Primary Gastrointestinal Stromal Tumor Patients Research Articles

Laparoscopic vs Open Treatment for Gastric and Non-Gastric Gastrointestinal Stromal Tumors: a Two-Center Experience.

We retrospectively reviewed the medical records of 109 patients who underwent curative laparoscopic or open resection for different types of gastrointestinal stromal tumors (GIST). Only primary GIST patients who did not receive preoperative chemotherapy or oral imatinib treatment were included in the analysis. We divided the patients into 2 groups according to the surgical approach:a laparoscopic group (LAP) and a laparotomic group (OPEN). Our aim was to confirm the feasibility and safety of laparoscopic surgery for GISTs that differed in size and location, and to assess its long-term oncologic outcome in terms of overall survival (OS) and disease-free survival (DFS). Furthermore, we performed a surgical short-term outcome analysis. The two groups did not differ with respect to age at operation, gender, BMI or comorbidities. Even the NIH and AFIP risk classifications were not significantly different between the two groups. Furthermore, in our analysis, there was no significant difference in mean tumor size or location between the two groups. Wedge resection was the most frequently performed procedure. The conversion rate was 7.8%. The operative time was 194.75 (60- 350) min for the open group and 181.70 (57-480) min for the laparoscopic group. Our data clearly indicated that the long-term oncologic outcome and DFS of laparoscopic resection were not inferior to those of traditional open operations and laparoscopic resection was still feasible in cases with large tumors: the median size of the tumor was 4.5 cm (3-25) and the tumor was larger than 4.5 cm in 47.7% of the cases in the LAP group. With regard to short-term outcomes, our study demonstrated that the LAP group had fewer complications, faster gastrointestinal recovery, reduced use of analgesic drugs and shorter postoperative hospital stay (each p<0.05). In conclusion, our experience confirms that GISTs are very uncommon cancers for which the prognosis is closely related to size, localization and class of risk. In light of our clinical data, laparoscopic resection for gastric and non-gastric GISTs is a safe, feasible and oncologically correct procedure. The most important advantage of this technique is that it ensures a better postoperative outcome compared with open surgery, without worsening the prognosis.

Molecular Profile of Gastrointestinal Stromal Tumors in Sixty-Eight Patients from a Single Swiss Institution

Introduction: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. It has distinct molecular features and primarily affects the KIT and PDGFRA genes. Objective: We wanted to assess the molecular profile of 68 GIST patients who were sequenced consecutively between 2014 and 2019 at our institute of pathology. Methods: Our cohort comprised 60 primary and 8 metastatic GIST patients; 43 and 57% of the cases, respectively, were analyzed by Sanger sequencing or next-generation sequencing (NGS). Results: Of the 60 primary GIST patients, 47 (78%) showed a KIT mutation; 2 cases showed a double KIT mutation, and 1 of these was a therapy-naive GIST. Nine (15%) patients harbored a PDGFRA mutation, 2 (3%) had a BRAF mutation, 1 (2%) had a PIK3CA mutation, and 1 (2%) did not show any mutation. One BRAF and the PIK3CA mutation have not been described in GIST before. All metastatic GIST harbored exclusively KIT mutations. Conclusion: A retrospective analysis of GIST sequenced at our institute revealed incidences of KIT and PDGFRA mutations comparable to those in other cohorts from Europe. Interestingly, we found 2 previously undescribed mutations in the BRAF and PIK3CA genes as well as 1 treatment-naive case with a double KIT mutation in exon 11.

The prognostic value of gastrointestinal bleeding in gastrointestinal stromal tumor: A propensity score matching analysis.

Background and objectivesWhether gastrointestinal (GI) bleeding indicates gastrointestinal stromal tumor (GIST) rupture and impacts prognosis is unclear. We examined the prognostic value of GI bleeding in GIST.MethodsPrimary GIST patients with (GB group) or without (NGB group) initial symptoms of GI bleeding were retrospectively studied. Propensity score matching (PSM) was conducted to reduce confounders.ResultsEight hundred patients were enrolled. Male gender [odds ratio (OR) = 1.517, P = 0.011], tumors in the small intestine (OR = 2.539, P < 0.001), and tumor size 5‐10 cm (OR = 2.298, P = 0.004) increased the odds of GI bleeding; age >60 years decreased the odds (OR = 0.683, P = 0.031). After PSM, 444 patients were included (222 in each group). Relapse‐free survival (RFS) (P = 0.001) and overall survival (OS) (P = 0.002) were both superior in the GB group. In subgroup analysis, the GB group achieved a superior RFS (P = 0.005) and OS (P = 0.007) in patients with small intestine GIST, but not stomach or colorectal GIST.ConclusionsGIST patients with age <60, male gender, tumors located in the small intestine, and tumors 5‐10 cm in size had a higher risk of GI bleeding. GIST patients with GI bleeding had a superior RFS and OS. This difference was statistically significant only in small intestine GIST.

Prognostic impact of preoperative neutrophil-lymphocyte ratio for surgically resected gastrointestinal stromal tumors.

Neutrophil–lymphocyte ratio (NLR) was shown to be prognostic value in various malignancies. There are limited data about predictive or prognostic role of NLR during gastrointestinal stromal tumors (GISTs) patients. This study evaluated the prognostic significance of preoperative NLR in patients with GIST.We retrospectively enrolled 72 primary GIST patients who received initial curative surgical resection with or without adjuvant imatinib therapy. The preoperative NLR in the peripheral blood was calculated. Univariate and multivariate Cox proportional hazard regression models were used to identify potential predictors of tumor outcomes.The NLR cut-off value of 4.18 was selected. Multivariate analysis revealed that high NLR was associated with a unfavorable prognosis of GISTs (P < .05). Tumor size, tumor location, and age were significantly correlated with the NLR (P < .05).High NLR was an unfavorable prognostic factor of overall survival in GISTs and may be a useful preoperative biomarker of the prognosis of GISTs.

Analysis of diagnosis and treatment of gastrointestinal stromal tumor recurrence and metastasis after postoperative adjuvant imatinib treatment

Objective To investigate the clinical characteristics, treatment strategies and curative effect of recurrence and metastasis of primary gastrointestinal stromal tumor (GIST) after complete resection along with adjuvant therapy with imatinib, and to analyze the risk factors of recurrence and metastasis after adjuvant therapy. Methods The demographic data, clinicopathological characteristics and follow-up data of 80 primary GIST patients who received adjuvant therapy with imatinib for at least 1-year duration and had already stopped taking imatinib from January 2005 to December 2017 in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were analyzed retrospectively. The survival analysis was performed using Kaplan-Meier approach. Univariate analysis was conducted using log-rank test. Multivariate analysis was produced by Cox regression model. Results Of the enrolled 80 patients, recurrence and metastasis were detected in 17 cases after completion of postoperative adjuvant therapy with imatinib, with a median recurrence time of 12 months. All the 17 patients showed no specific clinical manifestations. Liver metastasis, peritoneum metastasis and local recurrence were found in 9, 5 and 3 cases, respectively. In the 17 patients with recurrence and metastasis, 9 patients received imatinib monotherapy. Among the 9 patients, 6 achieved partial responses, while 3 demonstrated stable disease, and secondary drug resistance was found in 7 patients during the follow-up period, with a median progression-free survival of 35 months (95%CI: 15-55 months) and median overall survival of 49 months (95%CI: 30-68 months). A total of 7 patients with recurrence and metastasis were treated with imatinib after operation and achieved satisfying tumor control, and secondary drug resistance was found in 4 patients during the follow-up period, with a median progression-free survival of 31 months (95%CI: 6-56 months) and fell short of median overall survival. The remaining 1 patient gave up treatment. Univariate analysis showed that tumor location (χ2=4.120, P=0.042), preoperative neutrophil-to-lymphocyte ratio (NLR) (χ2=7.513, P=0.006) and preoperative platelet-to-lymphocyte ratio (PLR) (χ2=6.575, P=0.010) were associated with recurrence and metastasis of GIST patients after completion of adjuvant therapy. Multivariate analysis revealed that tumor location (HR=3.787, 95%CI: 1.126-12.732, χ2=4.631, P=0.031) was an independent prognostic factor for those patients. Conclusion GIST patients who are identified recurrence and metastasis after completion of adjuvant imatinib treatment show no specific clinical manifestations after stopping andjuvant therapy with imatinib. Compared with gastric GIST, non-gastric origin GIST has a higher risk of recurrence. Imatinib monotherapy and surgery combined with imatinib therapy are both effective in treating this subgroup of patients. Key words: Gastrointestinal stromal tumor; Neoplasm recurrence, local; Neoplasm metastasis; Imatinib

Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM). In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes predominantly on the Golgi apparatus. Both imatinib-sensitive and imatinib-resistant Kit (Kit(mut)) become fully auto-phosphorylated only on the Golgi and only if in a complex-glycosylated form. Kit(mut) accumulates on the Golgi during the early secretory pathway, but not after endocytosis. The aberrant kinase activity of Kit(mut) prevents its export from the Golgi to the PM. Furthermore, Kit(mut) on the Golgi signals and activates the phosphatidylinositol 3-kinase–Akt (PI3K–Akt) pathway, signal transducer and activator of transcription 5 (STAT5), and the Mek–Erk pathway. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the endoplasmic reticulum inhibits oncogenic signaling. PM localization of Kit(mut) is not required for its signaling. Activation of Src-family tyrosine kinases on the Golgi is essential for oncogenic Kit signaling. These results suggest that the Golgi apparatus serves as a platform for oncogenic Kit signaling. Our study demonstrates that Kit(mut)’s pathogenicity is related to its mis-localization, and may offer a new strategy for treating imatinib-resistant GISTs.

Clinicopathologic features and prognosis of primary gastrointestinal stromal tumor patients under 35 years of age: A 10-year retrospective study.

To investigate gastrointestinal stromal tumor (GIST) clinicopathologic characteristics in young adults. Clinicopathologic data from GIST patients under 35 years diagnosed at our hospital from January 2005 to December 2014 were retrospectively collected. Thirty-one (5.3%, 31/585) patients were included; 17 (54.8%) were female. The most common presentation and primary tumor site were gastrointestinal bleeding (n = 18, 58.1%) and the small intestine (n = 13, 41.9%), respectively. Fifteen (48.4%) GISTs were classified as having a high relapse risk; two (6.4%), intermediate; nine (29.0%), low; and five (16.1%), very low. All patients underwent tumor resection. With a median follow-up of 51 months for 20 (64.5%) patients, 12 (60%) were given imatinib methylate as adjuvant therapy. One (5%) patient died of peritoneal GIST dissemination, four (20%) developed abdominal recurrences, two (10%) had hepatic metastasis, and thirteen (65%) were disease free. The 5-year disease-free survival rate was 51.2%. GISTs rarely occur in young adults. The most common location is the small intestine. A slight female predominance was observed in the current study. Adjuvant therapy longer than the recommended duration may be beneficial for GISTs with a high relapse risk. Combined targeted therapy and surgery is appropriate for recurrent and metastatic GISTs in select patients. J. Surg. Oncol. 2016;114:977-981. © 2016 Wiley Periodicals, Inc.

Prognostic role of microscopically positive margins for primary gastrointestinal stromal tumors: a systematic review and meta-analysis.

The impact and management of microscopically positive margins in gastrointestinal stromal tumors (GISTs) remain unclear. The aim of this study is to estimate the prognostic value of surgical margins for disease-free survival (DFS) and overall survival (OS) in patients with primary GISTs. Twelve studies with 1985 GIST patients were included. The overall recurrence rate in R1 resection and R0 resection group was 0.364 (95% CI 0.299–0.429) and 0.296 (95% CI 0.161–0.430), respectively. Meta-analysis confirmed that a microscopically positive margin could significantly impact the disease-free survival (HR 1.596, 95% CI 1.128–2.258; I2 = 37.5%, P value = 0.091), but had no influence on overall survival (HR 1.430, 95% CI 0.608–3.363; I2 = 60.8%, P value = 0.013). Importantly, subgroup analysis revealed that adjuvant imatinib treatment could attenuate the risk of recurrence for primary GIST patients who received R1 resection. (HR 1.308, 95% CI 0.583–2.935; I2 = 53.2%, P value = 0.074). The level of evidence achieved in this study was “moderate” for DFS and “low” for OS. In conclusion, this study revealed that a microscopically positive margin is an unfavorable prognostic factor for GIST patients with R1 resection, and adjuvant imatinib treatment is proved to be effective.

&amp;lt;italic&amp;gt;MiR-320a&amp;lt;/italic&amp;gt; downregulation is associated with imatinib resistance in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Though imatinib improves the outcome, drug resistance remains the major problem for extending patient survival. Genetic mutation of the drug targets is the known mechanism for imatinib resistance. However, it cannot explain all of the phenomena of imatinib resistance, and numerous additional mechanisms have been proposed to account for imatinib resistance in various model systems. In this study, we applied the SYBR-green quantitative polymerase chain reaction-based array approach to screen the differentially expressed miRNAs between primary GIST patients and imatinib-resistant patients. The selected candidate miRNAs were validated in a cohort of 12 GIST patients. We found that low expression of miR-320a was correlated with short time to imatinib resistance, and proposed the potential mechanism of miR-320a for imatinib resistance.

SKP2 High Expression, KIT Exon 11 Deletions, and Gastrointestinal Bleeding as Predictors of Poor Prognosis in Primary Gastrointestinal Stromal Tumors

Background and AimsConsidering the indication of adjuvant therapy, the recurrence risk for primary gastrointestinal stromal tumor (GIST) after surgery needs to be accurately estimated. However, current risk stratification schemes may still have room for improvement. This study seeks to analyze prognostic factors for primary GISTs from 3 aspects, including clinicopathological parameters, immunohistochemical biomarkers, and gene mutational status, and attempts to find novel valuable factors predicting the malignancy potential of GISTs.MethodsRetrospective data from 114 primary GIST patients after R0 resection were collected. Clinicopathological data was obtained from medical records and re-evaluated. Immunohistochemical analysis was performed using the Tissue Microarray method for Ki67, p16, p27, p53, SKP2, CD133, and actin. KIT gene exons 9, 11, 13, and 17 and PDGFRα gene exons 12 and 18 were tested for mutations using PCR.ResultsUnivariate analysis revealed the following factors as poor prognostic indicators for relapse-free survival with a median follow-up of 50 months: male gender, gastrointestinal bleeding, mitotic index >5/50HPFs, tumor size >5 cm, non-gastric site, necrosis, epithelioid or mixed cell type, surrounding tissue invasion, Ki67>5%, p16>20%, p53 index >10, SKP2>10%, and KIT exon 11 deletion. Besides mitotic index, tumor size and site, SKP2 high expression (RR = 2.91, 95% CI: 1.41–5.99, P = 0.004) and KIT exon 11 deletion (RR = 2.73, 95% CI: 1.04–7.16, P = 0.041) were also independent risk factors in multivariate analysis, with gastrointestinal bleeding also showing a trend towards significance (RR = 1.88, 95% CI: 0.98–3.64, P = 0.059). In addition, gastrointestinal bleeding and SKP2 high expression showed a good ability to stratify high-risk patients further.ConclusionOur results show that gastrointestinal bleeding, SKP2 high expression, and KIT exon 11 deletions may be useful indicators of high recurrence risk for primary GIST patients.

Abstract 5364: AURA kinases as markers and targets in GIST

Abstract Mitotic index has been found to be an important prognostic factor in primary gastrointestinal stromal tumor (GIST). By using gene sets related to cell cycle (Proc Natl Acad Sci U S A. 2008; 22;105(3):955-60), we can stratify a group of patients with advanced GIST (J Clin Oncol 2008;26:4100-4108.) into two risk groups with distinct survival. So it is interesting to explore whether genes involved in regulation of cell cycle could be used as a target in treating GIST. Aurora kinase A (AURKA) and B (AURKB) were two important genes in cell cycle regulation. In the same cohort of patients, expression levels of both AURKA and AURKB were found higher in high risk group patients than those in low risk group. By using MTT assay, GIST882, an imatinib-sensitive GIST cell line, was relatively resistant to both AURKA inhibitor MLN8237 and AURKB inhibitor ZM447439 than GIST 48IM, an imatinib-resistant GIST cell line. MLN8237 could induce significant cell cycle arrest in both GIST cell lines, but apoptosis could only be seen in GIST48IM. On the other hand, after ZM447439 treatment, cell cycle inhibition could only be found in GIST48IM, and none of them had apoptosis. Instead, ZM447439 could induce autophagy in both cell lines. We then used immunohistochemistry (IHC) to examine 76 primary GIST patients. High expression of AURKA but not AURKB was more often seen in non-gastric GIST. In univariate analysis, patients with tumors having strong AURKA IHC staining, as well as large tumor size, high mitotic index and NIH high risk group, had significant lower survival than comparative groups. However, in the multivariate analysis, only high mitotic count and high AURKA expression were independent adverse prognostic factors. In conclusion, cell cycle-related genes could be used in predicting prognosis in advanced GIST, and cell cycle regulated genes such as AURKA and AURKB could be used as treatment targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5364. doi:10.1158/1538-7445.AM2011-5364

The Role of Imatinib Following Complete Resection of Primary Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumor (GIST) is a life-threatening disease, for which surgery is the standard of care. However, surgical resection of the primary tumor is associated with a high rate of recurrence and a low five-year overall survival (OS) rate. The introduction of the KIT protein kinase-targeted therapy imatinib mesylate has enhanced treatment options. It has demonstrated improvements in progression-free survival and OS in patients with unresectable and/or metastatic malignant GISTs. Based on this efficacy, imatinib has been evaluated as an adjuvant option in KIT-positive primary GIST patients who have undergone complete gross resection. Early data indicate that one-year adjuvant therapy with imatinib 400mg/day can prolong recurrence-free survival (RFS) in these patients. Preliminary data also indicate potential benefits of a higher imatinib dose (800mg/day) and a longer duration of adjuvant imatinib therapy. Currently, imatinib, at a recommended dose of 400mg/day, is approved by the US Food and Drug Administration (FDA) as an adjuvant therapy in adult patients who have undergone complete gross resection of KIT-positive GIST.

Detection and clinical significance of plasma vascular endothelial growth factor level in gastrointestinal stromal tumor patients

To investigate the clinical significance of plasma vascular endothelial growth factor (p-VEGF) levels in gastrointestinal stromal tumor (GIST) patients. The p-VEGF levels in 61 primary GIST patients, 18 patients with recurrence or metastasis, and 28 healthy blood donators (as control) were measured by enzyme-linked immunosorbent assay. Paired p-VEGF levels of pre- and post-treatment were obtained from 44 patients. One patient received 22 consecutive detections during the follow up. Primary and recurrent GIST patients had higher p-VEGF levels than healthy controls [(145.31+/-45.58) ng/L, (145.72+/-52.73) ng/L vs (89.86+/-18.30) ng/L] (P<0.01). And there were no significant differences between primary patients and patients with recurrence or metastasis (P>0.05). Significant difference were found in the p-VEGF levels between pre- and post-treatment patients (P<0.01). Post-treatment p-VEGF levels decreased markedly both in 26 primary and 11 recurrent patients [(101.81+/-27.63) ng/L and (112.45+/-38.58) ng/L]. As for the patient with 22 consecutive detections during the follow up, p-VEGF levels the period of were higher before surgery and after recurrence, and lower two months after surgery and during Glivec therapy. The p-VEGF level of GIST patients is significantly higher than that of healthy people, which will decrease markedly after effective management. Monitoring the p-VEGF level in GIST patients will be helpful to evaluate the therapeutic efficacy and predict the recurrence or metastasis.

Gastrointestinal Stromal Tumors in Koreans: It's Incidence and the Clinical, Pathologic and Immunohistochemical Findings

Seven hundred forty seven cases of gastrointestinal stromal tumors (GISTs) in Koreans who were diagnosed between 2001 and 2002 were analyzed to evaluate their occurrence and their clinical, pathologic and immunohistochemical findings. The most frequent location of tumor was in the stomach (63%), followed by the small intestine (30%), the colorectum (5%), and the esophagus (2%). c-kit expression was found in 93.6% of the cases, while CD34, SMA and S-100 protein was positive in 80.1%, 28.2%, and 20.2%, respectively. c-kit positivity was high in the stomach (94.2%) and small intestine (94.6%), while it was relatively low in the colorectum (85.0%), and esophagus (81.2%). The positivity for CD34 was correlated with the higher risk of GISTs (p=0.04). Follow up of the patients showed that 58 primary GISTs patients died and 20 of these patients were recurrent or metastatic at the time of diagnosis. The pathologic diagnosis to predict the risk of aggressive behavior of GISTs was correlated with the numbers of tumor, clinical stage, epithelioid histologic type, cellularity, cellular atypia, necrosis, and mucosal invasion (p=0.00). GISTs with a poor prognosis were closely related to the clinical stage at presentation, the locations of the tumor, and the ages of the patients.