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Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are a type of soft-tissue sarcoma (cancers of the muscles and other supporting tissues of the body). They may be found anywhere in or near the gastrointestinal tract; most commonly the stomach (50-60%) and small bowel (25-30%). Whilst they can occur at an age most people diagnosed with GIST are over 50.

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Kinsinger LA, Garber JC, Whipple O
A Review of Sleeve Gastrectomy Specimen Histopathology.
Am Surg. 2016; 82(11):1101-1104 [PubMed] Related Publications
With the increasing popularity of sleeve gastrectomy, many stomach specimens are being evaluated. Understanding the significance and treatment for unexpected pathology is important. This study examines the incidence of relevant histopathology of sleeve gastrectomy specimens. It evaluates previous data for each histopathology and provides recommendations for treatment. In this study, a retrospective review was performed for 241 patients who underwent sleeve gastrectomy from 2009 to 2014 at a single institution. Of the specimens, 122 had no significant histopathology, 91 had gastritis, 13 had lymphoid aggregates, 5 had hyperplasia, 3 had intestinal metaplasia, 3 had gastrointestinal stromal tumors (GISTs), and 3 had gastric polyps. Of the GISTs all had a low mitotic rate and the size of the tumor ranged from 1.5 to 4.5 cm. The findings of metaplasia may be a marker for increased risk of malignancy and may require additional surveillance. The findings of GIST may warrant interval imaging to survey for recurrence, though the likelihood of recurrence for the tumors in this study is less than 2 per cent based on previous studies.

Gao Z, Wang C, Xue Q, et al.
The cut-off value of tumor size and appropriate timing of follow-up for management of minimal EUS-suspected gastric gastrointestinal stromal tumors.
BMC Gastroenterol. 2017; 17(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUD: The detectable rate of minimal gastric GISTs has continuously increased. While the surveillance and management of GIST <2 cm have been deemed controversial or lack evidence-based approaches.  The aim of the current study is to propose a cut-off value of tumor size for treatment policy and the appropriate timing for endoscopic ultrasonography (EUS) follow-up in the minimal EUS-suspected gastric GIST patients.
METHODS: A single-institution retrospective study was performed. 69 patients with EUS-suspected gastric GISTs were studied from November 2008 to March 2015. 69 patients with minimal gastric GISTs ≤2 cm diagnosed by EUS were followed for a mean period of 29 months (range, 12 to 70). An at least 20% increase of the maximal diameter of the tumors was set as a significant change.
RESULTS: During follow-up, Of the 69 minimal EUS-suspected GISTs, 16 (23.2%) showed significant changes in size. 11 out of 69 GISTs (15.9%), 6 out of 43 GISTs (14.0%), 7 out of 30 GISTs (23.3%) showed significant changes in size, at 1 year, 2 years, and more than 3 years respectively. The receiver operating characteristic curve analysis showed that the tumor size cut-off was 9.5 mm. Only 4.7 and 3.7% of gastric EUS-suspected GISTs of <9.5 mm in size showed significant changes at 1 year and 2 years, while 9.5% at more than 3 years. 34.6, 31.3 and 55.6% of gastric EUS-suspected GISTs of ≥ 9.5 mm in size showed significant changes at 1 year, 2 years and more than 3 years.
CONCLUSIONS: Minimal EUS-suspected GISTs, larger than 9.5 mm may be associated with significant progression. The patients with a ≥ 9.5 mm GIST should have a EUS 6-12months, while <9.5 mm GIST may have a EUS extended to every 2-3 years.

Noto B, Weckesser M, Buerke B, et al.
Gastrointestinal Stromal Tumor Showing Intense Tracer Uptake on PSMA PET/CT.
Clin Nucl Med. 2017; 42(3):200-202 [PubMed] Related Publications
A 70-year-old man with suspected prostate cancer was referred for Ga-PSMA-HBED-CC PET/CT (short PSMA PET/CT) for staging of tumor extent. Apart from vivid tracer uptake in the prostate gland and osseous metastasis, PSMA PET/CT revealed a large soft tissue mass with calcifications in the left upper abdomen showing intense tracer uptake. Histologic examination revealed the mass to be a gastrointestinal stromal tumor.

Fujishima H, Etoh T, Hiratsuka T, et al.
Serosal and muscular layers incision technique in laparoscopic surgery for gastric gastrointestinal stromal tumors.
Asian J Endosc Surg. 2017; 10(1):92-95 [PubMed] Related Publications
INTRODUCTION: To minimize the resection of stomach tissue, especially for lesions close to the esophagogastric junction or pyloric ring, we developed laparoscopic wedge resection with the serosal and muscular layers incision technique (SAMIT) for gastric gastrointestinal stromal tumors.
MATERIALS AND SURGICAL TECHNIQUE: SAMIT involves resection of the mucosal and submucosal layers and then an incision in serosal and muscular layers around the tumor. SAMIT is simple and does not require special devices. The data of 13 patients who underwent laparoscopic wedge resection with SAMIT for primary gastric gastrointestinal stromal tumors were reviewed. No intraoperative complications were observed, and postoperative stenosis occurred in only one case of a middle stomach lesion. Adequate oncological resection was performed in all cases.
DISCUSSION: Laparoscopic wedge resection with SAMIT is technically and oncologically safe. It is useful for treating gastric gastrointestinal stromal tumors, including those close to the esophagogastric junction or pyloric ring.

Merten L, Agaimy A, Moskalev EA, et al.
Inactivating Mutations of RB1 and TP53 Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors.
Am J Clin Pathol. 2016; 146(6):718-726 [PubMed] Related Publications
OBJECTIVES: Loss-of-function mutations in TP53 and CDKN2A have been found at varying frequencies in gastrointestinal stromal tumors (GISTs), while no mutations of RB1 have been reported to date. The aim of the current study was to determine the mutation frequency of TP53, RB1, and CDKN2A in GISTs.
METHODS: A cohort of 83 primary untreated GISTs was analyzed for mutations in TP53, RB1, and CDKN2A by massive parallel sequencing. Tumors with mutations in TP53 and RB1 were analyzed by fluorescence in situ hybridization for the corresponding gene loci.
RESULTS: Two GISTs harbored inactivating mutations in RB1, and two other GISTs displayed inactivating mutations in TP53 All four tumors were KIT mutant high-risk tumors with highly cellular sarcomatous histomorphology and variable combinations of plump spindle cells to epithelioid highly atypical cells and high mitotic activity. Three of these patients developed recurrent or metastatic disease, while the fourth patient showed tumor rupture intraoperatively. The combined overall frequency of TP53 and RB1 mutations was 13% considering high-risk or malignant GISTs.
CONCLUSIONS: TP53 and RB1 mutations seem to be restricted to high-risk/malignant GISTs and occur at an equal although relatively low frequency.

Hamzaoui L, Medhioub M, Bouassida M, et al.
Gastrointestinal stromal tumours (GISTs): A descriptive study on 29 cases.
Arab J Gastroenterol. 2016; 17(4):185-187 [PubMed] Related Publications
BACKGROUND AND STUDY AIM: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, originating from Cajal cells in different sites of the digestive tract. The aim of the study is to report on epidemiological, clinical, histological, and therapeutic characteristics of GISTs.
PATIENTS AND METHODS: A retrospective descriptive study of 29 cases of GIST in gastroenterology and general surgery departments of Mohamed Tahar Maamouri Hospital (Nabeul, Tunisia) was conducted from January 2005 to March 2012.
RESULTS: Among the 29 patients, there were 18 males (62%) and 11 females (38%) with a median age of 63 years (range, 30-96years). The main symptoms were abdominal pain (40%) and weight loss (28%). The tumour was revealed by a complication in 5 cases (17%). Six patients (20.7%) had metastatic lesions. The most common sites were the stomach (41.4%) and the small intestine (17.3%). The median tumour size was 9.5cm (range, 1-30cm). Spindle cell tumours were the main histological type (62%). KIT was positive in the majority of cases (75%). Twenty-one patients with primary disease (72%) underwent a surgical resection. Imatinib was prescribed in 7 patients (24%). Sunitinib malate was indicated in 3 patients who had tumour progression under imatinib. Median survival was 17 months (range, 1-69months). Ten patients died.
CONCLUSION: The management of GISTs has considerably evolved during the last years. Surgical resection, which remains the mainstay of treatment, was indicated in the majority of patients. Imatinib treatment has not improved overall survival in metastatic and/or inoperable cases.

Yin Y, Xiang J, Tang S, et al.
A lower dosage of imatinib in patients with gastrointestinal stromal tumors with toxicity of the treatment.
Medicine (Baltimore). 2016; 95(49):e5488 [PubMed] Free Access to Full Article Related Publications
This study investigated the efficiency and safety of imatinib in the lower dose (300 mg/d) in patients with gastrointestinal stromal tumor (GIST) who cannot tolerate imatinib in the standard dose (400 mg/d).Steady-state imatinib trough concentration (Cmin) values in 18 patients with GIST who were taking 300 mg/d or 400 mg/d imatinib were measured. The clinical features, toxicity data, and follow-up data were collected.Around 18 patients with GIST were investigated in which 9 patients received 300 mg/d imatinib. The mean imatinib Cmin value of the 18 patients was 1841 ng/mL (1018-3897 ng/mL). The difference between the patients treated with 400 mg/d (n=9) and those treated with 300 mg/d (n = 9), which have imatinib Cmin values of 2122±1003 ng/mL and 1559±478 ng/mL, respectively, was not significant (P = 0.148). In total, 12 of the 18 patients had complete resection of the primary tumor, 8 of whom received postoperative imatinib 300 mg/d. After the average follow-up of 15.4 months, no recurrence was documented. Of the 6 patients with unresected GIST, 1 received imatinib 300 mg/d for 13 months. The tumor size of this patient continued to decrease. In contrast to patients treated with imatinib 400 mg/d, patients treated with imatinib 300 mg/d notably exhibited lesser drug-related side effects.Patients with GIST who exhibited intolerance to the standard dose of imatinib (400 mg/d), a lower dose of 300 mg/d could provide not only sufficient plasma Cmin and good disease control but also the alleviation of the side effects.

Arigami T, Uenosono Y, Ishigami S, et al.
Clinical Significance of the Glasgow Prognostic Score in Patients with Gastrointestinal Stromal Tumors.
Anticancer Res. 2016; 36(12):6687-6690 [PubMed] Related Publications
AIM: To assess the clinical utility of the Glasgow prognostic score (GPS) as a blood predictor of postoperative recurrence in patients with gastric gastrointestinal stromal tumors (GISTs).
PATIENTS AND METHODS: Twenty-nine patients with gastric GISTs undergoing gastrectomy were retrospectively reviewed. Patients were classified based on GPS criteria as follows: GPS of 2: elevated C-reactive protein (>1.0 mg/dl) and hypoalbuminemia (<3.5 g/dl), GPS of 1: one of these hematological abnormalities, and GPS of 0: neither elevated CRP nor hypoalbuminemia.
RESULTS: The National Institutes of Health (NIH) classification for a risk stratification demonstrated that 3 (10.3%), 15 (51.7%), 5 (17.2%), and 6 (20.7%) patients were at very low, low, intermediate, and high risk, respectively, of disease recurrence. GPS criteria classified 24 (82.8%), five (17.2%), and no (0%) patients into GPS of 0, 1, and 2, respectively. Postoperative recurrence was identified in five patients (17.2%). Disease recurrence correlated with a risk stratification based on the NIH or GPS classification (p=0.004 and p=0.024, respectively).
CONCLUSION: The GPS, as well as NIH classification, is a promising blood predictor of disease recurrence in patients with resectable gastric GISTs.

Poveda A, Martinez V, Serrano C, et al.
SEOM Clinical Guideline for gastrointestinal sarcomas (GIST) (2016).
Clin Transl Oncol. 2016; 18(12):1221-1228 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, and this disease has served as a paradigmatic model for successful rational development of targeted therapies. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. The Spanish Society of Medical Oncology (SEOM) guidelines provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

Jasek K, Buzalkova V, Minarik G, et al.
Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tumors.
Virchows Arch. 2017; 470(1):29-36 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are characterized by mutations in exons 9, 11, 13, and 17 of KIT or exons 12, 14, and 18 of PDGFRA gene. However, approximately 10 to 15 % of GISTs lack the mutations in KIT and PDGFRA, and these are referred to as wild-type GISTs which are less sensitive to tyrosine-kinase inhibitors. The aim of this study was to detect BRAF mutations in patients with wild-type GISTs. We applied a sensitive allele-specific PCR, which was optimized using the V600E mutation-harboring cell line RKO, followed by verification of the results by dideoxy sequencing. We selected 149 GIST patients without detectable mutations in KIT and PDGFRA genes from the Slovak national GIST register and analyzed biopsy specimens for the presence of BRAF mutations in exon 15. We identified nine patients with the V600E mutation. The BRAF-driven GISTs were primary gastric (n = 3), small intestinal (n = 3), colon (n = 1), and of uncertain origin (n = 1). We also included a liver metastasis of a patient with a simultaneous KIT exon 11-mutated intra-abdominal metastasis. We conclude that genome analysis of wild-type GISTs for mutations should include the BRAF gene, as its mutation status contributes to understanding of pathogenesis and might be important for decisions on therapy.

Xu H, Liu C, Chen Y, et al.
Diagnosis and treatment of gastrointestinal stromal tumor extending to prostate: A case report and literature review.
Medicine (Baltimore). 2016; 95(46):e5439 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Gastrointestinal stromal tumor (GIST) is the neoplasm of gastrointestinal tract.
PATIENT CONCERNS: The patient complained about the retention of urinary.
INTERVENTIONS: radical prostatectomy and the imatinib therapy.
OUTCOMES: No recurrence and metastasis have been found during a 14-month follow-up.
LESSONS: comprehensive treatment is necessary for the GIST treatment. Furthermore, we summarize a review of the literature of GIST occurring in the prostate gland treated by different methods and 4 kinds of rare diseases in prostate.

Liu Z, Liu S, Zheng G, et al.
Clinicopathological features and prognosis of coexistence of gastric gastrointestinal stromal tumor and gastric cancer.
Medicine (Baltimore). 2016; 95(45):e5373 [PubMed] Free Access to Full Article Related Publications
The coexistence of gastric gastrointestinal stromal tumor (GIST) and gastric cancer is relatively high, and its prognosis is controversial due to the complex and variant kinds of presentation. Thus, the present study aimed to explore the clinicopathological features and prognostic factors of gastric GIST with synchronous gastric cancer.From May 2010 to November 2015, a total of 241 gastric GIST patients were retrospectively enrolled in the present study. The patients with coexistence of gastric GIST and gastric cancer were recorded. The clinicopathological features and prognoses of patients were analyzed.Among 241 patients, 24 patients had synchronous gastric cancer (synchronous group) and 217 patients did not (no-synchronous group). The synchronous group presented a higher percentage of elders (66.7% vs 39.6%, P = 0.001) and males (87.5% vs 48.4%, P < 0.001) than the no-synchronous group. The tumor diameter, mitotic index, and National Institutes of Health degree were also significantly different between the 2 groups (all P < 0.05). The 5-year disease-free survival and disease-specific survival rates of synchronous group were significantly lower than those of no-synchronous group (54.9% vs 93.5%, P < 0.001; 37.9% vs 89.9%, P < 0.001, respectively). However, the 5-year overall survival rates between synchronous and gastric cancer groups were comparable (37.9% vs 57.6%, P = 0.474).The coexistence of gastric GIST and gastric cancer was common in elder male patients. The synchronous GIST was common in low-risk category. The prognosis of gastric GIST with synchronous gastric cancer was worse than that of primary-single gastric GIST, but was comparable with primary-single gastric cancer.

Inayat F, Saif MW
New Drug and Possible New Toxicity - Squamous Cell Carcinoma Following Imatinib in Patients with Gastrointestinal Stromal Tumors.
Anticancer Res. 2016; 36(11):6201-6204 [PubMed] Related Publications
BACKGROUND: Molecularly targeted therapy has revolutionized the treatment of advanced gastrointestinal stromal tumors (GISTs). Specifically, the consistent dependence of GISTs on proto-oncogene c-KIT signaling led to the development and successful implementation of imatinib, a small-molecule c-KIT inhibitor. Imatinib induces, rapid and sustained clinical benefit by blocking the signaling via c-KIT. The most frequently reported adverse reactions (>30%) include edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.
CASE SERIES: Herein, we report a case series of cutaneous squamous cell carcinoma (SCC) occurring secondary to imatinib in two patients treated for GISTs. Both patients were successfully managed with surgical resection of SCC and the discontinuation of the drug. Furthermore, we undertook a comprehensive literature review on this association. Few cases of cutaneous SCC secondary to imatinib therapy were reported in patients with chronic myeloid leukemia. However, there was no clinical evidence on causation of imatinib-associated SCC in patients with GIST.
CONCLUSION: To our knowledge, the present report is the first to describe imatinib-related SCC in patients undergoing treatment for GISTs. This implicates that safety and long-term tolerability of imatinib in patients with GISTs warrant rigorous testing and close monitoring.

Abu-Amna M, Awadie H, Bar-Sela G
Imatinib-induced Gastrointestinal Vascular Ectasia in a Patient with Advanced GIST: Case Report and Literature Review.
Anticancer Res. 2016; 36(11):6151-6154 [PubMed] Related Publications
BACKGROUND: Imatinib is generally well tolerated in the treatment of advanced gastrointestinal stromal tumors (GIST). Gastrointestinal vascular ectasia (GIVE) and gastric antral vascular ectasia (GAVE), while rare, are significant under-reported complications of imatinib therapy.
CASE REPORT: We present one patient with GIVE complicating imatinib therapy with a literature review of this rare side-effect.
RESULTS: A 68-year-old woman was diagnosed with advanced GIST, wild-type CKIT. After 3 months of treatment with imatinib, she had partial response. However, she was diagnosed with GAVE and, later, also with GIVE. During her 3-year imatinib treatment, she suffered from severe anemia and required blood transfusions. Conservative treatments were not helpful and the ectatic lesions resolved only with cessation of imatinib.
CONCLUSION: This confirms a causal relationship between GIVE and imatinib. GIVE and GAVE should be considered possible causes of anemia and upper gastrointestinal bleeding in patients receiving imatinib therapy.

Tan GH, Wong JS, Quek R, et al.
Role of upfront surgery for recurrent gastrointestinal stromal tumours.
ANZ J Surg. 2016; 86(11):910-915 [PubMed] Related Publications
BACKGROUND: Gastrointestinal stromal tumours (GISTs), despite complete surgical cytoreduction, are associated with recurrence rates of up to 50% at 2 years. At recurrence, tyrosine kinase inhibitor (TKI) therapy is recommended, conferring a survival of up to 55 months. Several studies have shown that patients with TKI-responsive recurrent GIST benefit from surgery. However, no studies have compared upfront surgery versus TKI alone.
METHODS: Data were retrospectively collected from patients with recurrent GIST treated at Singapore General Hospital and National Cancer Centre Singapore over a 12-year period. Our primary end points were disease-free and overall survival (OS).
RESULTS: A total of 186 patients underwent curative surgery for GIST between January 2000 and June 2012. Fifty-six (30%) patients experienced recurrence, of which 30 (54%) had resectable recurrent disease. Twenty-four patients underwent upfront surgery for their recurrence while the remaining six patients opted for non-surgical management. The median OS for all patients with recurrent GIST was 5.3 years (95% confidence interval (CI) 3.2-8.4). It was not reached for patients who underwent curative surgery for their recurrence, and was 3.9 years (95% CI 2.4-7.0) for patients who had palliative TKI and conservative management. There were significant differences in OS and disease-specific survival between patients who underwent curative surgery for recurrence compared with those who had not.
CONCLUSION: Our study shows that upfront surgery is a reasonable treatment strategy for selected patients with recurrent GIST.

Paulmichl A, Summer D, Manzl C, et al.
Targeting Gastrointestinal Stromal Tumor with (68)Ga-Labeled Peptides: An In Vitro Study on Gastrointestinal Stromal Tumor-Cell Lines.
Cancer Biother Radiopharm. 2016; 31(8):302-310 [PubMed] Related Publications
The gastrointestinal stromal tumor (GIST) is a rare disease with limited therapeutic options when resistance to tyrosine kinase inhibitor (TKI) treatment occurs. The authors investigated binding of various (68)Ga-labeled peptides, targeting receptors reported to be overexpressed in GIST, in different cell lines. For this purpose, three GIST cell lines were tested: GIST-T1, GIST882 (Imatinib sensitive), and GIST430 (Imatinib resistant). DOTA-NT 8-13 (targeting NTR1), DOTA-TATE (targeting SSTR2), CP04 (a minigastrin derivative targeting CCK2-R), VIP-DOTA (targeting VPAC2-R), and 2 DOTA-bombesin derivatives [targeting gastrin releasing peptide receptors (GRPR)] were radiolabeled with (68)Ga and incubated with the respective tumor cell and control cell lines. Membrane-bound and internalized activity was measured. Very low or no specific binding to GIST cells was found for all (68)Ga-labeled DOTA peptides except for bombesin derivatives indicating no or very low expression of respective receptors. Related to GRPR a pronounced specific binding to all GIST cell lines with no preference related to TKI resistance status was found, both for an agonist (AMBA) with high internalization and for an antagonist (NeoBOMB1) with mainly membrane-bound activity (with up to >80% bound/mg protein). GRPR expression was confirmed by immunohistochemistry. The results show that radiolabeled bombesin analogues, especially antagonists are very promising candidates for targeting GIST.

Takahashi T, Maruyama Y, Saitoh M, et al.
Synchronous Occurrence of Diffuse Large B-cell Lymphoma of the Duodenum and Gastrointestinal Stromal Tumor of the Ileum in a Patient with Immune Thrombocytopenic Purpura.
Intern Med. 2016; 55(20):2951-2956 [PubMed] Free Access to Full Article Related Publications
A 64 year-old woman with steroid-dependent immune thrombocytopenia developed anemia. Esophagogastroduodenoscopy revealed the presence of a tumor, which was diagnosed to be diffuse large B-cell lymphoma, in the second portion of the duodenum. (18)F-fluorodeoxy glucose positron emission tomography showed an increased uptake mass in the pelvic cavity as well as in the duodenum. Though the duodenal tumor disappeared after 4 cycles of chemotherapy, the pelvic mass did not shrink in size. As a result, laparoscopic resection of the pelvic tumor was performed and the tumor was histologically diagnosed to be a gastrointestinal stromal tumor. Subsequently, the patient was treated with 2 more cycles of the chemotherapy. Eventually, thrombocytopenia completely resolved.

Virani N, Pang J, Lew M
Cytologic and Immunohistochemical Evaluation of Low-Grade Spindle Cell Lesions of the Gastrointestinal Tract.
Arch Pathol Lab Med. 2016; 140(10):1038-44 [PubMed] Related Publications
Spindle cell lesions of the gastrointestinal tract are relatively uncommon compared with the frequency of their epithelial counterparts. Although gastrointestinal stromal tumors and leiomyomas are the most commonly encountered spindle cell lesions in the stomach and esophagus, respectively, there are other less common diagnostic entities that should be considered for accurate diagnoses as well as appropriate patient treatment and clinical follow-up. Given the morphologic overlap of low-grade spindle cell lesions on cytologic preparations, ancillary studies play a key role in differentiating these lesions from one another.

Nerich V, Fleck C, Chaigneau L, et al.
Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors for Patients with Advanced Gastrointestinal Stromal Tumors.
Clin Drug Investig. 2017; 37(1):85-94 [PubMed] Related Publications
INTRODUCTION: The management of advanced gastrointestinal stromal tumors (GISTs) has been modified considerably by the availability of costly tyrosine kinase inhibitors (TKIs); however, the best therapeutic sequence in terms of cost and effectiveness remains unknown.
OBJECTIVE: The aim of this study was to compare four potential strategies (reflecting the potential daily practice), each including imatinib 400 mg/day, as first-line treatment: S1 (imatinib400/best supportive care [BSC]); S2 (imatinib400/imatinib800/BSC); S3 (imatinib400/sunitinib/BSC); and S4 (imatinib400/imatinib800/sunitinib/BSC).
METHODS: A Markov model was developed with a hypothetical cohort of patients and a lifetime horizon. Transition probabilities were estimated from the results of clinical trials. The analysis was performed from the French payer perspective, and only direct medical costs were included. Clinical and economic parameters were discounted, and the robustness of results was assessed.
RESULTS: The least costly and effective strategy was S1, at a cost of €65,744 for 32.9 life months (reference). S3 was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of €48,277/life-year saved (LYS). S2 was dominated, and S4 yielded an ICER of €363,320/LYS compared with S3. Sensitivity analyses confirmed the robustness of these results; however, when taking into account a price reduction of 80 % for imatinib, S2 and S4 become the most cost-effective strategies.
CONCLUSION: Our approach is innovative to the extent that our analysis takes into account the sequential application of TKIs. The results suggest that the S1 strategy is the best cost-effective strategy, but a price reduction of imatinib impacts on the results. This approach must continue, including new drugs and their impact on the quality of life of patients with advanced GISTs.

Zhang P, Deng R, Liu K, et al.
Clinicopathologic features and prognosis of primary gastrointestinal stromal tumor patients under 35 years of age: A 10-year retrospective study.
J Surg Oncol. 2016; 114(8):977-981 [PubMed] Related Publications
OBJECTIVES: To investigate gastrointestinal stromal tumor (GIST) clinicopathologic characteristics in young adults.
METHODS: Clinicopathologic data from GIST patients under 35 years diagnosed at our hospital from January 2005 to December 2014 were retrospectively collected.
RESULTS: Thirty-one (5.3%, 31/585) patients were included; 17 (54.8%) were female. The most common presentation and primary tumor site were gastrointestinal bleeding (n = 18, 58.1%) and the small intestine (n = 13, 41.9%), respectively. Fifteen (48.4%) GISTs were classified as having a high relapse risk; two (6.4%), intermediate; nine (29.0%), low; and five (16.1%), very low. All patients underwent tumor resection. With a median follow-up of 51 months for 20 (64.5%) patients, 12 (60%) were given imatinib methylate as adjuvant therapy. One (5%) patient died of peritoneal GIST dissemination, four (20%) developed abdominal recurrences, two (10%) had hepatic metastasis, and thirteen (65%) were disease free. The 5-year disease-free survival rate was 51.2%.
CONCLUSIONS: GISTs rarely occur in young adults. The most common location is the small intestine. A slight female predominance was observed in the current study. Adjuvant therapy longer than the recommended duration may be beneficial for GISTs with a high relapse risk. Combined targeted therapy and surgery is appropriate for recurrent and metastatic GISTs in select patients. J. Surg. Oncol. 2016;114:977-981. © 2016 Wiley Periodicals, Inc.

Rodriquenz MG, Rossi S, Ricci R, et al.
Gastrointestinal stromal tumors (GISTs) and second malignancies: A novel "sentinel tumor"? A monoinstitutional, STROBE-compliant observational analysis.
Medicine (Baltimore). 2016; 95(38):e4718 [PubMed] Free Access to Full Article Related Publications
Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis.A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-α genes was performed in all patients. Following the involvement of KRAS mutation in many tumors' pathogenesis, analysis of KRAS was performed in patients with also second neoplasms.Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-α mutation (n. 2) and exon 18 PDGFR-α mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P = 0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months.The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis.

Patrikidou A, Le Cesne A
Key messages from the BFR14 trial of the French Sarcoma Group.
Future Oncol. 2017; 13(3):273-284 [PubMed] Related Publications
The BRF14 trial is a prominent study that investigated the effect of prolonged imatinib treatment in advanced gastrointestinal stromal tumor patients. The key messages deduced from this study are as follows: imatinib drastically improved progression-free and overall survival in advanced gastrointestinal stromal tumor patients. Treatment ought to be maintained indefinitely in nonprogressing patients, as interruption entails a high risk of progression, even in patients in complete response. Imatinib rechallenge is effective, achieving new disease control in patients progressing after imatinib interruption. Rechallenge response profiles reflect the initial responses, albeit of poorer quality. Imatinib interruption does not affect the incidence of secondary resistance; however, the imatinib-free interval influences the time to secondary resistance. Specific clinical, biological and molecular characteristics seem to identify the patients who are long responders to imatinib. Surgery of residual disease after maximal imatinib response improves progression-free and overall survival.

Chen X, Cao H, Wang S, et al.
Endoscopic submucosal dissection for silent gastric Dieulafoy lesions mimicking gastrointestinal stromal tumors: Report of 7 cases-a case report series.
Medicine (Baltimore). 2016; 95(36):e4829 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dieulafoy lesion is a rare but serious cause of gastrointestinal hemorrhage. However, some cases can be occasionally found without bleeding during the endoscopic screening, and the management remains unclear. The aim of this article was to report the efficacy and safety of endoscopic submucosal dissection (ESD) for silent gastric Dieulafoy lesions, which presented as protrusion lesions mimicking gastrointestinal stromal tumors (GISTs).
METHODS: Data from the patients with gastric protrusion lesions who underwent ESD from September 2008 to April 2016 in General Hospital, Tianjin Medical University, China were recorded. Seven cases with pathological diagnosis of Dieulafoy lesion without bleeding were enrolled for further analysis.
RESULTS: A total of 7 patients (2 males and 5 females) with mean age of 57.7 ± 4.15 years were pathologically diagnosed as Dieulafoy lesion. Four of the lesions were located in gastric antrum, 2 in the fundus, and 1 in the body of stomach, respectively. The mean sizes of the Dieulafoy lesions under white light endoscopy and endoscopic ultrasonography (EUS) were 1.06 ± 0.28 and 0.84 ± 0.29 cm. The origins of these lesions were submucosa (6/7, 85.7%) and muscularis propria (1/7, 14.3%). Three of them appeared with mixed echo under EUS, 3 with hypoechogenicity, and 1 with hyperechogenicity. En bloc complete resection was achieved in all the lesions by ESD with average time of 76.00 ± 16.86 minutes, and no intraoperative bleeding happened. In addition, all patients were followed up for 1 to 53 months, and no recurrence or long-term complications was observed.
CONCLUSION: Therefore, ESD can be an effective and safe treatment for silent gastric Dieulafoy lesions with clinical presentations of submucosal protrusion lesions mimicking GISTs.

Szucs Z, Thway K, Fisher C, et al.
Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.
Future Oncol. 2017; 13(2):185-194 [PubMed] Related Publications
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.

Szucs Z, Thway K, Fisher C, et al.
Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications.
Future Oncol. 2017; 13(1):93-107 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are composed of various molecular subtypes, with differing prognostic and predictive relevance. Previously, tumors lacking mutations in the KIT and PDGFRA genes have been designated as 'wild-type' GISTs; however, they represent a heterogeneous group currently undergoing further subclassification. Primary and secondary resistance to imatinib poses a significant clinical challenge, therefore ongoing research is trying to evaluate mechanisms to overcome resistance. Thorough understanding of the prognostic and predictive relevance of different genetic subtypes of GIST can guide clinical decision-making both in the adjuvant and the metastatic setting. Further work is required to identify tailored therapies for specific subgroups of GISTs wild-type for KIT and PDGFRA mutations and to identify predictive factors of resistance to currently approved systemic therapies.

Liang L, Fanzong L, Peixi Z, Cuihong H
Plexiform angiomyxoid myofibroblastic tumor of the stomach: A case report.
Diagn Cytopathol. 2017; 45(1):55-58 [PubMed] Related Publications
Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a rare mesenchymal tumor of the stomach. To date, about 40 cases of PAMT have been reported in the literature. This tumor is not specific in clinical manifestations and microscopically characterized by a plexiform growth pattern. Here, we report the case of an 11-year-old male patient who was diagnosed with PAMT. He had a complaint of right epigastric discomfort with episodic pain, gastroscopy displayed a submucosal bulge at the pylorus, and CT showed a mass in the right abdomen with uneven, delayed enhancement, and a partial gastrectomy revealed a tumor at the pylorus. Histologically, the tumor was multinodular and rich in blood vessels with thin wall; the interstitium had abundant myxomatous stroma; the tumor cells were spindle-shaped, star-shaped, or oval. Immunohistochemically, the tumor cells were positive for Calponin, Caldesmon, and SMA, but negative for CD34, ALK, S-100, desmin, CD117, and Dog-1. This patient was followed up for 12 months, and recurrence or metastasis was not observed. Diagn. Cytopathol. 2017;45:55-58. © 2016 Wiley Periodicals, Inc.

von Mehren M
Management of Gastrointestinal Stromal Tumors.
Surg Clin North Am. 2016; 96(5):1059-75 [PubMed] Related Publications
Gastrointestinal stromal tumors had the reputation for poor outcomes because of their lack of response to nonsurgical interventions. The discovery of gain-of-function mutations involving receptor tyrosine kinase growth factor receptors altered the biological understanding and management. Beginning in 2000, management of these tumors has changed dramatically because of the availability of tyrosine kinase inhibitors. The role of surgery continues to be refined. This article reviews how surgery and systemic therapy are being used, incorporating definitions of risk. Decisions on how to treat a patient is based on the risk of progression, pathologic characteristics, and tumor location.

Iqbal N, Sharma A, Shukla N, et al.
Advanced gastrointestinal stromal tumors: 10-years experience from a tertiary care centre.
Trop Gastroenterol. 2015 Jul-Sep; 36(3):168-73 [PubMed] Related Publications
BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. We aimed to study the pattern of presentation and treatment outcome of advanced GIST patients seen by us in a 10- year period.
METHODS: Medical records of GIST patients seen between years 2002-2012 were retrieved from institute as well as database maintained by authors. Patient included in this analysis had metastatic disease and unresectable and/or residual disease after surgery.
RESULTS: During the study period 62 patients fulfilled the inclusion criteria but 6 were lost to follow up before treatment and hence 56 patients were analysed. Median age was 45.5 years (range 17-70 years) with a male female ratio of 2:1. Thirty eight (67%) patients had metastatic disease whereas 32% patients had unresectable or incompletely resected disease. The most common primary site was small intestine in 24 (42.8%) which was followed by stomach in 11 (19.6%) patients. The most common site of metastases was liver in 27 (48%) patients. Median tumor size was 12 cm (range 4-50 cm). Thirty two (57%) patients had mitotic counts of > 5/50 HPF. All patients received imatinib. The most common response seen with imatinib was stable disease achieved in 29 (52%) patients. Imatinib was well tolerated by all patients without any drug discontinuation. The 5-year EFS and OS were 35% and 49%, respectively at a median follow up of 55 months. None of the patient or tumor factors were found to have prognostic significance in univariate survival analysis.
CONCLUSIONS: This is a single center experience of advanced GIST patients where small intestine was found to be the commonest disease site with imatinib producing disease stabilization in more than half of patients. Even though the survival was comparable to published reports, the major limitation was lack of mutation analysis.

Chabowski M, Szymanska-Chabowska A, Dorobisz T, et al.
A massive bleeding from a gastrointestinal stromal tumor of a Meckel's diverticulum.
Srp Arh Celok Lek. 2016 Mar-Apr; 144(3-4):219-21 [PubMed] Related Publications
INTRODUCTION: Meckel's diverticulum is the most common congenital anomaly of the gastro intestinal tract, present in about 2% of population.
CASE OUTLINE: The article presents the case of a 44-year-old otherwise healthy man with anemia, who was diagnosed lower gastrointestinal bleeding. An abdominal CT scan revealed a clearly demarcated solid tumor in hypogastric region, measuring 65 x 45 mm. A laparotomy through lower midline incision was performed. A surgical resection of a lesion of a Meckel's diverticulum was carried out and a final diagnosis of gastrointestinal stromal tumor was made.The patient made an uneventful recovery.
CONCLUSION: The preoperative diagnosis of a complicated Meckel's diverticulum may be challenging. CT is usually an adequate method to diagnose tumors arising from Meckel's diverticulum.

Stevanović D, Stojanović D, Jasarović D, et al.
Laparoscopic gastric wedge resection as the method of choice in the treatment of gastrointestinal stromal tumors--A case report.
Srp Arh Celok Lek. 2016 Mar-Apr; 144(3-4):211-4 [PubMed] Related Publications
INTRODUCTION: The gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. The surgery of resectable gastric GIST is the primary therapy for these tumors, but the decision regarding the surgical radicality of the procedures is still a point of discussion among surgeons and oncologists.
CASE OUTLINE: A 74-year-old patient was admitted to hospital with signs of bleeding from the upper parts of the gastrointestinal tract. Urgent gastroscopy was performed and a subepithelial gastric lesion with bleeding ulceration was noted in the region of the fornix. A computed tomography scan of the abdomen showed a tumor in the fornix region with the dimensions of 48 x 32 mm, which was growing mostly intraluminally. After an adequate preoperative preparation the patient underwent a laparoscopic wedge resection of gastric fornix with intramural tumor lesion. The histopathological analysis of the specimen showed a well differentiated GIST (histological grade Gi), of the spindle cell type. Based on the immunohistochemical analysis of thespecimen it was concluded that the patient was in the IA stage of the disease with a low risk of malignant progression. In the population of patients with GIST, this is the most common group (43%), with low malignant potential, and relapses present in only 3.6% of cases.The patient started with oral food intake on the first postoperative day, the first bowel movement occurred 36 hours after surgery, and the patient was released from hospital on the fourth postoperative day.
CONCLUSION: Based on the aforementioned, we consider that the laparoscopic gastric wedge resection is a safe and efficient surgical procedure. This is primary therapy for most common group of patients with resectable gastric GIST.

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