Gastrointestinal Stromal Tumors Research Articles

Monitoring advanced gastrointestinal stromal tumor with circulating tumor DNA.

This review explores the role of circulating tumor (ct)DNA as a biomarker for clinical decision-making and monitoring purposes in metastatic gastrointestinal stromal tumor (GIST) patients. We discuss key insights from recent clinical trials and anticipate the future perspectives of ctDNA profiling within the clinical landscape of GIST. The identification and molecular characterization of KIT/platelet-derived growth factor receptor alpha (PDGFRA) mutations from ctDNA in metastatic GIST is feasible and reliable. Such identification through ctDNA serves as a predictor of clinical outcomes to tyrosine-kinase inhibitors (TKIs) in metastatic patients. Additionally, conjoined ctDNA analysis from clinical trials reveal the evolving mutational landscapes and increase in intratumoral heterogeneity across treatment lines. Together, this data positions ctDNA determination as a valuable tool for monitoring disease progression and guiding therapy in metastatic patients. These collective efforts culminated in the initiation of a ctDNA-based randomized clinical trial in GIST, marking a significant milestone in integrating ctDNA testing into the clinical care of GIST patients. The dynamic field of ctDNA technologies is rapidly evolving and holds significant promise for research. Several trials have successfully validated the clinical utility of ctDNA in metastatic GIST, laying the foundations for its prospective integration into the routine clinical management of GIST patients.

Four and a half LIM domains 2 (FHL2) attenuates tumorigenesis of gastrointestinal stromal tumors (GISTs) by negatively regulating KIT signaling.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn't alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.

A rare case of extragastrointestinal stromal tumor of vocal cord - case report.

Gastrointestinal stromal tumors (GISTs) are the mesenchymal tumors of the gastrointestinal tract. Extra Gastrointestinal stromal tumors (EGISTs) are rare neoplasms that occur outside the gastrointestinal tract [1]. Miettinen et al. [2] described the first EGIST in 1999. EGIST accounts for 10% of all GISTs [3]. The main distinction between GIST and EGIST is the site of origin of the primary tumor, as GIST occurs throughout the GI tract, from the esophagus to the anus, whereas EGIST is a tumor without any connection with the intestinal wall and are reported in the retroperitoneum, mesentery, and omentum [4]. Hu et al. [5] reported a first case report of EGIST of larynx.We present a second case report of Extra-gastrointestinal stromal tumor of larynx a 47-year-old male reported to ENT Department Command Hospital Central Command Lucknow with complaints of Hoarseness. On examination found to have right vocal cord growth for which he underwent excision of right vocal cord growth. Histopathological examination showed typical of a spindle-cell GIST, showing strong immunoreactivity for CD 117, DOG1, Vimentin and CD 99. 6 months follow up post surgery with no recurrence.

Computed tomography radiogenomics: A potential tool for prediction of molecular subtypes in gastric stromal tumor.

Preoperative knowledge of mutational status of gastrointestinal stromal tumors (GISTs) is essential to guide the individualized precision therapy. To develop a combined model that integrates clinical and contrast-enhanced computed tomography (CE-CT) features to predict gastric GISTs with specific genetic mutations, namely KIT exon 11 mutations or KIT exon 11 codons 557-558 deletions. A total of 231 GIST patients with definitive genetic phenotypes were divided into a training dataset and a validation dataset in a 7:3 ratio. The models were constructed using selected clinical features, conventional CT features, and radiomics features extracted from abdominal CE-CT images. Three models were developed: ModelCT sign, modelCT sign + rad, and model CTsign + rad + clinic. The diagnostic performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis and the Delong test. The ROC analyses revealed that in the training cohort, the area under the curve (AUC) values for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic for predicting KIT exon 11 mutation were 0.743, 0.818, and 0.915, respectively. In the validation cohort, the AUC values for the same models were 0.670, 0.781, and 0.811, respectively. For predicting KIT exon 11 codons 557-558 deletions, the AUC values in the training cohort were 0.667, 0.842, and 0.720 for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic, respectively. In the validation cohort, the AUC values for the same models were 0.610, 0.782, and 0.795, respectively. Based on the decision curve analysis, it was determined that the modelCT sign + rad + clinic had clinical significance and utility. Our findings demonstrate that the combined modelCT sign + rad + clinic effectively distinguishes GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions. This combined model has the potential to be valuable in assessing the genotype of GISTs.

Small Bowel Gastrointestinal Stromal Tumors: The Value of CT Enterography in Assessing Pathological Aggressiveness.

This study aimed to characterize the computed tomography (CT) enterography features of the small bowel gastrointestinal stromal tumors (GIST) and to determine the association with pathological aggressiveness. Computed tomography enterography images of 30 patients with the histologically confirmed small bowel GIST were retrospectively enrolled. Tumor size, location, border, growth pattern, enhancement pattern, necrosis, calcification, ulceration, internal air, nodal metastasis, liver metastasis, peritoneal metastasis, and draining vein were evaluated. Relationships between imaging features and pathological aggressiveness were analyzed using χ 2 test or Fisher exact test. Correlations among CT features were analyzed using Spearman correlation analysis. There were significant differences in tumor size between different risk levels ( F = 8.388, P < 0.001). There were statistically significant differences in the 5 imaging manifestations of necrosis, ulcer, tumor boundary, drainage vein, and intratumoral gas ( P < 0.05). There was a significant negative correlation between tumor size and enhancement type as well as clear tumor boundary. There was a significant positive correlation between tumor size and necrosis, ulcer, drainage vein, intratumoral gas, liver metastasis, and peritoneal metastasis. Some CT enterography imaging features might be useful in the determination of the pathological aggressiveness in the patients with small bowel GIST.

Efficacy and histologic frequencies of endoscopic ultrasonography‐guided tissue acquisition using conventional fine‐needle aspiration needles for gastric subepithelial hypoechoic mass

AbstractIntroduction/PurposeFor gastric subepithelial lesions (GSELs) showing a hypoechoic mass (HM) on endoscopic ultrasonography (EUS) imaging, the utility of EUS‐guided tissue acquisition using conventional fine‐needle aspiration needles (EUS‐TA‐CFNAN) and the frequency of histological types remain unclear. This study aimed to examine this issue.MethodsThis prospective observational study enrolled 291 consecutive patients who underwent EUS‐TA‐CFNAN for GSELs showing an HM (GSELHM) on EUS imaging. Immunohistochemical analysis was performed for all EUS‐TA‐CFNAN and surgically resected specimens. The main outcome measures were the technical results of EUS‐TA‐CFNAN and the frequency of histological types in GSELHM.ResultsThe endoscopic ultrasound‐guided tissue acquisition using conventional fine‐needle aspiration needle diagnosis rate for GSELHM was 80.1% (95% confidence interval [CI]: 75.0–84.5, 233/291). It was significantly lower for antrum (P = 0.004) and lesions smaller than 2 cm (P = 0.003). There were no adverse events. The immunohistochemical diagnoses of EUS‐TA‐CFNAN included 149 cases of gastrointestinal stromal tumour (GIST) (51.2%), 48 cases of leiomyoma (16.5%), 11 cases of schwannoma (3.8%), 8 cases of the ectopic pancreas (2.7%), 5 cases of subepithelial lesion like cancer (1.7%), 12 cases of other lesions (4.1%), and 58 cases of undiagnosable lesions (19.9%). The frequency of malignant or potentially malignant tumour in GSELHM was 55.0% (95% CI: 49.1–60.8, 160/291). Surgery was performed in 149 patients according to the conclusive EUS‐TA‐CFNAN results, in which the diagnostic accuracy of EUS‐TA‐CFNAN was 97.3% (95% CI: 94.7–99.9, 145/149).ConclusionThe use of EUS‐TA‐CFNAN for GSELHMs is safe and accurate. Gastric subepithelial lesions showing a hypoechoic mass have a reasonably high possibility of containing malignant or potentially malignant tumours, including GISTs.

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients’ wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

Comparable long‑term survival outcomes of endoscopic treatment versus surgical treatment for gastrointestinal stromal tumors with a diameter of 5–10 cm

Currently, endoscopic treatment for small gastrointestinal stromal tumors (GIST) has been widely accepted. However, for tumors larger than 5 cm, endoscopic treatment has not been recognized by national guidelines as the standard therapy due to concerns about safety and adverse tumor outcomes. Therefore, this study compares the long-term survival outcomes of endoscopic treatment and surgical treatment for GIST in the range of 5–10 cm. We selected patients with GIST from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. Kaplan–Meier analysis and the log-rank test were employed to compare the long-term survival outcomes between endoscopic treatment and surgical treatment. A multivariate Cox proportional hazards model was used for analysis to identify risk factors influencing patient prognosis. To balance baseline data, we performed 1:1 propensity score matching (PSM). A total of 1223 GIST patients were included, with 144 patients (11.8%) received endoscopic treatment and 1079 patients (88.2%) received surgical treatment. Before PSM, there was no significant difference in the long-term survival rates between the two groups [5-year OS (86.5% vs. 83.5%, P = 0.42), 10-year OS (70.4% vs. 66.7%, P = 0.42)]. After adjusting for covariates, we found that the overall survival (HR = 1.26, 95% CI 0.89–1.77, P = 0.19) and cancer-specific survival (HR = 1.69, 95% CI 0.99–2.89, P = 0.053) risks were comparable between the endoscopic treatment group and the surgical treatment group. In the analysis after PSM, there was no significant difference between the endoscopic treatment group and the surgical treatment group. Our study found that for GIST patients with tumor sizes between 5 and 10 cm, the long-term OS and CSS outcomes were similar between the endoscopic treatment group and the surgical treatment group.

Imaging Gigantic Small Bowel Gastrointestinal Stromal Tumours Through Different Radiological Lenses: A Case Report

Gastrointestinal stromal tumours (GIST) account for 1–3% of all the gastrointestinal (GI) neoplasms. It is the most common mesenchymal tumour in the Gl tract. The majority of GISTs are KIT gene positive; however, it is necessary to diagnose them pre-operatively. Here, the authors report the case of a 65-year-old male who presented with pain and a lump in the umbilical region for the last 2 years. On abdominal ultrasound, there was a heterogeneously hypoechoic mass in the umbilical region, with lobulated margins and central necrotic areas. On small bowel series, the core of the mass showed faint contrast opacification. Contrast-enhanced CT of the abdomen showed a heterogeneously enhancing, lobulated exophytic lesion arising from the small bowel loops, the central core of the lesion demonstrating an air-contrast level. Under ultrasound guidance, the lesion was biopsied. Histopathological findings were suggestive of a spindle cell tumour. The sample was c-KIT positive. Hence, the diagnosis of GIST was confirmed. The patient was given imatinib after resection of the mass. Usually, a GIST of larger size has higher malignant and metastatic potential; however, this article shows a gigantic small bowel GIST with cavitation and heterogeneity in different imaging modality, and still has no metastasis on imaging or high mitotic activity, and nuclear atypia on histopathology. A radiologist should also know the imaging pattern on conventional imaging and ultrasound, apart from usual cross-sectional imaging.

The advent of the first electric driven EUS-guided 17 gauge core needle biopsy – A pilot study on subepithelial lesions

Background and aims This pilot study aimed to evaluate safety and tissue sampling from subepithelial lesions (SEL) in the upper gastrointestinal tract with a novel electric motor driven endoscopic ultrasonography (EUS)-guided 17-gauge (G) size core needle biopsy (CNB) instrument. Methods An investigator-led prospective open label, performance and safety control study, including seven patients (female n = 4, median 71 y, range 28–75) with a determined SEL (median size 30 mm, range 17–150 mm) in the upper digestive tract (stomach n = 6, duodenum n = 1) were eligible and later followed up 14 days after index procedure. All investigations were completed according to protocol with three FNB 22-G passes with four fanning strokes and two EndoDrill® 17-G passes with three fanning strokes. Results Quality of samples as ‘visible pieces’ (>5 mm): FNB (n = 5/7) (fragmented/blood imbibed n = 1, poor tissue quantity n = 1) compared with 17-G CNB (n = 7/7). Histological result which led to final diagnosis (leiomyoma n = 2, adenocarcinoma n = 1, schwannoma n = 1, neuroendocrine tumour n = 1, desmoid tumour n = 1 and gastrointestinal stromal tumour (GIST) n = 1) could be obtained with the 17-G CNB instrument in all seven patients. FNB technique reached correct diagnosis in six patients. No serious adverse event were recorded. Conclusions By using an electric driven 17-G biopsy device, a true cylinder of core tissue can be obtained in one single puncture from the area of interest reducing the need for a second sampling. The absolute benefit of EUS-guided CNB is that the sample can be handled and histologically prepared in the same manner as standard percutaneous core needle sample, e.g., breast and prostate cancer.

Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands: data from a cross-sectional multicentre study

PurposeThis study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life.MethodsA cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30.ResultsIn total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7–214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties.ConclusionEven in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.

Imaging of pediatric gastrointestinal tumors: A tertiary center experience over 19 years

PurposeGastrointestinal tract (GIT) tumors in children are rare and there is a scarcity of data on their imaging features. The purpose of this study was to determine thefrequency of various GIT tumor types in children and to identify key imaging characteristics. MethodsThis retrospective, single-center study was approved by the local ethics committee. Children with histologically proven GIT tumours (malignantand benign) who had imaging available on the institutional PACS between May 1, 2000 and Dec 31, 2019 were included. Demographic data and available imaging was reviewed by two blinded radiologists. ResultsIn total, 90 children (45 male, mean age 9.3 ± 4.3 years) with GIT tumours were included. The final diagnoses included polyps (n = 28), lymphomas/PTLD (n = 27), neuroendocrine tumours (n = 16), adenocarcinoma (n = 6), adenoma (n = 5), gastrointestinal stromal tumor (GIST) (n = 3), inflammatory myofibroblastic tumours (n = 2) and lastly leiomyoblastoma, leiomyoma and lipoma (1 each). All GIT segments were affected, but overall the small and large bowel had most lesions. Eighty-one percent children had a single lesion while remaining 19 % had multiple lesions. The neoplastic process manifested as intra-luminal lesion (58 %) or wall thickening (42 %) on imaging. Multiple cystic areas and vascular pedicle for polyps; and hypoechogenecity of the mass or wall thickening and aneurysmal dilatation for lymphomas, were the characteristic imaging features. None of the neuroendocrine tumours affecting appendix were seen on pre-resection imaging. ConclusionsVariety of benign and malignant tumors are seen throughout the childhood. Polyps, lymphomas and appendiceal neuroendocrine tumors are common lesions. Characteristic imaging features of juvenile polyps and lymphomas on ultrasound may help narrowing the differentials, and guide further work up.

Expression of TGF-β1 in Gastrointestinal Stromal Tumor (GIST) and the Occurrence of Frequent Desmoplasia.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms with variable behavior characterized by differentiation toward the interstitial cells of Cajal occurring anywhere in the gastrointestinal stromal tract. Frequently, GISTs have fibrous stroma within tumor cell proliferation areas, which is unlike other types of malignant tumors. If this desmoplasia is active, there is a possibility that some sort of transmitter exists between GIST cells and cells related to fibrosis in the tumor cell proliferation areas. Transforming growth factor (TGF)-β isoforms, particularly TGF-β1, are critical for fibrosis pathogenesis. TGF-β1 regulation of myofibroblasts and fibroblasts during fibrosis is well described. The induced fibroblast activation resulting in myofibroblast differentiation has been reported as an important source of collagen, glycoproteins, proteoglycans, and matrix metallopeptidases in wound healing and fibrosis. However, there are a few reports on the relationship between TGF-β1 and GISTs. This study aims to clarify TGF-β1 expression in 30 gastric GISTs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). For comparison, we also enrolled 30 samples of gastric tubular adenocarcinoma (GTAC). We confirmed TGF-β1 expression (H-score ≥50 points) in 57% of GIST and 13% of GTAC samples, a significant difference between the 2 tumor types ( P =0.001). We examined the TGF-β1 mRNA expression of 3 representative GIST samples, each having their respective immunostained areas detected by RT-PCR. Finding TGF-β1 expression may indicate that this cytokine plays a part in the formation of desmoplasia within GIST cell proliferative areas.

Gastrointestinal stromal tumors : Where do we stand?

For more than 20 years gastrointestinal stromal tumors (GIST) have been aparadigm for atargeted treatment with tyrosine kinase inhibitors. Afundamental prerequisite for aneoadjuvant or adjuvant treatment of localized GIST or an additive treatment of metastatic GIST is the molecular typing of tumors, ideally at the initial diagnosis. In addition, the possibility of ahereditary or syndromic predisposition must be considered because this results in consequences for the treatment and adifferent follow-up strategy.

Abstract CT290: Trial in progress: Evaluation of the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of 177Lu-NeoB in patients with advanced solid tumors expressing gastrin-releasing peptide receptor (GRPR)

Abstract Introduction: Many common cancers such as breast, lung, and prostate, plus several less common malignancies such as gastrointestinal stromal tumors (GIST) and glioblastoma (GBM) express or are associated with the Gastrin-Releasing Peptide Receptor (GRPR). Therefore, GRPR could be utilized for the development of innovative approaches to tumor imaging and therapeutic interventions. NeoB is a new generation bombesin analog, which binds to GRPR with high affinity/specificity. The structure of NeoB permits radiolabeling with gallium-68 [68Ga] (for imaging) or lutetium-177 [177Lu] (for therapy), making it suitable for theranostics. Pre-clinical and early phase clinical data confirmed the utility of [68Ga]-NeoB for identification of GRPR-expressing tumors and demonstrated the in vitro and in vivo antitumor activity of [177Lu]-NeoB. In the Phase IIa part of this first-in-human study of [177Lu]-NeoB (NeoRay; NCT03872778), we aim to characterize the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of [177Lu]-NeoB in patients with selected advanced solid tumors known to express GRPR. Methods: The Phase IIa part of this Phase I/IIa multi-center, open-label study will enroll approximately 50 adult patients (age ≥18 years old) with advanced/metastatic cancers and for whom no standard therapy is available, tolerated or appropriate. Patients will be enrolled across 4 cohorts: HR-positive, HER2-negative breast cancer (Cohort A), prostate cancer (Cohort B), GIST (Cohort C) or any solid tumor overexpressing GRPR including recurrent GBM, and who have moderate renal impairment (CrCl ≥30 mL/min - &amp;lt;60 mL/min; Cohort D). Eligible patients must have at least one measurable lesion with confirmed uptake of [68Ga]-NeoB and have an ECOG performance status of ≤1. Patients will be treated with [177Lu]-NeoB at the recommended Phase II dose (9.25 GBq [250 mCi]) for a minimum of 2 treatment cycles, each lasting 6 weeks. The primary endpoints are assessment of the disease control rate with [177Lu]-NeoB in cohorts A, B and C, and evaluation of the pharmacokinetics (PK), biodistribution and radiation dosimetry in patients with impaired renal function (Cohort D). Secondary endpoints include assessment of the antitumor activity, PK, distribution, radiation dosimetry, and impact on the quality of life of patients in the [177Lu]-NeoB cohorts (A, B and C) as well as the safety and tolerability of both [177Lu]-NeoB and [68Ga]-NeoB across all cohorts. Citation Format: Erik Mittra, Andrei Iagaru, Astrid Van der Veldt, Luigi Aloj, Jeffrey Wong, Loic Djaileb, Dhrubajyoti Pathak, Yongmin Liu, Lilja Solnes. Trial in progress: Evaluation of the safety, tolerability, whole-body distribution, radiation dosimetry and antitumor activity of 177Lu-NeoB in patients with advanced solid tumors expressing gastrin-releasing peptide receptor (GRPR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT290.

Abstract CT089: A phase 1 multi-center, open label, dose escalation study to evaluate the safety, pharmacokinetics (PK) and anti-tumor activity of T-1301, a novel small molecular multi-target kinase inhibitor, in patients with advanced solid tumors

Abstract Background: T-1301 is a novel small molecule multi-target kinase inhibitor, it also exhibited potent inhibitory activity against both wild type and mutant forms of various kinases, i.e., ABL1, FLT3, c-KIT, PDFGRA, RET, and TRKA. In in vitro studies, T-1301 effectively inhibited growth of acute myeloid leukemia (AML) as well as gastrointestinal stromal tumor (GIST) cells carrying mutations that are resistant to KIT-targeting tyrosine kinase inhibitors (TKIs) in clinical use. In animal studies, tumor regressions were observed in AML and GIST xenograft models, while growth inhibition were observed in various other types of solid tumor models. Method: This is an open label, multi-centered Phase 1 dose escalating study (NCT05156203). The primary objectives are to establish the maximal tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to assess the safety and tolerability of T-1301. The secondary objectives are to evaluate the pharmacokinetics (PK) and therapeutic response after receiving treatment. Eligible Patient should have histologically and cytologically confirmed advanced solid tumors (including lymphoma) with measurable or evaluable target lesion(s) per RICEST v1.1 and refractory to or without standard treatments, ECOG performance status 0-1, and adequate organ function. The dose escalation begins with accelerated titration and switch to the Bayesian Optimal Interval (BOIN) design when either one of the following events is observed in Cycle 1: the first instance of DLT, or any Grade 2 or higher drug-related adverse event (AE) in any patient. Then, at least 2 additional subjects are treated at the current dose level and the dose escalation will follow the Bayesian Optimal Interval (BOIN) design with cohorts of size 3-6.T-1301 is orally administered daily in a 28-day cycle (a 21-day consecutive dosing followed by a 7-day rest). The dosing schedule is once daily (QD) at the initial dose level and could be QD or twice daily starting with the second dose level according to the safety review committee (SRC) decision after reviewing the safety and PK data from each dose level. AEs are assessed according to CTCAE v5.0 and occurrence of dose limiting toxicity (DLT) is determined during the first cycle of treatment. The safety findings are reviewed by the SRC, which will determine the MTD and RP2D. Tumor response evaluation is performed after 2 cycles of treatment and assessed according to RECIST v1.1 criteria. For those who benefit from the study medication after 2 treatment cycles, intra-subject dose escalation for multiple times is allowed in extension study period. Patient recruitment began in December 2021 and is ongoing in Taiwan. Citation Format: Jen-Shi Chen, Ming-Huang Chen, Yi-Chang Liu, Wen-Chi Chou, Nai-Jung Chiang, Hui-Ching Wang, Ta-Sen Yeh, Shih-Feng Cho, Cheng-Hsu Wang, I-Fang Lee, Li-Tzong Chen. A phase 1 multi-center, open label, dose escalation study to evaluate the safety, pharmacokinetics (PK) and anti-tumor activity of T-1301, a novel small molecular multi-target kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT089.

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries

Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited. To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs. This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024. Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased. A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%). In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

Jejunojejunal intussusception induced by a gastrointestinal stromal tumor: a case report and literature review.

Intussusception is defined as the invagination of a proximal segment of the bowel into the adjoining or distal segment. In most adults with intussusception, there is a demonstrable lead point with a definite pathologic abnormality. The clinical features of intussusception include chronic intermittent abdominal pain, nausea and vomiting, constipation, and a palpable abdominal mass. The present case report describes a 62-year-old woman with a 2-week history of abdominal pain and 9-day history of vomiting. Clinical, imaging, and histologic evaluations revealed a jejunojejunal intussusception with a gastrointestinal stromal tumor as the lead point. A gastrointestinal stromal tumor should be considered as a possible lead point in adult patients with intussusception. The implication of reducing the intussusception prior to tumor resection requires further evaluation in view of the risk of venous embolism, including direct spread of malignant cells, in cases involving a large polypoid mass with a necrotic surface that extends to the serosa as shown by intraoperative examination. Accordingly, the rationale for adjuvant therapy with imatinib also requires further evaluation.

Contribution of genetic polymorphism in ABCB1 to individual variations of imatinib plasma levels in patients with gastrointestinal stromal tumor.

Imatinib mesylate (IM) is a first-line treatment option for the majority of patients diagnosed with gastrointestinal stromal tumors (GISTs). Although the clinical benefit is high, interindividual response is variable. This study thus aimed to assess how genetic polymorphisms can affect the blood levels of IM and treatment outcomes in patients with GIST. A total of 31 single-nucleotide polymorphisms (SNPs) in selected cytochrome P450 (P450), ATP-binding cassette transporter (ABC), solute carrier family (SLC), interleukin-4 receptor (IL4R), and vascular endothelial growth factor (VEGF) genes were genotyped using an SNP mass array platform. A total of 192 consecutive patients with GIST who received 400 mg of IM daily were enrolled into the study, with 1,485 blood samples being analyzed. According to genotypes, IM trough concentrations were tested and compared. Progression-free survival (PFS) and overall survival (OS) were also assessed. With a mean follow-up of 75.99 months, trough concentrations of imatinib were examined at average time points of 7.73 for each patient. Polymorphism in ABCB1 rs1045642 was found to be associated with steady-state IM trough plasma levels (P=0.008). Patients with the C genotype (CT + CC) of rs1045642 exhibited higher IM trough concentrations (1,271.09±306.69 ng/mL) compared to those with the TT genotype (1,106.60±206.05 ng/mL). No statistically significant differences in IM plasma concentration were observed for the other SNPs tested. None of the tested SNPs displayed a significant association with patients' survival in this study. This is the largest cohort study evaluating the associations of SNP and imatinib blood trough levels. The ABCB1 rs1045642 genetic polymorphism may exert an effect on the pharmacokinetics of imatinib. The presence of the C allele in ABCB1 rs1045642 is predictive of a higher plasma concentration of IM.

Current Perspectives on Small Bowel Tumors: Overview of Prevalence, Clinical Manifestations, and Treatment Approaches

Small bowel tumors (SBTs) constitute a rare yet increasingly recognized group of gastrointestinal neoplasms, accounting for less than 5% of all gastrointestinal cancers. Despite their infrequency, the incidence of SBTs has exhibited a notable upward trend, underscoring the importance of understanding these diverse and complex tumors. This review consolidates current knowledge on SBTs, encompassing epidemiology, risk factors, clinical manifestations, diagnostic advancements, and treatment modalities. Data from various sources are analyzed to present a comprehensive overview of the evolving landscape of SBTs. Our findings indicate that adenocarcinomas, carcinoid tumors, lymphomas, and gastrointestinal stromal tumors (GISTs) are the common SBTs. While adenocarcinoma and neuroendocrine tumors are the common types of SBTs in the West, GIST and lymphoma are more common in Asia. Common risk factors include genetic syndromes and inflammatory bowel diseases. There is variability in clinical presentations depending on the type of tumors. Although diagnostic challenges persist, advancements in imaging and endoscopic techniques have improved detection rates. Treatment strategies are evolving; surgical resection remains the mainstay for localized disease, augmented by systemic therapies and targeted agents for advanced stages. This review emphasizes the importance of early detection and individualized treatment approaches in improving outcomes for SBT patients. It addresses the need for ongoing research and innovation in managing these tumors.