Integrating Anatomical, Molecular and Clinical Risk Factors in Gastrointestinal Stromal Tumor of the Stomach

Abstract Background Adjuvant imatinib for 3 years is recommended to patients with high-risk gastrointestinal stromal tumor (GIST). Risk stratification is inaccurate, and risk assessments are further complicated by the increased use of neoadjuvant treatment. Anatomical criteria for prognostication have not been investigated. Methods Clinical, molecular, and anatomical variables were retrospectively studied in a population-based cohort of 295 patients with gastric GIST resected between 2000 and 2018. Gastric subsite was divided into the upper, middle, and lower thirds. Growth pattern was classified as luminal, exophytic, or transmural based on imaging and surgical reports. Results Of 113 tumors in the upper third of the stomach, 103 (91.2%) were KIT mutated, 7 (6.2%) were PDGFRA mutated, and 104 (92.0%) harbored genotypes sensitive to imatinib. Transmural tumors were strongly associated with a high mitotic index. Five-year recurrence-free survival (RFS) was 71% for patients with transmural tumors versus 96% with luminal or exophytic tumors (hazard ratio [HR] 8.45, 95% confidence interval [CI] 3.69–19.36; p < 0.001), and, in high-risk patients, 5-year RFS was 46% for patients with transmural tumors versus 83% with luminal or exophytic tumors (HR 4.47, 95% CI 1.71–11.66; p = 0.001). Among 134 patients with tumors > 5 cm, there were 29 recurrences. Only five patients with exophytic or luminal tumors had recurrent disease, of whom four had tumor rupture. Five-year RFS for patients with exophytic/luminal tumors >5 cm without rupture was 98%. Conclusions In the upper third, over 90% of tumors were sensitive to imatinib. Patients with exophytic or luminal tumors without rupture, irrespective of size, had an excellent prognosis and may not benefit from adjuvant therapy.

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A comprehensive characterization of anatomical and molecular risk factors in gastric gastrointestinal stromal tumor.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e23522 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e23522-e23522

Author(s):

Kjetil Boye ◽

Anne Marit Wiedswang ◽

Leonardo A. Meza-Zepeda ◽

Ivar Hompland ◽

Ingvild Lobmaier ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Tumor Growth ◽

Large Population ◽

Population Based ◽

Gastric Gist ◽

Imatinib Treatment ◽

High Risk Patients ◽

Risk Patients ◽

Upper Third

e23522 Background: Gastric gastrointestinal stromal tumors (GISTs) demonstrate a remarkable diversity in clinical behavior. Established risk criteria identify patients prone to recurrence with high sensitivity, but factors that could add specificity are needed. The aim of this study was to give a comprehensive picture of localized, gastric GIST and to investigate prognostic factors in a large population-based series. Methods: Patients with primary gastric GISTs completely resected between 2000 and 2018 were identified in the sarcoma database at Oslo University Hospital. Gastric subsite was divided into the upper, middle and lower thirds. Macroscopic growth pattern was coded as luminal, exophytic or transmural based on imaging and surgical reports. Mutation analysis was performed by Sanger sequencing of selected exons in KIT and PDGFRA and by targeted next-generation sequencing. Results: The cohort comprised 295 patients, representing 98% of patients in the region reported to the Cancer Registry of Norway. Of 292 tumors suitable for anatomical classification, 122 were located in the upper third of the stomach (41.8%), 120 in the middle (41.1%), and 50 in the lower third (17.1%). The number of luminal, exophytic and transmural tumors were 100 (34.1%), 94 (32.1%) and 99 (33.8%), and 2 tumors were not possible to classify. KIT mutations were detected in 183 of 256 tumors (71.5%), PDGFRA mutations in 62 (24.2%), whereas only 11 patients (4.3%) had KIT and PDGFRA wild-type tumors. Transmural tumors were larger, more often located in the upper third, had higher mitotic activity, and more frequently had KIT del557/558 mutations. KIT mutated tumors had a predilection for the upper two thirds and PDGFRA mutated tumors for the lower two thirds. Recurrences were rare among patients with luminal or exophytic tumors, with a 5-year RFS of 96% versus 71% with transmural tumors (HR 8.45; 95% CI 3.69-19.36; P< 0.001). RFS was inferior with transmural tumor growth also among high-risk patients, 46% versus 83% at 5 years ( P= 0.001). Excluding patients with tumor rupture, there was only one recurrence among 24 high-risk patients with luminal or exophytic primaries, of whom 11 did not receive adjuvant therapy. Conclusions: This study provides a comprehensive, population-based description of the anatomical and molecular landscape of gastric GIST, with findings of potential clinical relevance. Transmural tumor growth was a predictor of poor outcome and could supplement established risk factors in selecting patients for adjuvant imatinib treatment.

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A multinational phase II clinical trial of neoadjuvant imatinib for large gastrointestinal stromal tumor of the stomach.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.130 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 130-130

Author(s):

Han-Kwang Yang ◽

Yukinori Kurokawa ◽

Min-Hee Ryu ◽

Haruhiko Cho ◽

Sook Ryun Park ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Gastrointestinal Stromal Tumor ◽

Neoadjuvant Treatment ◽

Stromal Tumor ◽

Maximal Response ◽

R0 Resection ◽

Gastric Gist ◽

Efficacy And Safety ◽

Resection Rate

130 Background: Neoadjuvant therapy is expected to reduce the risk of primary surgery, such as rupture of the tumor, hemorrhage, and multi-visceral resection, and to improve survivals for patients with a large gastric gastrointestinal stromal tumor (GIST). This study aims to evaluate the efficacy and safety of neoadjuvant imatinib therapy for a large gastric GIST. Methods: Patients with gastric GIST, which is 10cm or larger and without metastasis, received neoadjuvant imatinib (400mg/day) for 6 months, and up to 9 months if maximal response is expected. Postoperative adjuvant imatinib was prescribed for at least 1 year and up to 3 years according to adjuvant treatment guideline. The primary endpoint was complete (R0) resection rate. A primary analysis were performed by the time all the operations were finished, to examine the efficacy and safety of the neoadjuvant treatment. Results: Between Feb 2010 and Sep 2014, 55 patients were enrolled in Japan and Korea. One patient with a jejunal GIST and one patient with PDGFRA-18 D842V mutation were excluded from analysis. Mean tumor diameter was 12cm (10-23). 86.8% of patients (46/53) completed neoadjuvant treatment. Dose reduction of imatinib was performed in 26.4% (14/53). The most frequent Grade 3 or 4 adverse events were G3 rash (5/53, 9.4%) and G3/4 neutropenia (4/53, 7.5%). Disease control rate (PR+SD) and response rate (PR) of neoadjuvant imatinib was 100% and 62.3% by RECIST, and 100% and 98.1% by Choi criteria, respectively. There was no case of CR or PD. 50 patients underwent operation, and R0 resection rate was 90.6% (n = 48, 95% CI 79.3% - 96.9%), which was significantly higher than the threshold value of 70% (p < 0.001). Combined resection of other organs (except gall bladder) was performed in 24.5% (n = 13), and 83.0% of patients (n = 44) could preserve ≥ 50% of the stomach. Postoperative complication occurred in 18.0% (9/50). Conclusions: Neoadjuvant imatinib treatment is effective and safe treatment option for a large primary GIST allowing high R0 resection rate with acceptable incidence of adverse events and postoperative complications. Clinical trial information: UMIN000003114.

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Article Commentary: The Role of Adjuvant Therapy in Gastrointestinal stromal Tumor after Operative Treatment

Clinical Medicine Gastroenterology ◽

10.4137/cgast.s3422 ◽

2009 ◽

Vol 2 ◽

pp. CGast.S3422

Author(s):

Ka-Ho Lok

Keyword(s):

High Risk ◽

Adjuvant Therapy ◽

Gastrointestinal Stromal Tumor ◽

Operative Treatment ◽

Stromal Tumor ◽

Recurrence Free Survival ◽

Free Survival

The treatment for localized advance gastrointestinal stromal tumor (GIST) is far from ideal. Up to 50% of patient developed post-operative recurrence and died within 5 years. Recently, imatinib was found to significantly improve recurrence-free survival in post-operative patients. The role of adjuvant therapy in high risk GIST patients is discussed.

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Prognostic Value of Bleeding in Gastrointestinal Stromal Tumors: A Meta-Analysis

Technology in Cancer Research & Treatment ◽

10.1177/15330338211034259 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110342

Author(s):

Xin Fan ◽

He Han ◽

Zhiyu Sun ◽

Liwen Zhang ◽

Gong Chen ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Gastrointestinal Stromal Tumor ◽

Meta Analysis ◽

Stromal Tumor ◽

Tumor Diameter ◽

Gi Bleeding ◽

Tumor Rupture ◽

Related Factors ◽

Free Survival ◽

Aging Factor

Background: Gastrointestinal bleeding is the most common clinical manifestation of gastrointestinal stromal tumor. It is of great significance to the prognosis of patients. But the results are controversial. The purpose of this study was to evaluate the relationship between gastrointestinal bleeding and clinical prognosis in patients with GIST. Methods: A systematic literature search was performed in Pumbed, Cochrane Library, EMBASE, ClinicalTrials.gov , CNKI, VIP and wanfang databases with the pattern of unlimited languages. 12 studies with 2781 individuals were included in the final analysis. The overall survival (OS), recurrence-free survival/disease-free survival (RFS/DFS) and related factors affecting bleeding in patients with gastrointestinal stromal tumor (GIST) were extracted. Hazard ratio (HR) and 95% confidence interval (CI) were used for in the meta-analysis. Results: A total of 12 articles were included in the study, including 2781 patients with GIST, including 845 patients with gastrointestinal bleeding. The OS of GIST patients with gastrointestinal bleeding was significantly worse (HR = 2.54, 95% CI = 1.13-5.73, P = 0.025). But there was no significant difference in RFS between gastrointestinal bleeding patients and non-bleeding patients (HR = 1.35, 95% CI = 0.70-2.61, P = 0.371). Further analysis of the related factors of GI bleeding in GIST patients was observed, besides the aging factor (HR = 1.02, 95% CI = 0.69-1.50, P = 0.929), Small intestinal stromal tumor (HR = 0.56, 95% CI = 0.41-0.76, P < 0.001), tumor diameter ≥ 5 cm (HR = 2.09, 95% CI = 1.20-3.63, P = 0.009), Mitotic index ≥ 5/50 HPF (HR = 1.66, 95% CI = 1.11-2.49, P = 0.014) and tumor rupture (HR = 2.04, 95% CI = 1.0-3.82, P = 0.026) all increased the risk of GI bleeding in patients with GIST. Conclusions: The OS of GIST patients with GI bleeding was worse than non-GI bleeding, but had no significant effect on RFS. Nevertheless the aging factor, the location of GIST in the small intestine, tumor diameter ≥ 5 cm, Mitotic index ≥ 5/50 HPF and tumor rupture all increased the risk of GI bleeding in patients with GIST.

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A Novel Pathological Prognostic Score (PPS) to Identify “Very High-Risk” Patients: a Multicenter Retrospective Analysis of 506 Patients with High Risk Gastrointestinal Stromal Tumor (GIST)

Journal of Gastrointestinal Surgery ◽

10.1007/s11605-018-3799-5 ◽

2018 ◽

Vol 22 (12) ◽

pp. 2150-2157 ◽

Cited By ~ 2

Author(s):

Xuechao Liu ◽

◽

Haibo Qiu ◽

Zhiming Wu ◽

Peng Zhang ◽

...

Keyword(s):

High Risk ◽

Gastrointestinal Stromal Tumor ◽

Retrospective Analysis ◽

Prognostic Score ◽

Stromal Tumor ◽

High Risk Patients ◽

Risk Patients ◽

Very High

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A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22031075 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1075

Author(s):

Luca Bedon ◽

Michele Dal Bo ◽

Monica Mossenta ◽

Davide Busato ◽

Giuseppe Toffoli ◽

...

Keyword(s):

Machine Learning ◽

Hepatocellular Carcinoma ◽

High Risk ◽

Progression Free Survival ◽

Low Risk ◽

Functional Enrichment ◽

Free Survival ◽

High Risk Patients ◽

Risk Of Progression ◽

Risk Patients

Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.

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Oral Metronomic Maintenance Therapy Can Improve Survival in High-Risk Neuroblastoma Patients Not Treated with ASCT or Anti-GD2 Antibodies

Cancers ◽

10.3390/cancers13143494 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3494

Author(s):

Xiaofei Sun ◽

Zijun Zhen ◽

Ying Guo ◽

Yuanhong Gao ◽

Juan Wang ◽

...

Keyword(s):

High Risk ◽

Conventional Treatment ◽

Maintenance Treatment ◽

Antibody Therapy ◽

Aggressive Treatment ◽

Newly Diagnosed ◽

Event Free Survival ◽

Free Survival ◽

Stage 4 ◽

Risk Patients

Despite aggressive treatment, the prognosis of high-risk NB patients is still poor. This retrospective study investigated the benefits of metronomic maintenance treatment (MT) in high-risk NB patients without ASCT or GD2 antibody therapy. Patients aged ≤ 21 years with newly diagnosed high-risk NB were included. Patients with complete/very good partial remission (CR/VGPR/PR) to conventional treatment received, or not, oral metronomic MT for 1 year. Two hundred and seventeen high-risk NB patients were enrolled. One hundred and eighty-five (85%) had a CR/VGPR/PR to conventional treatment, of the patients with stage 4, 106 receiving and 61 not receiving oral metronomic MT, and the 3-year event-free survival (EFS) rate was 42.5 ± 5.1% and 29.6 ± 6%, respectively (p = 0.017), and overall survival (OS) rate was 71.1 ± 4.7% and 59.4 ± 6.4%, respectively (p = 0.022). A total of 117 high-risk patients with oral metronomic MT had EFS rate of 42.7 ± 4.8%. The toxicity of MT was mild. For high-risk NB patients without ASCT or anti-GD2 antibody therapy, stage 4, MYCN amplication and patients with stage 4 not receiving oral metronomic MT after CR/VGPR/PR were independent adverse prognostic factors. Oral metronomic MT can improve survival in high-risk NB patients in CR/VGPR/PR without ASCT or anti-GD2 antibodies therapy.

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