A case-matched study of imatinib mesylate between different formulations on plasma trough concentration, adverse events, quality of life and outcomes in gastrointestinal stromal tumor patients.

Genike, the imatinib (IM)-alpha form is widely used in the treatment of gastrointestinal stromal tumor (GIST) patients in China. We wanted to investigate whether there are differences in IM plasma concentrations, adverse events, health-related quality of life (QOL) and outcomes between patients treated with Genike and Glivec. Thirty included GIST patients receiving IM treatment were matched to either Genike or Glivec according to gastrectomy, body weight, body surface area and sex. There was no statistically significant difference in IM trough plasma levels between the two groups. There were no significant differences in very common adverse events of IM between the Genike and Glivec groups. IM was well tolerated, although it was associated with a significant change in cognitive function (P < 0.001), fatigue (P = 0.015), pain (P = 0.015), nausea/vomiting (P = 0.029), insomnia (P = 0.019), diarrhea (P = 0.003) and financial difficulties (P < 0.001). Physical functioning, financial burden and insomnia were significantly different between the two groups (P = 0.026). Until Aug. 2022, there was no significant difference in time to imatinib treatment failure (TTF) between the two groups. In conclusion, there was no difference in IM plasma concentration and adverse events between Genike and Glivec. Both Genike and Glivec could partially decrease the QOL of GIST patients. Physical functioning was worse in Genike group than in Glivec group, while the economic burden and symptoms of insomnia in Glivec patients were worse. There was no significant difference in TTF between the two groups.

Association between human blood metabolome and the risk of gastrointestinal tumors.

BACKGROUND: The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian randomization (MR) study to comprehensively screen the blood metabolomes for potential causal mediators of five frequently encountered gastrointestinal tumors (Liver Cancer, Colorectal Cancer, Esophageal Cancer, Gastric Cancer and Pancreatic Cancer). METHODS: We selected a comprehensive set of 137 distinct blood metabolites derived from three large-scale genome-wide association studies (GWASs) involving a total of 147827 participants of European ancestry. The gastrointestinal tumors-related data were obtained from a GWAS conducted within the Finnish study. Through meticulous MR analyses, we thoroughly assessed the associations between blood metabolites and gastrointestinal tumors. Additionally, a phenome-wide MR (Phe-MR) analysis was employed to investigate the potential on-target side effects of metabolite interventions. RESULTS: We have identified 1 blood metabolites, namely isovalerylcarnitine (ORlog10: 1.01; 95%CI, 1.01-1.02; P = 1.81×10-7), as the potential causal mediators for liver cancer. However, no potential pathogenic mediators were detected for the other four tumors. CONCLUSIONS: The current systematic MR analysis elucidated the potential role of isovalerylcarnitine as a causal mediator in the development of liver cancer. Leveraging the power of Phe-MR study facilitated the identification of potential adverse effects associated with drug targets for liver cancer prevention. Considering the weighing of pros and cons, isovalerylcarnitine emerges as a promising candidate for targeted drug interventions in the realm of liver cancer prevention.

Monitoring advanced gastrointestinal stromal tumor with circulating tumor DNA.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

BCAT1, IKZF1 and SEPT9: methylated DNA biomarkers for detection of pan-gastrointestinal adenocarcinomas.

INTRODUCTION: Methylated circulating tumour DNA (ctDNA) blood tests for BCAT1/IKZF1 (COLVERA) and SEPT9 (Epi proColon) are used to detect colorectal cancer (CRC). However, there are no ctDNA assays approved for other gastrointestinal adenocarcinomas. We aimed to characterize BCAT1, IKZF1 and SEPT9 methylation in different gastrointestinal adenocarcinoma and non-gastrointestinal tumours to determine if these validated CRC biomarkers might be useful for pan-gastrointestinal adenocarcinoma detection. METHODS: Tissue DNA methylation data from colorectal (COAD, READ), gastroesophageal (ESCA, STAD), pancreatic (PAAD) and cholangiocarcinoma (CHOL) adenocarcinoma cohorts within The Cancer Genome Atlas were used for differential methylation analyses. Clinicodemographic predictors of BCAT1, IKZF1 and SEPT9 methylation, and the selectivity of hypermethylated BCAT1, IKZF1 and SEPT9 for colorectal adenocarcinomas in comparison to other cancers were each explored with beta regression. RESULTS: Hypermethylated BCAT1, IKZF1 and SEPT9 were each differentially methylated in colorectal and gastroesophageal adenocarcinomas. IKZF1 was differentially methylated in pancreatic adenocarcinoma. Hypermethylated DNA biomarkers BCAT1, IKZF1 and SEPT9 were largely stable across different stages of disease and were highly selective for gastrointestinal adenocarcinomas relative to other cancer types. DISCUSSION: Existing CRC methylated ctDNA blood tests for BCAT1/IKZF1 and SEPT9 might be usefully repurposed for use in other gastrointestinal adenocarcinomas and warrant further prospective ctDNA studies.

Metabolites, Healthy Lifestyle, and Polygenic Risk Score Associated with Upper Gastrointestinal Cancer: Findings from the UK Biobank Study.

Previous metabolomics studies have highlighted the predictive value of metabolites on upper gastrointestinal (UGI) cancer, while most of them ignored the potential effects of lifestyle and genetic risk on plasma metabolites. This study aimed to evaluate the role of lifestyle and genetic risk in the metabolic mechanism of UGI cancer. Differential metabolites of UGI cancer were identified using partial least-squares discriminant analysis and the Wilcoxon test. Then, we calculated the healthy lifestyle index (HLI) score and polygenic risk score (PRS) and divided them into three groups, respectively. A total of 15 metabolites were identified as UGI-cancer-related differential metabolites. The metabolite model (AUC = 0.699) exhibited superior discrimination ability compared to those of the HLI model (AUC = 0.615) and the PRS model (AUC = 0.593). Moreover, subgroup analysis revealed that the metabolite model showed higher discrimination ability for individuals with unhealthy lifestyles compared to that with healthy individuals (AUC = 0.783 vs 0.684). Furthermore, in the genetic risk subgroup analysis, individuals with a genetic predisposition to UGI cancer exhibited the best discriminative performance in the metabolite model (AUC = 0.770). These findings demonstrated the clinical significance of metabolic biomarkers in UGI cancer discrimination, especially in individuals with unhealthy lifestyles and a high genetic risk.

Circulating MiR-1290 as a potential diagnostic and disease monitoring biomarker of human gastrointestinal tumors.

BACKGROUND: Gastrointestinal tumors are a leading cause of mortality worldwide. As shown in our previous study, miR-1290 is overexpressed in colorectal cancer (CRC) and promotes tumor progression. We therefore aimed to explore the potential of circulating miR-1290 as a biomarker for gastrointestinal cancer. METHODS: A serum miRNA sequencing analysis was performed. Then, circulating miRNA detection technologies were established. The expression of miR-1290 was analyzed in gastrointestinal tumor cell lines and culture supernatants. Expression levels of circulating miR-1290 in clinical samples were examined. Associations between miR-1290 expression and clinicopathologic characteristics were analyzed. Xenograft models were generated to assess the fluctuation in serum miR-1290 levels during disease progression. RESULTS: Through miRNA sequencing, we identified that miR-1290 was overexpressed in serum samples from patients with CRC. We confirmed that human gastrointestinal tumor cells express and secrete miR-1290. The circulating miR-1290 levels was up-regulated in patients with pancreatic cancer (PC) (p < 0.01), CRC (p < 0.05), and gastric cancer (GC) (p < 0.01). High miR-1290 expression levels were associated with tumor size, lymphatic invasion, vascular invasion, distant metastasis, tumor differentiation and AJCC stage in patients with PC and CRC. The area under the curve (AUC) was 0.8857 in patients with PC, with 60.9% sensitivity and 90.0% specificity. The AUC was 0.7852 in patients with CRC, with 42.0% sensitivity and 90.0% specificity. In patients with GC, the AUC was 0.6576, with 26.0% sensitivity and 90.0% specificity. The in vivo model verified that the circulating miR-1290 level was significantly increased after tumor formation and decreased after drug treatment. CONCLUSIONS: Our findings indicate that circulating miR-1290 is a potential biomarker for gastrointestinal cancer diagnosis and monitoring.

Prognostic significance of programmed cell death-ligand 1 expression on circulating tumor cells in various cancers: A systematic review and meta-analysis.

BACKGROUND: The prognostic significance of programmed cell death-ligand 1 (PD-L1) expression on circulating tumor cells (CTCs) has been explored but is still in controversy. We performed, for the first time, a meta-analysis to systematically evaluate its prognostic value in human cancers. METHODS: Literature databases were searched for eligible studies prior to June 30, 2021. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for the associations of pre-treatment and post-treatment PD-L1+ CTCs with progression-free survival (PFS) and overall survival (OS). Subgroup analyses with regards to cancer type, treatment, CTC enrichment method, PD-L1 detection method, cut-off, and specifically the comparison model were performed. RESULTS: We included 30 eligible studies (32 cohorts, 1419 cancer patients) in our analysis. Pre-treatment PD-L1+ CTCs detected by immunofluorescence (IF) tended to predict better PFS (HR = 0.55, 95% CI 0.28-1.08, p = 0.084) and OS (HR = 0.61, 95% CI 0.36-1.04, p = 0.067) for immune checkpoint inhibitor (ICI) treatment, but were significantly associated with unfavorable survival for non-ICI therapies (PFS: HR = 1.85, 95% CI 1.21-2.85, p = 0.005; OS: HR = 2.44, 95% CI 1.69-3.51, p < 0.001). Post-treatment PD-L1+ CTCs predicted markedly worse PFS and OS. The prognostic value was obviously modulated by comparison models. Among patients with detectable CTCs, PD-L1+ individuals had comparable survival to PD-L1- individuals, except ICI treatment for which PD-L1+ may predict better PFS (HR = 0.42, 95% CI 0.17-1.06, p = 0.067). Patients with PD-L1+ CTCs had worse survival prognosis compared to those without PD-L1+ CTCs in overall analysis (PFS: HR = 2.10, 95% CI 1.59-2.77, p < 0.001; OS: HR = 2.55, 95% CI 1.70-3.81, p < 0.001) and in most subgroups. CONCLUSIONS: Our analysis demonstrated that PD-L1 positive expression on CTCs predicted better survival prognosis for ICI treatment but worse survival for other therapies, which thus can be potentially used as a prognostic marker of malignant tumor treatment. However, the prognostic value of PD-L1+ CTCs for ICI treatment needs validation by more large-scale studies in the future.

DNA methylation detection technology and plasma-based methylation biomarkers in screening of gastrointestinal carcinoma.

DNA methylation is of paramount importance for the evolution of human cancers. Its high sensitivity and specificity make it a potential biomarker for early cancer screening in the context of an increasing global burden of gastrointestinal (GI) carcinoma. More DNA methylation biomarkers are emerging with the development of liquid biopsy and sensitive DNA methylation detection technology. This review provides an overview of DNA methylation, focusing on the presentation and comparison of 5-methylcytosine detection technologies, and introduces the promising plasma-based cell-free DNA (cfDNA) methylation biomarkers published in recent years for early screening of GI carcinoma. Finally, we summarize and discuss the future of plasma cfDNA methylation markers detection as a clinical tool for early screening of GI carcinoma.

Lay abstract In the context of an increasing global burden of gastrointestinal (GI) carcinoma, early cancer screening is of paramount importance, so there is an urgent need for efficient and reliable potential biomarkers. More biomarkers are emerging with the development of noninvasive test and related detection technologies. This review provides an overview of certain potential biomarkers named DNA methylation, focusing on the presentation and comparison of related detection technologies for this type of biomarkers and introduces the promising plasma-based biomarkers published in recent years for early screening of GI carcinoma. Finally, we summarize and discuss the future of plasma-based biomarkers detection as a clinical tool for early screening of GI carcinoma.

Association between thiamine decrease and neuropsychiatric symptoms in gastrointestinal and hematological cancer patients receiving chemotherapy.

BACKGROUND: Clinical evidence of thiamine-related neuropsychiatric symptoms, including the initial stage, is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to severe thiamine deficiency. This study aimed to evaluate the relationship between thiamine decline and neuropsychiatric symptoms, including initial symptoms, and the effect of chemotherapy on serum thiamine levels in gastrointestinal and hematological cancer patients receiving chemotherapy. METHOD: We retrospectively identified 87 patients who were diagnosed with gastrointestinal and hematological cancers at our hospital. We evaluated the risk factors associated with neuropsychiatric symptoms, including initial symptoms (neuropsychiatric symptoms), the relationship between the presence of neuropsychiatric symptoms and serum thiamine levels, and changes in serum thiamine levels after chemotherapy. RESULTS: Logistic regression analysis identified thiamine decline as a significant factor associated with neuropsychiatric symptoms (p < 0.001, odds ratio = 0.040, 95% confidence interval [CI]: 0.010-0.163). The Mann-Whitney U test showed that patients with neuropsychiatric symptoms had significantly lower serum thiamine levels (19.5 ± 5.4 ng/mL, n = 39) than patients without neuropsychiatric symptoms (31.9 ± 14.2 ng/mL, n = 48) (p = 0.001). In hematological cancer patients, serum thiamine levels gradually declined after chemotherapy, with the lowest levels at 5-8 weeks (23.5 ± 7.6 ng/mL, P = 0.035 vs. 0 weeks, Wilcoxon rank sum test). CONCLUSION: Our study showed that a decrease in serum thiamine levels can be a risk factor for neuropsychiatric symptoms, and chemotherapy can lead to a decrease in serum thiamine levels.

An ionising radiation-induced specific transcriptional signature of inflammation-associated genes in whole blood from radiotherapy patients: a pilot study.

BACKGROUND: This communication reports the identification of a new panel of transcriptional changes in inflammation-associated genes observed in response to ionising radiation received by radiotherapy patients. METHODS: Peripheral blood samples were taken with ethical approval and informed consent from a total of 20 patients undergoing external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumours. Nanostring nCounter analysis of transcriptional changes was carried out in samples prior and 24 h post-delivery of the 1st radiotherapy fraction, just prior to the 5th or 6th fraction, and just before the last fraction. RESULTS: Statistical analysis with BRB-ArrayTools, GLM MANOVA and nSolver, revealed a radiation responsive panel of genes which varied by patient group (type of cancer) and with time since exposure (as an analogue for dose received), which may be useful as a biomarker of radiation response. CONCLUSION: Further validation in a wider group of patients is ongoing, together with work towards a full understanding of patient specific responses in support of personalised approaches to radiation medicine.

Dissecting Response to Cancer Immunotherapy by Applying Bayesian Network Analysis to Flow Cytometry Data.

Cancer immunotherapy, specifically immune checkpoint blockade, has been found to be effective in the treatment of metastatic cancers. However, only a subset of patients achieve clinical responses. Elucidating pretreatment biomarkers predictive of sustained clinical response is a major research priority. Another research priority is evaluating changes in the immune system before and after treatment in responders vs. nonresponders. Our group has been studying immune networks as an accurate reflection of the global immune state. Flow cytometry (FACS, fluorescence-activated cell sorting) data characterizing immune cell panels in peripheral blood mononuclear cells (PBMC) from gastroesophageal adenocarcinoma (GEA) patients were used to analyze changes in immune networks in this setting. Here, we describe a novel computational pipeline to perform secondary analyses of FACS data using systems biology/machine learning techniques and concepts. The pipeline is centered around comparative Bayesian network analyses of immune networks and is capable of detecting strong signals that conventional methods (such as FlowJo manual gating) might miss. Future studies are planned to validate and follow up the immune biomarkers (and combinations/interactions thereof) associated with clinical responses identified with this computational pipeline.

Risk of gastrointestinal cancer in patients with an elevated level of gamma-glutamyltransferase: A nationwide population-based study.

Emerging evidence that an elevated serum gamma-glutamyltransferase (GGT) level is associated with an increased risk of gastrointestinal cancer, but still controversial. The aim of this study to assess the relationship between GGT level and risk of gastrointestinal cancer, and the contribution of the interaction of hyperglycemia with elevated GGT level to the incidence of gastrointestinal cancer by the stratified analysis. A total of 8,120,665 Koreans who received medical checkups in 2009 were included. Subjects were classified according to the quartile of GGT level for women and men. The incidence rates of gastrointestinal cancer for each group were analyzed using Cox proportional hazards models. During follow-up, 129,853 cases of gastrointestinal cancer newly occurred (esophagus, 3,792; stomach, 57,932; and colorectal, 68,789 cases). The highest GGT quartile group showed an increased risk of gastrointestinal cancer (esophagus, hazard ratio = 2.408 [95% confidence interval, 2.184-2.654]; stomach, 1.121 [1.093-1.149]; and colorectal, 1.185 [1.158-1.211]). The risk increased significantly with the rise in GGT quartile level, regardless of the site of cancer. The stratified analysis according to glycemic status showed that the effect of elevated GGT was predominant in the risk of esophageal cancer. The effect of elevated GGT further increased the risk of stomach and colorectal cancers in diabetic patients. An elevated level of GGT was associated with an increased risk of gastrointestinal cancer, regardless of the site of cancer. The effect of the increase in GGT level on the risk of gastrointestinal cancer depended on the type of cancer and glycemic status.

Peripheral blood T-cell receptor repertoire as a predictor of clinical outcomes in gastrointestinal cancer patients treated with PD-1 inhibitor.

BACKGROUND: Identifying valid biomarkers for patient selection impressively promotes the success of anti-PD-1 therapy. However, the unmet need for biomarkers in gastrointestinal (GI) cancers remains significant. We aimed to explore the predictive value of the circulating T-cell receptor (TCR) repertoire for clinical outcomes in GI cancers who received anti-PD-1 therapy. METHODS: 137 pre- and 79 post-treated peripheral blood samples were included. The TCR repertoire was evaluated by sequencing of complementarity-determining region 3 (CDR3) in the TRB gene. The Shannon index was used to measure the diversity of the TCR repertoire, and Morisita's overlap index was used to determine TCR repertoire similarities between pre- and post-treated samples. RESULTS: Among all enrolled patients, 76 received anti-PD-1 monotherapy and 61 received anti-PD-1 combination therapy. In the anti-PD-1 monotherapy cohort, patients with higher baseline TCR diversity exhibited a significantly higher disease control rate (77.8% vs. 47.2%; hazard ratio [HR] 3.92; 95% confidence interval [CI] 1.14-13.48; P = 0.030) and a longer progression-free survival (PFS) (median: 6.47 months vs. 2.77 months; HR 2.10; 95% CI 1.16-3.79; P = 0.014) and overall survival (OS) (median: NA vs. 8.97 months; HR 3.53; 95% CI 1.49-8.38; P = 0.004) than those with lower diversity. Moreover, patients with a higher TCR repertoire similarity still showed a superior PFS (4.43 months vs. 1.84 months; HR 13.98; 95% CI 4.37-44.68; P < 0.001) and OS (13.40 months vs. 6.12 months; HR 2.93; 95% CI 1.22-7.03; P = 0.016) even in the cohort with lower baseline diversity. However, neither biomarker showed predictive value in the anti-PD-1 combination therapy cohort. Interestingly, the combination of TCR diversity and PD-L1 expression can facilitate patient stratification in a pooled cohort. CONCLUSION: The circulating TCR repertoire can serve as a predictor of clinical outcomes in anti-PD-1 therapy in GI cancers.

Blood biomarkers of bone metastasis in digestive tract malignant tumors.

Aim: To evaluate the role of clinical features and blood markers in patients with malignant digestive tract tumors bone metastasis. Materials & methods: A total of 267 patients were included in this trial. Age, gender, primary tumor site, metastatic sites, T/N stage, high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides, alkaline phosphatase, LDH, Ca levels, platelet, neutrophils to absolute value of lymphocytes (NLR), ratio of platelets to absolute values of lymphocytes (PLR) were analyzed. Results: T stage, lymph node metastasis, N stage and liver and lung metastasis were independent risk factors. LDH + alkaline phosphatase + NLR + PLR and LDH + NLR, respectively have higher predictive value for bone metastasis compared with patients with early-stage malignant digestive tract tumor and patients with advanced malignant digestive tract tumor without bone metastasis. Conclusion: Some clinical features or blood markers have the potential to detect bone metastasis early to avoid skeletal complications.

Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies.

OBJECTIVE: The aim of the study was to assess the impact of systemic markers of inflammation on the outcomes in patients with neuroendocrine tumors (NETs) treated with everolimus or placebo (as measured by baseline neutrophil-to-lymphocyte ratio [NLR] and lymphocyte-to-monocyte ratio [LMR]). METHODS: Patient data (gastrointestinal, pancreatic, and lung NETs) from 2 large phase 3 studies, RADIANT-3 (n = 410) and RADIANT-4 (n = 302), were pooled and analyzed. The primary end point was centrally assessed progression-free survival (PFS) as estimated by the Kaplan-Meier method. RESULTS: In the pooled population, elevated LMR (median PFS, 11.1 months; 95% confidence interval, 9.3-13.7; hazard ratio, 0.69; P < 0.001) and reduced NLR (median PFS, 10.8 months; 95% confidence interval, 9.2-11.7; hazard ratio, 0.75; P = 0.0060) correlated with longer PFS among all patients. These markers were also found to be prognostic in the everolimus- and placebo-treated subgroups. CONCLUSIONS: Data from this study suggest that LMR and NLR are robust prognostic markers for NETs and could potentially be used to identify patients who may receive or are receiving the most benefit from targeted therapies. As both are derived from a complete blood count, they can be routinely used in clinical practice, providing valuable information to clinicians and patients alike.

Circulating miR-21 as a potential biomarker in human digestive system carcinoma: a systematic review and diagnostic meta-analysis.

Purpose: Gastrointestinal cancers (GICs) account for about a quarter of cancers. Lately, the circulating microRNAs as a non-invasive biomarker for identifying and monitoring diseases have been recognized. Several studies have examined the role of miR-21 in digestive system carcinoma. We conducted a meta-analysis to assess the diagnostic role of miR-21 in GICs.Methods: Seventeen studies involving 1700 individuals were included in this meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, AUC, SROC, and Q* index were calculated based on true-positive, true-negative, false-negative, and false-positive. Moreover, the subgroup analyses have been performed for miR-21 based on sample types (serum/plasma), normalized genes (U6, miR-16, and miR-39), and ethnicity.Results: The pooled sensitivity 0.722 (95% CI: 0.70-0.74), specificity 0.820 (95% CI: 0.801-0.838), PLR 4.375 (95% CI: 3.226-5.933), NLR 0.308 (95% CI: 0.239-0.398), DOR 16.06 (95% CI: 9.732-26.53) as well as AUC 0.86, and Q* index 0.79 represented the high-grade diagnostic precision of miR-21 in identifying GICs (ESCC, GC, CRC, HCC, and PC).Conclusion: This meta-analysis demonstrated that circulating miR-21 levels can be used to monitor the digestive system carcinomas. Therefore, miR-21 can be a useful biomarker of progression and fair diagnosis in GICs patients.

Plasmatic and Urinary 5-Hydroxyindolacetic Acid Measurements in Patients With Midgut Neuroendocrine Tumors: A GTE Study.

CONTEXT: Although 24-hour urinary 5-hydroxyindolacetic acid (24u5HIAA) is a key biomarker in midgut neuroendocrine tumors (NETs), it may be inaccurate and inconvenient. OBJECTIVE: We compared the diagnostic performances of 24u5HIAA, overnight urinary 5HIAA (Ou5HIAA), and plasmatic 5HIAA (p5HIAA) in midgut NETs. METHODS: This prospective, multicenter study included 80 patients with metastatic midgut NETs and 17 control patients with irritable bowel syndrome. 24u5HIAA, Ou5HIAA, and p5HIAA were measured in urine and plasma collected on 2 consecutive days following a specific recommended diet. Reproducibility of the biomarkers was evaluated by the Spearman test. Diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUROC). Correlations with the main clinical features and declared observance to the specific diet were assessed using AUROC and logistic regression models. RESULTS: The reproducibility of 24u5HIAA, Ou5HIAA, and p5HIAA were excellent (ρ = 0.916; 0.897; 0.978, respectively, P < .001) with significant discrimination between patients and controls (AUROC = 0.795, P < .001; 0.757, P = .001; 0.717, P = .005, respectively). All 3 markers were correlated with the presence of carcinoid syndrome (AUROC = 0.702, P = .006; 0.701, P = .006; 0.697, P = .007, respectively), carcinoid heart disease (AUROC = 0.896; 0.887; 0.923, P < .001, respectively, P < .001), and liver metastatic involvement greater than 30% (AUROC = 0.827; 0.807; 0.849, P < .001, respectively, P < .001), independent from other traditional prognostic factors. Biomarker levels were similar between patients with optimal or suboptimal diet observance. CONCLUSION: Ou5HIAA and p5HIAA could be used as more convenient alternatives to 24u5HIAA in patients with metastatic midgut NETs. Prospective long-term studies with repeated dosages are needed.

Ki-67 labelling index is related to the risk classification and prognosis of gastrointestinal stromal tumours: a retrospective study.

BACKGROUND AND AIMS: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract with malignant potential. The current risk classification standard is unable to accurately evaluate the invasiveness and clinical outcomes of GISTs. Ki-67 labelling index (LI) may be an effective indicator in assessing tumour invasiveness and prognosis, however, its exact value in GISTs is still uncertain. The aims of our study were to evaluate the correlation of the Ki-67 LI and clinicopathological features of GISTs and to assess the potential value of the Ki-67 LI in GISTs classification and prognosis. METHODS: The clinical, pathological and prognostic data were collected and analysed to identify the independent influential factors of GISTs risk stratification and the predictors of GISTs prognosis. RESULTS: The Ki-67 LI was significantly associated with the clinicopathological features of tumour progression (P<0.05). It was an independent influential factor of GISTs risk classification (odds ratio: 1.322; 95% confidence interval: 1.031-1.696) (P=0.028), and the area under the curve (AUC) value of the Ki-67 LI on the discrimination ability of GISTs risk stratification was 0.906 (P<0.001). The optimal cutoff value of the Ki-67 LI was 6% (sensitivity of 87.5% and specificity of 76.2%), and patients with Ki-67 LI≥6% exhibited significantly poorer progression-free survival (PFS) than those with Ki-67 LI<6% (P<0.001). The AUC value of the Ki-67 LI for predicting PFS in postoperative patients was 0.813 (P=0.03). CONCLUSIONS: The Ki-67 LI has appreciated value to predict the risk grade and prognosis of GISTs. Patients with Ki-67 LI≥6% are prone to recurrence and metastasis after operation and may need a close follow-up.

Prospective Evaluation of the NETest as a Liquid Biopsy for Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors: An ENETS Center of Excellence Experience.

BACKGROUND: There is a substantial unmet clinical need for an accurate and effective blood biomarker for neuroendocrine neoplasms (NEN). We therefore evaluated, under real-world conditions in an ENETS Center of Excellence (CoE), the clinical utility of the NETest as a liquid biopsy and compared its utility with chromogranin A (CgA) measurement. METHODS: The cohorts were: gastroenteropancreatic NEN (GEP-NEN; n = 253), bronchopulmonary NEN (BPNEN; n = 64), thymic NEN (n = 1), colon cancer (n = 37), non-small-cell lung cancer (NSCLC; n = 63), benign lung disease (n = 59), and controls (n = 86). In the GEPNEN group, 164 (65%) had image-positive disease (IPD, n = 135) or were image-negative but resection-margin/biopsy-positive (n = 29), and were graded as G1 (n = 106), G2 (n = 49), G3 (n = 7), or no data (n = 2). The remainder (n = 71) had no evidence of disease (NED). In the BPNEN group, 43/64 (67%) had IPD. Histology revealed typical carcinoids (TC, n = 14), atypical carcinoids (AC, n = 14), small-cell lung cancer (SCLC, n = 11), and large-cell neuroendocrine carcinoma (LCNEC, n = 4). Disease status (stable or progressive) was evaluated according to RECIST v1.1. Blood sampling involved NETest (n = 563) and NETest/CgA analysis matched samples (n = 178). NETest was performed by PCR (on a scale of 0-100), with a score ≥20 reflecting a disease-positive status and >40 reflecting progressive disease. CgA positivity was determined by ELISA. Samples were deidentified and measurements blinded. The Kruskal-Wallis, Mann-Whitney U, and McNemar tests, and the area under the curve (AUC) of the receiver-operating characteristics (ROC) were used in the statistical analysis. RESULTS: In the GEPNEN group, NETest was significantly higher (34.4 ± 1.8, p < 0.0001) in disease-positive patients than in patients with NED (10.5 ± 1, p < 0.0001), colon cancer patients (18 ± 4, p < 0.0004), and controls (7 ± 0.5, p < 0.0001). Sensitivity for detecting disease compared to controls was 89% and specificity was 94%. NETest levels were increased in G2 vs. G1 (39 ± 3 vs. 32 ± 2, p = 0.02) and correlated with stage (localized: 26 ± 2 vs. regional/distant: 40 ± 3, p = 0.0002) and progression (55 ± 5 vs. 34 ± 2 in stable disease, p = 0.0005). In the BPNEN group, diagnostic sensitivity was 100% and levels were significantly higher in patients with bronchopulmonary carcinoids (BPC; 30 ± 1.3) who had IPD than in controls (7 ± 0.5, p < 0.0001), patients with NED (24.1 ± 1.3, p < 0.005), and NSCLC patients (17 ± 3, p = 0.0001). NETest levels were higher in patients with poorly differentiated BPNEN (LCNEC + SCLC; 59 ± 7) than in those with BPC (30 ± 1.3, p = 0.0005) or progressive disease (57.8 ± 7), compared to those with stable disease (29.4 ± 1, p < 0.0001). The AUC for differentiating disease from controls was 0.87 in the GEPNEN group and 0.99 in BPC patients (p < 0.0001). Matched CgA analysis was performed in 178 patients. In the GEPNEN group (n = 135), NETest was significantly more accurate for detecting disease (99%) than CgA positivity (53%; McNemar test χ2 = 87, p < 0.0001). In the BPNEN group (n = 43), NETest was significantly more accurate for disease detection (100%) than CgA positivity (26%; McNemar's test χ2 = 30, p < 0.0001). CONCLUSIONS: The NETest is an accurate diagnostic for GEPNEN and BPNEN. It exhibits tumor biology correlation with grading, staging, and progression. CgA as a biomarker is significantly less accurate than NETest. The NETest has substantial clinical utility that can facilitate patient management.