GI stromal tumors (GISTs) are mesenchymal neoplasms with variable natural histories, originating in the GI tract, most commonly in the stomach. They are frequently characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) oncogenic mutations. Surgical resection remains the cornerstone treatment for localized GISTs. Clinical trials have demonstrated the benefits of adjuvant imatinib in patients selected on the basis of recurrence risk and gene mutations, although the optimal duration of therapy is yet to be established. Some data suggest that longer durations of adjuvant imatinib (>3 years) may provide additional benefit, which is being investigated in ongoing trials. Management of imatinib-related adverse effects is essential during treatment, and longitudinal abdominal imaging is mandatory both during and after adjuvant therapy. Once GISTs are more advanced and unresectable, KIT- and PDGFRA-directed tyrosine kinase inhibitors (TKIs) become the key treatment in most patients with KIT mutation. Several TKIs have regulatory approval for advanced GISTs, but in most patients, resistance to TKIs eventually emerges, mainly from secondary resistance mutations in KIT. Each TKI has different coverage of oncogenic KIT mutations, suggested by preclinical and clinical findings, which has given rationale to an ongoing clinical trial that includes molecular selection as eligibility criteria. Furthermore, novel treatment approaches, from TKI combinations to an antibody-drug conjugate, are being investigated. Despite the significant advance in managing GISTs with KIT mutations, those without KIT or PDGFRA mutation, which consists of 10%-15% of patients with GIST, can be a clinical challenge in the advanced setting. These non-KIT/PDGFRA GISTs could be driven by genomic or epigenomic alterations in SDHx, NF1 mutations, and other genomic alterations. Non-KIT/PDGFRA GISTs are less responsive to currently available TKIs than GISTs driven by KIT/PDGFRA mutations, and each subset of non-KIT/PDGFRA GIST has distinctive biology and clinical features. Therefore, individualized, multidisciplinary, biology-based management and consideration for clinical trial enrollment are critical for non-KIT/PDGRFA GISTs.

Gastrointestinal stromal tumors (GISTs) are the most common sarcoma subtype. Patients with unresectable or metastatic GISTs harboring the D842V mutation in the PDGFRA gene have a poor prognosis due to intrinsic resistance to imatinib and all other approved tyrosine kinase inhibitors. Avapritinib, targeting this mutation, is the first agent approved for patients with unresectable or metastatic GIST that have the PDGFRA D842V mutation. This study assesses the effectiveness and safety of avapritinib in real-world clinical scenarios involving Spanish patients with this mutation.

The AVARWE study is a descriptive, retrospective, multicenter observational study of 21 patients treated with avapritinib across 13 Spanish centers from June 9, 2023, to December 18, 2023. Data collected included patient demographics, disease characteristics, treatment history, and response rates based on RECIST criteria. The main outcomes, progression-free survival (PFS) and overall survival (OS), were measured, with safety assessed through adverse events documentation according to CTCAE criteria.

Median PFS 35.6 was months and median OS was 42.2 months, with survival rates at 1, 5, and 3 years demonstrating avapritinib effectiveness. The objective response rate was 76.2% for partial response and 4.8% for complete response. Avapritinib enabled surgical intervention in previously unresectable cases and was generally well-tolerated, with manageable adverse events.

Avapritinib extends PFS and OS among patients with PDGFRA D842V-mutant GIST in real-world practice, mirroring pivotal trial outcomes. Its substantial activity supports its use as a first-line therapy for this subgroup. The manageable safety profile reinforces avapritinib viability for routine use. Given the rarity of these cases, it is advised to consult sarcoma-expert units.

PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.

This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.

One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.

This review aims to outline the current understanding of the molecular drivers and treatment paradigms of gastrointestinal stromal tumors, with a focus on recent developments in treatment in the advanced disease setting.

There have been recent advancements in our understanding of the molecular biology of gastrointestinal stromal tumors, including the identification of new genetic drivers and complex resistance mechanisms. We review the most recent findings in these areas, focusing on how new research insights are reshaping treatment strategies. Recent advancements in our understanding of the biology and treatment of GIST are paving the way for more personalized and effective therapeutic options. As knowledge of rare molecular subtypes, resistance mechanisms, and novel genomic techniques grows, new approaches are emerging in an effort to improve patient outcomes.

Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives.

We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays.

All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement.

This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.

Neuropsychiatric adverse events (AEs) significantly impact the quality of life of patients using avapritinib. However, the majority of current data comes from pre-marketing, with limited real-world studies. Our research aimed to explore post-marketing data of avapritinib. We evaluated the signals of avapritinib-related neuropsychiatric AEs by data mining using the FDA Adverse Event Reporting System (FAERS). Reporting odds ratio (ROR) and information component (IC) were employed to quantify the signals from the first quarter of 2020 through the fourth quarter of 2023. Subsequently, stratified analyses were conducted to further explore the effect of different stratification schemes on the association between avapritinib and neuropsychiatric AEs. Finally, a combination medication analysis was conducted to explore the impact of the co-administration of neuropsychiatric AEs. A total of 2029 neuropsychiatric AEs were reported, and 49 signals were detected, of which 5 were determined to be new signals. Avapritinib was significantly associated with the occurrence of neuropsychiatric AEs (ROR: 1.52, 95% CI: 1.44-1.61; IC: 0.43, IC025: 0.35). The stratified analysis found that gender, age and eight preferred terms (PTs), including cerebral haemorrhage, may affect the severity of AEs. Combination medication analysis showed that combining avapritinib with 19 other medications, including prochlorperazine, may increase the risk of neuropsychiatric AEs. The median time-to-onset (TTO) of avapritinib-related neuropsychiatric AEs was 32 (interquartile range [IQR] 2-200) days, with about 65% of cases occurring within the first three months of treatment. An increase in the signal for neuropsychiatric AEs was identified in post-marketing studies of avapritinib. Clinicians are advised to remain vigilant for such events, particularly during the initial stages of treatment with avapritinib.

British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up.

A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately.

Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).

The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial.

BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861.

Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib.

Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that primarily affect adults, with pediatric cases constituting only 0.5-2.7% of the total. Pediatric GISTs present unique clinical, genetic, and pathological features that distinguish them from adult cases. This literature review aims to elucidate these differences, emphasizing diagnostic and therapeutic challenges. We discuss the resistance of pediatric GISTs to conventional chemotherapy and highlight the importance of surgical intervention, especially in emergency situations involving intra-abdominal bleeding. The review also explores the molecular characteristics of pediatric GISTs, including rare mutations such as quadruple-negative wild-type GIST with an FGF3 gene gain mutation. To illustrate these points, we conclude with a case from our clinic involving a 15-year-old female with multiple CD117-positive gastric GISTs and a quadruple-negative wild-type genetic profile who required urgent surgical intervention following a failed tumor embolization. This case underscores the critical need for early diagnosis and individualized therapeutic strategies combining oncologic and surgical care to improve outcomes in pediatric GIST patients.

Desmoid tumors (DTs) are rare and locally aggressive with a high rate of local recurrence even with optimal surgical resection. Systemic treatments are often utilized for desmoid cases with high risk of surgical morbidity or for local and symptomatic control of recurrent disease. However, the systemic treatment options for DTs are limited with limited responses. Avapritinib is a tyrosine kinase inhibitor (TKI) approved in 2020 for adults with unresectable or metastatic gastrointestinal (GI) stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) Exon 18 mutation, including D842V mutations. In this case report, we describe a 55-year-old man with a history of D842V-mutant gastric GIST who presented several years after complete resection of the GIST with an enlarging soft tissue mass in the small intestine. After a nondiagnostic biopsy, the patient was started on avapritinib due to concerns for recurrent D842V-mutant GIST. The tumor had a partial response to treatment by RECIST 1.1 criteria, and the patient underwent surgical resection. The final pathology report revealed a sporadic DT. To our knowledge, this is the first known description of the activity of avapritinib in the treatment of a sporadic mesenteric DT, which is relevant given the limited treatment options for patients with this diagnosis. This clinical finding may be worth exploring in a dedicated clinical trial.

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.

Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs.

Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan.

Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival.

A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89).

We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.

Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice.

The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility.

As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available.

Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.

Endoscopic therapy (ET) of gastrointestinal stromal tumors (GIST) has become a viable treatment. We intended to compare long-term outcomes of ET versus surgical resection for 2-5 cm GIST using the Surveillance, Epidemiology, and End Results (SEER) database.

A multicenter retrospective study was conducted to compare the long-term outcomes of patients treated with ET and surgical resection for GIST. The multivariate Cox proportional hazards models were used to identify predictors for patients survival. To balance the clinicopathologic characteristics, a 1:1 propensity score matching (PSM) was utilized.

A total of 749 patients with 2-5 cm GIST were enrolled, of whom 113 accepted ET and 636 underwent surgical resection. Before PSM, there was no significant difference in long-term outcomes between ET and surgical resection (5-year overall survival (OS): 93.5% vs. 91.6%, P=0.374; 5-year cancer-specific survival (CSS): 99.1% vs. 96.5%, P=0.546; 10-year OS: 71.1% vs. 78.2%, P=0.374; 10-year CSS: 93.6% vs. 92.7%, P=0.546). After adjusting for the relevant variables using the multivariable Cox proportional hazards models, we observed that the ET and surgical resection groups were similar in OS (HR 0.726, 95%CI 0.457-1.153, P=0.175) and CSS (HR 1.286, 95%CI 0.474-3.488, P=0.621). After PSM, the long-term OS and CSS of patients with 2-5 cm GIST after ET and surgical resection were comparable.

We found that the long-term survival of patients with 2-5 cm gastric GIST after ET and surgical resection were comparable. Further high-quality studies are needed to confirm the role of ET in 2-5 cm GIST.

The significance of interstitial cells of Cajal (ICC) in the gastrointestinal tract has garnered increasing attention. In recent years, approximately 80 articles on ICC have been published annually in various journals. However, no bibliometric study has specifically focused on the literature related to ICC. Therefore, we conducted a comprehensive bibliometric analysis of ICC to reveal dynamic scientific developments, assisting researchers in exploring hotspots and emerging trends while gaining a global perspective.

We conducted a literature search in the Web of Science Core Collection (WoSCC) from January 1, 2013, to December 31, 2023, to identify relevant literature on ICC. We employed bibliometric software, namely VOSviewer and CiteSpace, to analyze various aspects including annual publication output, collaborations, research hotspots, current status, and development trends in this domain.

A total of 891 English papers were published in 359 journals by 928 institutions from 57 countries/regions. According to the keyword analysis of the literature, researchers mainly focused on "c-Kit," "expression," "smooth muscle," and "nitric oxide" related to ICC over the past 11 years. However, with "SIP syncytium," "ANO1," "enteric neurons," "gastrointestinal stromal tumors (GIST)," and "functional dyspepsia (FD)," there has been a growing interest in the relationship between ANO1, SIP syncytium, and ICC, as well as the role of ICC in the treatment of GIST and FD.

Bibliometric analysis has revealed the current status of ICC research. The association between ANO1, SIP syncytium, enteric neurons and ICC, as well as the role of ICC in the treatment of GIST versus FD has become the focus of current research. However, further research and collaboration on a global scale are still needed. Our analysis is particularly valuable to researchers in gastroenterology, oncology, and cell biology, providing insights that can guide future research directions.

Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown.

Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling.

GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes.

Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Soft tissue sarcomas (STSs), including gastrointestinal stromal tumors (GISTs), are mesenchymal neoplasms with heterogeneous clinical behavior and represent broad categories comprising multiple distinct biologic entities. Multidisciplinary management of these rare tumors is critical. To date, multiple studies have outlined the importance of biological characterization of mesenchymal tumors and have identified key molecular alterations which drive tumor biology. GIST has represented a flagship for targeted therapy in solid tumors with the advent of imatinib which has revolutionized the way we treat this malignancy. Herein, the authors discuss the importance of biological and molecular diagnostics in managing STS and GIST patients.

Myxoid glioneuronal tumors (MGNT) are low-grade glioneuronal neoplasms composed of oligodendrocyte-like cells in a mucin-rich stroma. These tumors feature a unique dinucleotide change at codon 385 in the platelet-derived growth factor receptor α (encoded by the PDGFRA gene), resulting in the substitution of lysine 385 into leucine or isoleucine. The functional consequences of these mutations remain largely unexplored. Here, we demonstrated their oncogenic potential in fibroblast and Ba/F3 transformation assays. We showed that the K385I and K385L mutants activate STAT and AKT signaling in the absence of ligand. Co-immunoprecipitations and BRET experiments suggested that the mutations stabilized the active dimeric conformation of the receptor, pointing to a new mechanism of oncogenic PDGF receptor activation. Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Finally, K385 substitution into another hydrophobic amino acid also activated the receptor. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.

The heterogeneous nature of tumors presents a considerable obstacle in addressing imatinib resistance in advanced cases of gastrointestinal stromal tumors (GIST). To address this issue, we conducted single-cell RNA-sequencing in primary tumors as well as peritoneal and liver metastases from patients diagnosed with locally advanced or advanced GIST. Single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Immunohistochemistry and multiplex immunofluorescence staining were used to further validate it. This analysis revealed unique tumor evolutionary patterns, transcriptome features, dynamic cell-state changes, and different metabolic reprogramming. The findings indicate that in imatinib-resistant TME, tumor cells with activated immune and cytokine-mediated immune responses interacted with a higher proportion of Treg cells via the TIGIT-NECTIN2 axis. Future immunotherapeutic strategies targeting Treg may provide new directions for the treatment of imatinib-resistant patients. In addition, IDO1+ dendritic cells (DC) were highly enriched in imatinib-resistant TME, interacting with various myeloid cells via the BTLA-TNFRSF14 axis, while the interaction was not significant in imatinib-sensitive TME. Our study highlights the transcriptional heterogeneity and distinct immunosuppressive microenvironment of advanced GIST, which provides novel therapeutic strategies and innovative immunotherapeutic agents for imatinib resistance.

Cancer treatments have recently shifted from broad-spectrum cytotoxic therapies to more focused treatments, maximizing anticancerous activity while reducing toxicity to healthy cells. These modern anticancer therapies (MATs) encompass a wide range of innovative molecules that include immune checkpoint inhibitors and other targeted anticancer therapies, comprising antibody drug conjugates and inhibitors of signal transduction. Some MATs are associated with ocular surface adverse events that can cause severe discomfort and even lead to loss of vision. While these complications remain rare, they are probably underreported. It is likely that both oncologists and ophthalmologists will come across MATs-associated ocular surface-adverse events in their practices, owing to the increasing number of patients being treated with MATs. Rapid identification of ocular surface-adverse events is crucial, as early intervention can manage these conditions to avoid vision loss and reduce negative impacts on quality of life. We discuss characteristics of ocular surface pathologies attributed to MATs, describe the suspected underlying pathophysiological mechanisms, and outline the main lines of treatment.

Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations.

In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable.

The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials.

Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS).

Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively).

Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings.

Recently, there has been an increased focus on cancer stem cells (CSCs) due to their resilience, making them difficult to eradicate. This resilience often leads to tumor recurrence and metastasis. CSCs adeptly manipulate their surroundings to create an environment conducive to their survival. In this environment, myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting epithelial-mesenchymal transition and bolstering CSCs' stemness. In response, CSCs attract MDSCs, enhancing their infiltration, expansion and immunosuppressive capabilities. This interaction between CSCs and MDSCs increases the difficulty of antitumor therapy. In this paper, we discuss the interplay between CSCs and MDSCs based on current research and highlight recent therapeutic strategies targeting either CSCs or MDSCs that show promise in achieving effective antitumor outcomes.

Molecular targeted therapies are the most important type of medical treatment for GIST, but the development of GIST drugs and their targets have not been summarized.

Drugs in the field of GIST were analyzed and collated through Pharmaprojects, ClinicalTrials. gov and PharmaGO databases.

As of 2021, there are 75 drugs that have appeared in the GIST clinical trials. The six most frequent targets in GIST clinical trials, in descending order of frequency, were KIT, PDGFRA, KDR (VEGFR2), FLT3, FLT1 (VEGFR1), and FLT4/VEGFR3. Only 8 drugs are in preclinical research. There are challenges in the development of new drugs for GIST.

This article analyzes and summarizes the general situation of GIST drugs, the target distribution of GIST drugs, and the trends in GIST drug-related clinical trials.

Due to the increasing recognition of gastrointestinal stromal tumor (GIST), novel insights have appeared in both preclinical and clinical research and begun to reshape the field. This study aims to map the research landscape through bibliometric analysis and provide a brief overview for the future of the GIST field.

We searched the Web of Science Core Collection without publication data restrictions for GISTs and performed a bibliometric analysis with CiteSpace and VOSviewer software.

In sum, 5,911 of 13,776 records were included, and these studies were published in 948 journals and written by 24,965 authors from 4,633 institutions in 100 countries. Referring to published reviews and bibliometric analysis, we classified the future trends in four groups. In epidemiological study, precise incidence and clinicopathological features in different regions and races might become potential hotspots. Novel therapy, such as drugs, modified strategies, radioligand therapy, was persistent hotspots in GIST fields, and ctDNA-guided diagnosis, monitoring, and treatment might meet future clinical needs. The debate over serosa surgery vs. mucosa surgery will remain active for a long time in GIST surgery, and function reserve surgery, biology-based surgery will play an important role in future. Moreover, rare GIST type, like NF-1-associated GIST, Carney triads and SDH mutant GIST, need more studies in pathogenesis and genetic mutation to provide appropriate treatment for this orphan GIST patients.

Potential hotspots in future GIST trends might involve epidemiology, agents, resection therapy and rare type GIST, moreover, researchers could pay more attention in these four fields.

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.