Gastrointestinal Stromal Tumors Patients Research Articles

Impact of surgical resection for gastrointestinal stromal tumor (GIST) patients with initially diagnosed synchronous hepatic metastases on long-term survival outcomes.

The effect of surgical resection on the long-term outcome of GIST patients with initially diagnosed synchronous hepatic metastases in the targeted therapy era is still uncertain. The main aims of this study were to investigate the role of surgery in the treatment of these patients and establish clinical predictive models for assessing prognosis. We identified these patients from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2018. The selection bias in comparisons was minimized by performing propensity score matching (PSM). The risk factors associated with long-term survival outcomes were identified by a Cox proportional hazards model and thus used to establish the nomograms. Nomograms were validated by concordance indexes (C-indexes), time-dependent receiver operator characteristic (ROC) curves, calibration plots, and decision curve analyses (DCA). Of these 523 eligible patients, there were 187 (35.8%) and 336 (64.2%) patients in the surgical and nonsurgical groups, respectively. Multivariate analysis revealed that surgical resection was an independent prognostic factor for OS (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.44-0.88, p=0.0068) and CSS (HR 0.51; 95% CI 0.33 - 0.77, p=0.0016). After PSM, it was found that surgical resection still showed significantly improved OS (5-year 54.9% vs 38.8%, p=0.028) and CSS (5-year 65.8% vs 50.3%, p=0.077). In addition, the C-indexes of the nomograms for OS and CSS prediction were 0.692 and 0.705, respectively, and the nomograms showed good consistency. This study revealed that surgical resection has a favorable impact on the long-term outcome of patients with synchronous GIST liver metastases, and the nomograms showed remarkable prediction performance for OS and CSS.

The association between fasting blood glucose and prognosis in gastrointestinal stromal tumor patients after curable resection.

Blood glucose has been demonstrated to serve as prognostic indicators in various malignancies. This study aimed to explore the relationship between fasting blood glucose (FBG) levels and the prognosis in patients with gastrointestinal stromal tumor (GIST) undergoing complete resection. Data were retrospectively collected from 256 patients with primary GIST underwent complete surgical resection or endoscopic excision. Patients were stratified into euglycemic group and hyperglycemic group. Patients' characteristics between groups were compared. Cox regression model was conducted to identify independent prognostic factors of disease-free survival (DFS). Both univariate analysis and multivariate analyses revealed that FBG ≥ 100mg/dl was associated with poor outcomes. Patients with FBG ≥ 100mg/dl tended to have more adverse features, more likely to suffer recurrence and a worse 5-year DFS than patients with FBG < 100mg/dl. Moreover, FBG levels helped distinguishing between patients with different survival outcomes in different risk categories defined by modified NIH systems. Our data provided the evidence that FBG is a useful prediction marker prognosis in patients with GIST undergoing curative surgery.

Local recurrence in primary localised resected gastrointestinal stromal tumours: A registry observational national cohort study including 912 patients

Background and objectivesPrevious literature showed a high risk of recurrence following surgical treatment in patients with gastrointestinal stromal tumours (GISTs). However, little is known about the patient- and treatment characteristics of local recurrences (LRs) in GIST patients. Therefore, this study aimed to better understand patterns of LR in surgically treated localised GIST and to describe treatment options based on our Dutch GIST Registry (DGR). MethodsData of primary surgically treated localised GIST between January 2009 until July 2021 were retrospectively retrieved from the DGR. ResultsOf 1452 patients registered in the DGR, 912 patients were included in this study. Only 3.8% (35/912) of patients developed LR, including 20 patients with LR only and 15 patients with simultaneous LR and distant metastases (DM). Median time to LR was 30 (interquartile range 8–53) months from date of surgery. Eleven percent (100/912) of patients developed only DM. A total of 2.3% (6/259) of patients treated with adjuvant treatment developed an LR during adjuvant therapy. Seventy percent of patients with LR only (14/20) were treated with surgery (85.7% R0), which was mostly combined with systemic treatment. ConclusionsPatients with primary surgically treated localised GIST have a limited risk of developing recurrence. Fifteen percent developed recurrence, of which one quarter developed an LR. Therefore, less intensified follow-up schedules could be considered, especially during treatment with adjuvant imatinib. In patients with LR only, potentially curative treatment strategies, including surgical (re-)resection, are often possible as treatment for LR.

KIT A502_Y503 duplication mutation serves as a potential and universal target for neoantigen peptide in Chinese GIST patients.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor with high prevalence of KIT and PDGFRA mutations. Few effective treatments can be exploited in imatinib or sunitinib resistant cases. While in immunotherapy, application of the highly individualized cancer neoantigen vaccines is hampered due to high economic and time cost. In this study we identified the most frequent mutation in Chinese GIST patients and predicted candidate neopeptide by next generation sequencing (NGS). Tumor tissues and matched blood samples of 116 Chinese GIST patients were collected. Genomic profile was detected through NGS, and 450 cancer genes were deeply sequenced. KIT mutations were identified, and long peptides containing the mutation were queried in NetMHCpan 4.0 tools to predict MHC class I binding of mutant peptides. The most frequent mutated genes in detected GIST patients were KIT (81.9%, 95/116), CDKN2A (18.97%, 22/116), and CDKN2B (15.52%, 18/116) in this cohort. The most common mutation of KIT was A502_Y503 duplication (15.93%, 18/113) in exon 9. Among the 116 cases, 103 were HLA I genotyped, and 101 were HLA II genotyped. In total, 16 samples with the mutation of KIT p.A502_Y503dup were identified to produce neoantigens with qualified HLA affinity. KIT hotspot mutation (p.A502_Y503dup) has the highest incidence, which may further eliminate the need for whole genome sequencing and patient-specific neoantigen prediction and synthesis. Therefore, for those carrying such mutation, accounting for around 16% of Chinese GIST patients and are usually less sensitive to imatinib, effective immunotherapies are in prospect.

Interruption of imatinib in advanced gastrointestinal stromal tumor after prolonged imatinib maintenance in the absence of gross tumor lesions.

Current guidelines recommend indefinite imatinib treatment for advanced gastrointestinal stromal tumor (GIST) patients. Imatinib-refractory progression-free survival (PFS) and overall survival were previously reported not to differ between GIST patients who interrupted imatinib and those who did not. Clinical outcomes of 77 consecutive patients with recurrent or metastatic GIST who interrupted imatinib treatment after maintaining years of imatinib treatment in the absence of gross tumor lesions were retrospectively analyzed. Associations between clinical factors and progression-free survival (PFS) following imatinib interruption were analyzed. The median time from the absence of gross tumor lesions to imatinib interruption was 61.5months. Since imatinib interruption, the median PFS was 19.6months, and 4 patients (26.3%) remained progression-free for longer than 5years. Among the patients who had progressive disease following the interruption, imatinib re-introduction led to an 88.6% objective response rate and a 100% disease control rate. Complete removal of the initial gross tumor lesion(s) and complete removal of the residual gross tumor lesion(s) by local treatment (vs. no local treatment or residual lesions after local treatment) were independently associated with favorable PFS. Interruption of imatinib following prolonged maintenance in the absence of gross tumor lesions led to disease progression in the majority of cases. However, re-introduction of imatinib resulted in effective tumor control. Unmaintained remission seems to be possible in some patients with metastatic or recurrent GIST after a prolonged remission with imatinib if there is complete removal of any gross tumor lesions.

A case report of successfully treated metachronous gastrointestinal stromal tumor and colon cancer

The diagnosis of gastrointestinal stromal tumor (GIST) has become relatively common in recent years, but little is known about its association with other malignancies. We present a rare case of successfully treated metachronous GIST and colon cancer with concurrent FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) chemotherapy and imatinib. A 63-year-old man presented with abdominal pain that had started 2 weeks ago, and endoscopic ultrasonography showed masses that were compatible with GIST on the duodenum. He underwent Whipple surgery. One year after the GIST diagnosis, two liver masses were found on abdominal computed tomography images taken for surveillance. A liver biopsy showed metastatic adenocarcinoma, not GIST. Colonoscopy was then performed to identify the primary site of the metastatic adenocarcinoma in the liver, and sigmoid colon cancer was found. He received 12 cycles of adjuvant FOLFOX concurrently with adjuvant imatinib. There were no serious adverse events of grade 3 or higher from either imatinib or chemotherapy. He has completed adjuvant imatinib and FOLFOX chemotherapy and there is no evidence of disease recurrence. When a synchronous or metachronous tumor is found in a GIST patient, the clinician should keep in mind the possibility of another primary tumor of different histopathology, as well as GIST recurrence.

Gastrointestinal Stromal Tumor in Patients Presenting to Khyber Teaching Hospital, Peshawar

Objective: To determine the frequency of presentations of gastrointestinal stromal tumor in patients presenting to Khyber Teaching Hospital, Peshawar. Study Design: Descriptive Cross Sectional Place and Duration of study: Department of General Surgery, MTI-KTH Peshawar. From 1st November, 2020 to 30 April, 2021. Methods: All patients were evaluated for their presentations (Abdominal Pain, Abdominal mass, Vomiting, Anemia, Weight loss and Hematemesis as per operational definition. All this data was noted and recorded on especially designed proforma. Results: As per frequencies and percentages for variable presentation, 42 (59.2%) patients had abdominal pain, 38 (53.5%) patients had abdominal mass, 36 (50.7%) patients had vomiting, 31 (43.7%) patients had anemia, 22 (31.0%) patients had weight loss while 11 (15.5%) patients had hematemesis. Conclusion: Our study demonstrated abdominal pain as the most common presentation of gastrointestinal stromal tumor in our local population as local evidence which was followed by abdominal mass and vomiting. Keywords: Abdominal Pain, Gastrointestinal Stromal Tumor, Vomiting

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Recurrent Retroperitoneal and Subhepatic EGIST – Case Report

Background GISTs (gastrointestinal stromal tumors) are a common mesenchymal tumor of the gastrointestinal tract. It is a diverse pathology that can occur in any portion of the gastrointestinal tract, from distal esophagus to anus. However, the stomach is the most common origin. GISTs evolve from small neoformations, to a large, metastasizing sarcoma. Their pathogenesis is linked with the KIT or PDGFRA mutations. GIST is to be suspected in cases where a round mass is encountered in close relations to the stomach, intestine or lower esophagus. It has to be differentiated with other neuroendocrine tumors, lymphomas and other rare cancers by means of a biopsy. Case presentation The 62 y/o male patient was diagnosed 4 years prior to the current events with GIST for which a surgical procedure of distal pancreatectomy, splenectomy and partial resection of curvatura major of the stomach was performed at another hospital. This was followed by chemotherapy as advised by the treating doctors. The patient presents to our clinic with the complaints of left flank pain for over a week, dysphagia and weight loss. CT shows a giant formation of the left flank, at the splenic lodge, with dimensions of 30 × 32 cm, with close proximity to the left kidney, abdominal aorta, the lienal flexure of colon, the stomach, superior mesenteric artery. Besides this, another 8 × 9 cm subhepatic formation is noted, which has a close vicinity to the portal vein and hepatic hilum. He underwent the surgical procedure for the extirpation of the both masses, also partial resection of curvatura major, vagotomy, Heineke-Mikulicz pyloroplasty, segmental hepatic flexure colon resection and end-to-end anastomosis. The procedure was tolerated well and he was discharged in good health. The following pathology report confirms GIST. Discussion Treatment of GISTs and EGISTs consists on the R0 resection of the mass, without the need for radical removal of healthy tissue since these types of tumors do not normally infiltrate adjacent tissue. If other organs are invaded it is recommended to perform an en-bloc resection, taking care to avoid the rupture of the mass, as to minimize the chances of peritoneal dissemination. A prompt adjuvant therapy including the use of selective tyrosine kinase inhibitors (imatinib) is strongly advised. The patient should be followed with periodic controls for recurrence. Conclusion There is a clear role surgery can play in improving the outcomes in such patients. However, some authors still debate whether surgery improves results in such patients. For this purpose, it is necessary to involve a team of oncologists, imaging specialists and experienced surgeons in the treatment plan of GIST patients to provide the best treatment. Keywords: General Surgery, Retroperitoneal EGIST, Hepatic EGIST, GIST. DOI: 10.7176/JEP/14-9-06 Publication date: March 31 st 2023

Cardiovascular-Specific Mortality among Gastrointestinal Stromal Tumor Patients: A Population-Based Analysis.

The overall risk of cardiovascular mortality (CVM) in cancer survivors has increased with time. The trend of CVM in patients with gastrointestinal stromal tumors (GISTs) remains unclear. This study is aimed at assessing the risks and independent predictors of CVM in GIST patients. Data of the GIST patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019). The standardized mortality ratio (SMR) was used to evaluate the risk of CVM, and a multivariate competing risk model was utilized to identify the predictors for CVM. A total of 12,058 patients with GIST were included in this study, of whom 477 (4.0%) patients died of cardiovascular disease (CVD). The SMR for CVM among GIST patients was significantly higher than in the general population (SMR, 3.23, 95% CI: 2.97-3.52), and all categories of CVD were associated with a significantly elevated SMR. The cumulative mortality of CVD was the lowest among all causes of death, while the CVM was the second most common cause of death in patients ≥ 80 years when stratified by age at diagnosis. Furthermore, male sex, older age at diagnosis, White race, unmarried, earlier year of diagnosis, and not receiving chemotherapy were the poor prognostic factors for CVM. The CVM risk in GIST patients was significantly higher relative to the general US population. Timely screening and cardioprotective interventions should be implemented to prevent the occurrence of CVM in patients with GIST.

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients.

Effect of tumor location on the efficacy of chemotherapy for gastrointestinal stromal tumors.

790 Background: Gastrointestinal stromal tumors (GISTs) arise from multiple sites within the gastrointestinal tract. Since the introduction of imatinib in 2002, patients have seen improved overall survival. However, a recent National Cancer Database (NCDB) study suggested no survival benefit to adjuvant imatinib for colorectal GIST patients. Another recent study showed that small bowel GISTs have larger median tumor size and higher incidence of tumors with at least 5 mitoses compared to gastric GISTs. These findings suggest a differential tumor biology for GISTs arising from different primary tumor sites, potentially conferring differential response to imatinib. In this NCDB study, we compare overall survival outcomes with and without chemotherapy, stratifying by primary tumor site. Methods: We queried the NCDB from 2004-2018 for patients with GIST histology. We excluded patients with age &lt;40, age&gt;80, high comorbidity score, and patients who received additional therapy other than surgery or chemotherapy. Of the 22,846 patients meeting criteria for our study, 27 patients had tumors originating from the anus, 454 from the colon, 173 from the esophagus, 15,296 from the stomach, 556 from the rectum, 32 from the rectosigmoid junction, and 6,308 from the small intestine. 8,983 (39%) received chemotherapy. Treatment with chemotherapy was used to extrapolate response to imatinib, the mainstay of treatment. Results: Cox proportional hazards analysis demonstrated increased hazard of death for chemotherapy, increasing age, and comorbidity score of 1. Positive predictive factors for survival included female sex and later year of diagnosis. For anal, esophageal, gastric, and rectosigmoid GIST patients, there was no statistically significant overall survival benefit for any treatment modality. For colonic GISTs, neoadjuvant chemotherapy combined with surgery improved overall survival. For rectal GISTs, adjuvant chemotherapy with surgery also provided survival benefit. For small intestinal GISTs, surgery alone or surgery with neoadjuvant, adjuvant, or both neoadjuvant and adjuvant chemotherapy improved overall survival. Conclusions: While our study is retrospective and limited as a NCDB study, our Kaplan-Meier survival analysis demonstrated survival benefit for chemotherapy only in patients with colon, rectal, or small intestinal GIST tumors. Our Cox proportional analysis demonstrated an overall negative survival impact for chemotherapy. These findings lend further support to the idea that differential tumor biology at each primary site may lead to differential response to imatinib. Overall, our study provides rationale for further investigating the heterogeneity of GIST tumor microenvironments, as these differences could contribute to the differential treatment outcomes.

The patient's perspective on side effects of tyrosine kinase inhibitors in the treatment of advanced and metastatic gastrointestinal stromal tumors.

Aim: To provide the gastrointestinal stromal tumor patient's perspective on side effects of tyrosine kinase inhibitors and compare this with that of healthcare professionals. Materials & methods: Semi-structured interviews were conducted with 19 patients with an advanced or metastatic gastrointestinal stromal tumor, as well as six healthcare professionals, and five patientsparticipated in a focus group. Thematic analysis was used to interpret the data. Results: Most participants (n=29) reported gastrointestinal symptoms followed by tiredness (n=25), edema (n=22), muscle cramps (n=21), skin problems (n=21), eye problems (n=11) and trouble sleeping (n=10). Patients, but not healthcare professionals, reported cognitive problems or symptoms of depression. Conclusion: These results underline the importance of including the patient's perspective, as there is a gap in symptom reporting between patients and healthcare professionals.

Prognostic significance of serum CA125 in the overall management for patients with gastrointestinal stromal tumors

BackgroundCarbohydrate antigen 125 (CA125) is elevated as a tumor marker in many carcinomas, but its association with gastrointestinal stromal tumor (GIST) has received less attention. This study intends to evaluate whether CA125 level can predict tumor progression and overall survival (OS) of GIST patients.MethodsWe retrospectively analyzed the clinical data and follow-up records of GIST patients who underwent surgical resection in Nanjing Drum Tower Hospital from August 2010 to December 2020. All patients were classified according to serum CA125 level. The relationship between CA125 and clinical outcomes was then examined.ResultsA total of 406 GIST patients were enrolled in this study, among which 46 patients had preoperative elevated serum CA125 level and 13 patients with high CA125 level both preoperative and postoperative were observed. Preoperative CA125 concentration was significantly related to rupture status, resection style, tumor site, tumor size, mitotic index, NIH risk grade and c-kit exons. According to Kaplan–Meier curve analysis, high expression of postoperative CA125 was significantly correlated with worse progression-free survival (PFS) and OS among patients with preoperative elevated CA125 level. Ultimately, Cox proportional regression model analysis revealed that increase of preoperative and concurrent postoperative CA125 concentration was an independent predictive factor for PFS.ConclusionsThe concurrent abnormality of serum CA125 before and after operation was an independent risk factor for GIST progression, suggesting its significance as a serum biomarker in the overall management of GIST patients.

Clinical characteristics and outcomes of gastrointestinal stromal tumor patients receiving surgery with or without TKI therapy: a retrospective real-world study

PurposeTo retrospectively analyze the clinical characteristics of patients undergoing surgical treatment for gastrointestinal stromal tumors (GISTs) in Ruijin Hospital and explore the relevant prognosis clinical factors after surgical treatment.MethodsWe screened out 1015 patients with GISTs diagnosed and treated during January 2010 to December 2019. We performed univariate analysis by the log-rank test and multivariate analysis by COX regression. The Kaplan–Meier method was used to estimate the disease-free survival (DFS) and overall survival (OS) of the whole group.ResultsAll 1015 patients in the whole group received radical surgery, and the proportion of patients with high, intermediate, and low risk was 31.1%, 21.7%, and 47.3%, respectively. Among the 480 low-risk patients, surgery could achieve radical therapy; only the Ki-67 index was related to DFS and OS (DFS: p = 0.032, OS: p = 0.009) among the 140 intermediate-risk patients with tumors located in the stomach, whether received Tyrosine kinase inhibitors (TKIs) therapy did not affect the prognosis of patients (DFS: p = 0.716, OS: p = 0.848). Among the 331 high-risk patients, those with non-gastric tumors (those outside the stomach, duodenum, and small intestine, HR 1.55, 95% CI 1.19–2.00, p < 0.001), tumor diameter > 10 cm (hazard ratio, HR 2.63, 95% confidence interval, CI 2.09–4.03, p < 0.001), as well as high-risk patients with mitotic rate > 10/50 HPF (HR 2.74, 95% CI 2.00–3.76, p < 0.001), the overall prognosis was obviously worse than that of other patients. For some high-risk patients, prolonged postoperative imatinib therapy could significantly improve the survival of patients (HR 0.43, 95% CI 0.15–0.66, p < 0.001).ConclusionsFor the vast majority of GIST patients, surgery can be curative; but in intermediate-risk patients, the Ki-67 index and postoperative TKI treatment are closely related to prognosis. For intermediate-risk patients whose primary tumor is the stomach, the value of TKI-targeted therapy after surgery seem be not necessary in our study. However, for some high-risk patients, the prognosis of patients can be improved by appropriately prolonging the treatment time of TKI.

Insights into the medical management of gastrointestinal stromal tumours: lessons learnt from a dedicated gastrointestinal stromal tumour clinic in North India.

The advent of molecular driver alterations has brought in a revolutionary transformation in the treatment landscape of gastrointestinal stromal tumour (GIST). However, there is a paucity of data regarding mutational testing prevalence and associated outcomes from India. It was a retrospective study. We reviewed the case records of all patients diagnosed with GIST in a tertiary care centre from 2015 to 2021. The clinicopathological, mutational analysis and treatment plans were recorded. The study cohort was characterised by descriptive statistics. Our study included 120 patients with a median age of 53 years (range: 28-77), with a male preponderance of 2:1. The most common site of the primary was the stomach (50%), followed by the small intestine (37%), with 55.8% of the patients having disseminated disease at presentation with a predominance of liver metastasis (67%). The prevalence of mutational analysis among patients prior to referral was 4%. 60.8% of the patients at our clinic had mutational analysis performed, and unavailability of analysis in the rest was due to financial constraints (12.5%), exhaustion of tissue (7.5%), reluctance to repeat biopsy (4.1%) and low-risk patients. We report c-kit in the majority (52%), platelet-derived growth factor receptor (PDGFR) in 19.2% and wild type in 16.4% along with the rarer subtypes: succinate dehydrogenase (SDH)-deficient GIST in 10.9% and Neurotrophic tyrosine receptor kinase (NTRK) fusion in 1.3%. Four of the eight SDH-deficient GIST patients had germline mutations (50%). The knowledge of driver mutations led to a change of treatment in 39.7% (29/73), i.e. stoppage of tyrosine kinase inhibitor (TKI) in 3, switch of TKI in 23, increase in TKI dose in 2 and upfront surgery in 1. The most common change was the use of sunitinib and regorafenib in patients with SDH-deficient GIST. Our study is one of the largest comprehensive series describing the clinical and mutational profile of GIST from India. The mutation testing rates at primary care centres continue to be low. Despite the hurdles, a large percentage of our patients underwent molecular testing, aiding in therapeutic decision-making.

Sunitinib therapy for imatinib-resistant and/or intolerant gastrointestinal stromal tumors: comparison of safety and efficacy between standard and reduced dosage regimens.

Sunitinib therapy for patients with imatinib-resistant and/or intolerant gastrointestinal stromal tumors (GISTs) often causes severe adverse events (AEs) that lead to treatment discontinuation. We retrospectively reviewed the clinical records of imatinib-resistant and/or intolerant GIST patients who underwent sunitinib therapy in our institutions between 2007 and 2020. Forty-one patients were enrolled and divided into two groups on the basis of the starting dosage: the standard dosage group (50mg/day, 21 patients) and the reduced dosage group (37.5mg/day, 20 patients). Tolerability, safety and clinical efficacy of the two groups were compared. Three patients (14%) in the standard dosage group and another three (15%) in the reduced dosage group (P=1.000) discontinued sunitinib therapy because of AEs. The incidences of grade 3 or more severe treatment-related AEs were 90 and 75%, respectively (P=0.238). Two possible treatment-related deaths were noted in the standard dosage group. Clinical efficacy was comparable between the two groups: median time to treatment failure and overall survival were 4.5months [interquartile range (IQR), 3.6-9.0] and 13.7months (IQR, 7.5-22.9) in the standard dosage group and 4.6months (IQR, 2.7-17.0) and 13.4months (IQR, 9.3-36.8) in the reduced dosage group, respectively. The reduced dosage of 37.5mg sunitinib tended to decrease toxicity and the incidences of severe AEs and treatment-related deaths. This reduced dosage regimen showed equivalent clinical efficacy including patient survival. The reduced dosage of 37.5mg sunitinib can be adopted as an alternative therapy for patients with imatinib-resistant and/or intolerant GISTs.

Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations

Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those with syndromic features. To assess whether expanded genetic testing of GIST patients could identify hereditary cancer predisposition, we analyzed matched tumor-germline sequencing results from 103 patients with GISTs over a 6-year period. Germline pathogenic/likely pathogenic (P/LP) variants in GIST-associated genes (SDHA, SDHB, SDHC, NF1, KIT) were identified in 69% of patients with KIT/PDGFRA-wildtype GISTs, 63% of whom did not have any personal or family history of syndromic features. To evaluate the frequency of somatic versus germline variants identified in tumor-only sequencing of GISTs, we analyzed 499 de-identified tumor-normal pairs. P/LP variants in certain genes (e.g., BRCA1/2, SDHB) identified in tumor-only sequencing of GISTs were almost exclusively germline in origin. Our results provide guidance for genetic testing of GIST patients and indicate that germline testing should be offered to all patients with KIT/PDGFRA-wildtype GISTs regardless of their history of syndromic features.

Simple Scoring Model Based on Enhanced CT in Preoperative Prediction of Biological Risk of Gastrointestinal Stromal Tumor.

Objective: To construct a simple scoring model for predicting the biological risk of gastrointestinal stromal tumors based on enhanced computed tomography (CT) features. Methods: The clinicopathological and imaging data of 149 patients with primary gastrointestinal stromal tumor were retrospectively analyzed in our hospital. According to the risk classification, the patients were divided into low-risk group and high-risk group. The features of enhanced CT were observed and recorded. Univariate and multivariate logistic regression models were used to determine the predictors of high-risk biological behaviors of gastrointestinal stromal tumor, and then a simple scoring model was constructed according to the regression coefficients of each predictor. The receiver operating characteristic curve was used to evaluate the predictive ability of the model. Results: There was no significant difference between the risk classification of gastrointestinal stromal tumor with gender and age (P = .168, .320), while significant difference was found between the tumor size and location (P < .001). Univariate and multivariate logistic regression analyses showed that tumor size, enlarged vessels feeding or draining the mass, peritumoral lymph node enlargement, and venous phase contrast enhancement rate were independent predictors of the biological risk of gastrointestinal stromal tumor (P < .05). The area under the curve value of tumor size, enlarged vessels feeding or draining the mass, peritumoral lymph node enlargement, and venous phase contrast enhancement rate as the high-risk predictor of gastrointestinal stromal tumor were 0.955, 0.729, 0.680, and 0.807, respectively. Receiver operating characteristic curve results showed that the area under the curve of the scoring model constructed based on enhanced CT features was 0.941 (95% confidence interval: 0.891-0.973). When the total score was >1, the sensitivity of the scoring model in diagnosing gastrointestinal stromal tumor was 85.58%, the specificity was 88.89%, the positive predictive value was 88.51%, the negative predictive value was 86.04%, and the accuracy was 86.18%. The results of DeLong test showed that the area under the curve of the scoring model was better than that of the receiver operating characteristic curve of tumor size, enlarged vessels feeding or draining the mass, peritumoral lymph node enlargement, venous phase contrast enhancement rate, and other indicators alone in predicting the high risk of gastrointestinal stromal tumor, and the differences were statistically significant (Z = 26.510, P < .001; Z = 3.992, P < .001; Z = 6.353, P < .001; Z = 4.052, P = .013). Conclusion: The simple scoring model based on enhanced CT features is a simple and practical clinical prediction model, which is helpful to make preoperative individualized treatment plan and improve the prognosis of gastrointestinal stromal tumor patients.

Prevalence of CKIT and PDGFRA Mutation in Gastrointestinal Stromal Tumors among Filipinos

Background: Gastrointestinal stromal tumors (GIST) is defined as specific, typically kit (CD117)-positive and CKIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation-driven mesenchymal tumors that can occur anywhere in the GI tract. GIST diagnosis relies heavily on immunohistomorphology. However, with the advent of molecular testing, the classification, diagnosis and targeted-therapy for gastrointestinal mesenchymal tumors have been greatly improved. In the Philippines, molecular testing is not yet readily available as in other countries. The local molecular profile of gastrointestinal stromal tumors is a point of investigation as treatment may be more tailored to the patients’ needs. Objective: This study aims to determine the prevalence of CKIT and PDGFRA mutations among formalin-fixed and paraffin embedded gastrointestinal stromal tumors and other gastrointestinal mesenchymal tumors in St. Luke’s Medical Center – Quezon City. Methods: A retrospective cross-sectional study of formalin fixed and paraffin embedded tumor samples diagnosed as Gastrointestinal Stromal Tumor from January 1, 2009 to December 31, 2017 will be analyzed for KIT and PDGFRA mutations. Result: The epidemiology of GIST remains constant in that mean age group is the 5th to 6th decade, with equal gender distribution, and stomach followed by small bowel are the most common sites. Mutational analysis of the GISTs showed predominantly KIT Exon 11 (47.83%) followed by CKIT Exon 9 (13.04%) and PDGFRA Exon 18 (10.87%). For KIT Exon 11, deletion is the most common mutations followed by point mutations. No mutation is detected in 47.83% of GISTs. Conclusion:&nbsp;Mutational analysis for CKIT-PDGFRA is warranted among GIST patients, as it may significantly influence treatment protocol in our patients.