The Potential CircRNAs in Imatinib Resistance of GIST

Background: Recent studies have found that circular RNA is an abundant RNA species, belongs to part of the competing endogenous RNA network(ceRNA), which was proved to play an important role in the development, diagnosis and progress of diseases.Methods: We determined the expression of circular RNAs in paired normal gastric tissues(N), primary GIST (gastrointestinal stromal tumor) tissues (Y or YC) and imatinib mesylate secondary resistance GIST tissues(C) with microarray and predicted 8677 dysregulated circular RNAs.Results: We identified 15 circRNAs was up-regulated and 8 circRNAs were down-regulated in C group. Gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these host linear transcripts that differentially express circular RNAs are involved in many key biological pathways., predicting the potential tumor-genesis and drug resistance mechanism was related with HIF-1 pathway, later we draw the cirRNA-miRNA-mRNA network involved in the HIF-1 pathway, found that several dysregulated circRNAs and the relationship between circRNA-miRNAs-mRNA, such as circRNA_06551, circRNA_14668, circRNA_04497, circRNA_08683, circRNA_09923(Green, down-regulation) and circRNA_23636, circRNA_15734(Red, up-regulation). Conclusions: Taken together, we identified a panel of dysregulated circRNAs that may be potential biomarkers even therapy relevant to the GIST, especially imatinib secondary resistance GIST.

The Potential circRNAs in Imatinib Resistance of GIST

Background: Circular RNAs are a recently (re-)discovered abundant RNA species, belongs to part of the competing endogenous RNA network(ceRNA), Which was proved to play a critical role in the development, diagnosis and progress of diseases. Methods: We analyzed the expression of circular RNAs in paired normal gastric tissues(N), primary GIST (gastrointestinal stromal tumor) tissues (Y or YC) and imatinib mesylate secondary resistance GIST tissues(C) with microarray and predicted 8677 dysregulated circular RNAs. Results: We identified 15 circRNAs was up-regulated and 8 circRNAs were down-regulated in C group. Gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified that the host linear transcripts of these differentially expressed circRNAs were involved in many critical biological pathways and molecular functions, predicting the potential tumor-genesis and drug resistance mechanism was related with HIF-1 pathway, later we draw the cirRNA-miRNA-mRNA network involved in the HIF-1 pathway, found that several dysregulated circRNAs and the relationship between circRNA-miRNAs-mRNA, such as circRNA_06551, circRNA_14668, circRNA_04497, circRNA_08683, circRNA_09923(Green, down-regulation) and circRNA_23636, circRNA_15734(Red, up-regulation). Conclusions: Taken together, we identified a panel of dysregulated circRNAs that may be potential biomarkers even therapy relevant to the GIST, especially imatinib secondary resistance GIST.

Histopathological Characteristics of Gastrointestinal Stromal Tumors in a Cohort of Vietnamese Patients

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal system. Histopathological examination takes an important part in confirming the subtypes of GISTs, to choose appropriate therapeutics for patients. This study aims to explore the histopathological characteristics and evaluate the relationship between malignant risk classification (according to Armed Forces Institute of Pathology criteria) and the histopathological features of GISTs in a cohort of Vietnamese patients. Methods: We reviewed 89 patients with primary GIST who underwent surgery between 2014 and 2019 at Hue Central Hospital, Vietnam. We investigated histopathological characteristics and immunohistochemical findings of all patients. Results: The average age was 55.9 ± 11.9 years. A tumor size of 2-5 cm accounted for 64.1%. The most common position was at the stomach which accounted for 48.5%. Among the subtypes of GIST, spindle cells were seen in 85.9% of patients; epithelial form 10.9%; multi-morphology (3.2%). 97.4% of the samples were positive for CD117, 61.5% of cases were positive for CD34; and no case was positive for Desmin. The rate of high-risk GIST was dominant (46.9%) as compared to the intermediate-risk (28.1%), low-risk (0.3%-2%), and very low-risk groups (4.7%). Conclusions: This study demonstrates the histopathological characteristics of GIST and emphasizes the significant rate of high-risk GIST.

Prognostic significance of preoperative plasma fibrinogen levels in primary gastrointestinal stromal tumours: a retrospective cohort study

Background Improved prediction of prognosis for gastrointestinal stromal tumours (GIST) has become increasingly important since the introduction of small molecule tyrosine kinase inhibitors. Here, we aimed to evaluate the prognostic significance of preoperative plasma fibrinogen (Fib) levels in patients with primary GIST and to analyze their correlations with clinicopathological characteristics.Methods A total of 201 previously untreated patients with primary GIST who had underwent radical surgery at our institution between October 2004 and July 2018 were enrolled. Patient demographics, clinicopathological characteristics, preoperative plasma Fib levels and recurrence-free survival (RFS) were analyzed. The optimal cut-off value for Fib levels was calculated using receiver operating characteristic curve analysis. RFS, the primary endpoint, was calculated by the Kaplan–Meier method and compared by the log-rank test. Univariate and multivariate Cox regression models were calculated.Results Patients in high Fib group had a shorter RFS compared with low Fib group (P < 0.001). In multivariate analysis, high preoperative plasma Fib levels were detected as an independent adverse prognostic factor (P = 0.004, hazard ratio 3.443, 95% confidence interval 1.498‒7.916). Furthermore, high preoperative plasma Fib levels also indicated a poor prognosis within the modified National Institutes of Health (mNIH) high-risk subgroup (P = 0.013). In addition, preoperative plasma Fib levels were showed a positive correlation with several prognostic factors, and even linearly with tumour size (Spearman correlation coefficient [ r ] = 0.411, P < 0.001).Conclusions High preoperative plasma Fib levels may indicate a poor prognosis in patients with primary GIST. As a cost-effective biomarker, preoperative assessment of plasma Fib levels may help to further risk stratification for patients with mNIH high-risk GIST and instruct the application of target therapy.

Neurofibromatosis 1 (NF1) and gastrointestinal stromal tumors (GISTs): Five-year experience from a regional center in United Kingdom.

11035 Background: NF1 is an inherited autosomal dominant condition characterised by multifocal neurofibromas, café au lait spots, Lisch nodules, freckling. GISTs are the most common mesenchymal tumour of the gastrointestinal tract occurring in NF1 patients. We present our 5 year experience of NF1 associated GISTs from a regional centre in United Kingdom. Methods: 15 patients with GISTs associated with NF1 syndrome were identified from the database. Clinical, pathological, molecular and treatment outcomes were analysed. Results: N = 15. Male-3 and female-12. Median age 46 years. 33% were multifocal and 67% unifocal. Primary site Stomach-6.6%, duodenum-33%, small bowel-67%, colon 6.6%. Presenting symptoms: Abdominal pain-47%, anemia/bleed-40% and incidental finding-13%. Tumour size 0.5-23 cm, median 9 cm. Mitotic index 0-15, median 4 mitoses/5mm2. Risk stratification-Low/intermediate risk 60% and high risk 40%. Histology was spindle cell in 87% and mixed in 13%. All GISTs were CD117 and DOG-1 +ve. SDHB expression was preserved in all GISTs. No activation mutations were detected in KIT (exons 9, 11, 13, 17), PDGFRA (exons 12, 14, 18) and BRAF. Treatment: 67% had the primary GIST resected. None had adjuvant imatinib. 6 patients had been treated with tyrosine kinase inhibitors. 1 partial response lasting < 3 months was observed with Imatinib. No durable responses were seen with Imatinib or Sunitinib or Regorafenib. All 5 patients with metastatic disease died within one year of diagnosis. Conclusions: GISTs associated with NF1 syndrome are rare. Median age of diagnosis is a decade earlier than KIT/PDGFRA mutated GISTs. We observed that NF1 associated GISTs occur predominantly in small bowel, are mostly spindle cell histology and have female preponderance. No durable responses were noted with Imatinib or Sunitinib or Regorafenib. There is an urgent need for systematic international collaboration to identify druggable pathways/targets in NF1 GISTs. Any trials should be multicentre/ multinational to expedite recruitment.

Italian survey of second tumors in patients with diagnosis of GIST (gastrointestinal stromal tumor).

11032 Background: GISTs are the most common mesenchymal tumors of the digestive tract. As of recent, new links are being made between GISTS and secondary malignancies. However, whether the coexistence of GISTs with other tumors is stochastic, or the result of related pathogenetic mechanisms is still unknown. Methods: We retrospectively reviewed clinical and molecular features from all GIST patients with second tumors treated in seven Italian GIST reference centers. Qualitative variables were compared using the Fisher exact test. Results: Clinical data of 184 patients with diagnosis of GIST were evaluated. Median age at diagnosis was 66 years, KIT exon 11 resulted the most frequent mutation (73%) while seven patients (3.8%) had a genetic syndrome. The most common primary GIST localizations were stomach (54%) and small intestine (33%). Second tumors arose mostly from gastrointestinal and genitourinary tract. Fourtythree patients had two primary tumors other than GIST and five patients had three other primary malignancies. According to Miettinen criteria, 45% of non-metastatic patients at diagnosis belong to low or very low-risk classes. We highlighted a significant correlation (P=0.002) between risk class and second/third tumor localization, with considerably high percentage of GI second malignancies in low/very low risk GISTs (table). Conclusions: The high frequency of second/third tumors reported in low and very low GIST calls for a careful follow-up also in these patients. Furthermore, this population requires further genetic investigation, NGS analysis is ongoing. [Table: see text]

Successful Perioperative and Surgical Treatment of a Rare Case of Extra-Gastrointestinal Stromal Tumor Arising in the Prostate Gland

We report a very uncommon case of a primary, non-metastatic gastrointestinal stromal tumor (GIST) arising in the prostate gland in a 60-year-old patient. The morphology and immunohistochemical profile of the disease resembled GIST of gastrointestinal origin, and the molecular driver of this malignancy was a double mutation in exons 11 and 13 of the KIT gene. The tumor was proliferating slowly, did respond to neoadjuvant therapy with the KIT-inhibiting agent imatinib and was cured by radical, retro-pubic prostatectomy followed by adjuvant imatinib treatment. We postulate that primary GIST tumors of the prostate can arise from prostatic interstitial cells, which are the pacemakers of smooth muscle contractility in the gland, and possibly share a common precursor with typical GIST and the interstitial cells of Cajal in the gastrointestinal tract.

Extended treatment with adjuvant imatinib (IM) for patients (pts) with high-risk primary gastrointestinal stromal tumor (GIST): The PERSIST-5 study.

11009 Background: Adjuvant IM reduces risk of recurrence and improves survival in pts with high-risk primary GIST. Joensuu et al 2016 demonstrated higher 5-yr overall survival (OS) rates of 91.9% vs 85.3% in pts treated with adjuvant IM for 3 vs 1 yr, respectively. It is unknown if further extension of treatment duration can improve outcome. Methods: PERSIST-5 is a single-arm, phase II trial that enrolled pts ≥18 yrs of age, who underwent macroscopically complete resection of primary KIT (+) GIST with high risk of recurrence within 12 wks prior to IM treatment. High risk was defined as primary GIST (any site) ≥2 cm with a mitotic count ≥ 5/50 HPF or non-gastric primary GIST ≥5 cm. Pts were treated with IM 400 mg/d for 5 yrs or until progression, relapse, or intolerance. Primary endpoint was recurrence-free survival (RFS, defined as time of treatment start to first recurrence or death). Results: IM was administered to 91 pts with a median age of 60 yrs (range 30-90). Median tumor size was 6.5 cm (range 2.3-30 cm; 55% gastric origin). Median treatment duration was 55.7 mos (range, 0.5-75). Forty-six (50.5%) pts completed study treatment. The 5- and 8-yr estimated RFS rates were 90% (95% CI, 80-95) and 81% (95% CI, 62-91), respectively. The 5- and 8 year OS rate was 95% (95% CI, 86-99). There were 7 recurrences; 1 pt recurred and died while on IM ( PDGFRA D842V mutation) and 6 pts recurred after IM discontinuation. Two pts died after IM discontinuation, unrelated to study treatment and without recurrence. Forty-five pts discontinued study treatment; common reasons included patient choice (20%), adverse events (AEs, 17%), protocol deviation (4%), and loss of follow-up (4%). The most common AEs of all grades (regardless of relationship to IM) were nausea (71%), diarrhea (63%), fatigue (50%), muscle spasm (41%), vomiting (39%), and periorbital edema (34%). Conclusions: Five yrs of IM treatment was effective in preventing recurrence in pts with sensitive mutations who underwent resection of primary GIST. Nearly half of the patients discontinued treatment early, and most recurrences occurred after IM discontinuation. Clinical trial information: NCT00867113.