Mutations of the c-Kit and PDGFRA gene in gastrointestinal stromal tumors among hakka population of Southern China.

AIMS: The aim of the present study was to investigate mutation status of the cKit and PDGFRA genes in patients with a gastrointestinal stromal tumor (GIST). METHODS: In total, 96 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 12, 13, 14, 17, and 18 in KIT and exons 12, 14, and 18 in PDGFRA. RESULTS: KIT mutations were detected in 65 cases (67.71%), of which 81.54% (53/65) were located on exon 11, 12.31% (8/65) were located on exon 9, 4.61% (3/65) were located on exon 17, which included a concomitant mutation of exon 9 and 11, and 4.08% (2/65) were located on exon 13, which included a concomitant mutation on exon 11. The most common mutation in exon 11 was deletion, which accounted for 77.36% (41/53) of the cases, followed by a point mutation observed in 22.64% (12/53) of the cases. Among the 31 GIST cases without a KIT mutation, a mutation in PDGFRA was detected in 5 cases (5.21%, 5/96; 16.13%, 5/31). With respect to gender, age, tumor max diameter, tumor position, and mitotic index, there were no significant differences between KIT/PDGFRA mutations and non-mutations. CONCLUSIONS: GIST mainly occurs in the stomach, and the cytological morphology is mainly spindle cells, and the mutations mainly occur in KIT genes. We need a large sample size to analyze the regularity of GIST gene mutations in Hakka population and understand the independent prognostic correlation of all KIT/PDGFRA genotypes.

Racial Disparity in Incidence and Survival for Gastrointestinal Stromal Tumors (GISTs): an Analysis of SEER Database.

BACKGROUND: Gastrointestinal tumors (GISTs) represent the most common mesenchymal tumors of the gastrointestinal tract. There has been limited data on GIST incidence and survival disparities between ethnic groups. AIMS: Assess disparities in incidence and survival among race in the USA in the era of available GIST histologic codes and treatment. METHODS: We queried Surveillance, Epidemiology, and End Results (SEER) database for GIST from 2002 to 2015, with diagnostic code 8936. RESULTS: Of the 7204 patients identified, 4928 (68.4%) were White, 1308 (18.2%) African American (AA), and 968 (13.4%) were classified as "Other" (American Indian/Alaskan Native, Asian/Pacific Islander). The overall incidence rate (IR) was 0.75 per 100,000. IR was highest among AA at 1.37/100,000, but 0.65/100,000 for Whites, 1.10/100,000 for Asians/Pacific Islanders, and 0.28/100,000 for American Indians/Alaskan Natives. The GIST incidence was twice as high for AA as for Whites (rate ratio [RR]: 2.12; 95% CI: 1.98-2.26; p < 0.001). There was higher proportion of Whites than AA, who underwent surgical extirpation. Median overall survival (OS) and GIST specific survival (GSS) were not reached for all race, which indicates more than half of the patients were still alive at end of follow-up period. In multivariate Cox model, belonging to "Other" had better OS (adjusted hazard ratio [aHR]; 0.73, 95% CI: 0.55-0.95, P = 0.021) for GIST, but no difference in prognosis and OS for AA and White [(aHR for whites; 0.84, 95% CI: 0.69-1.02, P = 0.071), AA = reference]. There was no difference in GSS among races. CONCLUSIONS: Significant racial disparity in incidence and overall survival for GIST exists, and efforts should be made to bridge this gap and improve outcomes for all races. The overall incidence rate for GIST was noted to be 7.5 per 1 million, and IR of GIST was twice as high for African Americans as compared to Whites. The "Other" racial group (American Indians/Alaskan Natives, Asians, and Pacific Islanders) had superior OS as compared to African Americans and Whites.

Relationship between efficacy of sunitinib and KIT mutation of patients with advanced gastrointestinal stromal tumors after failure of imatinib: A systematic review.

BACKGROUND: A large number of studies have shown that KIT mutations are closely related to the prognosis of gastrointestinal stromal tumors (GISTs). At the same time, sunitinib (SU) has become the second-line recommended drug for GISTs because of its efficacy. We initiated a systematic review to compare the efficacy of SU after failure of Imatinib (IM) in different KIT mutations. METHODS: We searched for SU-treated patients with advanced GISTs after failed IM treatment by using databases such as PubMed, EMBASE, and the Cochrane Library, up to March 2018. We conducted statistical analyses to calculate the odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) using fixed-effects and random-effects models by Review Manager 5.3 software. RESULTS: We included a total of 474 patients from 3 retrospective studies and 2 cohort studies. Patients with exon 9 mutations had higher clinical benefit (OR = 2.61, 95% CIs = 1.32-5.18, P = .006) rates and longer progression-free survival (progressive disease, HR = 0.51, 95% CIs = 0.36-0.72, P = .0001) compared with exon 11, but there was no statistically significant difference in overall survival (OS, HR = 0.93, 95% CIs = 0.34-2.55, P = .89) and there was greater heterogeneity (Tau = 0.72, Chi = 21.45, df = 3, P < .001, I = 86%). Subgroup analysis suggests that race may be one of the sources of heterogeneity. CONCLUSION: The results show that efficacy of SU is closely associated with KIT genotypes in GISTs. Moreover, racial factor also directly affects the prognosis of different KIT mutational status, so GISTs patients of different genotypes might also consider the use of targeted drugs in consideration of ethnic differences.

Clinicopathologic study of succinate-dehydrogenase-deficient gastrointestinal stromal tumors: A single-institutional experience in China.

Gastrointestinal stromal tumors (GISTs) that are not driven by kinase mutations, as are most GISTs, often show loss of function of the succinate dehydrogenase (SDH) complex and are considered SDH-deficient GISTs. SDH-deficient GISTs share many distinct characteristics compared with conventional GISTs. However, data regarding these characteristics, particularly among Asian people, are relatively limited. The objective of this study was to characterize the clinicopathologic characteristics, treatment, and prognosis of these uncommon GISTs.This retrospective observational study enrolled 12 patients with SDH-deficient GISTs, who were selected from 335 patients with GIST diagnosed at our institution between October 31, 2013 and October 31, 2016 by succinate dehydrogenase subunit B staining.There were 8 male and 4 female patients, with a median age of 57 years (range, 21-73 years). Ten patients (83.3%) were diagnosed at or after the age of 40 years and represented 7.2% (10/138) of the entire population of elderly patients with gastric GISTs. The tumor size ranged from 3 to 19 cm (median, 7 cm); the primary tumor was multifocal in 6 cases (50%), and tumors had a multinodular or plexiform architecture in 10 cases (83.3%). Ten cases (83.3%) showed pure epithelioid morphology, with the remaining 2 cases (16.7%) showing mixed histologic subtype. Lymph node metastasis was found at the time of primary resection in 50% (3/6) of patients. Four cases (33.3%) had distant metastasis at presentation. Four patients (33.3%) developed disease progression during imatinib treatment after initial resection, but all of these patients regained disease control when the treatment was altered to sunitinib targeted therapy.SDH-deficient GISTs arise exclusively in the stomach and account for approximately 7.4% (12/162) of gastric GISTs. Moreover, those affecting people older than 40 years are not uncommon and sunitinib may work well for cases showing treatment failure with imatinib.

Is multivisceral resection in locally advanced gastrointestinal stromal tumours an acceptable strategy?

BACKGROUND: Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumour of the gastrointestinal tract. Although the efficacy of targeted therapy cannot be over-emphasized, surgery remains the only curative primary treatment for patients with localized disease. The median size of GIST at diagnosis is approximately 5-7 cm; however, it is not uncommon for tumours to be as large as 30-40 cm and involving multiple viscera. METHODS: Data were retrospectively collected from patients with GISTs treated at the Singapore General Hospital and the National Cancer Centre Singapore over a 15-year period. Standard resection of GIST without any additional organ removal was termed as a single organ resection (SOR). If the tumour was adjacent to another organ, necessitating the removal of more than one organ, the procedure was defined as a multivisceral resection (MVR). We aim to evaluate the role of MVR in the management of large GISTs. RESULTS: A total of 187 patients underwent curative surgery for GIST between January 2000 and January 2014. Of the 187 patients, 40 (21%) underwent MVR whereas 147 (79%) had SOR. Patients in the MVR group had significantly larger tumour sizes (P < 0.001) yet R0 and R1 resection was achieved in all patients, and no intra-peritoneal rupture was reported. On comparison of MVR versus SOR groups, there was no significant difference in in-hospital morbidity and mortality. CONCLUSION: MVR may be required to achieve negative margins in patients with large GISTs, and can be performed with acceptable morbidity and mortality.

[C-KIT in gastrointestinal stromal tumors and associated malignancies: A Study in a population with genetic isolation]. / C-kit en tumores estromales gastrointestinales y neoplasias asociadas: estudio en población con aislamiento genético.

INTRODUCTION: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Numerous studies have reported the association between GIST and other neoplasms. OBJECTIVES: The aim of this study was to investigate the possible association between GIST and other tumors in a genetically isolated population. METHODS: A retrospective study was conducted of patients with GIST between 2002 and 2009 at our center. Epidemiological, pathological and family data in patients with GIST alone (group A) were compared with those in patients with GIST associated with other neoplasms (group B). A possible common genetic mechanism was investigated between GIST and associated malignancies by testing the detection of the immunohistochemical marker, CD117, in all tumors. RESULTS: Twenty-two patients with GIST were identified, 10 in group A (45%) and 12 in group B (55%). In group B, the associated tumor was malignant in 6 patients (50%) and benign in another 6 (50%). Of the 22 patients with GIST, 8 (36%) had a family history of malignancies. Of these 8 patients, 7 (87.5%) were in group B (p=0.03) and 3 (37.5%) showed the same pathological type of neoplasm as their relatives. All GIST were positive for CD117 whereas associated malignancies were negative for this marker. CONCLUSION: We did not find immunohistochemical positivity for CD117 in malignancies associated with GIST. Given the special characteristics of the study population, the association between GIST and associated malignancies may be incidental.

Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial.

BACKGROUND: The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p < 0.0001]. METHODS: A subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs). RESULTS: Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively). CONCLUSION: Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.

Clinico-pathological characteristics and prognostic factors of gastrointestinal stromal tumors among a Chinese population.

Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal tumors of the digestive tract. GISTs include a group of heterogeneous tumors with different morphology, biologic behavior, and genetic characteristics, so their epidemiology, clinico-pathological features and prognosis is distinct in different countries. The objective of this study is to analyze clinico-pathological characteristics and prognostic factors of GISTs among Chinese population. We investigated 112 GIST patients were diagnosed between July 2008 and January 2013 at the First Affiliated Hospital of Guangxi Medical University. Histologic evaluation and immunohistochemistry analysis was performed on paraffin-embedded tissue from the 112 GISTs. Overall survival analysis was carried out using the Kaplan-Meier method and the log-rank test. Multivariate analysis was performed according to Cox's proportional hazards model. Three and 5-year OS rates were 71.4 and 58.6% respectively. Univariate analysis showed that the following factors were significant in predicting OS: tumor site, tumor size, metastasis, resection margin status, cell type, invasion of adjacent organ, invasion of smooth muscle, mitotic rate, P53 and adjuvant therapy with imatinib (P<0.05). Multivariate analysis showed that tumor size, metastasis, resection margin status, mitotic rate, P53 and adjuvant therapy with imatinib were independent prognostic factors associated with OS. This may aid in the prediction of clinical evolution and guide treatments in patients with GIST in China.

Clinicopathological features and outcome of gastrointestinal stromal tumors in an Afro-Caribbean population.

OBJECTIVE: A retrospective observational study was done to describe the clinical and pathological profile of gastrointestinal stromal tumors (GISTs) in Afro-Caribbean patients at a tertiary care referral center over a 5-year period. RESULTS: Eighteen cases of GIST were identified over the period under review. Male to female ratio was 1.25:1, the mean age was 54.7 years, and abdominal pain (44%) and gastrointestinal bleeding (50%) were the predominant presenting symptoms. The majority of tumors were of gastric location (83%) and spindle cell morphology (66%). C-kit (CD117) positivity was found in 13 of 14 (93%) cases tested. Using current guidelines for assigning risk of aggressive behavior, 44% of tumors were considered high risk. Of the 10 patients with high-risk or intermediate-risk tumors, 4 died, 1 of which had developed resistance to imatinib therapy. CONCLUSION: In this group of patients, GISTs demonstrated predominantly gastric location and spindle cell morphology and a guarded outlook for more aggressive tumors, which is moderated in the long-term by imatinib resistance.

Sunitinib as a second-line therapy for advanced GISTs after failure of imatinib: relationship between efficacy and tumor genotype in Korean patients.

BACKGROUND: To assess the efficacy and safety of sunitinib with regards to primary genotypes of tumor in Korean patients with advanced gastrointestinal stromal tumors (GISTs) who failed an initial therapy of imatinib. METHODS: Clinical data were collected from 88 consecutive patients with metastatic/unresectable GISTs treated with sunitinib at the Asan Medical Center. RESULTS: The median time-to-progression (TTP) and overall survival (OS) times were 7.1 months and 17.6 months, respectively. Of the 74 patients tested for KIT (exons 9, 11, 13, 17) and PDGFRA (exons 12 and 18), patients with KIT exon 9 mutant GIST (n = 11, 14.9%) showed numerically better clinical benefit (objective response or stable disease ≥ 24 weeks) rate (63.6% vs 46.8%, p = 0.504) and TTP (median 13.6 mo vs 6.9 mo, p = 0.631) than those with KIT exon 11 mutant GIST (n = 47, 63.5%). The most common grade 3/4 adverse events included neutropenia (34.1%), thrombocytopenia (33.0%) and hand-foot skin reaction (25.0%). CONCLUSIONS: Sunitinib is an effective and safe second-line therapy for Korean patients with advanced GIST. The superior efficacy of sunitinib against GISTs with KIT exon 9 mutations appears to be similar in Korean patients to Western experience although statistical significance was not secured.

Disappearance of racial disparities in gastrointestinal stromal tumor outcomes.

BACKGROUND: The purpose of this study was to determine the effects of race, socioeconomic status, and demographic and clinical variables on the outcomes of gastrointestinal stromal tumors (GISTs). STUDY DESIGN: The Surveillance, Epidemiology, and End Results (SEER) database was queried for GIST and other intestinal mesenchymal tumors from 1992 to 2005. RESULTS: A total of 3,795 patients with mesenchymal tumors were identified. More than 88% of tumors were identified as GIST after the year 2000. Overall, patient demographics showed 53% men, 72.2% Caucasians, 15.6% African Americans, and 9.1% Hispanics. In patients diagnosed before the year 2000, 30-day surgical mortality was higher in African Americans (0.56% versus 0.76% Caucasians, p=0.012), although no difference was observed in tumor stage (p=0.446) or grade (p=0.495). African Americans underwent surgical extirpation less frequently (p=0.003). Multivariate analysis correcting for patient demographics, socioeconomic status, and clinical data demonstrated African-American race (hazards ratio 1.66, p < 0.001) and failure to undergo surgical extirpation (hazards ratio 2.930, p < 0.001) were independent predictors of poor prognosis. In patients diagnosed after 2000, 30-day surgical mortality was equivalent between races (0.46% versus 0.35%, p=0.517), and African Americans underwent surgical extirpation just as often as Caucasians did (p=0.153). Multivariate analysis for patients diagnosed after 2000 demonstrated no difference in survival by race (hazards ratio 1.27, p=0.126). CONCLUSIONS: Before 2000, African Americans were less likely to have surgery, and they demonstrated an overall increased mortality rate for GIST. Since 2000, African Americans have benefited from increased surgical resection rates, decreased perioperative mortality, and improved longterm survival. These changes have appeared to erase racial disparities in the treatment of GIST.

Metastatic gastrointestinal stromal tumors in the era of imatinib: improved survival and elimination of socioeconomic survival disparities.

BACKGROUND: Imatinib was approved in 2002 for unresectable and metastatic gastrointestinal stromal tumors. Our objective was to determine if the introduction of imatinib coincided with improved survival from metastatic gastrointestinal stromal tumor in the U.S. population and in specific socioeconomic groups. METHODS: Query of the Surveillance, Epidemiology, and End Results registry identified 552 patients with metastatic gastrointestinal stromal tumor between 1995 and 2004. Year of diagnosis was categorized into two periods, 1995 to 2000 and 2001 to 2004, to account for the effect of imatinib. Kaplan-Meier and multivariate Cox regression analyses were used to examine differences in survival between periods and among socioeconomic groups. RESULTS: Median survival increased from 12 to 33 months from 1995 to 2000 to 2001 to 2004 (P < 0.001); survival at 47 months increased from 21% to 41%, respectively (P < 0.001). Median survival times for White, Black, Hispanic, and Asian or Pacific Islander, and for low-, middle-, and high-income groups increased significantly in the era of imatinib (all P < 0.05). On multivariate analysis, Black race [hazard ratio, 1.96; 95% confidence interval (95% CI), 1.15-3.32; P = 0.013], Hispanic race (hazard ratio, 2.11; 95% CI, 1.14-3.88; P = 0.017), and low income (hazard ratio, 1.81; 95% CI, 1.13-2.89; P = 0.014) were associated with the poorest survival during the 1995 to 2000 period. During 2001 to 2004, these disparities in survival were no longer statistically apparent. CONCLUSIONS: Survival from metastatic gastrointestinal stromal tumor has improved significantly in the era of imatinib. This improvement has been uniform across all socioeconomic groups, with concomitant elimination of socioeconomic survival disparities potentially due to an assistance program intended to provide universal access to imatinib therapy.