Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Optical second-harmonic generation imaging for identifying gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors arising in the digest tract.It brings a challenge to diagnosis because it is asymptomatic clinically.It is well known that tumor development is often accompanied by the changes in the morphology of collagen fibers.Nowadays,an emerging optical imaging technique,second-harmonic generation(SHG),can directly identify collagen fibers without staining due to its noncentrosymmetric properties.Therefore,in this study,we attempt to assess the feasibility of SHG imaging for detecting GISTs by monitoring the morphological changes of collagen fibers in tumor microenvironment.We found that collagen alterations occurred obviously in the GISTs by comparing with normal tissues,and furthermore,two morphological features from SHG images were extracted to quantitatively assess the morphological difference of collagen fibers between normal muscular layer and GISTs by means of automated image analysis.Quantitative analyses show a significant difference in the two collagen features.This study demonstrates the potential of SHG imaging as an adjunctive diagnostic tool for label-free identification of GISTs.

Neurofibromatosis type 1 with multiple gastrointestinal stromal tumors:A case report

BACKGROUND Neurofibromatosis type 1(NF1)is characterized by café-au-lait patches on the skin and the presence of neurofibromas.Gastrointestinal stromal tumor(GIST)is the most common non-neurological tumor in NF1 patients.In NF1-associated GIST,KIT and PDGFRA mutations are frequently absent and imatinib is ineffective.Surgical resection is first-line treatment.CASE SUMMARY A 56-year-old woman with NF1 was hospitalized because of an incidental pelvic mass.Physical examination was notable for multiple café-au-lait patches and numerous subcutaneous soft nodular masses of the skin of the head,face,trunk,and limbs.Her abdomen was soft and nontender.No masses were palpated.Digital rectal examination was unremarkable.Abdominal computed tomography was suspicious for GIST or solitary fibrous tumor.Laparoscopy was performed,which identified eight well-demarcated masses in the jejunum.All were resected and pathologically diagnosed as GISTs.The patient was discharged on day 7 after surgery without complications.No tumor recurrence was evident at the 6-mo follow-up.CONCLUSION Laparoscopy is effective for both diagnosis and treatment of NF1-associated GIST.

Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors:A case report

BACKGROUND Sunitinib,a multi-targeted tyrosine kinase inhibitor(TKI),has been approved for the salvage treatment of gastrointestinal stromal tumors(GIST).Hyperammonemic encephalopathy is a rare but severe complication of sunitinib use.Here,we present the case of a 66-year-old male with metastatic GIST without underlying liver cirrhosis who developed sunitinib-induced hyperammonemic encephalopathy.CASE SUMMARY A 66-year-old male with metastatic GIST was admitted because of reduced consciousness.Imatinib was administered as the first-line systemic therapy.He experienced repeated episodes of peritonitis due to tumor perforation,and surgery was performed.Progressive disease was confirmed based on increased liver metastasis,and sunitinib was initiated as a salvage treatment.However,23 d after the third course of sunitinib,he presented to the emergency room with an episode of altered consciousness and behavioral changes.Based on the patient clinical history and examination findings,sunitinib-induced encephalopathy was suspected.Sunitinib was discontinued,and the patient was treated for hyperammonemia.The patient had a normal level of consciousness four days later,and the serum ammonia level gradually decreased.No further neurological symptoms were reported in subsequent follow-ups.CONCLUSION TKI-induced hyperammonemic encephalopathy is potentially life-threatening.Patients receiving TKIs experiencing adverse reactions should undergo systemic evaluation and prompt treatment.

Relationship between multi-slice computed tomography features and pathological risk stratification assessment in gastric gastrointestinal stromal tumors

BACKGROUND Computed tomography(CT)imaging features are associated with risk stratification of gastric gastrointestinal stromal tumors(GISTs).AIM To determine the multi-slice CT imaging features for predicting risk stratification in patients with primary gastric GISTs.METHODS The clinicopathological and CT imaging data for 147 patients with histologically confirmed primary gastric GISTs were retrospectively analyzed.All patients had received dynamic contrast-enhanced CT(CECT)followed by surgical resection.According to the modified National Institutes of Health criteria,147 lesions were classified into the low malignant potential group(very low and low risk;101 lesions)and high malignant potential group(medium and high-risk;46 lesions).The association between malignant potential and CT characteristic features(including tumor location,size,growth pattern,contour,ulceration,cystic degeneration or necrosis,calcification within the tumor,lymphadenopathy,enhancement patterns,unenhanced CT and CECT attenuation value,and enhancement degree)was analyzed using univariate analysis.Multivariate logistic regression analysis was performed to identify significant predictors of high malignant potential.The receiver operating curve(ROC)was used to evaluate the predictive value of tumor size and the multinomial logistic regression model for risk classification.RESULTS There were 46 patients with high malignant potential and 101 with low-malignant potential gastric GISTs.Univariate analysis showed no significant differences in age,gender,tumor location,calcification,unenhanced CT and CECT attenuation values,and enhancement degree between the two groups(P>0.05).However,a significant difference was observed in tumor size(3.14±0.94 vs 6.63±3.26 cm,P<0.001)between the low-grade and high-grade groups.The univariate analysis further revealed that CT imaging features,including tumor contours,lesion growth patterns,ulceration,cystic degeneration or necrosis,lymphadenopathy,and contrast enhancement patterns,were associated with risk stratification(P<0.05).According to binary logistic regression analysis,tumor size[P<0.001;odds ratio(OR)=26.448;95%confidence interval(CI):4.854-144.099)],contours(P=0.028;OR=7.750;95%CI:1.253-47.955),and mixed growth pattern(P=0.046;OR=4.740;95%CI:1.029-21.828)were independent predictors for risk stratification of gastric GISTs.ROC curve analysis for the multinomial logistic regression model and tumor size to differentiate high-malignant potential from low-malignant potential GISTs achieved a maximum area under the curve of 0.919(95%CI:0.863-0.975)and 0.940(95%CI:0.893-0.986),respectively.The tumor size cutoff value between the low and high malignant potential groups was 4.05 cm,and the sensitivity and specificity were 93.5%and 84.2%,respectively.CONCLUSION CT features,including tumor size,growth patterns,and lesion contours,were predictors of malignant potential for primary gastric GISTs.

Preoperative prediction of malignant potential of 2-5 cm gastric gastrointestinal stromal tumors by computerized tomography-based radiomics

BACKGROUND The use of endoscopic surgery for treating gastrointestinal stromal tumors(GISTs)between 2 and 5 cm remains controversial considering the potential risk of metastasis and recurrence.Also,surgeons are facing great difficulties and challenges in assessing the malignant potential of 2-5 cm gastric GISTs.AIM To develop and evaluate computerized tomography(CT)-based radiomics for predicting the malignant potential of primary 2-5 cm gastric GISTs.METHODS A total of 103 patients with pathologically confirmed gastric GISTs between 2 and 5 cm were enrolled.The malignant potential was categorized into low grade and high grade according to postoperative pathology results.Preoperative CT images were reviewed by two radiologists.A radiological model was constructed by CT findings and clinical characteristics using logistic regression.Radiomic features were extracted from preoperative contrast-enhanced CT images in the arterial phase.The XGboost method was used to construct a radiomics model for the prediction of malignant potential.Nomogram was established by combing the radiomics score with CT findings.All of the models were developed in a training group(n=69)and evaluated in a test group(n=34).RESULTS The area under the curve(AUC)value of the radiological,radiomics,and nomogram models was 0.753(95%confidence interval[CI]:0.597-0.909),0.919(95%CI:0.828-1.000),and 0.916(95%CI:0.801-1.000)in the training group vs 0.642(95%CI:0.379-0.870),0.881(95%CI:0.772-0.990),and 0.894(95%CI:0.773-1.000)in the test group,respectively.The AUC of the nomogram model was significantly larger than that of the radiological model in both the training group(Z=2.795,P=0.0052)and test group(Z=2.785,P=0.0054).The decision curve of analysis showed that the nomogram model produced increased benefit across the entire risk threshold range.CONCLUSION Radiomics may be an effective tool to predict the malignant potential of 2-5 cm gastric GISTs and assist preoperative clinical decision making.

Efficacy and safety of endoscopic resection in treatment of small gastric stromal tumors: A state-of-the-art review

Gastrointestinal stromal tumors can occur in any part of the gastrointestinal tract,but gastric stromal tumors(GSTs)are the most common.All GSTs have the potential to become malignant,and these can be divided into four different grades by risk from low to high:Very low risk,low risk,medium risk,and high risk.Current guidelines all recommend early complete excision of GSTs larger than 2 cm in diameter.However,it is not clear whether small GSTs(sGSTs,i.e.,those smaller than 2 cm in diameter)should be treated as early as possible.The National Comprehensive Cancer Network recommends that endoscopic ultrasonographyguided(EUS-guided)fine-needle aspiration biopsy and imaging(computed tomography or magnetic-resonance imaging)be used to assess cancer risk for sGSTs detected by gastroscopy to determine treatment.When EUS indicates a higher risk of tumor,surgical resection is recommended.There are some questions on whether sGSTs also require early treatment.Many studies have shown that endoscopic treatment of GSTs with diameters of 2-5 cm is very effective.We here address whether endoscopic therapy is also suitable for sGSTs.In this paper,we try to explain three questions:(1)Does sGST require treatment?(2)Is digestive endoscopy a safe and effective means of treating sGST?and(3)When sGSTs are at different sites and depths,which endoscopic treatment method is more suitable?

Laparoscopic management of gastric gastrointestinal stromal tumors: A retrospective 10-year single-center experience

AIM To determine the feasibility,safety,and oncological outcome of laparoscopic resection of gastric gastrointestinal stromal tumors(GISTs)based on favorable or unfavorable location.METHODS Our hospital database included 207 patients who underwent laparoscopic removal of gastric GISTs from January 2004 to September 2015.Patient demographics,clinical presentation,surgery,histopathology,postoperative course,and oncological outcomes were reviewed and analyzed.RESULTS Gastric GIST in favorable locations was present in81/207(39.1%)cases,and in unfavorable locations in 126/207(60.9%)cases.Overall mean tumor size was 3.28±1.82 cm.No conversions occurred,and complete R0 resection was achieved in 207(100%)cases.There were three incidences of iatrogenic tumor rupture.The feasibility and safety of laparoscopic surgery were comparable in both groups with no statistical difference between unfavorable and favorable location groups,respectively:for operative time:83.86±44.41 vs 80.77±36.46 min,P=0.627;conversion rate:0%vs 0%;estimated blood loss:27.74±45.2vs 29.59±41.18 m L,P=0.780;tumor rupture during surgery:0.90%vs 2.82%,P=0.322;or postoperative complications:3.74%vs 7.04%,P=0.325.The follow-up period recurrence rate was 1.89%with no significant differences between the two groups(3.03%vs 0%,P=0.447).Overall 5-year survival rate was98.76%and survival rates were similar between the two groups:98.99%vs 98.39%,P=0.623(unfavorable vs favorable,respectively).CONCLUSION The laparoscopic approach for gastric GISTs is safe and feasible with well-accepted oncological surgical outcomes.Strategies for laparoscopic resection should be selected according to the location and size of the tumor.Laparoscopic treatment of gastric GISTs in unfavorable locations should not be restricted in gastrointestinal centers.

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

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal(GI)tract and are thought to arise from precursors of the interstitial cells of Cajal.GISTs can arise anywhere in the GI tract,but most commonly originate from the stomach and small intestine.The majority of GISTs occur as a result of activating mutations in two receptor protein tyrosine kinases:KIT and/or platelet-derived growth factor receptor-α.Mutational analyses allow for predicting patient prognosis and treatment response.Clinical presentations can vary from no symptoms,typical in the case of small incidentally found tumors,to GI bleeding,abdominal discomfort,and ulcer-related symptoms when the tumor is enlarged.Imaging plays a critical role in the diagnosis and management of these tumors with multiphasic computed tomography serving as the imaging modality of choice.Magnetic resonance imaging and positron emission tomography-computed tomography can serve as imaging adjuncts in lesion characterization,especially with liver metastases,and subsequent staging and assessment for treatment response or recurrence.Surgical resection is the preferred management for small GISTs,while tyrosine kinase inhibitors−imatinib mesylate and sunitinib malate−serve as crucial molecular-targeted therapies for locally advanced and metastatic GISTs.This review article highlights the clinical presentation,pathology and molecular cytogenetics,imaging features,and current management of GISTs.

Efficacy evaluation of imatinib treatment in patients with gastrointestinal stromal tumors:A meta-analysis

AIM:To perform a meta-analysis to derive a more precise estimation of imatinib treatment for different genotypes of gastrointestinal stromal tumors(GIST).METHODS:Studies were identified by searching PubMed and Embase.Inclusive criteria were patients with exon 9-mutant,exon 11-mutant or wide type(WT) GIST,receiving chemotherapy of imatinib for clinical trial,and efficacy evaluation was cumulative response (CR)including complete response and partial response.The odds ratios(OR)for CR in stem cell factor receptor (KIT)mutation patients vs WT genotype patients,KIT exon 11-mutant genotype patients vs KIT exon 9-mutant genotype patients and KIT exon 9-mutant genotype patients vs WT genotype patients were calculated with 95%confidence interval(CI)for each study as an estimation of the efficacy of imatinib.RESULTS:Five studies including 927 patients were involved in this meta-analysis.The overall OR(KIT group vs WT group)was 3.34(95%CI:2.30-4.86,P <0.00001,P heterogeneity=0.04).The overall OR in KIT exon 11 group vs KIT exon 9 group was 3.29(95%CI: 2.17-5.00,P<0.00001,P heterogeneity=0.33).The overall OR in KIT exon 9 group vs WT group was 1.23(95% CI:0.73-2.10,P=0.44,P heterogeneity=0.42).CONCLUSION:Most patients with different genotypes of GIST and KIT exon 11-mutant will benefit from the individualized treatment of imatinib.

New advances in radiomics of gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are uncommon neoplasms of the gastrointestinal tract with peculiar clinical,genetic,and imaging characteristics.Preoperative knowledge of risk stratification and mutational status is crucial to guide the appropriate patients’treatment.Predicting the clinical behavior and biological aggressiveness of GISTs based on conventional computed tomography(CT)and magnetic resonance imaging(MRI)evaluation is challenging,unless the lesions have already metastasized at the time of diagnosis.Radiomics is emerging as a promising tool for the quantification of lesion heterogeneity on radiological images,extracting additional data that cannot be assessed by visual analysis.Radiomics applications have been explored for the differential diagnosis of GISTs from other gastrointestinal neoplasms,risk stratification and prediction of prognosis after surgical resection,and evaluation of mutational status in GISTs.The published researches on GISTs radiomics have obtained excellent performance of derived radiomics models on CT and MRI.However,lack of standardization and differences in study methodology challenge the application of radiomics in clinical practice.The purpose of this review is to describe the new advances of radiomics applied to CT and MRI for the evaluation of gastrointestinal stromal tumors,discuss the potential clinical applications that may impact patients’management,report limitations of current radiomics studies,and future directions.

Laparoscopic versus open resection of gastric gastrointestinal stromal tumors

The aims of this study were to explore whether laparoscopic surgical resections of gastric gastrointestinal stromal tumors （GISTs） would produce better perioperative and similar oncologic outcomes compared with open surgical resection in Chinese patients. Thirty-six gastric GISTs cases were divided into a minimally invasive laparoscopic group and open resection group, depending on the surgical approach that was used. The general preoperative information, operative time, incision length, intraoperative blood loss, postoperative time to first flatulence, postoperative complications, postoperative hospital stay, total hospitalization costs, and such follow-up data as recurrence, metastasis, and mortality rates were compared between two groups. Among the 36 gastric GISTs, 15 received laparoscopic surgical treatment （laparoscopy group, n=15）, and 21 received routine open resection treatment （open resection group, n=21）. The laparoscopy group and the open resection group showed statistically significant differences （P〈0.05） in incision length （7.8±2.3 vs. 16.9±3.8 cm）, postoperative time to first flatulence （3.8±1.3 vs. 5.1±2.1 d）, postoperative hospitalization time （7.6±2.5 vs. 11.3±3.7 d）, and total cost of hospitalization （RMB 28,239±5,521 vs. RMB 23,761±5,362）. There were no statistically significant differences （P〉0.05） between the laparoscopy group and the open resection group in operative time （147.8±59.3 vs. 139.2±62.1 min） and intraoperative blood loss （149.8±98.9 VS. 154.2±99.3 mL）. Both groups had no postoperative complications, no recurrence and metastasis, and no postoperative mortality. There were no statistically significant differences between the two groups in postoperative complications, postoperative recurrence and metastasis, and postoperative mortality. In conclusion, compared with open resection, the laparoscopic resection of gastric GISTs offers the advantages of less trauma, faster recovery, and shorter hospital stay.

Clinical and prognostic significance of CC chemokine receptor type 8 protein expression in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal neoplasms of the gastrointestinal tract.Surgical resection and tyrosine kinase inhibitors are defined as the main treatments but cannot cure patients with advanced GIST,which eventually develops into recurrence and acquired drug resistance.Therefore,it is necessary to identify prognostic biomarkers and new therapeutic targets for GISTs.CC chemokine receptor type 8(CCR8)protein participates in regulation of immune responses.Recent studies on CCR8 in nonsmall cell lung cancer and colorectal cancer showed that it was highly expressed in tumor-infiltrating regulatory T cells and correlated with a poor prognosis.AIM To detect CCR8 expression in GIST tissues and analyze its relationships with clinicopathological features and prognosis in patients with GISTs.METHODS Tissue samples were used for the tissue microarrays construction.The microarrays were then subjected to immunohistochemical analyses to detect CCR8 expression.Next,Kaplan–Meier analysis was utilized to calculate the survival rate of patients with complete follow-up data,and the potential prognostic value of CCR8 was evaluated by Cox regression analysis.Finally,a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes single-gene enrichment chart of CCR8 was constructed using the STRING database.RESULTS CCR8-positive signals were detected as brown or brown-yellow particles by immunohistochemistry located in the cytoplasm.Among 125 tissue samples,74 had CCR8 high expression and 51 had low or negative expression.Statistical analyses suggested CCR8 was significantly correlated with tumor size,mitotic index,AFIP-Miettinen risk classification and tumor location.Kaplan–Meier and multivariate analyses showed that patients with low or negative CCR8 expression,mitotic index<5/high-power fields(HPF)and tumor diameter<5 cm had a better prognosis.Based on the STRING database,CCR8 was significantly enriched in biological processes such as tumor immunity,T lymphocyte chemotaxis,migration and pathways like the nuclear factor-κB and tumor necrosis factor pathways as well as intestinal immune regulation networks.CONCLUSION CCR8 is a prognostic biomarker for malignant potential of GISTs,with high expression correlated with malignancy and poor prognosis.

Imatinib mesylate in clinically suspected gastric stromal tumors

Gastrointestinal stromal tumors （GISTs） occur most frequently in the stomach.Diagnosis of gastric GIST is not always clear before surgery.Flexible endoscopy may suggest the nature of the lesion （a bulky tumor with preserved mucosa）; however,biopsy is rarely diagnostic.Therefore,diagnostic medication with safe drugs may provide a feasible way under such conditions after an informed consent is obtained.Based on the excellent efficacy of imatinib mesylate （IM） in the treatment of GIST,we successfully applied it in the diagnostic medication of two patients with clinically suspected gastric stromal tumors.In conclusion,the diagnostic medication with IM can be an alternative option for patients with suspected GIST that can not be confirmed pathologically.

Laparoscopic resection of gastrointestinal stromal tumors:Does laparoscopic surgery provide an adequate oncologic resection?

Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract.Surgical resection remains the mainstay of non-metastatic disease.However,the ability to provide an adequate oncologic resection using laparoscopic surgery is still an area of debate.This is a thorough review of the current literature,looking particularly at the use of laparoscopic surgery for larger GISTs and the long-term oncologic outcomes compared to the results of open surgery.Laparoscopic resections provide an adequate oncologic result for GISTs of all sizes,including those greater than 5 cm in size.

Prognostic significance of hemoglobin,albumin,lymphocyte,platelet in gastrointestinal stromal tumors:A propensity matched retrospective cohort study

BACKGROUND The combined index of hemoglobin,albumin,lymphocyte,and platelet(HALP)can reflect systemic inflammation and nutritional status simultaneously,with some evidence revealing its prognostic value for some tumors.However,the effect of HALP on recurrence-free survival(RFS)in patients with gastrointestinal stromal tumors(GISTs)has not been reported.AIM To investigate the prognostic value of HALP in GIST patients.METHODS Data from 591 untreated patients who underwent R0 resection for primary and localized GISTs at West China Hospital between December 2008 and December 2016 were included.Clinicopathological data,preoperative albumin,blood routine information,postoperative treatment,and recurrence status were recorded.To eliminate baseline inequivalence,the propensity scores matching(PSM)method was introduced.Ultimately,the relationship between RFS and preoperative HALP was investigated.RESULTS The optimal cutoff value for HALP was determined to be 31.5 by X-tile analysis.HALP was significantly associated with tumor site,tumor size,mitosis,Ki67,National Institutes of Health(NIH)risk category,and adjuvant therapy(all P<0.001).Before PSM,GIST patients with an increased HALP had a significantly poor RFS(P<0.001),and low HALP was an independent risk factor for poor RFS[hazard ratio(HR):0.506,95%confidence interval(95%CI):0.291-0.879,P=0.016].In NIH high-risk GIST patients,GIST patients with low HALP had a worse RFS than patients with high HALP(P<0.05).After PSM,458 GIST patients were identified;those with an increased HALP still had significantly poor RFS after PSM(P<0.001)and low HALP was still an independent risk factor for poor RFS(HR:0.558,95%CI:0.319-0.976,P=0.041).CONCLUSION HALP was significantly correlated with postoperative pathology and postoperative treatment.Furthermore,HALP showed a strong ability to predict RFS in GIST patients who underwent radical resection.

Angiogenesis in gastrointestinal stromal tumors:From bench to bedside

Gastrointestinal stromal tumors(GISTs)are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000.They most commonly occur in the elderly during the eighth decade of life affecting predominantly the stomach,but also the small intestine,the omentum,mesentery and rectosigmoid.The available treatments for GIST are associated with a significant rate of recurrent disease and adverse events.Thorough understanding of GIST’s pathophysiology and translation of this knowledge into novel regimens or drug repurposing is essential to counter this challenge.The present review summarizes the existing evidence about the role of angiogenesis in GIST’s development and progression and discusses its clinical underpinnings.

Use of omental patch and endoscopic closure technique as an alternative to surgery after endoscopic full thickness resection of gastric intestinal stromal tumors: A series of cases

BACKGROUND Gastrointestinal stromal tumors(GISTs)originate from interstitial cells of Cajal.GISTs can occur anywhere along the gastrointestinal tract.Large lesions have traditionally been removed surgically.However,with recent innovations in advanced endoscopy,GISTs located within the stomach are now removed endoscopically.We describe a new innovative endoscopic technique to close large and hard to access defects after endoscopic full-thickness resection of gastric GISTs.CASE SUMMARY We present a series of three patients who were diagnosed with a gastric GIST.All patients underwent full-thickness endoscopic resection.In all cases,for closure of the surgical bed,conventional endoscopic techniques including hemoclips,endoloop and suturing were unsuccessful.We performed a new technique in which we pulled omental fat into the gastric lumen and completely closed the defect using endoscopic devices.All patients performed well post-procedure and computed tomography was carried out one day after the procedures which showed no extravasation of contrast.CONCLUSION The omental plug technique may be used as an alternative to surgery in selected cases of gastric perforation.

Current surgical management of duodenal gastrointestinal stromal tumors

Duodenal gastrointestinal stromal tumors(D-GISTs)are uncommon mesenchymal tumors and are managed differently to common duodenal epithelial tumors.They may pose surgical challenges due to their unique but complex pancreaticoduodenal location of the gastrointestinal tract near the ampulla of Vater,pancreas,mesenteric blood vessels,biliary and pancreatic ducts.The surgical management of D-GISTs can be performed safely with good oncological outcomes provided an adequate resection margin can be achieved.The current surgical options of resectable primary D-GISTs varies with increasing complexity depending on the location,size and involvement of surrounding structures such as wedge resection with primary closure,segmental resection with small bowel anastomosis or radical pancreaticoduodenectomy.Laparoscopic approaches have been shown to be feasible and safe with good oncological outcomes in experienced hands.The minimally invasive techniques including robotic-assisted approach will likely increase in the future.D-GISTs have a prognosis comparable to gastric and other small bowel GISTs.However,the heterogeneity of different studies and the limited use of systemic tyrosine kinase inhibitor in the neoadjuvant and adjuvant settings may influence the overall survival of resected D-GISTs.The use of limited resection when condition allows is recommended due to lower surgical morbidity,less postoperative complications and better oncologic outcomes.

Role of succinate dehydrogenase deficiency and oncometabolites in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.Approximately 85%of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha(PDGFRA).The remaining GISTs,referred to as wild-type(WT)GISTs,are often deficient in succinate dehydrogenase complex(SDH),a key metabolic enzyme complex in the tricarboxylic acid(TCA)cycle and electron transport chain.SDH deficiency leads to the accumulation of succinate,a metabolite produced by the TCA cycle.Succinate inhibitsα-ketoglutarate-dependent dioxygenase family enzymes,which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation,hypoxia responses,and m6A mRNA modification.For this reason,succinate and metabolites with similar structures,such as D-2-hydroxyglutarate and fumarate,are considered oncometabolites.In this article,we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.