Cancer-derived exosomes as novel biomarkers in metastatic gastrointestinal cancer.

Gastrointestinal cancer (GIC) is the most prevalent and highly metastatic malignant tumor and has a significant impact on mortality rates. Nevertheless, the swift advancement of contemporary technology has not seamlessly aligned with the evolution of detection methodologies, resulting in a deficit of innovative and efficient clinical assays for GIC. Given that exosomes are preferentially released by a myriad of cellular entities, predominantly originating from neoplastic cells, this confers exosomes with a composition enriched in cancer-specific constituents. Furthermore, exosomes exhibit ubiquitous presence across diverse biological fluids, endowing them with the inherent advantages of non-invasiveness, real-time monitoring, and tumor specificity. The unparalleled advantages inherent in exosomes render them as an ideal liquid biopsy biomarker for early diagnosis, prognosticating the potential development of GIC metastasis.In this review, we summarized the latest research progress and possible potential targets on cancer-derived exosomes (CDEs) in GIC with an emphasis on the mechanisms of exosome promoting cancer metastasis, highlighting the potential roles of CDEs as the biomarker and treatment in metastatic GIC.

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

PURPOSE: This 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. METHODS: A 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. RESULTS: In 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. CONCLUSION: Even 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.

Endoscopic submucosal dissection for the treatment of a large inflammatory fibroid polyp in the gastric antrum prolapsing into the duodenum: A case report.

RATIONALE: Inflammatory fibroid polyp (IFP), also known as Vanek tumor, is a rare, benign gastrointestinal lesion characterized by its inflammatory and fibroid histological features. IFP is often discovered incidentally during endoscopic examinations. It is exceedingly rare for an IFP to prolapse into the duodenum and results in incomplete obstruction of the pylorus. PATIENT CONCERNS: A 64-year-old male patient was admitted to the hospital with recurrent episodes of melena over a 6-month period, along with complaints of dizziness and fatigue in the past 10 days. DIAGNOSES: Gastroscopy showed a giant polypoid mass on the posterior wall of the gastric antrum, prolapsing into the duodenum. Abdominal computer tomography (CT) confirmed the tumor protruding into the duodenum. Pathologic examination of the resected specimen confirmed the IFP diagnosis. INTERVENTIONS: The giant tumor was completely and successfully excised using endoscopic submucosal dissection (ESD). After the surgery, the patient underwent acid suppression and fluid replenishment therapy. OUTCOMES: The patient responded well to ESD and was discharged in stable condition. As of the submission of the case report, there has been no recurrence of the tumor after a 5-month follow-up, and the patient is still under follow-up. LESSONS: While IFPs have traditionally been managed surgically, ESD demonstrates promising treatment outcomes, avoiding the need for surgical distal gastrectomy, and emerges as a safe and effective treatment option.

Surufatinib combined with transarterial embolization versus surufatinib monotherapy in patients with liver metastatic neuroendocrine tumors: Study protocol for a prospective, randomized, controlled trial.

BACKGROUND: More than half of neuroendocrine tumor (NET) patients will experience liver metastasis, and interventional therapy represented by transarterial embolization (TAE) is the main local treatment method. Surufatinib is recommended as a standard systemic treatment for advanced NETs. The efficacy and safety of surufatinib combined with TAE in the treatment of liver metastasis are undetermined. This study was conducted to compare the clinical outcome of surufatinib combined with TAE versus surufatinib monotherapy in liver metastatic NETs. METHODS: This is a prospective, multicenter, open-label, and randomized controlled trial. Patients diagnosed with liver metastatic NETs will be enrolled. Participants are randomly assigned in a 1:1 ratio to either the experimental group or the control group. Patients will be treated with surufatinib plus TAE in the experimental group, while patients in the control group will receive surufatinib monotherapy. The primary endpoint is progression-free survival (PFS) assessed by a blinded independent image review committee (BIIRC). The secondary endpoints are investigator-assessed PFS, liver-specific objective response rate (ORR), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of adverse events. DISCUSSION: This is the first prospective study to investigate the efficacy of surufatinib combined with TAE. We expect this trial to propose a new and effective treatment strategy for liver metastatic NETs.

Application of the convolution neural network in determining the depth of invasion of gastrointestinal cancer: a systematic review and meta-analysis.

BACKGROUND: With the development of endoscopic technology, endoscopic submucosal dissection (ESD) has been widely used in the treatment of gastrointestinal tumors. It is necessary to evaluate the depth of tumor invasion before the application of ESD. The convolution neural network (CNN) is a type of artificial intelligence that has the potential to assist in the classification of the depth of invasion in endoscopic images. This meta-analysis aimed to evaluate the performance of CNN in determining the depth of invasion of gastrointestinal tumors. METHODS: A search on PubMed, Web of Science, and SinoMed was performed to collect the original publications about the use of CNN in determining the depth of invasion of gastrointestinal neoplasms. Pooled sensitivity and specificity were calculated using an exact binominal rendition of the bivariate mixed-effects regression model. I2 was used for the evaluation of heterogeneity. RESULTS: A total of 17 articles were included; the pooled sensitivity was 84% (95% CI, 0.81-0.88), specificity was 91% (95% CI, 0.85-0.94), and the area under the curve (AUC) was 0.93 (95% CI, 0.90-0.95). The performance of CNN was significantly better than that of endoscopists (AUC: 0.93 vs 0.83, respectively; P = .0005). CONCLUSION: Our review revealed that CNN is one of the most effective methods of endoscopy to evaluate the depth of invasion of early gastrointestinal tumors, which has the potential to work as a remarkable tool for clinical endoscopists to make decisions on whether the lesion is feasible for endoscopic treatment.

Retrospective Analyses of PD-L1, LAG-3, TIM-3, OX40L Expressions and MSI Status in Gastroenteropancreatic Neuroendocrine Neoplasms.

We investigated expressions of PD-L1, LAG-3, TIM-3, and OX40L as immune checkpoint proteins, and MSI (repetitive short-DNA-sequences due to defective DNA-repair system) status were analyzed with immunohistochemistry from tissue blocks. Of 83 patients, PD-L1 expression was observed in 18.1% (n = 15) of the patients. None of the patients exhibited LAG-3 expression. TIM-3 expression was 4.9% (n = 4), OX40L was 22.9% (n = 19), and 8.4% (n = 7) of the patients had MSI tumor. A low-to-intermediate positive correlation was observed between PD-L1 and TIM-3 expressions (rho: 0.333, p < 0.01). Although PD-L1 expression was higher in grade 3 NET/NEC, MSI status was prominent in grade 1/2 NET.

Risk factors for positive resection margins after endoscopic resection for gastrointestinal neuroendocrine tumors.

BACKGROUND: In recent years, the incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has remarkably increased due to the widespread use of screening gastrointestinal endoscopy. Currently, the most common treatments are surgery and endoscopic resection. Compared to surgery, endoscopic resection possesses a higher risk of resection margin residues for the treatment of GI-NETs. METHODS: A total of 315 patients who underwent surgery or endoscopic resection for GI-NETs were included. We analyzed their resection modality (surgery, ESD, EMR), margin status, Preoperative marking and Prognosis. RESULTS: Among 315 patients included, 175 cases underwent endoscopic resection and 140 cases underwent surgical treatment. A total of 43 (43/175, 24.57%) and 10 (10/140, 7.14%) patients exhibited positive resection margins after endoscopic resection and surgery, respectively. Multivariate regression analysis suggested that no preoperative marking and endoscopic treatment methods were risk factors for resection margin residues. Among the patients with positive margin residues after endoscopic resection, 5 patients underwent the radical surgical resection and 1 patient underwent additional ESD resection. The remaining 37 patients had no recurrence during a median follow-up of 36 months. CONCLUSIONS: Compared with surgery, endoscopic therapy has a higher margin residual rate. During endoscopic resection, preoperative marking may reduce the rate of lateral margin residues, and endoscopic submucosal dissection may be preferred than endoscopic mucosal resection. Periodical follow-up may be an alternative method for patients with positive margin residues after endoscopic resection.

Biomarker discovery and validation for gastrointestinal tumors: A comprehensive review of colorectal, gastric, and liver cancers.

Gastrointestinal (GI) malignancies, encompassing gastric, hepatic, colonic, and rectal cancers, are prevalent forms of cancer globally and contribute substantially to cancer-related mortality. Although there have been improvements in methods for diagnosing and treating GI cancers, the chances of survival for these types of cancers are still extremely low. According to the World Cancer Research International Fund's most recent figures, stomach cancer was responsible for roughly one million deaths worldwide in 2020. This emphasizes the importance of developing more effective tools for detecting, diagnosing, and predicting the outcome of these cancers at an early stage. Biomarkers, quantitative indications of biological processes or disease states, have emerged as promising techniques for enhancing the diagnosis and prognosis of GI malignancies. Recently, there has been a considerable endeavor to discover and authenticate biomarkers for various GI cancers by the utilization of diverse methodologies, including genomics, proteomics, and metabolomics. This review provides a thorough examination of the current state of biomarker research in the field of gastrointestinal malignancies, with a specific emphasis on colorectal, stomach, and liver cancers. A thorough literature search was performed on prominent databases such as PubMed, Scopus, and Web of Science to find pertinent papers published until November, 2023 for the purpose of compiling this review. The diverse categories of biomarkers, encompassing genetic, epigenetic, and protein-based biomarkers, and their potential utility in the fields of diagnosis, prognosis, and treatment selection, are explored. Recent progress in identifying and confirming biomarkers, as well as the obstacles that persist in employing biomarkers in clinical settings are emphasized. The utilization of biomarkers in GI cancers has significant potential in enhancing patient outcomes. Ongoing research is expected to uncover more efficient biomarkers for the diagnosis and prognosis of these cancers.

Survival benefit of surgery for second primary esophageal cancer following gastrointestinal cancer: a population-based study.

BACKGROUND: The incidence of second primary malignancy is increasing. However, although there is some information on second primary esophageal cancer (SPEC) itself, there is no study or guideline on the use of surgery for SPEC after gastrointestinal cancer (SPEC-GC). Thus, this study aimed to gather evidence for the benefits of surgery by analyzing a national cohort and determining the prognostic factors and clinical treatment decisions for SPEC-GC. METHODS: Data for patients with SPEC-GC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019. The prognostic factors of SPEC-GC were investigated by stepwise Cox proportional hazards regression and Kaplan-Meier analyses for overall survival and cancer-specific survival. RESULTS: A total of 8308 patients with SPEC were selected, including 582 patients with SPEC-GC. Multivariate analysis revealed that surgery, year of diagnosis, scope of regional lymph node surgery, tumor differentiation grade, SEER historic stage, and triple therapy were significant predictors of survival outcomes (P < .05). Surgery seemed to improve the prognosis of patients with SPEC-GC significantly compared with no surgery and chemoradiotherapy (P < .001). CONCLUSIONS: Surgery should be considered as the main treatment for SPEC-GC. Surgery, year of diagnosis, scope of regional lymph node surgery, tumor differentiation grade, SEER historic stage, and triple therapy were found to be independent prognostic factors for these patients. These factors should be considered in the clinical diagnosis and treatment of SPEC-GC.

Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery.

Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.

Epidemiology of gastroenteropancreatic neuroendocrine neoplasms: a review and protocol presentation for bridging tumor registry data with the Italian association for neuroendocrine tumors (Itanet) national database.

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083).

Registry-derived stage (RD-Stage) for capturing stage at diagnosis for pancreatic carcinoma in Australia.

INTRODUCTION: Stage of pancreatic carcinoma at diagnosis is a strong prognostic indicator of morbidity and mortality, yet is poorly notified to population-based cancer registries ("cancer registries"). Registry-derived stage (RD-Stage) provides a method for cancer registries to use available data sources to compile and record stage in a consistent way. This project describes the development and validation of rules to capture RD-Stage (pancreatic carcinoma) and applies the rules to data currently captured in each Australian cancer registry. MATERIALS AND METHODS: Rules for deriving RD-stage (pancreatic carcinoma) were developed using the American Joint Commission on Cancer (AJCC) Staging Manual 8th edition and endorsed by an Expert Working Group comprising specialists responsible for delivering care to patients diagnosed with pancreatic carcinoma, cancer registry epidemiologists and medical coders. Completeness of data fields required to calculate RD-Stage (pancreatic carcinoma) and an overall proportion of cases for whom RD stage could be assigned was assessed using data collected by each Australian cancer registry, for period 2018-2019. A validation study compared RD-Stage (pancreatic carcinoma) calculated by the Victorian Cancer Registry with clinical stage captured by the Upper Gastro-intestinal Cancer Registry (UGICR). RESULTS: RD-Stage (pancreatic carcinoma) could not be calculated in 4/8 (50%) of cancer registries; one did not collect the required data elements while three used a staging system not compatible with RD-Stage requirements. Of the four cancer registries able to calculate RD-Stage, baseline completeness ranged from 9% to 76%. Validation of RD-Stage (pancreatic carcinoma) with UGICR data indicated that there was insufficient data available in VCR to stage 174/457 (38%) cases and that stage was unknown in 189/457 (41%) cases in the UGICR. Yet, where it could be derived, there was very good concordance at stage level (I, II, III, IV) between the two datasets. (95.2% concordance], Kendall's coefficient = 0.92). CONCLUSION: There is a lack of standardisation of data elements and data sources available to cancer registries at a national level, resulting in poor capacity to currently capture RD-Stage (pancreatic carcinoma). RD-Stage provides an excellent tool to cancer registries to capture stage when data elements required to calculate it are available to cancer registries.

Small Intestine Gastrointestinal Clear Cell Sarcoma: A Case Report and Review of the Literature.

Gastrointestinal clear cell sarcoma (GICCS)/malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare form of cancer with aggressive clinical behavior. It has distinct pathological, immunohistochemical, ultrastructural, and molecular features. Herein, we present the case of a 20-year-old woman with no notable medical history who presented to the outpatient department with complaints of abdominal pain and vomiting. Symptoms had been evolving for 3 months. The physical examination revealed slight abdominal tenderness and melena. Biological investigations revealed iron-deficiency anemia. The upper and lower endoscopies showed no abnormalities. Magnetic resonance enterography revealed small bowel wall thickening of 15 mm × 2 mm. Exploratory laparotomy revealed an ileal mass with mesenteric lymphadenopathy. A wide resection of the mass was then performed. The final pathological report confirmed the diagnosis of small bowel GICCS/GNET. After 11 months of follow-up, the patient presented with mesenteric lymph node metastases.

Predictive and prognostic biomarkers in gastrointestinal tract tumours.

Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.

ASO Practice Guidelines Series: Surgical Management of Gastrointestinal (Midgut) Neuroendocrine Neoplasms.

Gastrointestinal midgut neuroendocrine neoplasms (NENs) are a heterogeneous group of uncommon malignancies. For well-differentiated NENs, known as neuroendocrine tumors (NETs), surgery is a cornerstone of management in localized and metastatic disease. Because of heterogeneous tumor behaviour, association with endocrine syndrome, and prognosis, the management of NETs must be individualized to all these factors in addition to the primary site. With the fast pace of advancement in the field, both for therapies and understanding of tumoral etiology and behaviour, it is important for surgical oncologists to remain updated on guidelines recommendations and suggested treatment pathways. Those guidelines provide important guidance for management of NETs but are largely based on expert opinions and interpretation of retrospective evidence. This article reviews highlights of most recent practice guidelines for midgut (gastric, duodenal, small intestinal, and appendiceal) NETs.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Risk stratification model for incidentally detected gallbladder polyps: A multicentre study.

PURPOSE: We aimed to develop a 4-level risk stratification model using a scoring system based on conventional ultrasound to improve the diagnosis of gallbladder polyp. METHOD: Patients with histopathologically confirmed gallbladder polyps were consecutively recruited from three medical centres. Conventional ultrasound findings and clinical characteristics were acquired prior to cholecystectomy. Risk factors for neoplastic and malignant polyps were used to build a risk stratification system via interobserver agreement and multivariate logistic regression analysis. The model was retrospectively trained using 264 pre-surgical samples and prospectively validated using 106 pre-surgical samples. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and malignant polyp rate. RESULTS: In total, 370 patients (mean age, 51.68 ± 14.41 years, 156 men) were enrolled in this study. Size (≥12 mm), shape (oblate or round), single, vascularity, gallbladder stone or sludge were considered risk factors for neoplastic polyps. Size (≥14 mm), shape (oblate), single, disrupted gallbladder wall, and gallbladder stone or sludge were risk factors for malignant polyps (all p < 0.05). In the scoring system, the sensitivity, specificity, and AUC of score ≥ 9 in diagnosing neoplastic polyps were 0.766, 0.788, and 0.876 respectively; and the sensitivity, specificity, and AUC of score ≥ 15 in diagnosing malignant polyps were 0.844, 0.926, and 0.949 respectively. In our model, the malignancy rates at the four levels were 0 % (0/24), 1.28 % (2/156), 9.26 % (5/54), and 70.37 % (38/54), respectively. CONCLUSIONS: The 4-level risk stratification model based on conventional ultrasound imaging showed excellent performance in classifying gallbladder polyps.

Recent advances for treatment of upper gastrointestinal malignancy.

Recent prospective trials for esophageal cancer, gastric cancer, and gastrointestinal stromal tumor (GIST) are encouraging. This manuscript reviews selected recently published studies. Not surprisingly, immunotherapy dominates the current clinical trial landscape. However, targeted biologic therapies and standard chemotherapy remain critical to the treatment of gastric and esophageal cancer while imatinib remains the backbone for advanced or metastatic GISTs. For all three cancers, surgical resection remains important when intent of treatment is potential cure.

Alteration of the immunophenotype and cytokine profiles in patients affected by neuroendocrine neoplasms.

PURPOSE: Neuroendocrine neoplasms (NENs) are tumors that arise from cells of the endocrine system and are most common in the gastrointestinal tract, the pancreas, and the lungs. Their incidence is rapidly increasing and the therapeutic options available are limited. METHODS: Since the immune system can interfere with tumor growth and response to therapy, using flow cytometry we investigated the immunophenotype in samples of peripheral blood leukocytes from patients with pancreatic (Pan-NENs) and pulmonary NENs (Lung-NENs). Moreover, we performed a multiplex analysis of 13 key cytokines and growth factors essential for the immune response in the plasma of NEN patients and controls. RESULTS: Patients presented with a higher percentage of granulocytes, a lower percentage of lymphocytes, and an increase in the granulocytes to lymphocytes ratio compared to healthy donors. These alterations were more marked in patients with metastasis. Somatostatin analogs (SSAs) restored the immunophenotype of patients to that seen in healthy donors. Finally, Pan-NEN patients showed a higher plasma concentration of IP-10, MCP-1, and IL-8 compared to healthy donors, suggesting a potential role for these cytokines as diagnostic biomarkers. CONCLUSION: This study highlighted differences in the immunophenotype of patients with Pan- and Lung-NENs compared to healthy individuals; these alterations were partially restored by therapy.