Surgery

4) Switch to Sunitinib

B) Generalized progression 1) Escalate Imatinib dose 2) Switch to Sunitinib

Options on progression on Sunitinib 1) Investigational agent 2) Clinical Trial

Primary localized GIST

First-line therapy Surgery

Adjuvant Imatinib Define high risk profiling

Neoadjuvant Imatinib 1) Primary surgery would be mutilating 2) Irresectable tumor

3) Inoperable patient

Recently, mutational studies play a major role in predicting response and resistance of various genetic subtypes to Imatinib therapy.

Imatinib gained a world-wide acceptance as the first-line systemic therapy that has been used in palliative, neoadjuvant, and recently in adjuvant settings. Those who acquire resistance or became intolerant to Imatinib can be switched into Sunitinib which widely accepted as the second-line systemic therapy. Many alternative drugs are introduced but they are still investigational.

Surgery is considered for localized primary disease and for limited resectable metastatsis. Radiofrequency ablation is used as a local approach for limited hepatic metastatic disease.

The European Society of Medical Oncology ESMO therapeutic consensus with some modifications is shown in table 3.42

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10 Choi H, Charnsangavej C, and de Castro Faria S, et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol 2004; 183: 1619–1628

11 Levy AD, Remotti HE, Thompson WM, and Sobin LH, Miettinen M. Gastrointestinal stromal tumors: radiologic features with pathologic correlation. Radio Graphics 2003; 23:283–304.

12 Burkill GJ, Badran M, Al-Muderis O, et al. Malignant gastrointestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread. Radiology 2003; 226:527–532. 13 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205–216. 14 Choi H, Charnsangavej C, de Castro Faria S, et al. CT evaluation

of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am J Roentgenol 2004; 183: 1619– 1628.

15 Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004; 45:357–365.

16 Chi H, Charnsangavej C, Macapinlac H, et al. Correlation of computed tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate [abstract]. Proc Am Soc Clin Oncol 2003; 22:819.

17 Francois Guilhot.Indications for ImatinibMesylate therapy and clinical management .The Oncologist vol.9.number 3, 2004. 18 Michael C. Heinrich etal, Kinase mutations and Imatinib

response in patients with metastatic Gastro intestinal tumors. Journal of clinical oncology, vol. 21, No. 23 Dec ember1, 2003:pp 4342-4349.

19 Blanke GD etal ,long term follow-up of a phase II randomized trial in advanced gastrointestinal stromal GIST patients treated with Imatinib mesylate Proc Am Soc ClinOnc.2006; vol 24 (18 s) Abstract 9528.

20 Demetri et al, Efficacy and safety of Imatinib mesylate in advanced gastrointestinal stromal tumors. New England Journal of Medicine .347:472-480.August 15, 2002.

21 Blackstein ME. Clinical benefit of Imatinib in patients with metastatic gastrointestinal stromal tumors GIST negative for the expression of CD 117 in the S 0033.Proc Am Soc Clin Oncol June 1,2005;vol 23 No 16 S, Abstract 9010

22 Verweij J .Early efficacy comparison of two doses of Imatinib for the treatment of advanced gastro-intestinal stromal tumors GIST: Interim results of a randomized phase III trial from EORTC-STBSG, ISG, and AGITG.ProcAm Soc Clin Oncol.2003; 22Abstract 3272

23 Rankin C .Phase III dose-randomized study of Imatinib mesylate STI 571 for GIST: Intergroup S0033 results.Proc Am Soc Clin Oncol.2003; 22 Abstract 3271

24 Rankin C, Dose effect of Imatinib in patients with metastatic GIST-Phase III Sarcoma group study S0033.Proc Am Soc Clin Oncol 2004;24 Abstract 9005

25 Zalcberg JR et al.Outcome of patients with advanced gastro-intestinal stromal tumors crossing over to a daily Imatinib dose of 800 mg .Eur J Cancer 2005;41:pp 1751-1757

26 Van Glabbeke et al.Comparison of two doses of Imatinib of unresectable or metastatic gastro intestinal stromal tumors: A meta-analysis based on 1,640 patients Proc Am Soc Clin Oncol 2007; 25(18s) Abstract 10004

27 Martin J et al .Prognostic value of pathologic variables and mutations type in patients with surgical resection of gastrointestinal tumors .A GEIS study.Proc Am SocClin Oncol.2004;23:821 Abstract 9029.

28 Casali PG et al, Tumor response to Imatinib mesylate in advanced GIST.Proc Am Soc Oncol.2004; 23:821.Abstract 9028 29 DeMatteo et al, and the American College of Surgeons Oncology Group ACOSOG Intergroup Adjuvant GIST Study Team. Adjuvant Imatinib mesylate increases recurrence free survival in patients with completely resected localized primary gastrointestinal stromal tumors: North American Intergroup phase III trial ACOSOG Z9001 .Proc Am Soc Clin Oncol 2007; 25(18s) Abstract 10079.

30 DeMatteo R.P Efficacy of adjuvant Imatinib following complete resection of localized, primary GISTs at a high risk of recurrence. The US Intergroup phase II trial ACOSOG Z900 Abstract 8 at 2008 Gastro-intestinal symposium

31 Haller et al, 07 Feb; 14(2):525-532.Epub 2006 Dec 2

32 Nilsson B, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era: a population-based study in western Sweden. Cancer 2005; 103(4): 821–829.

33 Dileo P et al.Safety and efficacy of percutanous radio-frequency ablation in patients with metastatic GIST with clonal evolution of lesions refractory to Imatinib mesylate .Proc Am Soc Clin Oncol .2004; 23:820 Abstract 9024.

34 Van Den Abbeele.Effects of cessation of Imatinib mesylate therapy in patients with Imatinib-refractory GIST as visualized by FDG-PET scanning Proc Am Soc Clin Oncol 2004; 23 Abstract 3012.

35 Demetri GD et al, NCCN Task Force Report: Management of patients with gastrointestinal stromal tumors –update of the NCCN clinical practice Guidelines .J Nat Compr Canc Netw 2007; 5 (Supplement 2):S1-29(surgery)

36 Demetri GD et al,SU 11248 ,a multi-targeted tyrosine kinase inhibitor ,can overcome Imatinib resistance caused by diverse genomic mechanisms in patients with metastatic GIST Proc Am Soc Clin Oncol 2004; 23:820 Abstract 3001.

37 Casali et al, Updated results from a phase III trial of Sunitinib in GIST patients for whom Imatinib therapy failed due to resistance or intolerance.Proc Am Soc Clin Oncol ,2006;24( 18s) Abstract 9513

38 Van Oosterom et al, Combination signal transduction inhibition: A phase I/II trial of the oral m-TOR-inhibitor Everolimus and Imatinib mesylate in patients with gastrointestinal stromal tumor refractory to Imatinib.Prosc.Am.Soc.Clin.Oncol 2004; 23:820 Abstract 3002

39 Fletcher JA et al.Kit mutations in GISTs Curr.Opin.Genet.Dev 2007 Feb; 17(1):3-7

40 Nimeiri H.S Activity of Sorafenib in patients with Imatinib and Sunitinb resistant GISTs: A phase II trial of university of Chicago phase II Consotium.2008 Gastrointestinal symposium Abstract 7

41 Kumaresan S. AJR 2005; 184:803-811

Figure

Figure 1. Contrast-enhanced CT scan shows a homogeneousextra-luminal mass arising from the greater curvature of thestomach

Figure 1.

Contrast-enhanced CT scan shows a homogeneousextra-luminal mass arising from the greater curvature of thestomach p.3
Fig. 2 Gastric GIST with multiple hepatic metastases.
Fig. 2 Gastric GIST with multiple hepatic metastases. p.3
Fig. 3 Post therapy Scan showing mesenteric edema.
Fig. 3 Post therapy Scan showing mesenteric edema. p.4
Table (2) Immunohistochemical Properties ofGastrointestinal Mesenchymal Tumors (41)

Table (2)

Immunohistochemical Properties ofGastrointestinal Mesenchymal Tumors (41) p.7
Table (3) Therapeutic approaches (42)

Table (3)

Therapeutic approaches (42) p.8
table 3.42emission tomography for the early prediction of response inadvanced soft tissue sarcoma treated with imatinib mesylate

table 3.42emission

tomography for the early prediction of response inadvanced soft tissue sarcoma treated with imatinib mesylate p.8

References

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