Tumor-associated tertiary lymphoid structure predicts postoperative outcomes in patients with primary gastrointestinal stromal tumors.
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ABSTRACT:
SUBMITTER: Lin Q
PROVIDER: S-EPMC7153826 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There are multiple tumor-infiltrating lymphocytes (TILs) and relevant immune checkpoints existing in gastrointestinal stromal tumor (GIST), which provides opportunities and rationales for developing effective immunotherapies. Recent studies have suggested that checkpoint TIM-3/Gal-9 plays a pivotal role on immune response in multiple tumors, similar to the PD-1/PD-L1, emerging as a potential therapeutic target. However, their functions in GIST are unrevealed. Hence, the expression of immune checkpoints TIM-3 and Gal-9, as well as the infiltration of CD8+ T cells and NK cells, is described in 299 cases of GIST specimens. The results showed that TIM-3 and Gal-9 are mainly expressed in TILs, rarely in tumor cells. Expression levels of TIM-3 and Gal-9 significantly differ in varying risks of GIST and exert opposite distribution trends. Indicated by prognosis analysis, high TIM-3 expression of TILs was associated with improved outcome, while low expression levels of TIM-3 in combination with low amounts of CD8+ and CD56+ TILs predict extremely poor survival. The integrated analysis of TIM-3+, CD8+, and CD56+ TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3+ TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.
| S-EPMC7907748 | biostudies-literature
Project description:Intratumoral immune infiltrate was recently reported in gastrointestinal stromal tumors (GISTs). However, the tumor-intrinsic factors that dictate GIST immunogenicity are still largely undefined. To shed light on this issue, a large cohort (82 samples) of primary untreated GISTs, representative of major clinicopathological variables, was investigated by an integrated immunohistochemical, transcriptomic, and computational approach. Our results indicate that tumor genotype, location, and malignant potential concur to shape the immunogenicity of primary naive GISTs. Immune infiltration was greater in overt GISTs compared with that in lesions with limited malignant potential (miniGISTs), in KIT/PDGFRA-mutated tumors compared with that in KIT/PDGFRA WT tumors, and in PDGFRA-mutated compared with KIT-mutated GISTs. Within the KIT-mutated subset, a higher degree of immune colonization was detected in the intestine. Immune hot tumors showed expression patterns compatible with a potentially proficient but curbed antigen-specific immunity, hinting at sensitivity to immunomodulatory treatments. Poorly infiltrated GISTs, primarily KIT/PDGFRA WT intestinal tumors, showed activation of Hedgehog and WNT/β-catenin immune excluding pathways. This finding discloses a potential therapeutic vulnerability, as the targeting of these pathways might prove effective by both inhibiting pro-oncogenic signals and fostering antitumor immune responses. Finally, an intriguing anticorrelation between immune infiltration and ANO1/DOG1 expression was observed, suggesting an immunomodulatory activity for anoctamin-1.
| S-EPMC7710278 | biostudies-literature
Project description:BACKGROUND:The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are considered to reflect the systemic inflammatory response and clinical prognosis. However, the independent prognostic values of the NLR and PLR for patients with gastrointestinal stromal tumor (GIST) remain debatable. This study aims to evaluate the prognostic value of preoperative NLR and PLR in GIST patients. METHODS:We retrospectively reviewed all GIST patients diagnosed and surgically treated at Union Hospital between 2005 and 2018. The preoperative NLR and PLR were calculated to evaluate recurrence-free survival (RFS) and overall survival (OS) by Kaplan-Meier analysis. Univariate and multivariate Cox regression analyses were performed to estimate the independent prognostic values. RESULTS:The median follow-up time was 49?months (interquartile range, 22-74?months). The preoperative PLR was significantly increased in the GIST patients with intermediate and high tumor risks. Increases in the NLR (?2.34) and PLR (?185.04) were associated with shorter RFS and OS (P?<?0.01). Moreover, the multivariate analysis revealed that elevated PLR was an independent factor for shorter RFS (hazard ratio [HR]: 3.041; 95% confidence interval [CI]: 2.001-4.622; P?<?0.001) and OS (HR: 1.899; 95% CI: 1.136-3.173; P?=?0.014). CONCLUSIONS:The preoperative PLR is a potential biomarker of GIST and is related to the clinical outcome. An elevated preoperative PLR predicts poor prognosis of patients with primary GIST after complete surgical resection.
| S-EPMC7178594 | biostudies-literature
Project description:Background: Surgery has been the primary treatment in patients with localized gastrointestinal stromal tumors (GISTs) for many decades, whereas it remains controversial regarding the efficacy of primary tumor resection for metastatic GISTs treated with chemotherapy, and likewise it is unclear who would benefit from the surgical resection. Methods: GISTs patients with distant metastases were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016. Cox proportional hazards regression models were used to identify prognostic factors of overall survival (OS) and cancer-specific survival (CSS). Kaplan-Meier analyses and log-rank tests were conducted to assess the effectiveness of surgery on survival. Results: In total, of 455 patients with metastatic GISTs, 235 patients (51.6%) underwent primary tumor resection and 220 patients (48.4%) did not. Median survival of patients in resection group was 72 (95% CI: 62.90-81.10) months vs. 40 (95% CI: 29.53-50.47) months for those in non-resection group (p < 0.001). Similarly, surgery in conjunction with chemotherapy led to a favorable impact on survival than chemotherapy alone (OS: 72 vs. 40 months, p < 0.001; CSS: 74 vs. 44 months, p < 0.001). Multivariable analysis showed that both OS (HR: 0.581, 95% CI: 0.386-0.874, p = 0.009) and CSS (HR: 0.663, 95% CI: 0.439-0.912, p = 0.042] were dramatically improved in patients with surgical removal of primary site, as well as primary tumor size between 5 and 10 cm, while increasing age was predictive of poorer survival. Stratified analysis revealed that patients with tumor locations in the stomach demonstrated a prolonged survival after surgery, with no significant differential surgical effect between the stomach and small intestine. Conclusions: Our study preliminarily suggests that carefully selected patients with metastatic GISTs might prolong survival after treatment of surgery, especially those with a primary tumor between 5 and 10 cm and a tumor located in the stomach.
| S-EPMC7466430 | biostudies-literature
Project description:Background and objectivesFrailty disproportionately impacts older patients with gastrointestinal cancer, rendering them at increased risk for poor outcomes. A frailty index may aid in preoperative risk stratification. We hypothesized that high modified frailty index (mFI) scores are associated with adverse outcomes after tumor resection in older, gastrointestinal cancer patients.MethodsPatients (60-90 years old) who underwent gastrointestinal tumor resection were identified in the 2005-2012 NSQIP Participant Use File. mFI was defined by 11 previously described, preoperative variables. Frailty was defined by an mFI score >0.27. The postoperative course was evaluated using univariate and multivariate analysis.Results41 455 patients (mean age 72.4 years, 47.4% female) were identified. The most prevalent form of cancer was colorectal (69.3%, n = 28 708) and 2.8% of patients were frail (n = 1,164). Frail patients were significantly more likely to have increased length of stay (11.7 vs 9.0 days), major complications (29.1% vs 17.9%), and 30-day mortality (5.6% vs 2.5%), (all P < 0.001). Multivariate analysis identified mFI as an independent predictor of major complications (OR 1.52, 95%CI 1.39-1.65, P < 0.001) and 30-day mortality (OR 1.48, 95%CI 1.24-1.75, P < 0.001).ConclusionsmFI was associated with the incidence of postoperative complications and mortality in older surgical patients with gastrointestinal cancer.
| S-EPMC7064809 | biostudies-literature
Project description:Gastrointestinal stromal tumors (GISTs) comprise a biologically diverse group of neoplasms with respect to activating mutations in either KIT or PDGFRA genes, histology, anatomic site of origin, and clinical aggressiveness. In this study, we applied the high resolution array-based comparative genomic hybridization (array-CGH) technology to 66 primary GISTs (40 gastric and 26 non-gastric, 48 with KIT- and 18 with PDGFRA-mutations) for identification of novel high-level alterations and for characterization of genotype-related genomic changes. All cases had genomic imbalances with the highest occurrence of chromosome 14q (73%), 1p (62%), 22q (59%), 15q (38%) and 13q (29%) losses. Our data indicate that loss of chromosome 14 and/or 22 is an early change in GIST tumorigenesis irrespective of tumor genotype. Furthermore, DNA copy number changes showed a site dependent pattern. These included lower incidence of losses at 14q (87% vs. 35%), and higher frequency of losses at 1p (45%, vs. 85%) and 15q (17% vs. 69%) in non-gastric versus gastric site (p<0.001 for all). However, in the multivariate analysis with adjustment to tumor risk stratification, only the chromosome 14q loss site-dependent pattern of distribution retained its significance. These findings suggest that loss of chromosome 14q is a relatively late genetic event in the development of non-gastric GISTs, the lack of which is most likely substituted by the accumulation of chromosomes 1p/15q and other changes. The novel minimal overlapping regions of deletion at chromosome 1p (1p36.32-1p35.2, 1p34.1, and 1p22.1-1p21.3), 13q (13q14.11-q14.2 and 13q32.3-q33.1) and 15q23 were delineated, which point to chromosomal regions that may harbor genes relevant to the development of these neoplasms. Keywords: comparative genomic hybridization, genotype, site dependent changes
2006-11-08 | GSE5336 | GEO
Project description:BackgroundThe surgical management of duodenal gastrointestinal stromal tumors (DGIST) is poorly characterized. Limited resection may be technically feasible and oncologically safe, but anatomic considerations may compromise the resection margins due to the proximity of critical structures, thereby necessitating more extensive resections such as pancreaticoduodenectomy.MethodsPatients undergoing surgery for DGIST at two institutions from 1994 to 2014 were identified. Clinicopathologic and survival data were analyzed to compare outcomes in patients treated with limited or radical resection.ResultsSixty patients underwent surgery for DGIST. Pancreaticoduodenectomy was performed in 38 % while the rest underwent limited resections. The most common type of limited resection was wedge resection and primary closure (49 %) followed by segmental resection with an end-to-end or side-to-side duodenojejunostomy (27 %). The pancreaticoduodenectomy group tended to have larger tumors with the majority located in D2/3 (87 %) and at the mesenteric border (91 %). The pancreaticoduodenectomy group also had significantly greater intraoperative blood loss, longer operative time, longer hospital stay, and higher 90-day morbidity and readmission rates. The 5-year relapse-free survival, recurrence-free survival, and overall survival for the pancreaticoduodenectomy versus limited resection were 81 versus 56 % (p = 0.05), 64 versus 53 % (p = 0.5), and 76 versus 72 % (p = 0.6), respectively. A surgical algorithm based on the location and size of the tumor is proposed.ConclusionsLimited resection of DGIST is safe, but may be associated with lower 5-year relapse-free survival. Pancreaticoduodenectomy is recommended for selected patients with DGIST when an R0 resection cannot be performed without removing the ampulla or part of the pancreas.
| S-EPMC5199143 | biostudies-literature
Project description:Compared to gastric gastrointestinal stromal tumor (GIST), hepatic GIST is very rare in clinic. Reports on clinicopathological feature and prognosis of this rare disease are limited in literature. The purpose of this study was, therefore, to summarize clinical and pathological features as well as prognosis of the primary hepatic GIST. One case of primary hepatic GIST from our center and 22 cases reported in MEDLINE or China National Knowledge Infrastructure (CNKI) were enrolled into this study. Clinicopathological features as well as survival data of hepatic GIST were analyzed and compared with 297 gastric GISTs and 59 small intestinal GISTs from our center. Majority of the 22 cases (95.7%) of hepatic GIST was larger than 5 cm in size, and 75.0% of the tumors were over 5/50 HPF in mitotic index. Most of the hepatic GISTs (85.7%) displayed spindle cell shape in morphology. All of the hepatic GIST (100%) enrolled in this study were classified as high-risk category by the National Institute of Health (NIH) risk classification. The 5-year median disease-free survival (DFS) time was 24.0 months and 5-year disease-specific survival (DSS) rate was 33.3%, respectively. Distribution of clinicopathological features was significantly different among hepatic, gastric, and small intestinal GIST. The DFS and DSS of hepatic GIST were significantly lower than those of the other two groups. Majority of the hepatic GIST is large in size and highly malignant. Prognosis of the primary hepatic GIST is worse than that of gastric GIST and small intestinal GIST.
| S-EPMC5055144 | biostudies-literature
Project description:BackgroundThe effect of neoadjuvant therapy (NAT) with imatinib versus upfront resection (UR) followed by adjuvant therapy (AT) with imatinib on the outcomes of gastrointestinal stromal tumors (GIST) is unknown.MethodsThis is a retrospective study at a high-volume center. All the patients with primary localized GIST were identified in a hospital database from 2007 to 2021. The endpoints included local recurrence-free survival (LRFS), distance recurrence-free survival (DRFS), and overall survival (OS). Cox regression was used to perform multivariate survival analyses. The sensitivity analysis was conducted with the inverse probability of treatment weighting (IPTW) method.ResultsA total of 211 patients were included (Group A: UR + AT, n=140; Group B: NAT + resection + AT, n=71). In the entire cohort, 5-year DRFS, LRFS, and OS were 85.6%, 90.7%, and 92.5%, respectively. In the multivariate analysis, better DRFS was linked to NAT, tumor size of 5 cm, and AT. Sixteen patients (11.4%) in Group A and 1 (1.4%) in Group B had distant recurrences after AT discontinuation. The sensitivity analysis by IPTW provided approximately similar results. An interaction effect was observed between NAT and tumor location on DRFS. In non-gastric GISTs, NAT was associated with better DRFS [hazard ratio =0.131, 95% confidence interval (CI): 0.017-0.989, P=0.049], which was not the case in gastric GIST (P=0.08). NAT was not independently associated with LRFS or OS.ConclusionsWhen compared to UR + AT, NAT + resection + AT may reduce the risk of distant recurrence in localized GIST and may be especially beneficial for patients with non-gastric GISTs.
| S-EPMC10007957 | biostudies-literature
Project description:ObjectivesTo develop a mutation-based radiomics signature to predict response to imatinib in Gastrointestinal Stromal Tumors (GISTs).MethodsEighty-two patients with GIST were enrolled in this retrospective study, including 52 patients from one center that were used to develop the model, and 30 patients from a second center to validate it. Reference standard was the mutational status of tyrosine-protein kinase (KIT) and platelet-derived growth factor α (PDGFRA). Patients were dichotomized in imatinib sensitive (group 0 - mutation in KIT or PDGFRA, different from exon 18-D842V), and imatinib non-responsive (group 1 - PDGFRA exon 18-D842V mutation or absence of mutation in KIT/PDGFRA). Initially, 107 texture features were extracted from the tumor masks of baseline computed tomography scans. Different machine learning methods were then implemented to select the best combination of features for the development of the radiomics signature.ResultsThe best performance was obtained with the 5 features selected by the ANOVA model and the Bayes classifier, using a threshold of 0.36. With this setting the radiomics signature had an accuracy and precision for sensitive patients of 82 % (95 % CI:60-95) and 90 % (95 % CI:73-97), respectively. Conversely, a precision of 80 % (95 % CI:34-97) was obtained in non-responsive patients using a threshold of 0.9. Indeed, with the latter setting 4 patients out of 5 were correctly predicted as non-responders.ConclusionsThe results are a first step towards using radiomics to improve the management of patients with GIST, especially when tumor tissue is unavailable for molecular analysis or when molecular profiling is inconclusive.
| S-EPMC10362081 | biostudies-literature