Pimitespib, an oral heat shock protein 90 inhibitor, significantly prolonged progression-free survival in patients with advanced gastrointestinal stromal tumors (GIST) in CHAPTER-GIST-301 study. This expanded access program was conducted to evaluate the safety and efficacy of pimitespib in Japanese patients with advanced GIST.

This multicenter, open-label, single-arm study was conducted in patients (≥ 20 years) with histologically confirmed GIST who had been previously treated with imatinib, sunitinib and regorafenib and had an Eastern Cooperative Oncology Group performance status of 0-1. Patients received pimitespib 160 mg/day for five days, followed by a 2-day rest, in 21-day cycles.

Between February and August 2022, 23 patients were enrolled (median age 59.0 years). Over a median pimitespib treatment duration of 81.0 days, adverse events occurred in 22 patients (95.7%). The most common adverse events were diarrhea (73.9%), nausea (39.1%) and increased blood creatinine (30.4%). Serious adverse events occurred in two patients (tumor hemorrhage and tumor pain); neither was related to pimitespib. One patient had grade 3 diarrhea that was considered treatment-related. Four patients (17.4%) had eye disorders, all of which were grade 1 and treatment-related. The median progression-free survival was 4.2 months (95% confidence interval [CI] 1.9-6.2), the overall response rate was 0% (95% CI 0-16.1) and the disease control rate was 66.7% (95% CI 43.0-85.4).

Pimitespib was well tolerated and effective in patients with advanced GIST in real-world practice in Japan. No new safety signals were identified.

jRCT2031210526 registered 1 February 2022.

This review discusses the ways in which the health care provider (or more broadly, the provision of medical care) can cause harm to the bowel and highlights the appearance of such untoward events on imaging. The etiologies are myriad, and as such, the radiologist must remain vigilant in identifying the presence of suspected and unsuspected injuries. Specific attention is given to complications from medication and external radiation therapy, as these interventions and their timing are often not known by the radiologist.

Macrocycles have gained significant attention in drug discovery, with over 70 macrocyclic compounds currently in clinical use. Despite this progress, the effective methods for designing macrocycles remain elusive. In this study, we present Macro-Hop, a reinforced learning framework designed to rapidly and comprehensively explore the macrocycle chemical space. Macro-Hop efficiently generates novel macrocyclic scaffolds that not only align with predefined physicochemical properties but also exhibit 3D structural similarities to a specified reference compound. As a proof of concept, we applied Macro-Hop to design a new series of macrocycle inhibitors targeting PDGFRαD842 V kinase. The representative compound L7 exhibited high potency against PDGFRαD842 V in both biochemical and cellular assays with IC50 values of 23.8 and 2.1 nM, respectively. L7 effectively inhibited clinically relevant secondary mutants PDGFRαD842 V/G680R (IC50 = 64.1 nM) and PDGFRαD842 V/T674I (IC50 = 27.6 nM), highlighting the rapid effectiveness of wet-leb validation with Macro-Hop.

Metastatic and recurrent gastrointestinal stromal tumors (GISTs) present challenging clinical management. Imatinib is the standard first-line therapy, improving survival and reducing tumor burden in the neoadjuvant use, facilitating surgical intervention. This systematic review and meta-analysis assessed the efficacy of neoadjuvant imatinib in metastatic/recurrent GISTs, highlighting its potential to enhance surgical outcomes and overall patient management.

A systematic search was conducted in PubMed, Embase and Scopus (end-of-search: February 13, 2025) for records on neoadjuvant imatinib therapy in recurrent/metastatic GISTs. Pooled proportions and 95% confidence intervals were calculated with common-effect and random-effects models. Subgroup and meta-regression analysis were performed, addressing heterogeneity and examining any potential association between the factors that varied and the outcomes reported. The present meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

The search identified 957 articles, and 14 were analyzed. The meta-analysis of proportions indicated that 2-year and 5-year PFS were 76% (95% CI 58-88%) and 43% (95% CI 17-74%), respectively, while 2-year and 5-year OS were 84% (95% CI 78-89%) and 60% (95% CI 51-68%), respectively. The pooled R0 resection rate was 82% (95% CI 64-92%), associated positively with that of radiological partial response (PR) (β = 3.92, p < 0.001). Further meta-regression analysis yielded no significant association with preoperative imatinib duration.

The present meta-analysis of trials and studies on metastatic or recurrent GISTs highlights key insights into post-surgery patient outcomes following neoadjuvant treatment with imatinib. Pooled effect estimates revealed promising 2-year and 5-year PFS rates of 76% and 43%, respectively, and 2-year and 5-year OS rates of 84% and 60%, respectively. Furthermore, the high pooled R0 resection rate of 82% emphasizes a substantial surgical efficacy in this population, while it was significantly correlated with successful R0 resections in patients with favorable outcomes.

To determine if an alternating regimen of the tyrosine kinase inhibitors imatinib and regorafenib improved outcomes in patients with advanced gastrointestinal stromal tumors.

ALTGIST (NCT02365441) was a randomized phase II study of standard treatment of imatinib (Arm A) compared with an experimental alternating regimen of imatinib and regorafenib (Arm B). Primary outcome was best objective tumor response (OTR) at nine months.

Seventy-six eligible patients (Arm A 36, Arm B 40) enrolled were evaluable. Median follow-up was 46.0 months (range 6.5-64.6). Best responses and OTR were similar at 9 months. Eighteen (50.0%) Arm A patients and twelve (30.0%) Arm B patients discontinued treatment due to progressive disease. No Arm A patients stopped protocol therapy due to unacceptable toxicity, with 12 (30.0%) stopping in Arm B. Twelve (33.2%) Arm A patients and 12 (30.0%) Arm B patients experienced at least one serious adverse event, mostly grade 3. Secondary endpoints of PFS at 1 and OS at 1 year were not statistically different.

Alternation of imatinib and regorafenib did not impact on 9 months objective response nor on the secondary objectives of PFS and OS. Patients in the alternating arm experienced more toxicity and protocol discontinuations.

NCT02365441.

For patients with advanced gastrointestinal stromal tumors (GISTs) carrying the c-kit exon 11 mutation, imatinib (IM) at a standard dosage of 400 mg per day is the preferred first-line treatment. In cases where treatment with IM fails, there is an urgent need for a more precise assessment method to determine whether to switch therapies or escalate the IM dosage. This approach will enhance clinical decision-making and optimize patient outcomes.

To investigate IM plasma concentration's role in second-line treatment decisions for c-kit 11-mutated advanced GISTs post-IM failure.

Patients with advanced GIST harboring c-kit 11 mutation who experienced failure with IM 400 mg per day as first-line treatment at our hospital were retrospectively analyzed. Patients were categorized into a low plasma (LP) concentration group (LP group, < 1100 ng/mL) and high plasma (HP) concentration group (HP group, ≥ 1100 ng/mL). Each group was further subdivided into Group A (dose-escalation group) and Group B (drug-switch group). Baseline characteristics were compared and Kaplan-Meier curves were used to analyze the survival of patients.

Seventy-five patients were included in the analysis. For the LP group (n = 28), Group A (n = 14) had longer overall survival (OS) than Group B (n = 14) (P = 0.02). No differences were observed between the two subgroups in disease control rate (DCR), objective response rate, and progression-free survival (PFS) (P > 0.05). For the HP group (n = 47), Group B (n = 18) had a higher DCR and longer PFS than Group A (n = 29) (P = 0.008 and P = 0.03, respectively). No difference in OS was observed between the two subgroups (P > 0.05).

Increasing IM dosage for c-kit 11-mutated advanced GISTs post-IM failure may prolong OS if plasma concentration is < 1100 ng/mL. Switching tyrosine kinase inhibitors may improve DCR and PFS if ≥ 1100 ng/mL.

Subepithelial esophageal tumors (SET) are normally benign intramural esophageal lesions of mesenchymal origin. Although rare, the incidence of SET has increased in recent decades due to the more widespread use of endoscopy and diagnostic imaging. The current review aims to provide an overview of the histopathologic spectrum and the most frequent entities including leiomyoma and gastrointestinal stromal tumor (GIST), diagnostic workup, and multidisciplinary treatment options. Staging for SET should include endoscopy, endoscopic ultrasonography (EUS), and tissue sampling. Current consensus guidelines recommend that SET suggestive of gastrointestinal stromal tumor (GIST) larger than 20 mm or lesions with high-risk stigmata should undergo tissue sampling. Most SET have an excellent long-term outcome, but malignancy may be present in certain subtypes. Asymptomatic SET without high-risk stigmata discovered incidentally usually do not require specific treatment. However, depending on the size and location of the lesion symptoms may occur. Therapeutic interventions range from endoscopic interventional resections to major surgical procedures. Enucleation via minimally invasive or robotic-assisted access remains the standard of care for most SET sub-entities.

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.

Methylthioadenosine phosphorylase (MTAP) is an essential metabolic enzyme in the purine and methionine salvage pathway. In cancer, MTAP gene copy number loss (MTAP loss) confers a selective dependency on the related protein arginine methyltransferase 5. The impact of MTAP alterations in gastrointestinal (GI) cancers remains unknown although hypothetically druggable. Here, we aim to investigate the prevalence, clinicopathological features and prognosis of MTAP loss GI cancers.

Cases with MTAP alterations were retrieved from The Cancer Genome Atlas (TCGA) and a real-world cohort of GI cancers profiled by next-generation sequencing. If MTAP alterations other than loss were found, immunohistochemistry was performed. Finally, we set a case-control study to assess MTAP loss prognostic impact.

Findings across the TCGA dataset (N=1363 patients) and our cohort (N=508) were consistent. Gene loss was the most common MTAP alteration (9.4%), mostly co-occurring with CDKN2A/B loss (97.7%). Biliopancreatic and gastro-oesophageal cancers had the highest prevalence of MTAP loss (20.5% and 12.7%, respectively), being mostly microsatellite stable (99.2%). In colorectal cancer, MTAP loss was rare (1.1%), while most MTAP alterations were mutations (5/7, 71.4%); among the latter, only MTAP-CDKN2B truncation led to protein loss, thus potentially actionable. MTAP loss did not confer worse prognosis.

MTAP alterations are found in 5%-10% of GI cancers, most frequently biliopancreatic and gastro-oesophageal. MTAP loss is the most common alteration, identified almost exclusively in MSS, CDKN2A/B loss, upper-GI cancers. Other MTAP alterations were found in colorectal cancer, but unlikely to cause protein loss and drug susceptibility.

Neoadjuvant imatinib therapy plays a crucial role in the management of gastrointestinal stromal tumors (GISTs), but its impact across various mutational profiles remains uncertain.

The aim of this study is to describe the clinicopathological features and to assess the response and surgical outcomes of neoadjuvant imatinib in GIST patients exhibiting diverse mutational profiles.

We conducted a retrospective study, extracting data from the Dutch GIST Registry, including patients treated with neoadjuvant imatinib. Response rate was the primary outcome, and secondary outcomes were the time on neoadjuvant treatment and resection margins (R0 vs. R1/R2), respectively.

Between 2009 and 2021, 326 patients were treated with neoadjuvant imatinib, of which 264 (80.9%) underwent resection. A total of 197 (74.6%) of them had a KIT-exon 11 mutation, 19 (7.3%) had other KIT mutations, 10 (3.8%) had PDGFRA D842 mutations, 21 (6.8%) had other PDGFRA mutations, 2 (0.7%) had NTRK mutation, 1 (0.4%) had an SDH mutation, and 17 (6.4%) had WT GISTs. Patients with KIT-exon 11 mutations demonstrated a higher rate of partial response to imatinib (60.5% vs. 33.3%; p = 0.00). A positive resection margin (R1 or R2) was observed in 14 (21.2%) patients with a non-KIT exon 11 mutations and in 11 (5.5%) patients with a KIT-exon 11 mutation (p = 0.00). Moreover, non-KIT exon 11 mutation patients had a shorter median duration of neoadjuvant therapy (5.3 months, range 0.5-21.0) compared to patients with a KIT exon 11 mutation (8.8 months, range 0.2-31.3; p < 0.001).

Our study highlights the variability in treatment response associated with different GIST mutational profiles. Patients with a KIT-exon-11 mutation tended to respond more favorably to neoadjuvant imatinib in terms of partial response and surgical outcomes.

Sarcomas are rare mesenchymal tumors with a propensity for hematogenous metastasis. Gastrointestinal stromal tumor (GIST) is the most common histologic subtype and the most common source of hepatic metastases. In the case of metastatic GIST, neoadjuvant imatinib can be used as a selection tool for the judicious application of surgery, where treatment-responsive patients who undergo resection to prevent the development of treatment-resistant clones have associated 10-year actuarial survival of 40%. Further advances for many of the non-GIST sarcoma subtypes will depend on the development of improved systemic therapies and evaluation of their activity in subtype or molecularly defined trials.

Gastrointestinal Stromal Tumors (GISTs) have seen significant advancements in their diagnosis and management, driven by targeted therapeutic development and molecular testing. The identification of mutations in genes such as KIT and PDGFRA has transformed treatment approaches, particularly through targeted therapies like imatinib, which have improved patient outcomes. This review explores the critical role of genomic testing in GIST, highlighting its importance in accurate diagnosis, treatment planning, and long-term surveillance for KIT/PDGFRA negative, SDH-deficient GISTs. SDH-deficient GISTs arise from mutations or epigenetic changes affecting the succinate dehydrogenase complex. The complexity of SDH-deficient GISTs, including their association with hereditary syndromes such as Hereditary Paraganglioma-Pheochromocytoma and/or hypermethylation of the SDHC promoter, underscores the need for comprehensive germline testing. Despite the availability of guidelines, variability exists in genomic testing recommendations across different regions, necessitating a unified approach. This review proposes a simplified algorithm for the genomic workup of GIST, and suggests all individuals with SDH-deficient GIST, regardless of germline testing result, require monitoring for additional SDHx-related tumors, given the lack of widely available methylation and full gene SDHA analysis.

Gastrointestinal stromal tumors (GISTs) are rare cancers originating from Cajal's stromal cells in the gastrointestinal tract. The most common driver mutation in these cancers is the KIT mutation. This report presents a case of response to low-dose imatinib in a patient with GIST harboring KIT exon 11 W557_K558 deletion.

In June 2023, an 82-year-old male developed perineal pain. Computed tomography (CT) imaging revealed a mass measuring >9 cm, extending from the rectum to the prostate. Submucosal tumor biopsy revealed a tumor with CD117-positive and DOG1-positive spindle-shaped cells leading to a diagnosis of GIST. c-Kit gene mutation analysis detected a W557_K558 deletion in exon 11. Treatment with imatinib (400 mg/day) was initiated in late October 2023 to preserve organ function; the dose was reduced to 300 mg/day after 5 days of treatment and further reduced to 200 mg/day after 10 days, with continued treatment at this dose. The CT performed in January, April, and June 2024 showed that the rectal GIST had shrunk. The blood imatinib concentration remained at approximately 650 ng/ml from January to March 2024 and decreased to 391 ng/ml in May 2024.

The response rate of GISTs to imatinib is influenced by genetic mutations. GIST with KIT exon 11 W557_K558 deletion is associated with a high risk of recurrence. In vitro data showed that low-dose imatinib was effective in such cases. Low-dose imatinib is a treatment option for patients with GIST harboring KIT exon 11 W557_K558 deletion who are intolerant to high-dose imatinib.

Many patients with cancer exhibit primary or rapid secondary resistance to targeted therapy (TT). We hypothesized that a higher number of altered oncogenic signaling pathways [pathway alteration load (PAL)] would reduce the benefit of TT which only intervenes in one pathway. This hypothesis was tested in the Drug Rediscovery Protocol (DRUP).

DRUP is a prospective, pan-cancer, non-randomized clinical trial (NCT02925234) that treats patients with therapy-refractory metastatic cancer and an actionable molecular profile using matched off-label targeted and immunotherapies. All patients treated with TT with available clinical outcomes and whole genome sequencing were included. PAL was determined based on driver gene alterations and correlated with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Outcomes were validated in the independent Hartwig Medical database of metastatic cancers.

In 154 patients treated with TT, the median PAL was 3. Patients with a PAL below median (n = 60) demonstrated a higher CBR (41.7% versus 25.5%, odds ratio 0.48, P = 0.051), longer PFS [median 4.7 versus 2.9 months, adjusted hazard ratio (aHR) 1.70, P = 0.020] and OS (median 13.7 versus 5.6 months, aHR 3.80, P < 0.001) compared with those with PAL ≥3. Two hundred and fifty-eight patients in the Hartwig database showed similar results for CBR (54.2% versus 36.7%, odds ratio 2.04, P = 0.009) and PFS (7.0 versus 4.2 months, aHR 1.55, P = 0.009).

In our population, PAL emerged as a pan-cancer determinant of outcome to TT. Our findings support refined patient selection for TT and highlight the rationale for combinatorial treatment strategies in patients with multiple affected pathways.

Less than 5% of GI stromal tumors (GISTs) are driven by the loss of the succinate dehydrogenase (SDH) complex, resulting in a pervasive DNA hypermethylation pattern that leads to unique clinical features. Advanced SDH-deficient GISTs are usually treated with the same therapies targeting KIT and PDGFRA receptors as those used in metastatic GIST. However, these treatments display less activity in the absence of alternative therapeutic options. Therefore, it is critical to identify novel actionable alterations in SDH-deficient GIST.

We performed a single-center, retrospective analysis of patients with SDH-deficient GIST together with next-generation sequencing (NGS) analysis from their respective tumor samples to identify mutations and copy number alterations and chromosomal alterations. NGS-tailored treatment was implemented whenever possible.

Seventeen tumor samples from 14 patients with SDH-deficient GIST underwent NGS. Mutational load was low, although three patients (21%) displayed molecular events in relapse samples leading to PI3K/mTOR pathway hyperactivation. mTOR inhibition with everolimus obtained a sustained tumor response in a heavily pretreated patient. Other alterations, largely present in late-stage patients, uncovered genes involved in cell cycle regulation, telomere maintenance, and DNA damage repair. Chromosomal arm-level alterations differed from the canonical cytogenetic progression in KIT/PDGFRA-mutant GIST.

This molecular landscape of SDH-deficient GIST uncovers novel molecular alterations, mostly in relapse and/or previously pretreated patients. The identification of genetic events leading to PI3K/mTOR dysregulation together with the remarkable activity of everolimus in one patient showcases the clinical relevance of this pathway, validates the utility of NGS in this population, and poses everolimus as a novel therapeutic alternative. Several other alterations were found at the genetic and genomic levels, underscoring novel biological processes likely involved during tumor evolution.

Patient-centered precision oncology strives to deliver individualized cancer care. In lung cancer, preclinical models and technological innovations have become critical in advancing this approach. Preclinical models enable deeper insights into tumor biology and enhance the selection of appropriate systemic therapies across chemotherapy, targeted therapies, immunotherapies, antibody-drug conjugates, and emerging investigational treatments. While traditional human lung cancer cell lines offer a basic framework for cancer research, they often lack the tumor heterogeneity and intricate tumor-stromal interactions necessary to accurately predict patient-specific clinical outcomes. Patient-derived xenografts (PDXs), however, retain the original tumor's histopathology and genetic features, providing a more reliable model for predicting responses to systemic therapeutics, especially molecularly targeted therapies. For studying immunotherapies and antibody-drug conjugates, humanized PDX mouse models, syngeneic mouse models, and genetically engineered mouse models (GEMMs) are increasingly utilized. Despite their value, these in vivo models are costly, labor-intensive, and time-consuming. Recently, patient-derived lung cancer organoids (LCOs) have emerged as a promising in vitro tool for functional precision oncology studies. These LCOs demonstrate high success rates in growth and maintenance, accurately represent the histology and genomics of the original tumors and exhibit strong correlations with clinical treatment responses. Further supported by advancements in imaging, spatial and single-cell transcriptomics, proteomics, and artificial intelligence, these preclinical models are reshaping the landscape of drug development and functional precision lung cancer research. This integrated approach holds the potential to deliver increasingly accurate, personalized treatment strategies, ultimately enhancing patient outcomes in lung cancer.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the digestive tract. Despite multiple therapeutic advances, patients with advanced disease frequently develop resistance to tyrosine kinase inhibitors (TKIs), and therefore represent a therapeutic challenge. We employed whole genome sequencing (WGS) on three metastatic GISTs refractory to various TKIs and explored a publicly available cohort of 499 GISTs. This study sheds light on the clinical importance of alterations in cell cycle genes such as cyclin-dependent kinase 2 A (CDKN2A), and cyclin-dependent kinase 2B (CDKN2B), their frequent alteration in metastatic GISTs and their potential role in tumor progression of this neoplasm. Likewise, new structural variations were identified in cyclin-dependent kinase 12 (CDK12). Whole genome profiling of metastatic GIST provides new insights to advance precision care of the disease, focusing on new therapeutic possibilities, especially for emerging targets such as CDK12.

The purpose of this study was to determine if dual-energy CT (DECT) vital iodine tumor burden (ViTB), a direct assessment of tumor vascularity, allows reliable response assessment in patients with GIST compared to established CT criteria such as RECIST1.1 and modified Choi (mChoi). From 03/2014 to 12/2019, 138 patients (64 years [32-94 years]) with biopsy proven GIST were entered in this prospective, multi-center trial. All patients were treated with tyrosine kinase inhibitors (TKI) and underwent pre-treatment and follow-up DECT examinations for a minimum of 24 months. Response assessment was performed according to RECIST1.1, mChoi, vascular tumor burden (VTB) and DECT ViTB. A change in therapy management could be because of imaging (RECIST1.1 or mChoi) and/or clinical progression. The DECT ViTB criteria had the highest discrimination ability for progression-free survival (PFS) of all criteria in both first line and second line and thereafter treatment, and was significantly superior to RECIST1.1 and mChoi (p < .034). Both, the mChoi and DECT ViTB criteria demonstrated a significantly early median time-to-progression (both delta 2.5 months; both p < .036). Multivariable analysis revealed 6 variables associated with shorter overall survival: secondary mutation (HR = 4.62), polymetastatic disease (HR = 3.02), metastatic second line and thereafter treatment (HR = 2.33), shorter PFS determined by the DECT ViTB criteria (HR = 1.72), multiple organ metastases (HR = 1.51) and lower age (HR = 1.04). DECT ViTB is a reliable response criteria and provides additional value for assessing TKI treatment in GIST patients. A significant superior response discrimination ability for median PFS was observed, including non-responders at first follow-up and patients developing resistance while on therapy.

An analytical method for the determination of imatinib (IMA, the primary treatment for chronic myeloid leukemia), based on the fluorescence properties of graphene quantum dots (GQDs), is reported in this work. The method is addressed to the analytical control of IMA in biological and pharmaceutical samples, due to the present interest in the control of the doses of this anticancer drug, as well as the therapeutic monitoring. The whole method involves the use of a solid-phase extraction (SPE) procedure, followed by an evaporation step, for the treatment of biological samples. For that, tC18 sorbent cartridges were used. After the sample treatment, the solution containing the analyte was mixed with an aqueous solution of GQDs at pH 7.2, and the fluorescent quenching of GQDs was measured. IMA was determined in the 10-250 µg L-1 range, with a limit of detection of 21 µg L-1 and a precision of 1.5% as relative standard deviation, measured in terms of reproducibility. The recovery for biological samples was in the 84-113% range.

The liver is the most common site of gastrointestinal stromal tumor (GIST) metastasis. Most patients who develop metastases gradually develop multiline drug resistance during long-term systematic treatment. We aimed to evaluate the benefit of surgery during the systematic treatment of GIST liver metastases.

Data on GISTs with liver metastasis were retrieved from the Surveillance, Epidemiology, and End Results database. This study included 607 patients, of whom 380 patients were treated with chemotherapy alone (Chemo group) and 227 patients underwent surgery in addition to chemotherapy (Chemo&Surg group). The primary outcomes were cancer-specific survival (CSS) and overall survival (OS). Propensity score matching (PSM) was performed to balance the baseline factors.

According to the multivariate analysis, surgery benefitted both CSS and OS (P < 0.001). After PSM, surgical resection still showed significant benefits in terms of both CSS and OS (P < 0.001). Surgery combined with chemotherapy increased the median CSS by at least 63 months and the median OS by at least 76 months. Subgroup analysis of the Chemo&Surg group revealed that the timing of surgery was not an independent influencing factor for either CSS or OS.

We found that performing additional surgery, in addition to systematic therapy, for GIST liver metastasis resulted in improved CSS and OS. These benefits were not affected by the timing of surgery during systemic treatment.

Differentiation therapy is an alternative strategy used in treating chronic myelogenous leukemia to induce the differentiation of immature or cancerous cells toward mature cells and inhibit tumor cell proliferation. We aimed to explore N-glycans' roles in erythroid differentiation using the sodium butyrate (NaBu)-induced model of K562 cells (WT/NaBu cells). Here, using lectin blot, flow cytometry, real-time PCR, and mass spectrometry analyses, we demonstrated that the mRNA levels of N-acetylglucosaminyltransferase Ⅲ ((encoded by the MGAT3 gene) and its product (bisected N-glycans) were significantly increased during erythroid differentiation. To address the importance of GnTN-acetylglucosaminyltransferase-Ⅲ in this progress, we established a stable MGAT3 KO K562 cell line using the CRISPR/Cas9 technology. Compared to WT/NaBu cells, MGAT3 KO significantly impeded the progression of erythroid differentiation, as shown in decreased cell color and levels of erythroid markers, glycophorin A (CD235a), and β-globin. Consistently, MGAT3 KO mitigated the inhibitory impact of NaBu on cell proliferation. During induction, MGAT3 KO suppressed the cellular phosphorylated tyrosine and phospho-extracellular signal-regulated kinase (ERK)1/2 levels. Inhibition of the ERK/mitogen-activated protein kinase signaling pathway using U0126 blocked erythroid differentiation while concurrently suppressing the expression levels of MGAT3 and bisected N-glycans. Furthermore, the lack of bisecting GlcNAc modification on c-Kit and transferrin receptor 1 (CD71) suppressed cellular signaling and accelerated the degradation of the CD71 protein, respectively. Our study highlights the critical role of MGAT3 in regulating erythroid differentiation associated with the ERK/mitogen-activated protein kinase signaling pathway, which may shed light on identifying new differentiation therapy in chronic myelogenous leukemia.

Whole slide image (WSI) classification is of great clinical significance in computer-aided pathological diagnosis. Due to the high cost of manual annotation, weakly supervised WSI classification methods have gained more attention. As the most representative, multiple instance learning (MIL) generally aggregates the predictions or features of the patches within a WSI to achieve the slide-level classification under the weak supervision of WSI labels. However, most existing MIL methods ignore spatial position relationships of the patches, which is likely to strengthen the discriminative ability of WSI-level features.

In this paper, we propose a novel positional encoding-guided transformer-based multiple instance learning (PEGTB-MIL) method for histopathology WSI classification. It aims to encode the spatial positional property of the patch into its corresponding semantic features and explore the potential correlation among the patches for improving the WSI classification performance. Concretely, the deep features of the patches in WSI are first extracted and simultaneously a position encoder is used to encode the spatial 2D positional information of the patches into the spatial-aware features. After incorporating the semantic features and spatial embeddings, multi-head self-attention (MHSA) is applied to explore the contextual and spatial dependencies of the fused features. Particularly, we introduce an auxiliary reconstruction task to enhance the spatial-semantic consistency and generalization ability of features.

The proposed method is evaluated on two public benchmark TCGA datasets (TCGA-LUNG and TCGA-BRCA) and two in-house clinical datasets (USTC-EGFR and USTC-GIST). Experimental results validate it is effective in the tasks of cancer subtyping and gene mutation status prediction. In the test stage, the proposed PEGTB-MIL outperforms the other state-of-the-art methods and respectively achieves 97.13±0.34%, 86.74±2.64%, 83.25±1.65%, and 72.52±1.63% of the area under the receiver operating characteristic (ROC) curve (AUC).

PEGTB-MIL utilizes positional encoding to effectively guide and reinforce MIL, leading to enhanced performance on downstream WSI classification tasks. Specifically, the introduced auxiliary reconstruction module adeptly preserves the spatial-semantic consistency of patch features. More significantly, this study investigates the relationship between position information and disease diagnosis and presents a promising avenue for further research.

The prognosis of patients with metastatic GIST and imatinib-sensitive primary mutations has significantly improved. However, limited data are available to inform patients about outcomes across different lines of treatment. This retrospective analysis aims to evaluate patient outcomes at a large German GIST referral center over the past 15 years.

Overall survival (OS) and progression-free survival (PFS) were analyzed in patients with metastatic GIST, with diagnosis of metastases between 2008 and 2021, when at least three lines of treatment were available in Germany (n = 174).

The median overall survival far exceeds historical data for patients with primary exon 11 and exon 9 mutations (median OS in palliative treatment with imatinib: 7.1 years; median OS in second-line palliative treatment with sunitinib: 2.9 years; median OS in third-line palliative treatment with regorafenib: 1.9 years). Among those patients who received palliative imatinib treatment, no significant difference in median OS survival was observed between those who had received perioperative imatinib for localized disease and those who did not. Furthermore, the location of metastases significantly impacted survival, whereas the time between the initial diagnosis and the diagnosis of metastases had no significant effect on survival.

In conclusion, this study provides a novel, real-world reference for survival outcomes in patients with metastatic GIST.

Gastrointestinal stromal tumors (GIST) are rare in the rectum. These usually present with symptoms produced by compression of pelvic organs or bleeding. Surgery is the treatment of choice, however, at times the surgery can be mutilating and organ preservation may not be possible. In such cases imatinib can be used. We report a case of rectal GIST that presented with urinary obstruction and obstipation treated with long-term imatinib with very good response and relief of symptoms, which prompted the patient to refuse surgery and resulted in organ preservation.

Diffuse large B-cell lymphoma (DLBCL) includes the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, which differ in cell of origin, genetics, and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCL in vitro and in vivo. We validated three chemically distinct NAMPTis for their on-target activity based on biochemical and genetic rescue approaches and found the ratio between NAMPT and PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher antitumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacologic and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs. Significance: Targeted therapies have emerged for the ABC subtype of DLBCL, but not for the GCB subtype, despite the evidence of a significant subset of high-risk cases. We identify a drug that specifically targets a subset of GCB-DLBCL and provide preclinical evidence for BCL2 translocations as biomarkers for their identification.

Gastrointestinal stromal tumor (GIST) is characterized by well-defined oncogenes. Despite the significant improvement in treatment outcomes with adjuvant imatinib therapy for patients, drug resistance remains a major challenge for GIST therapy. This review focuses on the mechanisms contributing to drug resistance phenotype in GIST, such as primary imatinib-resistant mutants, secondary mutations, non-covalent binding of TKI to its target, tumor heterogeneity, re-activation of pro-survival/proliferation pathways through non-KIT/PDGFRA kinases, and loss of therapeutic targets in wild-type GIST. Corresponding suggestions are proposed to overcome drug-resistance phenotype of GIST. This review also summarizes the suitability of currently approved TKIs on different KIT/PDGFRA mutations and updates related clinical trials. Recent potent drugs and emerging strategies against advanced GISTs in clinical trials are presented. Additionally, metabolic intervention offers a new avenue for clinical management in GIST. A landscape of metabolism in GIST and metabolic changes under imatinib treatment are summarized based on currently published data. The OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA mutants. Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.

Imatinib-induced skin rash poses a significant challenge for patients with gastrointestinal stromal tumor, often resulting in treatment interruption or discontinuation and subsequent treatment failure. However, the underlying mechanism of imatinib-induced skin rashes in gastrointestinal stromal tumor patients remains unclear. A total of 51 patients (27 with rash and 24 without rash) were enrolled in our study. Blood samples were collected concomitantly with the onset of clinical manifestations of rashes, and simultaneously collecting clinical relevant information. The imatinib concentration and untargeted metabolomics were performed by ultra-high-performance liquid chromatography-tandem mass spectrometry. There were no significant differences in age, gender, imatinib concentration and white blood cells count between the rash group and the control group. However, the rash group exhibited a higher eosinophil count (P<0.05) and lower lymphocyte count (P<0.05) compared to the control group. Untargeted metabolomics analysis found that 105 metabolites were significantly differentially abundant. The univariate analysis highlighted erucamide, linoleoylcarnitine, and valine betaine as potential predictive markers (AUC≥0.80). Further enriched pathway analysis revealed primary metabolic pathways, including sphingolipid signaling pathway, sphingolipid metabolism, cysteine and methionine metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, and biosynthesis of amino acids. These findings suggest that the selected differential metabolites could serve as a foundation for the prediction and management of imatinib-induced skin rash in gastrointestinal stromal tumor patients.

Gastrointestinal stromal tumors (GISTs) present a complex clinical landscape, where precise preoperative risk assessment plays a pivotal role in guiding therapeutic decisions. Conventional methods for evaluating mitotic count, such as biopsy-based assessments, encounter challenges stemming from tumor heterogeneity and sampling biases, thereby underscoring the urgent need for innovative approaches to enhance prognostic accuracy.

The primary objective of this study was to develop a robust and reliable computational tool, PROMETheus (Preoperative Mitosis Estimator Tool), aimed at refining patient stratification through the precise estimation of mitotic count in GISTs.

Using advanced Bayesian network methodologies, we constructed a directed acyclic graph (DAG) integrating pertinent clinicopathological variables essential for accurate mitotic count prediction on the surgical specimen. Key parameters identified and incorporated into the model encompassed tumor size, location, mitotic count from biopsy specimens, surface area evaluated during biopsy, and tumor response to therapy, when applicable. Rigorous testing procedures, including prior predictive simulations, validation utilizing synthetic data sets were employed. Finally, the model was trained on a comprehensive cohort of real-world GIST cases (n=80), drawn from the repository of the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, with a total of 160 cases analyzed.

Our computational model exhibited excellent diagnostic performance on synthetic data. Different model architecture were selected based on lower deviance and robust out-of-sample predictive capabilities. Posterior predictive checks (retrodiction) further corroborated the model's accuracy. Subsequently, PROMETheus was developed. This is an intuitive tool that dynamically computes predicted mitotic count and risk assessment on surgical specimens based on tumor-specific attributes, including size, location, surface area, and biopsy-derived mitotic count, using posterior probabilities derived from the model.

The deployment of PROMETheus represents a potential advancement in preoperative risk stratification for GISTs, offering clinicians a precise and reliable means to anticipate mitotic counts on surgical specimens and a solid base to stratify patients for clinical studies. By facilitating tailored therapeutic strategies, this innovative tool is poised to revolutionize clinical decision-making paradigms, ultimately translating into improved patient outcomes and enhanced prognostic precision in the management of GISTs.

A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i-k (IC50 = 35-116 nM) and the 5-methoxy derivative 4e (IC50 = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k. In addition, the most active compound 4k, having an ATP-competitive mechanism of action, proved to be also a potent inhibitor of CLK1/CLK4 (IC50 = 20 and 26 nM) and, to a lesser extent, of haspin (IC50 = 76 nM) kinases. In silico docking studies within the DYRK1A, CLK1/CLK4 and haspin ATP binding sites were carried out to understand the interactions of our tetracyclic derivatives 4 with these targets. Antiproliferative activities on U87/U373 glioblastoma cell lines of the most potent compound 4k showed a moderate effect (IC50 values between 33 and 46 μM). Microsomal stabilities of the designed compounds 4a-m were also investigated, showing great disparities, depending on benzo[b]thiophene ring 5-substitution.

Therapeutic drug monitoring of imatinib is widely performed to individualize imatinib dosage. While N-desmethyl imatinib is an active metabolite of imatinib, its concentrations are not routinely determined.

Imatinib and N-desmethyl imatinib trough plasma concentrations at steady-state were obtained from 295 patients with either chronic myeloid leukemia or gastrointestinal stromal tumor to see whether N-desmethyl imatinib provided additional information. Pharmacokinetic data were analyzed using a nonlinear mixed effect approach. Correlations between several pharmacokinetic metrics of drug exposure were evaluated.

The mean value of the N-desmethyl imatinib/imatinib ratio of trough concentrations was 0.31 with half of the values between 0.23 and 0.37. N-desmethyl imatinib and total (i.e., N-desmethyl imatinib plus imatinib) trough plasma concentrations or area under the curve values were closely correlated with imatinib values. The distribution of imatinib or total concentrations between patients requiring imatinib dosage adjustment, or not, was similar.

These results do not clearly support routine N-desmethyl monitoring since it does not provide additional information to imatinib data.

Recent developments in technology have led to rapid advances in precision medicine, especially due to the rise of next-generation sequencing and molecular profiling. These technological advances have led to rapid advances in research, including increased tumor subtype resolution, new therapeutic agents, and mechanistic insights. Certain therapies have even been approved for molecular biomarkers across histopathological diagnoses; however, translation of research findings to the clinic still faces a number of challenges. In this review, the authors discuss several key challenges to the clinical integration of precision medicine, including the blood-brain barrier, both a lack and excess of molecular targets, and tumor heterogeneity/escape from therapy. They also highlight a few key efforts to address these challenges, including new frontiers in drug delivery, a rapidly expanding treatment repertoire, and improvements in active response monitoring. With continued improvements and developments, the authors anticipate that precision medicine will increasingly become the gold standard for clinical care.

Obesity, one of the most common chronic conditions affecting the human race globally, affects several organ systems, including the respiratory system, where it contributes to onset and high burden of asthma. Childhood onset of obesity-related asthma is associated with high persistent morbidity into adulthood.

In this review, we discuss the disease burden in children and adults to highlight the overlap between symptoms and pulmonary function deficits associated with obesity-related asthma in both age ranges, and then discuss the potential role of three distinct mechanisms, that of mechanical fat load, immune perturbations, and of metabolic perturbations on the disease burden. We also discuss interventions, including medical interventions for weight loss such as diet modification, that of antibiotics and anti-inflammatory therapies, as well as that of surgical intervention on amelioration of burden of obesity-related asthma.

With increase in obesity-related asthma due to increasing burden of obesity, it is evident that it is a disease entity distinct from asthma among lean individuals. The time is ripe to investigate the underlying mechanisms, focusing on identifying novel therapeutic targets as well as consideration to repurpose medications effective for other obesity-mediated complications, such as insulin resistance, dyslipidemia and systemic inflammation.

Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.

A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial β-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells.

HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer.

This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model.

This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.

Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract, the treatment of which represents a significant breakthrough in targeted cancer therapy. Given its overall rare nature, genomic differences and clinical implications between demographic groups have not been previously investigated.

Anonymized demographic, clinical, and genomic data from 1,559 GIST patients in the American Association for Cancer Research Project GENIE database were analyzed using cBioPortal and custom Python scripts. Data on patient demographics, genomic alterations, and co-occurrence genetic alerations were collected and classified according to clinical implications using the OncoKB database. χ2 tests for differences in genomic alterations were used across various demographic factors and mutual exclusivity analysis was employed to identify co-mutation patterns.

Male patients demonstrated higher incidence of PDGFRA mutation (14.56% vs. 8.05%; p < 0.001), while female patients had higher likelihood of NF1 mutations (7.46% vs. 3.23%; p = 0.001). Asian patients had higher alteration rates at KIT (85.59%; p = 0.002). Co-occurrence analysis revealed KIT alterations frequently co-occurred with CDKN2A (q < 0.001), MTAP (q = 0.045), and PTEN (q = 0.056), while there was mutual exclusivity with PDGFRA (q < 0.001), NF1 (q < 0.001), and BRAF (q = 0.015). CDKN2A alterations co-occurred with MTAP (q < 0.001) and PIK3CA (q = 0.015), while being mutually exclusive with TP53 (q = 0.002) and NF1 (q = 0.007). Trends were similar among patients who had received no prior medical treatment. Imatinib-resistant mutations were more common among male patients (25.6% vs. 18.9%; p = 0.0056) and individuals under 55 (27.3% vs. 20.9%; p = 0.0228). Among patients with imatinib-resistant mutations, 77.78% had sunitinib resistance, while 70.25% maintained sensitivity to ripretinib.

Sex and race/ethnic differences in genomic alterations, as well as co-mutations, were prevalent among patients with GIST. Variations in mutational profiles highlight the importance of distinct genetic drivers that may be targeted to treat different patient populations.