Tyrosine kinase inhibitors (TKI) significantly reduce the risk of recurrence and metastasis and prolong survival in patients with gastrointestinal stromal tumors (GIST), but drug resistance is often inevitable. Immunotherapy has been proven effective in multiple solid tumors, but the efficacy in GIST is unclear. The efficacy of immunotherapy depends on the tumor microenvironment (TME). Tumor-infiltrating immune cells and immune checkpoints are important components of TME, which not only participate in the regulation of tumor immune response but are also the key target of immunotherapy. A comprehensive analysis of them can clarify the mechanism of tumor immune escape. This review found that there are abundant tumor-infiltrating immune cells in GIST, which play an important role in tumor immune surveillance and escape. Although early clinical studies have shown that patients with GIST have a good tolerance to immunotherapy, the curative effect is not satisfactory. Therefore, how to select the responders of immunotherapy and coordinate the relationship between immunotherapy and TKIs is the key issue to be explored. At the same time, the gradual deepening of basic research and large sample prospective clinical trials will certainly provide more strategies for the application of immunotherapy in GIST.
Humans ; Gastrointestinal Stromal Tumors/drug therapy* ; Prospective Studies ; Immunotherapy/methods* ; Tumor Microenvironment ; Protein Kinase Inhibitors/pharmacology*

Tumor rupture is a common clinical event in the process of tumorigenesis, progression, diagnosis and treatment of gastrointestinal stromal tumor, which is closely associated with tumor recurrence, metastasis and poor prognosis. Tumor rupture may be associated with some intrinsic biological aggressiveness qualities, such as large tumor size, high mitotic count, and KIT exon 11 deletion mutations involving codons 557 and 558, and may be relatively more frequent with small intestine GIST and excellent response to imatinib neoadjuvant therapy resulting in tumor tissue rapid liquefacient and necrosis. The triggering factors involve sudden increase in abdominal pressure, external pressure, collision and improper surgical operation, etc. Tumor rupture is considered as an important risk factor of recurrence after macroscopically complete resection of tumor, and an indication for determining interval or even lifelong adjuvant therapy with imatinib according to guidelines. However, there is no consensus or universally accepted definition of tumor rupture, and, consequently, its incidence varies greatly across reported series and lacks detailed epidemiological data. Without pre-defined criteria, it is difficult to assess the clinical significance of rupture. We reviewed the relevant literature and international guidelines, and generally divided tumor rupture into spontaneous rupture and iatrogenic rupture. Based on the Oslo criteria, we proposed the following six definitions for tumor rupture: (1) tumor fracture or spillage; (2) blood-stained ascites; (3) gastrointestinal perforation at the tumor site; (4) microscopic infiltration of an adjacent organ; (5) intralesional dissection or piecemeal resection; (6) incisional biopsy. The following types of minor defects of tumor integrity should not be defined as rupture: (1) mucosal defects or spillage contained within the gastrointestinal lumen; (2) microscopic tumor penetration of the peritoneum or iatrogenic damage only to the serosa; (3) uncomplicated transperitoneal needle biopsy; (4) R1 resection. In addition, we further emphasize the importance of identifying risk factors of tumor rupture, prevention and positive intervention.
Antineoplastic Agents/therapeutic use* ; Gastrointestinal Stromal Tumors/drug therapy* ; Humans ; Imatinib Mesylate/therapeutic use* ; Neoplasm Recurrence, Local ; Prognosis ; Retrospective Studies ; Rupture, Spontaneous

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.
Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use* ; Chemotherapy, Adjuvant ; Cross-Sectional Studies ; Female ; Gastrointestinal Stromal Tumors/drug therapy* ; Humans ; Imatinib Mesylate/therapeutic use* ; Male ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy*

Antineoplastic Agents/therapeutic use* ; Gastrointestinal Stromal Tumors/drug therapy* ; Humans ; Liver ; Liver Neoplasms/drug therapy* ; Lung ; Naphthyridines/therapeutic use* ; Urea/analogs & derivatives*

Antineoplastic Agents ; adverse effects ; Consensus ; Gastrointestinal Neoplasms ; drug therapy ; Gastrointestinal Stromal Tumors ; drug therapy ; Humans ; Protein Kinase Inhibitors ; adverse effects

OBJECTIVE: To investigate the efficacy of transanal endoscopic microsurgery (TEM) combined with imatinib for rectal gastrointestinal stromal tumors(GIST). METHODS: Clinical data of 35 patients with rectal GIST undergoing TEM at Peking Union Medical College Hospital from February 2008 to May 2017 were analyzed retrospectively. Operation details, postoperative recovery condition, and follow-up information were reviewed. The differences in clinicopathological features and perioperative parameters were compared between patients who received neoadjuvant therapy (12 patients, imatinib mesylate, oral, 400 mg daily for 6 months before surgery) and those without neoadjuvant therapy (23 patients). RESULTS: Of 35 patients, 18 were males and 17 were females with the mean age of (49.3±13.3) years. Mean tumor diameter was (1.8±1.1) cm and mean distance from lower tumor margin to anal verge was (4.0±1.8) cm. Mean operative time was (82.4±21.1) minutes and mean blood loss was (11.7±7.5) ml. No conversion to laparotomy occurred. Complete resection with negative margins was achieved in all cases. Complications were classified according to Clavien-Dindo system: 4 cases of grade I, 3 of grade II and 1 of grade IIIb. The tumor size in patients who received neoadjuvant therapy reduced from (3.1±1.2) cm to (2.6±1.2) cm, though it was still larger than the tumor size in patients without neoadjuvant therapy[(1.5±0.8) cm, P<0.01]. No significant difference in operative time was found between patients with and without neoadjuvant therapy [(76.7±24.8) minutes vs. (85.4±18.8) minutes, P>0.05]. Thirty patients (85.7%) were followed up for (50.3±36.6) months, and no local recurrence or metastasis was observed. CONCLUSIONS TEM is safe and effective in the treatment of rectal GIST. Preoperative neoadjuvant therapy is beneficial to TEM in treating larger tumors without increasing operating time. Satisfactory follow-up result is observed.
Adult ; Female ; Gastrointestinal Stromal Tumors ; drug therapy ; surgery ; Humans ; Imatinib Mesylate ; therapeutic use ; Male ; Middle Aged ; Rectal Neoplasms ; drug therapy ; surgery ; Retrospective Studies ; Transanal Endoscopic Microsurgery ; standards ; Treatment Outcome

OBJECTIVE: To investigate the biological behavior characteristics of gastrointestinal stromal tumors (GIST) with PDGFRA mutation and the patients' survival, and elucidate the efficacy of imatinib therapy. METHODS: Patients with PDGFRA D842V and non-D842V mutations were screened from a database of 1163 patients with GIST who were treated at Peking University Cancer Hospital from 2003 to 2018. Clinicopathological data of these patients were collected, including gender, age, tumor size, mitotic phase, primary position, metastatic site, and expressions of CD117, CD34, DOG-1. The association of gene mutations with biological behavior of GIST, prognosis of patients, and efficacy of imatinib therapy was examined. Fisher's exact test was used to compare the clinical characteristics of the two groups. Kaplan-Meier method was used to analyze overall survival and recurrence-free survival. RESULTS: A total of 27 patients with PDGFRA mutations were screened, among whom the D842V mutation was 1.6%(19/1 163), and the rate of non-D842V mutation was 0.7%(8/1 163). There were 11 male patients and 8 female patients of D842V mutation with male to female ratio of 1.38:1 and median age of 56 (35-72) years. There were 4 male patients and 4 female patients of non-D842V mutations with male to female ratio of 1:1 and median age of 51.5 (34-82) years. The primary lesions of D824V mutation were located in stomach for 18 cases and in parenteral area for 1 case. The primary lesions of non-D842V mutation were located in stomach for 6 cases, in jejunoileum for 1 case and in colorectum for 1 case. The proportion of nuclear fission <5/50 HPF in PDGFRA mutation GIST was 17/27. Among D842V mutation patients, mitotic phase <5/50 HPF accounted for 11/19, mitotic phase >10/50 HPF accounted for 3/19, and 5-10/50 HPF accounted for 5/19. Among non-D842V mutation patients, mitotic phase <5/50 HPF accounted for 6/8, 5-10/50 HPF accounted for 2/8. Of D842V mutation patients, positive CD117 was found in 15 cases(15/19); positive DOG-1 was found in 15 cases(15/19); positive CD34 was found in 16/17 cases. Among patients with non-D842V mutation, 7 patients were positive for CD117(7/8); only 5 patients were tested for CD34, and all 5 patients were positive(5/5); only 3 patients were tested for DOG-1, and all 3 cases were positive (3/3). The 3-year recurrence-free survival rate after radical resection in D842V mutation patients was 51.9%, and that in non-D842V mutation patients was 62.5% without significant difference(P=0.380). Recurrence-free rate did not decreased in patients with D842V mutation after adjuvant imatinib treatment and the benefit rate of first-line treatment with imatinib in patients with advanced disease was zero. CONCLUSIONS The PDGFRA gene mutation rate is low, mostly derived from gastric GIST. D842V and non-D842V mutations present inert biological behavior. D842V mutation GIST is resistant to imatinib, and non-D842V mutation GIST can obtain benefit from imatinib treatment.
Adult ; Aged ; Aged, 80 and over ; Drug Resistance, Neoplasm ; genetics ; Female ; Gastrointestinal Stromal Tumors ; drug therapy ; genetics ; Humans ; Imatinib Mesylate ; therapeutic use ; Male ; Middle Aged ; Mutation ; genetics ; Neoplasm Recurrence, Local ; genetics ; Prognosis ; Proto-Oncogene Proteins c-kit ; genetics ; Receptor, Platelet-Derived Growth Factor alpha ; genetics

Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor derived from Cajal cells originating from the myotonic plexus. The expression of tyrosine kinase (KIT) membrane receptors that are active on KIT is inhibited by the KIT inhibitor imatinib mesylate. GISTs are resistant to conventional chemotherapy, and radiation therapy is not significantly beneficial for GISTs. With the development of imatinib mesylate, approximately 81.6% of patients with advanced and metastatic GIST exhibit an effect above the stabilization response, thereby increasing the survival time. However, imatinib mesylate alone is unlikely to cure metastatic GISTs. Even with a partial or stable response, imatinib mesylate may be used for a longer time period. However, resection of grossly visible lesions should be considered for patients with a stable response during surgical treatment. In this study, we present a case of GIST with liver metastasis after imatinib mesylate treatment, which was followed up without recurrence after partial resection.
Drug Therapy ; Gastrointestinal Stromal Tumors ; Humans ; Imatinib Mesylate ; Liver ; Membranes ; Neoplasm Metastasis ; Protein-Tyrosine Kinases ; Recurrence

The functional mutation of c-kit and platelet-derived growth factor receptor α (PDGFRA) which encode proto-oncogene receptor tyrosine kinase are the crucial pathogeneses of gastrointestinal stromal tumors(GISTs). 80%-85% c-kit gene mutation including exon 11,exon 9,exon 13,exon 17 and 5%-10% PDGFRA gene mutation such as exon 18, exon 12 are examined in GISTs. Neither of c-kit or PDGFRA gene mutation are called wide type GISTs. The pathogeneses of wild type GISTs are not clear. The deficiency of succinate dehydrogenase B(SDHB)-related insulin-like growth factor 1(IGF-1R) activation, BRAF gene mutation and neurofibromatosis type 1 may be related to progression of wild type GISTs. More than half of metastatic GISTs patients receiving imatinib treatment can develop to c-kit secondary mutations, which are responsible for secondary resistance. However, the reasons of imatinib resistance in GISTs without c-kit secondary mutation need to be explored. At present, many clinical trials are ongoing to evaluate new drugs in GISTs treatment, including nilotinib, masitinib, pazopanib, dovitinib, ponatinib, dasatinib, crenolanib, linsitinib and immunotherapy, which may bring resistance GISTs treatment to new hope. Next generation sequencing (NGS) and liquid biopsy will be very important in GISTs research and clinical practice.
Benzimidazoles ; therapeutic use ; Exons ; Gastrointestinal Stromal Tumors ; drug therapy ; genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Imatinib Mesylate ; Mutation ; Piperidines ; Protein Kinase Inhibitors ; therapeutic use ; Proto-Oncogene Proteins c-kit ; genetics ; Pyrimidines ; therapeutic use ; Quinolones ; therapeutic use ; Succinate Dehydrogenase ; genetics ; Sulfonamides

OBJECTIVETo investigate the treatment methods and prognostic factors of high-risk gastrointestinal stromal tumor (GIST).

METHODSClinicopathological date and follow-up data of 108 patients with high-risk GIST from January 2002 to February 2016 treated at our department were retrospectively reviewed. The patients were divided into two groups according to whether they received adjuvant therapy after surgery. A group of patients received imatinib adjuvant therapy(adjuvant therapy group, 69 cases). Another group of patients were not treated with imatinib until they were found to have disease progression(follow-up observation group, 39 cases). The survival rate and recurrence rate were compared between two groups, and the risk factors of prognosis were analyzed by Cox regression model.

RESULTSAll the cases were followed up with a median time of 48 months(1 to 161 months). Recurrence and / or metastasis occurred in 57(52.8%) patients during follow-up. The postoperative recurrence and / or metastasis rate was 34.8%(24/69) and 84.6%(33/39) respectively in the adjuvant therapy group and the follow-up observation group, the difference was statistically significant(P=0.000). Twenty-eight(25.9%) patients died. The 1-, 3-, 5-, 10-year survival rates of the 108 patients undergoing follow-up were estimated to be 99.8%, 87.7%, 76.0% and 42.7% respectively. The 5-year survival rates were 79.3% and 72.3% in the adjuvant therapy group and the follow-up observation group, the difference was not statistically significant (P=0.648). Univariate analysis showed that mitotic count, radical degree and tumor rupture were predictive factors of survival after resection of primary high-risk GIST (all P<0.05). Multivariate analysis using Cox regression model revealed that the mitotic count (P=0.013, RR=2.400, 95%CI:1.206 to 4.779) and radical degree(P=0.003, RR=3.968, 95%CI:1.609 to 9.784) were independent prognostic factors.

CONCLUSIONComprehensive treatment of radical surgery combined with targeted therapy and close followed up can lead to better long-term survival of high-risk patients with GIST.

Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Combined Modality Therapy ; Disease Progression ; Female ; Follow-Up Studies ; Gastrointestinal Stromal Tumors ; drug therapy ; pathology ; surgery ; Humans ; Imatinib Mesylate ; therapeutic use ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Recurrence, Local ; Postoperative Period ; Prognosis ; Retrospective Studies ; Risk Factors ; Survival Rate