Hormonal tumor mapping for liver metastases of gastroenteropancreatic neuroendocrine neoplasms: a novel therapeutic strategy.

PURPOSE: In patients with metastatic functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), it is unknown what degree of tumor reduction is required to eliminate hormonal symptoms. We aimed to reduce hormonal symptoms derived from advanced GEP-NENs by efficient minimal intervention, constructing a hormonal tumor map of liver metastases. METHODS: Between 2013 and 2019, we treated 12 insulinoma or gastrinoma patients with liver metastases. Liver segments containing hormone-producing tumors were identified by injecting calcium gluconate via the hepatic arteries and monitoring the change in serum hormone concentration in the three hepatic veins. A greater-than-twofold increase in hormone concentration indicated a tumor-feeding vessel. RESULTS: Cases included eight insulinomas and four gastrinomas. Primary lesions were functional in three patients and nonfunctional in 9. Nine patients showed hormonal step-up indicating the presence of functional lesions; eight showed step-up in tumor-bearing liver segments, while one with synchronous liver metastases showed step-up only in the pancreatic region. Five patients underwent surgery. Serum hormone concentration decreased markedly after removing the culprit lesions in 3; immediate improvement in hormonal symptoms was achieved in all patients. Three patients with previous surgical treatment who showed step-up underwent transcatheter arterial embolization, achieving temporary improvement of hormonal symptoms. Four patients showed unclear localization of the hormone-producing tumors; treatment options were limited, resulting in poor outcomes. CONCLUSION: Hormonal tumor mapping demonstrated heterogeneity in hormone production among primary and metastatic tumors of GEP-NENs. Minimally invasive treatment based on hormonal mapping may be a viable alternative to conventional cytoreduction.

GMrepo v2: a curated human gut microbiome database with special focus on disease markers and cross-dataset comparison.

GMrepo (data repository for Gut Microbiota) is a database of curated and consistently annotated human gut metagenomes. Its main purposes are to increase the reusability and accessibility of human gut metagenomic data, and enable cross-project and phenotype comparisons. To achieve these goals, we performed manual curation on the meta-data and organized the datasets in a phenotype-centric manner. GMrepo v2 contains 353 projects and 71,642 runs/samples, which are significantly increased from the previous version. Among these runs/samples, 45,111 and 26,531 were obtained by 16S rRNA amplicon and whole-genome metagenomics sequencing, respectively. We also increased the number of phenotypes from 92 to 133. In addition, we introduced disease-marker identification and cross-project/phenotype comparison. We first identified disease markers between two phenotypes (e.g. health versus diseases) on a per-project basis for selected projects. We then compared the identified markers for each phenotype pair across datasets to facilitate the identification of consistent microbial markers across datasets. Finally, we provided a marker-centric view to allow users to check if a marker has different trends in different diseases. So far, GMrepo includes 592 marker taxa (350 species and 242 genera) for 47 phenotype pairs, identified from 83 selected projects. GMrepo v2 is freely available at: https://gmrepo.humangut.info.

Cell-Free DNA and Clinical Characteristics in Patients with Small Intestinal or Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Neuroendocrine tumors (NETs) are rare and characterized by a heterogeneous clinical course and an unmet need for better prognostic markers. Plasma cell-free DNA (cfDNA) has prognostic value in other malignancies but is not previously investigated in NETs. We studied cfDNA levels in patients with mainly low-grade small intestinal NET -(siNET) or pancreatic NET (pNET) and evaluated the prognostic potential of cfDNA. MATERIALS AND METHODS: We included 70 NET patients, siNET (n = 50) and pNET (n = 20). Plasma cfDNA levels were determined by droplet digital PCR for the beta-2-microglobulin gene every 6 months during a period of 3 years, including in a subgroup of 19 patients during peptide receptor radionuclide therapy (PRRT) therapy. RESULTS: cfDNA levels were higher in both siNET and pNET compared to a previously established healthy cohort (p < 0.0001). -cfDNA levels did not predict overall survival (crude hazard ratio [HR] 0.95 [0.57-1.58], p = 0.837, adjusted for smoking status HR 0.77 [0.51-1.17], p = 0.22). The impact of cfDNA level on progression-free survival showed different trends in siNET and pNET. There was no effect of PRRT treatment on cfDNA levels and no difference in cfDNA levels between patients with and without progressive disease after PRRT (ANOVA p = 0.66). cfDNA levels were significantly higher in never-smokers and previous smokers than in current smokers (p = 0.029). DISCUSSION/CONCLUSION: cfDNA levels are higher in NET patients than in healthy controls; however, there was no association with prognosis, and cfDNA levels were unaffected by PRRT. Our observations suggest that cfDNA levels are not associated with the disease course in low-grade NET in contrast to other malignancies.

Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors: A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection.

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

Sensitivity and Specificity of the NETest: A Validation Study.

BACKGROUND: Secretory tumor markers traditionally measured in patients with neuroendocrine tumors (NET) are lacking sensitivity and specificity, and consequently they are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population of metastatic well-differentiated NETs of gastroenteropancreatic and lung origin and to evaluate NETest specificity in a mixed population of metastatic non-NET gastrointestinal (GI) malignancies and healthy individuals. DESIGN AND METHODS: Forty-nine patients with metastatic NETs, 21 patients with other metastatic GI cancers, and 26 healthy individuals were enrolled in the study. Samples were sent in a blinded fashion to a central laboratory, and an NETest value of 0-13% was considered normal. RESULTS: Using 13% as the upper limit of normal, the sensitivity of the NETest was 98% (95% CI 89-100%). The overall specificity was 66% (95% CI 51-79%), with 16 false-positive results. Specificity was 81% (95% CI 62-92%) among 26 healthy individuals and 48% (95% CI 26-70%) among patients with other GI malignancies. Using an updated normal range of 0-20%, sensitivity was unchanged, but specificity improved to 100% among healthy participants and to 67% among patients with other cancers. CONCLUSIONS: The sensitivity of the NETest is exceptionally high (>95%) in a population of metastatic, well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20% but relatively low when evaluating patients with other GI malignancies.

Blood Molecular Genomic Analysis Predicts the Disease Course of Gastroenteropancreatic Neuroendocrine Tumor Patients: A Validation Study of the Predictive Value of the NETest®.

Reliable prediction of disease status is a major challenge in managing gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of the study was to validate the NETest®, a blood molecular genomic analysis, for predicting the course of disease in individual patients compared to chromogranin A (CgA). NETest® score (normal ≤20%) and CgA level (normal <100 µg/L) were measured in 152 GEP-NETs. The median follow-up was 36 (4-56) months. Progression-free survival was blindly assessed (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Optimal cutoffs (area under the receiver operating characteristic curve [AUC]), odds ratios, as well as negative and positive predictive values (NPVs/PPVs) were calculated for predicting stable disease (SD) and progressive disease (PD). Of the 152 GEP-NETs, 86% were NETest®-positive and 52% CgA-positive. -NETest® AUC was 0.78 versus CgA 0.73 (p = ns). The optimal cutoffs for predicting SD/PD were 33% for the NETest® and 140 µg/L for CgA. Multivariate analyses identified NETest® as the strongest predictor for PD (odds ratio: 5.7 [score: 34-79%]; 12.6 [score: ≥80%]) compared to CgA (odds ratio: 3.0), tumor grade (odds ratio: 3.1), or liver metastasis (odds ratio: 7.7). The NETest® NPV for SD was 87% at 12 months. The PPV for PD was 47 and 64% (scores 34-79% and ≥80%, respectively). NETest® metrics were comparable in the watchful waiting, treatment, and no evidence of disease (NED) subgroups. For CgA (>140 ng/mL), NPV and PPV were 83 and 52%. CgA could not predict PD in the watchful waiting or NED subgroups. The NETest® reliably predicted SD and was the strongest predictor of PD. CgA had lower utility. The -NETest® anticipates RECIST-defined disease status up to 1 year before imaging alterations are apparent.

Assessment of biomarkers influencing treatment success on small intestinal lymphoma in dogs.

This study aimed to determine a reliable therapeutic biomarker for localized small intestinal lymphoma (SIL) in dogs based on clinical and histopathological features. We retrospectively investigated 84 dogs with localized SIL, including 36 dogs receiving surgery and 48 dogs receiving chemotherapy. The dogs receiving surgery were divided into two subgroups: 18 dogs (group 1) with overall survival (OS) <120 days (median OS) and 18 dogs (group 2) with OS ≥120 days. Correspondingly, the dogs receiving chemotherapy were divided into 24 dogs (group 3) with OS <98 days (median OS) and 24 dogs (group 4) with OS ≥98 days. Clinical, haematological, histopathological and immunohistochemical analyses were comparatively evaluated among the four subgroups. There was no significant difference in OS between the surgery and chemotherapy groups. In dogs receiving surgery, the rate of Ki67-positive cells was significantly increased in group 1 compared to group 2 and showed no significant difference between groups 3 and 4. In dogs receiving chemotherapy, the rate of O6-methylguanine-DNA methyltransferase (MGMT) was significantly higher in group 3 than in group 4 and showed no significant difference between groups 1 and 2. Additionally, our data showed that OS in dogs with higher Ki67 expression might be significantly increased by chemotherapy than by surgery, that of those with higher MGMT expression might be significantly increased by surgery than by chemotherapy, and Ki67 and MGMT were independent of each other. Indices of Ki67 and MGMT are suggested therapeutic biomarkers to determine the optimal first-line treatment for localized SIL in dogs.

Regular chromogranin A monitoring facilitated the early detection of a gastrointestinal neuroendocrine tumour in a patient with type 1 diabetes.

Not required for Clinical Vignette.

True Chromogranin A concentrations in plasma from patients with small intestinal neuroendocrine tumours.

Objective: The incidence of enteropancreatic neuroendocrine tumours (NET) is increasing. Chromogranin A (CgA) in plasma is a marker in patients suspected of NET tumours. CgA, however, is a precursor protein subjected to cellular processing that challenges quantitation and hence the use of CgA in diagnostics.Materials and methods: CgA concentrations in plasma sampled from 130 well-characterized patients with small intestinal NETs and from 30 healthy subjects were measured with eight commercial CgA kits, an in-house radioimmunoassay (RIA) and a processing-independent assay (PIA). For the evaluation of diagnostic accuracy, we performed regression analyses and plotted receiver-operating characteristic curves (ROC). The specificity was further assessed by size chromatography.Results: Five commercial assays (Thermo-Fisher, DRG Diagnostics, Eurodiagnostica (RIA and ELISA), and Phoenix), displayed a diagnostic accuracy with area under the curve (AUC) values >0.90, whereas three immunoassays (Yanaihara, CisBio RIA, and CisBio ELISA) discriminated poorly between disease stages (AUC: 0.60-0.78). Compared with the in-house assays, however, even the most accurate commercial immunoassay still missed patients with metastatic disease. Chromatography showed non-uniform patterns of large and small CgA fragments in plasma.Conclusion: Available commercial immunoassays measure CgA in plasma with gross variability. Three commercial CgA immunoassays discriminate so poorly between health and disease that they should not be used. The highest diagnostic accuracy was obtained with processing-independent measurement of total CgA concentrations in plasma.

Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors.

BACKGROUND: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. METHODS: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. RESULTS: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. CONCLUSIONS: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.

Serum proteome profiles to differentiate Crohn disease from intestinal tuberculosis and primary intestinal lymphoma: A pilot study.

The differential diagnosis of Crohn disease (CD) from intestinal tuberculosis (ITB) and primary intestinal lymphoma (PIL) is challenging in patients who exhibit atypical clinical characteristics. The aim of the present study was to explore the serum proteome profiles of CD, PIL and ITB and to identify their differentiations.Treatment-naïve patients with CD (n = 10), PIL (n = 10) and ITB (n = 10) were enrolled in the present study. Differentially expressed proteins (DEPs) in patient serum samples were compared between groups using tandem mass tag labeled proteomic technology. A principal component analysis (PCA) plot and volcano maps were also visualized. Functional pathway analysis was performed using Reactome. The Area under the Curve (AUC) was calculated for each DEP.A total of 818 proteins were identified through proteomic quantification. Among them, 108 DEPs were identified to be differentiated between CD and ITB, 105 proteins between CD and PIL and 55 proteins between ITB and PIL. The proteome from the three groups was distinguishable in the PCA plot. The results revealed that 19, 12, and 10 proteins (AUC ≥ 0.95) were differentially expressed between CD and PIL, CD and ITB, and PIL and ITB, respectively. Among these DEPs, tumor necrosis factor ligand superfamily member 13 was higher in CD than in ITB and PIL. Peroxiredoxin-5, T-complex protein 1 subunit Gamma, CutA, and Fibulin-5 were increased in CD and PIL when compared with ITB. The levels of fibrinogen chains were also significantly higher in patients with PIL compared with CD.The current study demonstrated that serum proteome was distinguishable among patients with CD, PIL, and ITB. The identified proteins may assist in the clinical differentiation among them.

Prognostic role of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with midgut neuroendocrine tumors undergoing resective surgery.

AIM: Several studies demonstrated the prognostic value of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and platelet-to-white blood cells ratio (PWR) in different types of tumors. However, there is no information about a possible role of NLR, PLR and PWR as predictor of presence of metastasis or multifocal disease in patients undergoing surgery with curative intent for midgut NET. The aim of our study was to test the role of preoperative NLR, PLR and PWR as predictors of patients undergoing surgery with curative intent for midgut NET. METHODS: We retrospectively enrolled seven foregut, 35 midgut and six hindgut NET patients with gastrointestinal neuroendocrine tumors operated in our Units from January 2005 to June 2016. Details about preoperative laboratory data, surgical operation, histology and follow-up were retrieved. Non-parametric statistics, ROC curve analysis and survival analysis were used. RESULTS: NLR was significantly higher in patients with distant metastasis (p = 0.04). The ROC curve analysis indicated that a threshold value of NLR of 2.6 predicted the presence of peritoneal metastasis with a specificity of 100% and a sensitivity of 71% and an overall accuracy of AUC = 0.81 (95%CI: 0.59-0.94), p = 0.05. PLR and PWR was not be associated to metastasis but tended to be associated to multifocal disease. CONCLUSION: In patients with midgut NET, an impaired adaptive immune response, as suggested by a high NLR ratio, was associated to the presence of distant metastasis and in particular of peritoneal metastasis. This information may be helpful when planning the treatment of a patient with a midgut NET.

Novel Prognostic Factors in Resected Small Bowel Adenocarcinoma.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy affecting approximately 3000 patients per year in the United States, and there is limited evidence prognosticating patients with resected SBA. We aimed to evaluate prognostic factors and the role of adjuvant therapy in patients with resected SBA. PATIENTS AND METHODS: Two hundred forty-one patients who had resected stage I-III SBA were retrospectively identified at a single tertiary referral institution. Overall survival (OS) analysis was performed by the Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed to identify significant variables by univariate and multivariate analysis. RESULTS: Median OS for the entire group was 54.5 months (95% confidence interval [CI], 37.2-81.2 months), with 5- and 10-year OS of 48% and 35%. Median follow-up was 113.7 months (95% CI, 97.9-126.6 months). For patients with stage III disease who received adjuvant therapy, the median OS was 33.8 months (95% CI, 27.8-78.8) compared to 24.7 months (95% CI, 11.5-37.8) for patients with no adjuvant therapy (P < .01). Male sex, advanced T stage, advanced N stage, increased positive lymph node ratio, lymphocyte-to-monocyte ratio < 1.56, presence of residual disease, and earlier date of diagnosis predicted worse survival on univariate analysis. Age > 60 years, lymphocyte-to-monocyte ratio < 1.56, and advanced T stage were identified as independent negative predictors of OS for all patients by multivariate analysis. CONCLUSION: Advanced age, advanced T stage, and lymphocyte-to-monocyte ratio < 1.56 independently predicted survival in resected SBA. Adjuvant therapy is associated with improved survival in patients with resected stage III SBA.

[Determination of thresholds values for platelet serotonin and urinary 5-HIAA concentrations for the biological diagnosis of digestive neuroendocrine tumors]. / Quelles valeurs de référence pour la concentration de la sérotonine plaquettaire et du 5-HIAA urinaire pour le diagnostic des tumeurs neuroendocrines digestives ?

OBJECTIVES: Platelet serotonin and its urinary metabolite 5-HIAA (5-hydroxyindolacetic acid) are the main biomarkers measured for the detection of neuroendocrine tumors (NET). We observe in our laboratory many false positives or false negatives for the 2 assays using threshold values given by the manufacturer. We aim to determine our own local threshold values for a better detection of gastrointestinal NETs. METHODS: We studied patients with measurement of platelet serotonin and/or urinary 5-HIAA in University Hospital of Tours between January 2005 and June 2016. We established an « index ¼ cohort with 75% of patients to determine local threshold value for the 2 parameters. A "validation" cohort constituted with 25% of remaining patients allowed us to compare the performances of manufacturer's values with local threshold values. RESULTS: Two hundred ninety patients were included, with 19 suffering from NETs. Local threshold value for platelet serotonin was determined at 5.13 amol/platelet, the one for urinary 5-HIAA at 3.60 µmol/mmol urinary creatinine. Platelet serotonin specificity was better with local threshold value for identical sensibility (0.75). Urinary 5-HIAA sensibility was improved with local threshold value (1 vs 0.667) for identical specificity (0.902). CONCLUSION: Using our local threshold value for platelet serotonin and urinary 5-HIAA improved diagnostic performances of these biochemical markers to detect NETs.

Serotonin levels and 1-year mortality in patients with neuroendocrine tumors: a systematic review and meta-analysis.

Aim: Elevated serotonin in patients with neuroendocrine tumors (NETs) may impact heart failure incidence but a quantitative relationship has not been established. Materials & methods: Systematic review and meta-analysis of studies assessing 24-h urinary 5-hydroxyindoleacetic acid (u5-HIAA) and mortality in patients with NETs (2007-2017) with a primary outcome of 1-year mortality risk and 24-h u5-HIAA. Results: We identified 1715 records of which 12 studies including 755 patients (3442 person-years with 376 deaths) were eligible for meta-analysis. Mean u5-HIAA was 149.2 mg/24 h (standard deviation: 96.6) and mortality was 13.0%. The meta-regression equation showed an 11.8% (95% CI: 8.9-17.0%; I2  = 93.0%) increase in 1-year mortality for every ten-unit increase in u5-HIAA. Conclusion: Serotonin measured by its metabolite u5-HIAA is predictive of 1-year all-cause mortality in patients with NETs.

Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy?

BACKGROUND: Blood-based, cancer-associated biomarkers may detect subjects at risk of having neoplastic diseases. The aim of the present study was to evaluate whether elevated serological protein biomarker levels may identify adenoma patients, who are at increased risk of being diagnosed with subsequent primary malignancy. METHODS: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy due to symptoms of colorectal neoplasia. Follow-up time was ten years, and identified adenoma patients, who were diagnosed with subsequent primary intra- or extra-colonic malignant diseases. The biomarker levels were also determined in 400 subjects, who underwent diagnostic colonoscopy, had clean colorectum and were without apparent co-morbidity; these levels were used as reference levels. In the present study, biomarkers were interpreted as elevated when levels were above the reference intervals adjusting for age and gender. The 1-year and 5-years cumulative incidences were calculated. RESULTS: Primary malignancies were identified in 175 (19%) of the 923 subjects diagnosed with adenomas at the primary bowel endoscopy. In detail, 20 of the 175 subjects were diagnosed with colorectal cancer (CRC) and 155 subjects with extra-colonic cancers. Thirty patients were diagnosed with malignancy within the first year. Three groups were established: 0: no elevated biomarkers; 1: 1 of the 4 biomarkers elevated; and 2: ≥2 biomarkers elevated. The cumulative 5-years incidence of malignancy was: 0: 6.9%; 1: 11.8%; and 2: 17.5% (p = .0009). CONCLUSION: Elevated blood-based, cancer-associated protein biomarker levels in subjects diagnosed with adenomas at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy.

Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms: Is It Really Game Over? A Systematic Review and Meta-analysis.

OBJECTIVES: Little is known about chromogranin A (CgA) during follow-up of gastroenteropancreatic neuroendocrine neoplasms. We hypothesized that serial CgA monitoring might be useful for the assessment of tumor progression, and we performed a systematic review of the literature and meta-analysis. METHODS: A bibliographical search was performed in PubMed using "chromogranin A" and "neuroendocrine tumors" and "follow-up" and "biomarker" to identify all pertinent articles published in the last 10 years. RESULTS: Eight studies were included in current meta-analysis. Chromogranin A as a follow-up marker shows sensitivity between 46% and 100% and specificity between 68% and 90%. The meta-analysis results showed an overall accuracy of 84% (95% confidence interval [CI], 81-86.6), a cumulative sensitivity of 74.6% (95% CI, 61.9-85.4), and a cumulative specificity of 84.7% (95% CI, 81.3-87.7). These data indicate that circulating CgA has a better overall accuracy in the follow-up setting; it can be used to rule the diagnosis of recurrence/progression in, rather than to rule it out. CONCLUSIONS: Chromogranin A is more reliable when used to monitor disease progression and response to treatment and for the early detection of recurrence after treatment rather than in the diagnostic setting. It is more sensible to use this marker in those cases where the initial values were impaired.

Role of biomarker tests for diagnosis of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.

The Role of the Acute Octreotide Suppression Test in Detecting Patients with Neuroendocrine Neoplasms.

BACKGROUND: Serum chromogranin A (CgA) is routinely used as a biomarker in patients with neuroendocrine neoplasms (NENs). Several conditions and comorbidities may be associated with falsely elevated CgA, often leading to extensive diagnostic evaluation, which may be costly and harmful. The aim of this study was to analyze the effectiveness of the acute octreotide suppression test (AOST) in differentiating falsely elevated serum CgA. METHODS: Our prospective study enrolled 45 patients from two different patient cohorts: (1) 29 patients with suspicion or presence of NENs (extensive workup and subsequent biopsy confirmed 16 NENs); (2) 16 consecutive patients admitted via the Emergency Department without NENs (non-NENs). AOST was performed after an overnight fast. Baseline CgA was measured, after which 0.25 mg of octreotide was administered subcutaneously. CgA was measured 3 and 6 h after administration. RESULTS: Baseline CgA levels were similar in NENs and non-NENs. At the end of the AOST, CgA decreased by a median of 83.3% (41.0-127.4) in non-NENs and 13.8% (0.0-43.6) in NENs (p < 0.001). In patients with increased baseline CgA, a decrease in CgA at the 6th hour of < 51.3% had 90.0% sensitivity and 88.9% specificity in detecting NENs. In patients with normal baseline serum CgA, a decrease in CgA at the 3rd hour of < 17.6% had 83.3% sensitivity and 81.8% specificity in detecting patients with NENs. The diagnostic accuracy of the AOST in the entire study population was 86.7%. CONCLUSIONS: AOST is a promising tool to increase the diagnostic accuracy of serum CgA.