Gastrointestinal Stromal Tumors (GISTs)

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Gastrointestinal stromal tumors: three decades of lessons

Gastrointestinal stromal tumors: three decades of lessons

Gastrointestinal stromal tumors have been a diagnostic dilemma to the medical science in the past decades because of the clinical presentation and improper classification. These tumors generally arise in the gastrointestinal tract especially the stomach, however extraintestinal GISTs are not uncommon. The clinical presentation may vary from an indolent to aggressive course depending upon the tumor size, site of involvement, and mitotic figures. The advancements in histopathology, imaging techniques and molecular diagnostics allowed us to know the nature, mutations and biologic behavior of these tumors. Activating mutations of cKIT, PDGFRA or some other downstream key molecules endows the cells of Cajal with the capacity to grow as GIST. These mutant cells are amenable to newer therapeutic regimen, like imatinib mesylate that inhibits activation of the KIT and PDGFα proteins by binding to the adenosine triphosphate binding pocket required for receptor phosphorylation and activation. Apart from drug therapy, surgery is still the only potential curative treatment, if the tumor is amenable to it. Combinations of newer diagnostic techniques, surgical methods, and adjuvant or neoadjuvant therapies have opened doors to treat these cases in a far more efficient way.
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Management of hemorrhage in gastrointestinal stromal tumors: a review

Management of hemorrhage in gastrointestinal stromal tumors: a review

Abstract: Gastrointestinal stromal tumors (GISTs) are relatively common mesenchymal tumors. They originate from the wall of hollow viscera and may be found in any part of the digestive tract. The prognosis of patients with stromal tumors depends on various risk factors, including size, location, presence of mitotic figures, and tumor rupture. Emergency surgery is often required for stromal tumors with hemorrhage. The current literature suggests that stro- mal tumor hemorrhage indicates poor prognosis. Although the optimal treatment options for hemorrhagic GISTs are based on surgical experience, there remains controversy with regard to optimum postoperative management as well as the classification of malignant potential. This article reviews the biological characteristics, diagnostic features, prognostic factors, treatment, and postoperative management of GISTs with hemorrhage.
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Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach

Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach

Ménétrier disease and gastrointestinal stromal tumors (GISTs) are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases (RTKs). In Ménétrier disease, overexpression of TGF-α, a ligand for the RTK EGFR, results in selective expansion of surface mucous cells in the body and fundus of the stomach. In GISTs, somatic mutations of the genes encoding the RTK KIT (or PDGFRA in a minority of cases) result in constitutive kinase activity and neoplastic transformation of gut pacemaker cells (interstitial cells of Cajal). On the basis of the involvement of these RTKs in the pathogenesis of these disorders, Ménétrier disease patients have been effectively treated with a blocking monoclonal antibody specific for EGFR and GIST patients with KIT and PDGFRA tyrosine kinase inhibitors.
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Gastrointestinal Stromal Tumors: Experience from a Single Surgical Unit

Gastrointestinal Stromal Tumors: Experience from a Single Surgical Unit

Although gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract (GIT), overall they are rare neoplasms ranking a distant third in prevalence behind adenocarcinomas and lymphomas [1]. They may also originate from the mesentery and the omentum. In the past, these tumors were a poorly defined pathological entity with uncertainty regarding the origin and terminology often being confused with leiomyomas and leiomyosarcomas. Kindblom in 1998 first hypothesized the origin of these tumors from pluripotential mesenchymal stem cells of the gastrointestinal tract which are programmed to differentiate into the interstitial cell of Cajal (ICC) [2]. These tumors have microscopic features in common with the myenteric plexus subtype of ICC that are found in stomach and intestines, including frequent expression of CD34, embryonic smooth muscle myosin heavy chain, and the intermediate filament nestin. The observation that ICC cells can be immunohistochemically highlighted with an antibody to KIT (CD 117) led to the discovery that KIT is also strongly expressed in most GISTs [3,4]. These not only substantiated the hypothesis that GISTs arise from or share a common stem cell with the ICC, but it also provided a new, more sensitive and specific marker for its diagnosis. Gain-of-function mutations in exon 11 of the c-kit proto-oncogene are associated with most GISTs [5].
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Original Article Impact of serosal involvement/extramural growth on the risk of synchronous and metachronous peritoneal spread in gastrointestinal stromal tumors: proposal for a macro- scopic classification of GIST

Original Article Impact of serosal involvement/extramural growth on the risk of synchronous and metachronous peritoneal spread in gastrointestinal stromal tumors: proposal for a macro- scopic classification of GIST

Abstract: Background: Peritoneal and hepatic metastases are the main routes of spread of gastrointestinal stromal tumors (GIST). However, criteria to predict the site and pattern of recurrence in individual cases are still lacking. Pa- tients: We retrospectively analyzed 67 consecutive GISTs with complete gross descriptions to correlate macroscopic patterns with clinical course. Primary endpoint was the appearance of synchronous or metachronous peritoneal dis- ease. Tumors were classified into type I (luminal/intramural) and type II (extramural) based on the macroscopic/ histologic presence or absence of normal tissue between deeper tumor border and serosa, respectively. Results: Patients were 35 men and 32 women (mean age, 64 yrs) with gastric (n=32), small bowel (n=30) and large bowel (n=5) GISTs. Based on the above proposal, 22 tumors were classified as type I and 45 as type II. Type I tumors were predominantly gastric (18/22; P<0.001) and frequently had very low/low risk (14/22; P<0.001) whereas type II tu- mors were predominantly intestinal (31/45; P<0.001) and often of intermediate/high risk (36/45; P<0.001). Ten patients had synchronous peritoneal spread and 6/30 patients with a mean follow-up of 29 months developed meta- chronous peritoneal spread at a mean of 27 months. Tumor rupture was seen in 2 patients (3%). Thus, 16/40 pa- tients (40%) had synchronous or metachronous peritoneal progression. Taken by gross type, peritoneal progression was seen in 15/30 type II compared to 1/10 type I tumors (p=0.032). Conclusion: this study points to extramural growth as a predictor of peritoneal recurrence in GIST, probably as a consequence of tumor rupture or due to micro- scopic serosal penetration. This study aimed at alerting surgical pathologists to the importance of careful gross and microscopic assessment of resection specimen harboring GIST to allow for reliable prospective evaluation of serosal involvement as an adverse prognostic factor in GIST.
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Management Colorectal Gastrointestinal Stromal Tumors (Gists) in Surabaya

Management Colorectal Gastrointestinal Stromal Tumors (Gists) in Surabaya

Introduction: Colorectal gastrointestinal stromal tumors (GISTs) mesenchymal tumor is very un- common. GISTs effect mostly on the stomach and small intestine and rarely occur in the colon, rectum and esophagus, that originating from precursors of the interstitial cells that originate of Cajal. The symptoms of gastrointestinal stromal tumor depend on the site and size of the tumor, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumors may, however, be asymptomatic. Some of the patients with gastrointestinal stromal tumor have bloody stools, obstruction and abdominal pain as the commonest manifestation. Immunocyto- chemical staining for CD117 is helpful in confirming the diagnosis. Case presentation: We report 3 new cases of GISTs: two occurred at the rectal and the other at descending Colon. Two cases are over 50 years of age and, and all cases the chief complain of bowel obstruction, abdominal pain in two cases, and one case with anemia and urine retention. All the patients were operated and were permormed pathology examinatiom. All case ware positive result for immunocytochemical stain- ing CD117. All cases we had presented had size more than 5 cm are considered as unfavorable prognostic factors to Fletcher criteria, all patients scheduled for chemotherapy with Glivec but just one patient continued to used Glivec. Post surgery follows up one patient post milles with urinary incontinence complaints found and that patients are trained to CIC (intermittent cathete- rization). Conclusion: Colorectal gastrointestinal stromal tumors are very rare and can present as mass abdomen. Resection and chemotherapy are the treatment of choice.
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Prognostic impact of gastrointestinal bleeding and expression of PTEN and Ki 67 on primary gastrointestinal stromal tumors

Prognostic impact of gastrointestinal bleeding and expression of PTEN and Ki 67 on primary gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) constitute the most common mesenchymal neoplasms of the gastrointes- tinal (GI) tract, and the incidence has increased significantly over the past three decades [1,2]. Gain-of-function muta- tions in c-kit and, less commonly, the platelet derived growth factor receptor α (PDGFRA) oncogene are believed to be the driving force of GISTs [3,4]. All GISTs have malig- nant potential, varying from small lesions to aggressive sar- comas. Disease relapse is not uncommon, even where tumors are R0 resected. The application of imatinib mesy- late (IM), a small-molecule tyrosine kinase inhibitor, has dramatically promoted the disease-free survival of GISTs. However, side effects and resistance to IM pose new chal- lenges in the management of GISTs. Thus, an accurate risk classification scheme has become increasingly crucial for selecting patients who are most likely to benefit from adju- vant IM therapy. National Institutes of Health (NIH) con- sensus criteria [5], Armed Forces Institute of Pathology (AFIP) criteria [6], and modified NIH consensus criteria [7] are used frequently to estimate the risk of recurrence after surgery in GISTs. However, even the latest risk stratification system may still have room for improvement.
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Update on imatinib for gastrointestinal stromal tumors: duration of treatment

Update on imatinib for gastrointestinal stromal tumors: duration of treatment

Abstract: Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future. Keywords: adjuvant, c-KIT, mutations, resistance, treatment, gastrointestinal stromal tumors, imatinib
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Syndromic gastrointestinal stromal tumors

Syndromic gastrointestinal stromal tumors

During the review process and after acceptance of this manuscript, data relevant with respect to SDH-deficient GISTs, one of the main topics of the present review, have been published: 1) Ben-Ami et al. (Ben-Ami E, Barysauskas CM, von Mehren M, Heinrich MC, Corless CL, Butrynski JE, et al. Long-term follow-up of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosin kinase inhibitor therapy. Ann Oncol. 2016; doi: 10.1093/ annonc/mdw228) reported that regorafenib induced objective responses and durable benefit in SDH-deficient GISTs; 2) Boikos et al. (Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors. A report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016; doi: 10.1093/annonc/mdw228) propose genotype rather than presence or absence of chondromas as the discriminating factor between CT and CSS.
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Original Article Prognostic analysis of primary extra-gastrointestinal stromal tumors

Original Article Prognostic analysis of primary extra-gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common type of gastrointestinal mesen- chymal tumors. C-Kit genetic mutation and KIT (CD117) expression have been observed in the majority cases of GIST [1, 2]. The prognosis of patients with GISTs is correlated with the tumor site, mitotic count, size, and expression of Ki-67 [3, 4]. The observations of mesenchymal tumors growing outside of the gastrointestinal tract, also called extra-gastrointestinal stromal tumors (EGISTs), have been increasingly report- ed in recent years; these tumors present the morphology, immunohistochemical features, and molecular biological characteristics, which are similar to those of GISTs. Only a few reports of EGISTs are available in the literature due to its low incidence compared with other tumors. In this retrospective study, we analyzed several predictive factors including clinical and patho- logical parameters on the diseases-free surviv- al (DFS) of 42 EGISTs patients.
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Histopathological and clinical characteristics of duodenal gastrointestinal stromal tumors as predictors of malignancy

Histopathological and clinical characteristics of duodenal gastrointestinal stromal tumors as predictors of malignancy

Japanese proactively seek medical examination includ- ing fiber-optic gastroscopy (FGS) and abdominal ultra- sonography. This enables early detection of duodenal GISTs. In our study, 12 of 20 duodenal GISTs (60%) were found incidentally, and 5 of these 12 cases were detected endoscopically. In addition, 7 cases (35%) were recognized by FGS performed to investigate the cause of gastrointestinal bleeding or the cause of anemia. Therefore, 12 patients (60%) had their duodenal GISTs detected by endoscopy. In our study, 60% of patients were at very low or low risk from aggressive tumor behavior according to modified AFIP consensus criteria for risk stratification of GISTs, in which the main contributor to risk is tumor size [12]. Gastrointestinal stromal tumors in Japanese patients have been reported to contain similar genetic mutations to GISTs in patients from other countries [14]. The early de- tection of GISTs allows prevention of metastasis or local tumor invasion and improved prognosis for patients with duodenal GISTs.
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Efficacy and Tolerability of Imatinib Mesylate In Advanced Gastrointestinal Stromal Tumors

Efficacy and Tolerability of Imatinib Mesylate In Advanced Gastrointestinal Stromal Tumors

Imatinib mesylate is a selective inhibitor of certain protein tyrosine kinases: the intracellular ABL kinase, the chimeric BCR-ABL fusion oncoprotein of chronic myeloid leukemia, the trans-membrane receptor KIT, and the platelet-derived growth factor receptors. Imatinib is highly active in patients with chronic myeloid leukemia and other Philadelphia chromosome–positive leukemias, in which it inhibits the dysregulated kinase activity of the BCR-ABL fusion protein. Imatinib blocks the constitutive activity of KIT receptor tyrosine kinase in the cells of gastrointestinal stromal tumors. This was supported by pre-clinical and clinical trials. Exposure of these cells to Imatinib blocked the kinase activity of KIT, arrested proliferation, and caused apoptotic cell death. 3
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Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.

Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.

Primary and secondary resistance to currently available licensed tyrosine kinase inhibitors poses a real clinical challenge in the management of advanced gastrointestinal stromal tumors. Within the frame of early phase clinical trials novel systemic treatments are currently being evaluated to target both the well explored and novel emerging downstream effectors of KIT and PDGFRA signaling. Alternative therapeutic approaches also include exploring novel inhibitors of the KIT/PDGFRA receptors, immune checkpoint and cyclin-dependent kinase inhibitors. The final clinical trial outcome data for these agents are highly anticipated. Integration of new diagnostic techniques into routine clinical practice can potentially guide tailored delivery of agents in the treatment of a highly polyclonal, heterogeneous disease such as heavily pretreated advanced gastrointestinal stromal tumor.
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Gastrointestinal Stromal Tumors  in the 21st Century

Gastrointestinal Stromal Tumors in the 21st Century

Gastrointestinal stromal tumors though rare, are the commonest primary mesenchymal neoplasm of the ga- strointestinal tract. These tumors are heterogeneous with respect to patient demographics affected, clinical pres- entation, tumor size, mitotic count, histologic subtypes, and malignant potential. The recognition that GIST is a disease driven by an oncogenic kinase mechanism and the development of novel targeted tyrosine kinase inhi- bitors such as imatinib mesylate (Gleevec), has revolutionized the clinical understanding and management of GIST in the 21 st century. Accurate recognition of GIST by the expression of CD117 (c-kit) and/or DOG-1 now clearly defines this family of tumors. There is a growing body of evidence to suggest that additionally, complex epigenetic alterations occur during GIST tumorigenesis, which correlates with tumor aggressiveness. The de- coding of this molecular signature may help in predicting clinical behavior/susceptibility to standard treatment. Mediators of the epigenetic mechanisms and the recognition of other specific molecular abnormalities may serve as potential therapeutic targets in the future.
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Gastrointestinal Stromal Tumors: Review Article

Gastrointestinal Stromal Tumors: Review Article

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.

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Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

Approximately 85% to 90% of all cases of gastrointestinal stromal tumors (GIST) are associated with gain-of-func- tion mutations in the gene KIT [1-4]. A further 5% to 10% of cases of GIST are associated with activating mutations in the platelet-derived growth factor receptor alpha (PDGFRα) gene [1,4,5]. Activating Kit mutations in GIST occur principally in the extracellular domain, the jux- tamembrane domain (which regulates receptor dimeriza- tion), kinase domain I, and kinase domain II (or activation loop) [1]. Imatinib, a small-molecule inhibitor of Kit and PDGFRα, represents an effective first-line ther- apy option for patients with advanced GIST [6]. Imatinib is a potent inhibitor of wild-type Kit and juxtamembrane domain Kit mutants, while Kit activation loop mutants are resistant [1,7]. Secondary imatinib resistance is most
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Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib

Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib

possible. Patients were categorized based on response to TKI at the time of surgery (stable disease which included patients initially with unresectable or metastatic GIST who achieved a drug response to render all disease resectable and whose tumors were not growing at the time of surgery, limited disease progression or generalized disease progression) and surgical result (no evidence of disease, minimal residual disease or bulky residual disease). Results of this single center study sug- gested that response to TKI was significantly associated with surgical outcome. Seventy-eight percent of patients with stable disease at the time of surgery were rendered radiographically disease-free post-operatively, as compared to 25% and 7% of patients with limited progression and generalized progression respectively. Conversely bulky residual disease remained after surgery in 4%, 16%, and 43% of these patients respectively. One-year progression-free survival in patients with stable dis- ease, limited progression and generalized progression was 80%, 33%, and 0%. The median time to progression for patients with limited and generalized disease progression was 7.7 months and 2.9 months respectively, while the median time to progression for patients with stable disease has not been reached after a median follow-up of 14.6 months (range, 0.5 to 36.4 months). One-year overall survival was 95%, 86%, 0% respectively. The authors concluded that patients with advanced GISTs exhibiting stable disease or limited progression on TKI have prolonged survival after debulking procedures while surgery has little to offer in the setting of generalized progression. While it is clear that patients with generalized disease progression are unlikely to benefit from surgery, it is unclear from this study whether the improved progression-free and overall survival seen in patients with stable disease and limited disease progression was a result of surgical intervention or inherent tumor biology and response to TKI.
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Synchronous gastrointestinal cancer and gastrointestinal stromal tumors: a single institution experience

Synchronous gastrointestinal cancer and gastrointestinal stromal tumors: a single institution experience

under 4 cm. Moreover, in a retrospective study of 207 pa- tients who underwent gastrectomy or esophagectomy for non-GIST neoplasms, 15 synchronous GISTs in the upper gastrointestinal tract of 11 (5.3 %) patients were found with an average size of 0.5 cm (0.1–4.0 cm) [7]. After a median follow-up of 11 months (2–36 months), no patient experienced GIST recurrence. Synchronous GISTs that were incidentally found during the resection of other gastrointestinal neoplasms may not negatively affect long- term survival, although they often pose very low or low risk of malignant potential. Small GISTs (<2 cm) may be asymptomatic and nonmalignant when diagnosed but have a potential for malignant transformation. In the present study, there were five patients with intermediate/ high risk in the non-synchronous group, and they might more likely to experience tumor progression than that of patients with very low/low risk.
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Two staging systems for gastrointestinal stromal tumors in the stomach: which is better?

Two staging systems for gastrointestinal stromal tumors in the stomach: which is better?

Background: The prognosis of a gastrointestinal stromal tumor (GIST) is influenced by its anatomic site; however, few studies on the prognosis of gastric GISTs have been reported. The aims of this study were to evaluate long-term prognoses of patients who underwent surgical resection for gastric GISTs and to compare the clinical efficacy of two staging systems: the National Institutes of Health (NIH) consensus criteria and the 7th Union for International Cancer Control/American Joint Committee on Cancer (UICC/ AJCC) tumor-node-metastasis (TNM) staging system.

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Surgical resection for gastrointestinal stromal tumors (GIST): experience on 25 patients

Surgical resection for gastrointestinal stromal tumors (GIST): experience on 25 patients

A combined European/Australian study [2,12] has been started, in order to test the effectiveness of a new chemo- therapy regimen based on imatinib mesylate STI-571: a tyrosine kinase receptors inhibitor [6], highly selective on GISTs and able to perform a "target" therapy, based on the c-KIT expression (CD117) of these tumors. Preliminary results of the first phase trials demonstrated up to 80% of partial response in patients suffering from metastatic or recurrent GISTs treated by imatinib.

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