Referral patterns of GIST patients: data from a nationwide study.

BACKGROUND: This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. PATIENTS AND METHODS: This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. RESULTS: This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. CONCLUSION: A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

Hallmarks and novel insights for gastrointestinal stromal tumors: A bibliometric analysis.

BACKGROUND: Due to the increasing recognition of gastrointestinal stromal tumor (GIST), novel insights have appeared in both preclinical and clinical research and begun to reshape the field. This study aims to map the research landscape through bibliometric analysis and provide a brief overview for the future of the GIST field. METHODS: We searched the Web of Science Core Collection without publication data restrictions for GISTs and performed a bibliometric analysis with CiteSpace and VOSviewer software. RESULTS: In sum, 5,911 of 13,776 records were included, and these studies were published in 948 journals and written by 24,965 authors from 4,633 institutions in 100 countries. Referring to published reviews and bibliometric analysis, we classified the future trends in four groups. In epidemiological study, precise incidence and clinicopathological features in different regions and races might become potential hotspots. Novel therapy, such as drugs, modified strategies, radioligand therapy, was persistent hotspots in GIST fields, and ctDNA-guided diagnosis, monitoring, and treatment might meet future clinical needs. The debate over serosa surgery vs. mucosa surgery will remain active for a long time in GIST surgery, and function reserve surgery, biology-based surgery will play an important role in future. Moreover, rare GIST type, like NF-1-associated GIST, Carney triads and SDH mutant GIST, need more studies in pathogenesis and genetic mutation to provide appropriate treatment for this orphan GIST patients. CONCLUSIONS: Potential hotspots in future GIST trends might involve epidemiology, agents, resection therapy and rare type GIST, moreover, researchers could pay more attention in these four fields.

[Gastrointestinal stromal tumors: a retrospective study]. / Tumeurs stromales gastro-intestinales: une étude rétrospective.

Introduction: although rare, gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the digestive tract. The aim of this work is to study the clinical, paraclinical, therapeutic and evolutionary features of GIST. Methods: we conducted a descriptive retrospective, monocentric study (April 2017-April 2021) collecting data from the medical records of all patients with GIST treated at the medical oncology department of the University Hospital of Mostaganem. Results: we collected data from the medical records of 23 patients, with a median age of 54.4 years, sex ratio 1.8, over a period of 4 years. Abdominal pain was the most frequent symptom (78.3%, n=18); 47.8% of patients (n=11) had a tumor in the small bowel. The diagnosis was made at an early stage in 69.6% of cases (n=16). Surgical treatment was performed in 20 of the 23 patients, 18 of whom with R0. Of the 15 operated patients with a localized tumor, 13 received adjuvant medical treatment (Imatinib). Disease progression was reported in three patients treated with imatinib, then 2nd line therapy (Sunitinib) was started. During the study period, all patients were alive except two who died due to disease progression. Conclusion: the diagnosis of GIST is mainly based on histology and immunohistochemistry, which is often not performed by our pathologists. Molecular biology makes it possible to predict the prognosis and consequently adapt the therapies. The outcome of patients with GIST is often favorable but marked by recurrences despite a supposedly curative treatment requiring prolonged monitoring.

Outcomes of Patients with Gastrointestinal Stromal Tumors in the Past Decade.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the gastrointestinal tract (GIT) that represent approximately 1 to 2 percent of primary gastrointestinal (GI) cancers. Owing to their rarity, very little is known about their overall epidemiology, and the prognostic factors of their pathology. The current study aimed to evaluate the independent determinants of mortality in patients diagnosed with GISTs over the past decade. METHODS: Our study comprised 2374 patients diagnosed with GISTs from 2000 to 2017 from the Surveillance, Epidemiology, and End Results (SEER) database. We analyzed the baseline characteristics, and overall mortality (OM), as well as the cancer-specific mortality (CSM) of GISTs. Variables with a p value < 0.01 in the univariate Cox regression were incorporated into the multivariate Cox model, to determine the independent prognostic factors. RESULTS: Multivariate Cox proportional hazard regression analyses of factors affecting the all-cause mortality and GIST-related mortality among US patients between 2010 and 2017 revealed a higher overall mortality in non-Hispanic Black patients (HR = 1.516, 95% CI 1.172-1.961, p = 0.002), patients aged 80+ (HR = 9.783, 95% CI 4.185-22.868, p = 0), followed by those aged 60-79 (HR = 3.408, 95% CI 1.488-7.807, p = 0.004); male patients (HR = 1.795, 95% CI 1.461-2.206, p < 0.001); patients with advanced disease with distant metastasis (HR = 3.865, 95% CI 2.977-5.019, p < 0.001), followed by cases with regional involvement via both direct extension and lymph node involvement (HR = 3.853, 95% CI 1.551-9.57, p = 0.004); and widowed patients (HR = 1.975, 95% CI 1.494-2.61, p < 0.001), followed by single patients (HR = 1.53, 95% CI 1.154-2.028, p = 0.003). The highest CSM was observed in the same groups, except widowed patients and patients aged 60-79. The highest CSM was also observed among patients that underwent chemotherapy (HR = 1.687, 95% CI 1.19-2.392, p = 0.003). CONCLUSION: In this updated study on the outcomes of patients with GISTs, we found that non-Hispanic Black patients, male patients, and patients older than 60 years have a higher mortality with GISTs. Furthermore, patients who have received chemotherapy have a higher GIST-specific mortality, and married patients have a lower mortality. However, we do not know to what extent these independent prognostic factors interact with each other to influence mortality. This study paves the way for future studies addressing these interactions. The results of this study may help treating clinicians to identify patient populations associated with a dismal prognosis, as those may require closer follow-up and more intensive therapy; furthermore, with married patients having a better survival rate, we hope to encourage clinicians to involve family members of the affected patients early in the disease course, as the social support might impact the prognosis.

SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022)

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. 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. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and 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 (AU)

The rare entity of gastrointestinal leiomyosarcomas: An Italian multicenter retrospective study in high-volume referral centers.

BACKGROUND: After a huge efficacy of imatinib in treating patients with gastrointestinal stromal tumors (GISTs) was proven, a maximum effort was made to make a differential diagnosis between GISTs and gastrointestinal leiomyosarcomas (GI-LMS), showing the latter to be an extremely rare tumor entity. Limited data on GI-LMS biology, clinical behavior and drug-sensibility are available, and the clinical decision-making in this subgroup of patients is usually challenging. METHODS: We conducted a multicenter, retrospective observational study on patients with diagnosed GI-LMS from 2004 to 2020 within six high-volume referral centers in Italy. RESULTS: Thirty-three patients had diagnosis of KIT-negative GI-LMS confirmed by sarcoma-expert pathologist. The most common site of origin was the intestine. Twenty-two patients had localized disease and underwent surgery: with a median follow-up of 72 months, median disease-free survival was 42 months. Overall survival (OS)-rate at 5 years was 73% and median OS was 193 months. Five out of 10 patients with local relapse received a salvage surgery, and 2/5 remained with no evidence of disease. Thirteen patients received neoadjuvant (6) or adjuvant (7) chemotherapy, and 2/13 patients remained free from relapse. The median OS for patients with metastatic LMS was 16.4 months. CONCLUSION: GI-LMS is very rare and extremely aggressive subgroup of sarcomas with a high tendency to systemic spread. Localized GI-LMS at diagnosis may be cured if treated with adequate surgery with or without (neo) adjuvant chemotherapy, while de-novo metastatic disease appeared to have a poor prognosis. Clinical effort to understand GI-LMS biology and clinical behavior and to develop active treatment strategy, especially for metastatic-disease, is warranted.

Update of epidemiology, survival and initial treatment in patients with gastrointestinal stromal tumour in the USA: a retrospective study based on SEER database.

OBJECTIVES: An updated epidemiological analysis of gastrointestinal stromal tumour (GIST), the change of cancer-specific survival (CSS) and patterns of initial treatment are of interest. DESIGN: A retrospective study using data from the Surveillance, Epidemiology and End Results (SEER) database. SETTING AND PARTICIPANTS: A total of 5625 patients with GIST diagnosed between 2010 and 2019 were identified. PRIMARY OUTCOME MEASURES: Age-standardised incidence rate (ASIR) and annual prevalence rate were calculated. SEER combined stage, period CSS rate and initial treatment were summarised. All the data were calculated by SEER*Stat software. RESULTS: From 2010 to 2019, the ASIR of GIST increased from 0.79 to 1.02 per 100 000 person-years, with an increase of 2.4% annually. The increase was across age and sex subgroups. The prevalence trend was similar with the ASIR trend in each subgroup. The stage distributions were similar between different age groups, but varied among different primary tumour sites. More importantly, a stage shift from regional stage to localized stage at diagnosis was found, which may result in the improvement of CSS over years. Overall, the 5-year CSS rate of GIST was approximately 81.3%. Even for metastatic GIST, the rate exceeded 50%. Surgery was the most common treatment regimen for GIST, followed by surgery and systemic treatment. Whereas approximately 7.0% patients were undertreated, which was more pronounced among patients with distant and unknown stages. CONCLUSIONS: The findings of this study suggest an improving early detection of GIST and an improving ability of accurate staging. Though most patients are effectively treated and perform good survivals, approximate 7.0% patients may be undertreated.

SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022).

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. 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. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and 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.

A New Online Dynamic Nomogram: Construction and Validation of a Predictive Model for Distant Metastasis Risk and Prognosis in Patients with Gastrointestinal Stromal Tumors.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the digestive tract, among which patients with distant metastases tend to have a poor prognosis. This study aimed to develop a model for predicting distant metastasis in GIST patients and to develop two models for monitoring overall survival (OS) and cancer-specific survival (CSS) in GIST patients with metastasis. This would allow us to develop an optimal, individualized treatment strategy. METHODS: We reviewed demographic and clinicopathological characteristics data from 2010 to 2017 of patients diagnosed with GIST in the Surveillance, Epidemiology, and End Results (SEER) database. The data of the external validation group was reviewed from the Forth Hospital of Hebei Medical University. Univariate and multivariate logistic regression analyses were used to confirm the independent risk factors for distant metastasis in the GIST patients, and univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factors for OS and CSS in the GIST patients with distant metastasis. Subsequently, three web-based novel nomograms were developed, which were evaluated by the receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). RESULTS: Of the 3639 patients who met the inclusion criteria, 418 (11.4%) had distant metastases. The risk factors for distant metastasis in GIST patients included sex, primary site, grade, N stage, tumor size, and mitotic count. For OS, the independent prognosis factors for GIST patients with metastasis included age, race, marital, primary site, chemotherapy, mitotic count, and metastasis at the lung, and for CSS, age, race, marital, primary site, and metastasis at the lung were the independent prognosis factors. Three web-based nomograms were constructed based on these independent factors, respectively. The ROC curves, calibration curves, and DCA were performed in the training, testing, and validation sets which confirmed the high accuracy and strong clinical practice power for the nomograms. CONCLUSION: Population-based nomograms can help clinicians predict the occurrence and prognosis of distant metastases in patients with GIST, which may be helpful for clinicians to formulate clinical management and appropriate treatment strategies.

Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers.

Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.

Extra-gastrointestinal stromal tumors (EGISTs): A case report for a mischief entity.

BACKGROUND: Extra-gastrointestinal stromal tumor is a rare subtype of soft tissue sarcomas with significantly variable presentation, management, and prognosis. This makes it crucial to report the different institutional experiences of encountering extra-gastrointestinal stromal tumors (EGIST). CASE PRESENTATION: We report 3 cases of EGIST diagnosis at American University of Beirut Medical Center for 2 males and 1 female in the 5th, 6th, and 7th decades of life, respectively. For the first case, the tumor was initially suspected to be ovarian cancer, but biopsy revealed a diagnosis of EGIST, and the patient was started on neoadjuvant therapy. In the second case, the tumor was retro-gastric and prelim diagnosis was gastric cancer but again biopsy revealed an EGIST histopathology, and the patient underwent surgery and adjuvant treatment. For the third case, a previous history of testicular cancer prompted an initial suspicion of recurrence with metastasis but biopsy and immunohistochemistry staining revealed EGIST with related markers. The patient underwent treatment at a different institution in his home country. CONCLUSION: This report sheds light on the importance of keeping EGIST amongst any differential list for abdominal and pelvic tumors. It also shows that EGIST-focused studies are needed to assess the effectiveness of the different treatment modalities available when utilized specifically for EGIST. This would allow for better oncological outcomes and improved quality of life.

Gastrointestinal stromal tumors of the upper GI tract: population-based analysis of epidemiology, treatment and outcome based on data from the German Clinical Cancer Registry Group.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors. They are most frequently located in the stomach but are also found in the esophagus and the gastroesophageal junction (GEJ). Information regarding the prognostic factors associated with upper gastrointestinal GIST is still scarse. METHODS: In this study, datasets provided by the German Clinical Cancer Registry Group, including a total of 93,069 patients with malignant tumors in the upper GI tract (C15, C16) between 2000 and 2016 were analyzed to investigate clinical outcomes of GIST in the entire upper GI tract. RESULTS: We identified 1361 patients with GIST of the upper GI tract. Tumors were located in the esophagus in 37(2.7%) patients, at the GEJ in 70 (5.1%) patients, and in the stomach in 1254 (91.2%) patients. The incidence of GIST increased over time, reaching 5% of all UGI tumors in 2015. The median age was 69 years. The incidence of GIST was similar between males and females (53% vs 47%, respectively). However, the proportion of GIST in female patients increased continuously with advancing age, ranging from 34.7% (41-50 years) to 71.4% (91-100 years). Male patients were twice as likely to develop tumors in the esophagus and GEJ compared to females (3.4% vs. 1.9% and 6.7% vs. 3.4%, respectively). The median overall survival of upper gastrointestinal GIST was 129 months. The 1-year, 5-year, and 10-year OS was 93%, 79%, and 52% respectively. Nevertheless, tumors located in the esophagus and GEJ were associated with shorter OS compared to gastric GIST (130 vs. 111 months, p = 0.001). The incidence of documented distant metastasis increased with more proximal location of GIST (gastric vs. GEJ vs. esophagus: 13% vs. 16% vs. 27%) at presentation. CONCLUSION: GIST of the esophagus and GEJ are rare soft tissue sarcomas with increasing incidence in Germany. They are characterized by worse survival outcomes and increased risk of metastasis compared to gastric GIST.

Progress in the Treatment of Small Intestine Cancer.

OPINION STATEMENT: Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.

ACG Clinical Guideline: Diagnosis and Management of Gastrointestinal Subepithelial Lesions.

Subepithelial lesions (SEL) of the GI tract represent a mix of benign and potentially malignant entities including tumors, cysts, or extraluminal structures causing extrinsic compression of the gastrointestinal wall. SEL can occur anywhere along the GI tract and are frequently incidental findings encountered during endoscopy or cross-sectional imaging. This clinical guideline of the American College of Gastroenterology was developed using the Grading of Recommendations Assessment, Development, and Evaluation process and is intended to suggest preferable approaches to a typical patient with a SEL based on the currently available published literature. Among the recommendations, we suggest endoscopic ultrasound (EUS) with tissue acquisition to improve diagnostic accuracy in the identification of solid nonlipomatous SEL and EUS fine-needle biopsy alone or EUS fine-needle aspiration with rapid on-site evaluation sampling of solid SEL. There is insufficient evidence to recommend surveillance vs resection of gastric gastrointestinal stromal tumors (GIST) <2 cm in size. Owing to their malignant potential, we suggest resection of gastric GIST >2 cm and all nongastric GIST. When exercising clinical judgment, particularly when statements are conditional suggestions and/or treatments pose significant risks, health-care providers should incorporate this guideline with patient-specific preferences, medical comorbidities, and overall health status to arrive at a patient-centered approach.

Challenge of gastro-intestinal stromal tumor management in low-income countries: example of Benin.

BACKGROUND: GISTs are rare tumors but the most frequent mesenchymal tumors of the digestive tract. Diagnosis and treatment are challenging in low-income countries due to relatively poor access to immunohistochemistry and targeted therapy. In Africa, there are few studies about it. Imatinib, an oral targeted therapy, has been available in Benin since 2010 and free since 2016. This study describes the diagnosis and therapeutic management of GIST in Cotonou, Benin. METHODS: This is a descriptive cross-sectional study, with retrospective data collection over a 10-year period from 2010 to 2020, focused on patients with histological confirmed gastro-intestinal stromal tumor (GIST). Cases were identified using the registry database and the archival files of the Hubert Koutoukou Maga National University Hospital of Cotonou (CNHU-HKM). RESULTS: Fifteen GISTs were identified during the study period. The median age was 52 and the sex ratio was 2:1 (10 males and 5 females). The most frequent symptom was abdominal pain (n = 12). Delay in care seeking after onset of symptoms ranged from 24 h to 15 years. The most common site for GISTs was the stomach (n = 8). The median tumor size was 11 cm and the majority (n=10) was metastatic or locally advanced at the time of diagnosis. The tumors were often spindle-shaped at histology (n = 13) and the majority expressed KIT (n = 14). Most of the tumors (n = 12) were at high risk of recurrence according to the Joensuu scoring system. The availability of imatinib has improved the outcome of GIST with response in all cases it was used in neoadjuvant setting (n = 7). CONCLUSION: GISTs are rare tumors and preferentially affect the stomach in Cotonou). Most of the tumors were large, unresectable at the time of diagnosis and at high risk of recurrence. Access to imatinib has revolutionized the management of those tumors in our country.

NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022.

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs.

Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5-7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset.

A Gastroenterologist's Approach to the Diagnosis and Management of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. These tumors have been shown to harbor oncogenic mutations of the c-kit tyrosine kinase receptor or platelet-derived growth factor receptor alpha (PDGFRA). Immunohistochemical analysis of GISTs allows for the differentiation of these tumors from other mesenchymal tumors of the GI tract such as leiomyomas and leiomyosarcomas. All GISTs have the potential to behave in a malignant fashion. Tumor location, size, and mitotic index are factors used to predict the risk of malignant behavior. Endoscopy and endoscopic ultrasound play a critical role in the diagnosis of GISTs and can yield important information to further risk-stratify tumors and determine management. This article provides a gastroenterologist's perspective on the diagnosis and management of GISTs.

Integrated Antitumor Activities of Cellular Immunotherapy with CIK Lymphocytes and Interferons against KIT/PDGFRA Wild Type GIST.

Gastrointestinal stromal tumors (GISTs) are rare, mesenchymal tumors of the gastrointestinal tract, characterized by either KIT or PDGFRA mutation in about 85% of cases. KIT/PDGFRA wild type gastrointestinal stromal tumors (wtGIST) account for the remaining 15% of GIST and represent an unmet medical need: their prevalence and potential medical vulnerabilities are not completely defined, and effective therapeutic strategies are still lacking. In this study we set a patient-derived preclinical model of wtGIST to investigate their phenotypic features, along with their susceptibility to cellular immunotherapy with cytokine-induced killer lymphocytes (CIK) and interferons (IFN). We generated 11 wtGIST primary cell lines (wtGISTc). The main CIK ligands (MIC A/B; ULBPs), along with PD-L1/2, were expressed by wtGISTc and the expression of HLA-I molecules was preserved. Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. We found that CIK produce a high level of granzyme B, IFNα and IFNγ. CIK-conditioned supernatant was responsible for part of the observed tumoricidal effect, along with positive bystander modulatory activities enhancing the expression of PD-L1/2 and HLA-I molecules. IFNα, but not In, had direct antitumor effects on 50% (4/8) of TKI-resistant wtGISTc, positively correlated with the tumor expression of IFN receptors. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting.