Adult Gastrointestinal Stromal Tumors Research Articles

Molecular features of gastrointestinal stromal tumors “wild-type” (<i>KIT/PDGFRA</i> WT)

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Their main features are the expression of CD117 (KIT) and mutations of KIT or PDGFRA in 85 % of patients. however, 10–15 % of adult GIST and 85 % of pediatric GIST do not have KIT/PDGFRA mutations (KIT/PDGFRA WT GIST or “wild-type” GIST). The prognosis and clinical course of these tumors and GIST with KIT/PDGFRA mutations differ. “Wild-type” GIST are quite heterogeneous group of tumors in terms of clinical phenotype, genetic etiology, and molecular pathways. Gastrointestinal stromal tumors are divided into SDH-deficient and SDH-competent based on the succinate dehydrogenase (SDH) complex. SDH-deficient GIST occur predominantly in children and young patients with Carney–Stratakis syndrome and Carney triad; there are also sporadic tumors. More than half of SDH-deficient GIST contain mutations in SDHA, SDHB, SDHD or SDHC, while the rest are caused by hypermethylation of the SDHC promoter. SDH-competent “wild-type” GIST include tumors with BRAF, RAS, or NF1 mutations that activate the RAS-RAF-MAPK pathway and KIT/PDGFRA/SDH/RAS-P WT GIST subtype or “quadruple wild type” GIST. The genomic profiles of these tumors and GIST with KIT/PDGFRA mutation or SDH deficiency differ significantly. One of the features of “quadruple wild type” GIST is activation of the FGFR (fibroblast growth factor receptors) signaling pathway due to chimeric FGFR, FGFR mutations, or overexpression of FGF (fibroblast growth factor). Another feature is chimeric genes containing fragments of NTRK, BRAF, FGFR and other genes that behave as oncogene drivers. In “quadruple wild-type” GIST the somatic mutations in TP53, MAX, MEN1, CTNND2, CHD4, ARIDIA and other genes were revealed as well as in the cell cycle genes RB1, CDK4, CDKN1B. There is no specific treatment for patients with “wild-type” GIST; the choice of drug is determined by the genetic disorder. There is a need to improve our understanding of the molecular mechanisms underlying the different GIST subtypes to develop more effective therapeutic approaches.

SUCCINATE DEHYDROGENASE SUBUNIT B DEFICIENT PEDIATRIC GIST

Case report Gastrointestinal stromal tumors (GISTs) occur exceedingly rare in children and adolescents. Eighty five percent of pediatric GISTs and 15 % of adult GISTs lack oncogenic mutations in KIT and PDGFRA. The results of tyrosine kinase inhibitor therapy in GIST cases with SDH deficiency are limited and controversial. Here, we would like to present a pediatric SDH deficient GIST case treated with surgery and Imatinib Mesylate. We obtained a good response with Imatinib Mesylate.

Distress in soft-tissue sarcoma and gastrointestinal stromal tumours patients-Results of a German multicentre observational study (PROSa).

Soft tissue sarcomas (STS) and gastrointestinal stromal tumours (GIST) are a group of rare malignant tumours with a high and heterogenous disease burden. As evidence is scarce, we analysed the prevalence of increased emotional distress and identified distress-associated factors in these patients. The PROSa-study (Burden and medical care of sarcoma) was conducted between 2017 and 2020 in 39 study centres. Cross-sectional data from adult STS and GIST patients were analysed. Distress was measured with the Patient Health Questionnaire (PHQ-4). The relation of socioeconomic and clinical factors with distress was explored in adjusted logistic regression models. Among 897 patients, 17% reported elevated anxiety and 19% reported depression. Unemployed patients (odds ratio [OR] 6.6; 95% CI 2.9-15.0), and those with a disability pension (OR 3.1; 95% CI 1.9-5.0) were more likely to experience distress compared to employed patients. Also, patients with a disability pass had higher odds of increased distress than those without (OR 1.8; 95% CI 1.2-2.7). Lowest distress was observed in patients 2 to <5years and ≥5years after diagnosis (comparison: <6months) (OR 0.4; 95% CI 0.2-0.6) and (0.3; 95% CI 0.2-0.6). Patients with thoracic STS (vs. lower limbs) had twice the odds to experience distress (OR 2.0; 95% CI 1.1-3.6). Distress was seen almost twice as often in patients with progressive disease (vs. complete remission) (OR 1.7; 95% CI 1.1-2.8). The prevalence of elevated distress in STS and GIST patients is high. In unemployed patients, in those with a disability pension and in newly diagnosed patients a noticeable increase was observed. Clinicians should be aware of these factors and consider the social aspects of the disease.

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients.

Simple SummaryGastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs mainly develop in older adults, and the median age of diagnosis is 60–65 years. The incidence of GISTs in young adult patients, defined as adults before 40, is less than 10%. The frequency and type of molecular abnormalities in this group of patients are different from those in older patients. In this publication, we focus on the specificity of GISTs in young people and the principles of therapeutic management and management of the side effects of treatment.Gastrointestinal stromal tumors (GISTs) originate from Cajal’s cells and are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs in young adults, i.e., patients before the age of 40, are rare and differ from those in older patients and GISTs in children in terms of the molecular and clinical features, including the location and type of mutations. They often harbor other molecular abnormalities than KIT and PDGFRA mutations (wild-type GISTs). The general principles of therapeutic management in young patients are the same as in the elderly. Considering some differences in molecular abnormalities, molecular testing should be the standard procedure to allow appropriate systemic therapy if needed. The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration.

Quality of life of GIST patients with and without current tyrosine kinase inhibitor treatment: Cross-sectional results of a German multicentre observational study (PROSa).

We investigated the health-related quality of life (HRQoL) of patients with gastrointestinal stromal tumours (GIST). In the multicentre PROSa study, the HRQoL of adult GIST patients was assessed between 2017 and 2019 using the European Organisation for Research and Treatment of Cancer HRQoL questionnaire (EORTC QLQ-C30). We performed group comparisons and multivariate linear regressions. Among 130 patients from 13 centres, the mean global HRQoL was 63.3 out of 100 points. Higher sores indicate better HRQoL. The highest restrictions were in emotional, social, role functioning, insomnia, fatigue, and pain. In multivariate linear regression, we found no significant differences between patients receiving tyrosine kinase inhibitor (TKI) treatment and those without TKI treatment as well as between patients treated with curative or with palliative intent. Patients who received multiple lines of TKI treatment had the most restrictions, notably in physical (unstandardized regression coefficient [B] = -15.7), role (B = -25.7), social (B = -18.4), and cognitive functioning (B = -19.7); fatigue (B = 15.93); general health (B = -14.23); and EORTC-sum score (B = -13.82) compared to all other patients. The highest HRQoL restrictions were in GIST patients receiving multiple lines of TKI therapy. Underlying causes need further investigation.

Germline mutations in MSH2 and ATM gene in patients with GIST (gastrointestinal stromal tumor) and second epitelial tumors.

e23520 Background: In adult GISTs are frequently sporadic, while rarely GISTs are linked to Carney Triad and Carney-Stratakis Syndrome and NF1. GISTs with second primary tumors are reported in 4-33% of patients in literature and genetic counseling is suggested to explore an underlying germline mutations pathway. Methods: In our Academic Hospital Centre (EURACAN member) in Florence, Italy, we are following patients with GIST and multiple primary tumors with genetic counseling (72 GISTs with second tumors/185 patients with GIST) and germline analysis of the following genetic panel is performed as clinically indicated: BRCA1, BRCA2, MUTYH, MLH1, MSH2, MSH6, CDH1, ATM, TP53, PTEN, CHECK2, PALB2, BARD1, BRIP1, BLM, RAD51C, RAD51D, XRCC2, PMS2, MRE11A, RAD50, NBN, FAM175A, EPKAM, TSK1, MEN1 by sequencing analysis with Illumina MiSeq by kit multiplicom BRCA Hereditary cancer Mastr plus, and bioinformatic analysis by software SOPHIADDM (Sophia genetics) for point genetic alterations of BRCA1 NM_007294.3, BRCA2 NM_000059.3, MUTYH NM_000249, MSH2 NM_000251, MSH6 NM_000179, CDH1 NM_00444360, ATM NM_000051, TP53 NM_000546, PTEN NM_000314, CHEK2 NM_001005735, PALB2 NM_024675, BARD1 NM_000465, BRIP1 NM_032043, BLM NM_000057, RAD51C NM_002876, RAD51D NM_001142571, XRCC2 NM_005431, PMS2 NM_000535, MRE11A NM_005590, RAD50 NM_006732, NBN NM_002485, FAM175A NM_139076, EPCAM NM_002354, STK1 NM_000455, MEN1 NM_000244 and MLPA (Multiplex Ligation-dependent Probe Amplification) test analysis for patients with kit P087-BRCA1,P045-BRCA2(CHEK2, P248-MLH1-MSH2, P003-MLH1/MSH2, P072-MSH6-MUTYH (MRC-Holland). Results: In 3 patients germline mutations have been observed: 1 patient showed the c.1192dupG, p.(Ala398Glyfs*19) pathogenic mutation in exon 7 of MSH2 gene, confirmed by Sanger Sequencing, 1 patient showed c.565-?_1130+?del mutation consisting in heterozygous 3-4-5-6 exons deletion of MSH2 gene, confirmed by MLPA analysis, and in 1 patient the following ATM alteration has been identified in heterozygosis: ATM c.5319+2T &gt; C, p.(?). In the 2 patients with Lynch syndrome with colon adenocarcinoma (MSI-H), synchronous GISTs (1 patient quadruple WT and 1 patient kit ex 11 mutated ) were diagnosed; in the patient with ATM mutation, the diagnosis of GIST (kit ex 11 mutated) occurred after prostate adenocarcinoma and before colon adenocarcinoma (MSI-H). Conclusions: Our analysis suggests that GIST diagnosis could be tumor-related to multiple hereditary tumor syndromes as Lynch Syndrome and Ataxia-Teleangectasia syndrome, the latter being linked in eterozygosis to tumor susceptibility to breast in female. This report represents a high value in terms of genetic counseling for relatives and in terms of therapeutic implications for the patients.

Update on Molecular Genetics of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10–15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called “wt-GISTs”. Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.

Ripretinib for the treatment of advanced gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by activating mutations of the KIT and/or PDGFRA genes. Prior to the development of tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis because conventional cytotoxic chemotherapy was relatively ineffective. However, TKIs that inhibit the most common driver mutations in KIT or PDGFRA have revolutionized the treatment of GISTs over the past two decades. Notwithstanding, ongoing management challenges relate to the development of secondary mutations in these genes, resulting in tumor progression. Due to both the intra- and inter-patient heterogeneity of these secondary mutations in GISTs, optimal treatment requires an agent that blocks as many mutant genes as possible. Ripretinib – a novel switch-control TKI – inhibits many of the most common primary and secondary activating KIT and PDGFRA mutants involved in GIST progression through a dual mechanism of action. In the pivotal INVICTUS phase III trial, patients with advanced GIST that had progressed on at least imatinib, sunitinib, and regorafenib and who received ripretinib experienced significantly longer progression-free survival (primary endpoint) as well as prolongation of overall survival, compared with those receiving placebo. Treatment with ripretinib was associated with durable improvements in quality-of-life indices and a manageable toxicity profile. The most frequent side effects were common to the class of TKIs used in the management of GIST. These results led to the approval of ripretinib for treatment of advanced GIST in adults who have received three or more TKIs, including imatinib. Ripretinib is also under investigation in the second-line treatment of advanced GIST in a phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with advanced GIST after treatment with imatinib.Plain language summary Use of ripretinib for the treatment of gastrointestinal stromal tumors (GISTs) Gastrointestinal stromal tumors (GISTs) are a rare type of tumor most commonly located in the stomach and small intestine but can develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs vary in extent depending on location of the primary tumor and include a feeling of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs carry initial mutations in genes that control specific enzymes called tyrosine kinases. Historically, treatment of GISTs was limited because traditional chemotherapy is ineffective against these tumors. However, with the introduction of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors (TKIs)], survival has been extended substantially. However, many GISTs go on to develop secondary mutations that render them resistant to a given TKI. Prior to the approval of ripretinib, four TKIs were available for the treatment of GIST: imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used until resistance develops or patients are unable to tolerate the side effects of treatment, after which the next drug is started. Ripretinib was recently approved by the FDA as the fourth drug in the usual treatment sequence recommended for patients with advanced GIST who have progressed (or are treatment intolerant) after receiving three or more TKIs, including imatinib. Approval of ripretinib was based on the results of the INVICTUS trial, which demonstrated that the drug significantly improves the time patients have without progression of the disease or death compared with placebo. The most common side effects related to ripretinib were hair loss, muscle pain, nausea, fatigue, hand-foot syndrome, and diarrhea, although most events were not very severe. Ripretinib is being further studied as the second TKI used in patients with GIST who have progressed on or could not tolerate first-line treatment with imatinib.

163P Gastrointestinal stromal tumours (GIST) in adolescents and young adults (AYA) in an Asian institution from 2002 to 2018

GIST is not common in AYA patients and the data on AYA GISTs are limited. In our institution, the typical adult GIST patient is male (52.9%), with mutations in KIT (53.6%) or PDGFR (4.2%), has gastric as the primary location (54.4%), and a five-year overall survival (OS) of 51%. We studied the clinical and genetic characteristics and prognoses of AYA GISTs. All GIST patients diagnosed between the ages of 16-39 at National Cancer Centre Singapore from 1 January 2002 to 31 December 2018 were included. We retrospectively studied their clinico-molecular characteristics and outcomes. 41 AYA GIST patients were seen with a median age of 34 years old. 25 patients (61.0%) were male. 27 patients (65.9%) were Chinese. 9 (22.0%) had metastatic disease at diagnosis. The tumours were primarily in the jejunum/ileum (41.5%, n=17) or stomach (34.1%, n=14). 25 patients (61.0%) had tumor mutation testing performed. Of these, 19 (76%) had KIT and one (4%) had PDFGRA. 5 (20%) were KIT/PDGFR wildtype. Of those with KIT mutations, 17 (89.5%) were in exon 11, while 2 (10.5%) were in exon 9. The PDGFRA mutation was in exon 18. No data is available on genetic syndromes. 24 patients (58.4%) received curative-intent treatment with 3 (12.5%) subsequently had local recurrences. 14 (58.3%) received imatinib in a neoadjuvant/adjuvant setting. 17 patients (41.5%) received palliative-intent treatment with 13 (76.4%) receiving palliative imatinib. 9 (52.9%) had Sunitinib after progression. The median follow-up was 48 months (0-165). 6 patients (14.6%) had demised. Median OS for all patients was 162.0 months (95% CI: 80.8– 243.2) with no significant differences with regards to age (p=0.07), gender (p=0.91), presence of a sensitising mutation (KIT Exon 9 and 11) (p=0.26), and treatment intent (p=0.2). A significant OS difference was found between patients undergoing curative or palliative intent (162.0 vs 65.0 months, p=0.001) and in patients with different primary tumor location (p=0.029). Out of the 6 patients with uncommon primary tumor locations, 3 had demised. AYA GISTs differ from adult GIST. In our series, 61.0% had tumor mutation analysis performed. AYA GIST also has a higher rate of small intestine primary. Further studies are needed to evaluate the low mutation and genetic testing and clinico-molecular differences to better understand how these affect outcomes.

LENVAGIST - A multicenter, comparative, placebo-controlled, double-blinded, phase II study of the efficacy of lenvatinib in patients with locally advanced or metastatic GIST after failure of imatinib and sunitinib.

TPS11568 Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2nd and 3rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or &gt; 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .

Pediatric gastrointestinal stromal tumor: Report of two novel patients harboring germline variants in SDHB and SDHC genes

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and rarely occur in pediatric patients. 85% of pediatric GISTs and 15% of adult GISTs lack of KIT or PDGFRA mutations. 40% of these “wild-type” GISTs present loss of function mutations in genes encoding for the subunits of the succinate dehydrogenase (SDH) complex. Germline mutations in SDH complex genes have been described in patients with the Carney–Stratakis syndrome (CSS), a rare inherited condition that predisposes to GIST and paraganglioma. We report two pediatric patients with multifocal GIST, harboring respectively a novel and a previously reported loss-of-function germline variant, in SDHC and SDHB genes.

Abstract 1686: Comprehensive genomic and transcriptomic profiling of gastrointestinal stromal tumors

Abstract Most adult gastrointestinal stromal tumors (GIST) are driven by activating KIT or PDGFRA mutations. The remaining 10-15% of cases, often referred to as wildtype (WT) GIST, display either alterations of the succinate dehydrogenase complex (SDH) or RAS pathway mutations. To gain additional insight into the biology of GIST, we performed whole-exome or genome and RNA sequencing in 38 GIST patients (WT, n=15; KIT-mutant, n=21; PDGFRA-mutant, n=2) enrolled in a prospective molecular stratification trial of NCT Heidelberg/Dresden and the German Cancer Consortium (DKTK) designed for younger adults with advanced-stage cancer across histologies and patients with rare tumors (NCT/DKTK MASTER). Of the 15 patients with WT GIST, 3 had pathogenic germline mutations in NF1 and 9 harbored SDH alterations (germline, n=5; somatic, n=4). In the 3 patients with quadruple-negative GIST - defined by the absence of KIT, PDGFRA, SDH, or RAS pathway alterations - we detected novel gene fusions affecting RET, FGFR2, and FGF4, respectively. To delineate biologically relevant subgroups of GIST based on RNA sequencing data from the entire cohort (n=34), we used 3 different clustering methods and 4 different measures of stability and consistency. Despite the underlying clinical and molecular heterogeneity, we identified 3 distinct transcriptional subgroups that were characterized by (i) SDH deficiency, (ii) recurrent somatic RB1 alterations and mutational signatures associated with defective homologous recombination DNA repair, and (iii) elevated PDGFRA expression, respectively. Furthermore, we used random forest analysis to identifiy genes that are significantly (p&amp;lt;0.005) differentially expressed between the 3 subgroups. Interestingly, quadruple-negative cases did not form a separate cluster or clustered within a specific subgroup. Collectively, our data illustrate the molecular heterogeneity of advanced-stage GIST and support comprehensive molecular profiling approaches to capture the entire spectrum of clinically actionable genetic alterations, such as diverse fusion genes affecting kinase signaling pathways in quadruple-negative cases or pathogenic germline mutations in patients with inconspicuous family histories. The finding of two separate transcriptional clusters among patients with SDH-proficient GIST may be reflective of distinct regulatory pathways whose molecular underpinnings and clinical actionability warrant further study. Citation Format: Peter Horak, Matea Hajnic, Laura Gieldon, Mario Hlevnjak, Susan Richter, Barbara Hutter, Johanna Falkenhorst, Sebastian Uhrig, Gregor Warsow, Nagarajan Paramasivam, Stefan Gröschel, Barbara Klink, Simon Kreutzfeldt, Christoph Heining, Christoph E. Heilig, Martina Fröhlich, Stephan Richter, Christian Brandts, Wilko Weichert, Philipp Jost, Olaf Neumann, Marc Zapatka, Albrecht Stenzinger, Alexander Marx, Benedikt Brors, Evelin Schröck, Sebastian Bauer, Peter Hohenberger, Hanno Glimm, Claudia Scholl, Stefan Fröhling. Comprehensive genomic and transcriptomic profiling of gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1686.

Cognitive impairment and treatment effects among gastrointenstinal stromal tumor survivors: Results of a large online survey.

e23092 Background: Cancer-related cognitive impairment (CRCI) is chronic and negatively affects quality of life (QOL) for a large portion of cancer survivors. To date, no studies have exclusively examined CRCI among gastrointestinal stromal tumor (GIST) survivors. Tyrosine kinase inhibitors (TKI), such as imatinib mesylate, have greatly increased median survival of individuals with GIST, so evaluating CRCI for this group is important. We report results of a large online survey of GIST survivors to ascertain prevalence, course and features of CRCI. Methods: A web-based survey utilizing validated patient reported outcomes (PRO’s) and de-identified demographic questions was developed. Respondents answered questions on age, gender, education, medical/cancer history and treatment. Estimated IQ was derived from demographic indexing. The FACT-Cog V3 and PROMIS Short Forms 8a assessed cognitive complaints, fatigue, mood, and anxiety. The survey was distributed through GIST Support International, the GIST Cancer Research Fund, Sarcoma Patients EuroNet and the Life Raft Group. Results: Across 4 continents, 485 adult GIST survivors (median age = 59 years, 71.8% female, 88.7% Caucasian) completed the survey. Respondents were 6.29 (sd = 5.19) years post-diagnosis with 88.0% percent on, or at least having started, imatinib. A majority (63.9%) indicated significant negative QOL impact as assessed by FACT-Cog Perceived Cognitive Impairments scale (PCI). PCI did not correlate with emotional distress or fatigue, as in other cancer samples. Type of surgery, current use/non-use of imatinib or other therapy was not associated with PCI. However, GIST survivors ≥ 5 years post-diagnosis had significantly worse PCI scores than survivors &lt; 5 years post-diagnosis (p &lt; 0.05). No differences between survivors with/without B12 deficiency or anemia were found and PCI did not correlate with cognitive reserve (years of education or IQ). Conclusions: Nearly two-thirds of GIST survivors report significant QOL impact of CRCI. Those with ≥ 5 year survival report worse cognitive symptoms, regardless of being on or off current TKI and cognitive symptoms do not appear associated with emotional distress or fatigue. CRCI among GIST survivors appears long term but further research to objectively determine CRCI magnitude and trajectory is warranted.

Current treatment strategies in pediatric gastrointestinal stromal cell tumor.

Gastrointestinal stromal tumors (GIST) are exceedingly rare tumors in the pediatric population. As a result, many clinicians either may never see this diagnosis or will encounter it only a few times throughout their careers. Additionally, the more we discover about this disease, it becomes evident that it represents a distinct clinical entity from adult GIST. Many of the treatments and strategies used to combat the adult tumor are either ineffective or may be harmful to the pediatric population with this disease. The unique tumor biology found in pediatric GIST necessitates unique approaches and treatment strategies in order to achieve the best clinical outcome. This review aims to discuss the most recent data available on the different therapeutic modalities utilized in cases of Pediatric GIST.

Latest advances in adult gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common GI tract mesenchymal tumors. GIST patients are optimally managed by a precision medicine approach. Herein, we discuss the latest advances in precision medicine and ongoing clinical trials relevant to GIST. Circulating tumor DNA for detection of mutational changes could replace tissue biopsies and radiographic imaging once validated. Most GISTs are KIT/PDGFRα mutated, and despite the good clinical response to imatinib, treatment is generally not curative, more often due to secondary mutations. New mechanisms to bypass this resistance by inhibiting KIT downstream pathways and by targeting multiple KIT or PDGFRα mutations are being investigated. Immunotherapy for GIST patients is in its infancy. These approaches may lead to more effective, less toxic therapies.

Congenital gastrointestinal stromal tumor: A rare case with rarer presentation

Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial tumors of the gastrointestinal tract. Adults between fifth and seventh decades of life are most often affected. GIST is rare in pediatric age group, and GIST in neonates is so rare that not much is known about their clinical presentation and behavior. We report a case of congenital GIST in a term male neonate who presented with acute abdomen. The tumor had caused distal ileal obstruction leading to dilatation of the proximal segment associated with perforation peritonitis. The involved intestinal segment was excised, and end-to-end anastomosis was performed; however, the newborn succumbed to postsurgery. The tumor histomorphologically resembled adult GIST with spindle and epithelioid areas. Immunohistochemically, the tumor was positive for vimentin, however was negative for actin, desmin, S-100, CD34 as well as c-Kit (CD117). This is probably the first case of a congenital GIST causing intestinal obstruction associated with perforation peritonitis. The report highlights the point of distinction between adult and congenital GIST, in terms of clinical presentation, histochemical markers, prognostic factors, and behavior.

Prognosis and management of adult wild type gastrointestinal stromal tumours (GISTs): A pooled analysis and review of literature

A pooled review was performed to determine survival in adult WT GIST (Wild Type GastroIntestinal Stromal Tumours) and compare the same with pediatric WT GISTs. Electronic databases were searched using the terms “Wild type” AND “GIST”. Eighty-two adult patients from 14 studies were included in the pooled analysis. Cumulative survival was greater than 50% in both age groups, hence medial survival could not be computed. Mean survival in adults was 15.7 years ± 0.78 and in children was 18.8 years ± 1.3 (p = 0.241). Median disease free survival in adults was 10 years while 5-year overall survival was 88%. There was no statistically significant difference in the survival between the two groups (p = 0.241). Overall survival in adults with WT GISTs is favourable compared to other adult GIST subtypes likely reflects a common molecular pathway similar to pediatric GIST.

Capsule endoscopy in the diagnosis of an exophytic gastrointestinal stromal tumor in the small intestine of a young adult woman: A case report.

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that mainly arise in the gastrointestinal tract. They are usually asymptomatic and are incidentally discovered during endoscopy or surgery. Diagnosis is confirmed by histological examination of the specimen. This is the case report of an asymptomatic GIST of the small intestine diagnosed by wireless capsule endoscopy. The tumor was initially suspected to be a leiomyoma, as GISTs in young adults are rare and are mainly discovered incidentally during colorectal cancer screening. The patient was a 35-year-old woman with occult gastrointestinal bleeding, with a normal medical history. An endoscopic assessment of the upper and lower GI tract (gastroscopy and colonoscopy) was performed, but did not reveal any abnormalities. Subsequently, an exophytic tumor initially suspected as leiomyoma or external pressure was detected in the small intestine by capsule endoscopy. A computed tomography scan was suggestive of a soft tissue tumor arising from the small intestine. A surgical specimen was obtained and the immunohistochemical examination revealed that the tumor was positive for CD117 and discovered on GIST-1 markers, while the markers of carcinoma, melanoma and lymphoma were negative, which was consistent with a diagnosis of a low-risk GIST with a mitotic count of <5/50 high-power fields. In this study, we aimed to present in detail the capsule endoscopic and radiological characteristics, as well as the findings of the histological examination of the surgical specimen. In conclusion, when occult blood is detected in the stool, even when gastroscopy and colonoscopy reveal no abnormal findings, small intestinal lesions should be suspected. Exophytic small intestinal GISTs, although rare, particularly in younger patients, they should be considered by physicians in the differential diagnosis of obscure GI bleeding of unknown origin, in order to reduce morbidity and mortality. Capsule endoscopy may be considered to be the first choice as a diagnostic tool for obscure GI bleeding.

An Unusual Case of Sigmoid Colon Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumors (GIST), uncommon mesenchymal tumors, are driven by KIT or plateletderived growth factor receptor alpha (PDGFRA) mutations. They are most commonly diagnosed in older adults (median 62-63 years) presenting with GI bleeding or peptic ulcer-like symptoms, and most are found in the stomach (approximately 60%). GISTs are much more rarely diagnosed in the colon ( < 1%), with the sigmoid colon most commonly affected. We review the case of a 90-year-old white man who presented with one day of painless bright red blood per rectum. He denied abdominal pain, nausea, and vomiting. Past medical history included atrial fibrillation on warfarin, stroke, prostate cancer with retropubic radical prostatectomy, and hypertension. The patient was hemodynamically stable with a benign abdominal examination. Rectal examination revealed maroon blood but no hemorrhoids, fissures, or masses. Laboratory evaluation revealed hemoglobin 7.3 g/dL, WBC 7.6x10(9), INR 2.73, and creatinine 0.6 mg/dL. Electrolytes were unremarkable. A CT abdomen/pelvis revealed extensive bowel wall thickening focally, at the junction of the sigmoid and descending colon, with adjacent stranding (Figure 1). The patient underwent his index colonoscopy revealing a nearly-obstructing, necrotic, ulcerated mass with overlying clot 45 cm from the anal verge. (Figure 2). Several cold forceps biopsies were taken diagnosing a gastrointestinal stromal tumor, spindle cell subtype. Within the biopsy specimen there was no mucosal ulceration or mitoses and the ki-67 proliferative index was < 1%. By immunohistochemistry, the tumor cells expressed CD117 (c-kit), CD34, and SMA, and were negative for S100. Neither the c-KIT nor PDGFRA gene mutation was detected. Given the extent of disease and the patient's comorbidities, surgical resection was not pursued and he was initiated on imatinib 400 mg daily. At six months the patient was tolerating therapy well aside from lower extremity edema, a common side effect of imatinib.Figure 1Figure 2An estimated 12-15% of adult GIST lack KIT and PDGFRA mutations, which are mutually exclusive, and are classified as wild type. This case highlights the importance of using several histopathology markers to aid in the diagnosis of GIST. Over 95% of GIST express CD117 and 70-90% also express CD34, as was seen in this case. Those with the mutations are more likely to respond to imatinib therapy, a tyrosine kinase inhibitor., which allows therapy to be individualized.

Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST).

BackgroundAbout 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813–3825, 2004; Hematol Oncol Clin North Am 23:15–34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes.MethodsWe performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis.ResultsWe found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG).ConclusionWe report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-685) contains supplementary material, which is available to authorized users.