Biochemical Markers for Neuroendocrine Tumors: Traditional Circulating Markers and Recent Development-A Comprehensive Review.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain.

Improvements and future perspective in diagnostic tools for neuroendocrine neoplasms.

INTRODUCTION: Neuroendocrine neoplasms (NENs) represent a complex group of tumors arising from neuroendocrine cells, characterized by heterogeneous behavior and challenging diagnostics. Despite advancements in medical technology, NENs present a major challenge in early detection, often leading to delayed diagnosis and variable outcomes. This review aims to provide an in-depth analysis of current diagnostic methods as well as the evolving and future directions of diagnostic strategies for NENs. AREA COVERED: The review extensively covers the evolution of diagnostic tools for NENs, from traditional imaging and biochemical tests to advanced genomic profiling and next-generation sequencing. The emerging role of technologies such as artificial intelligence, machine learning, and liquid biopsies could improve diagnostic precision, as could the integration of imaging modalities such as positron emission tomography (PET)/magnetic resonance imaging (MRI) hybrids and innovative radiotracers. EXPERT OPINION: Despite progress, there is still a significant gap in the early diagnosis of NENs. Bridging this diagnostic gap and integrating advanced technologies and precision medicine are crucial to improving patient outcomes. However, challenges such as low clinical awareness, limited possibility of noninvasive diagnostic tools and funding limitations for rare diseases like NENs are acknowledged.

Lower oesophageal sphincter identification for gastro-oesophageal reflux monitoring: The step-up method revisited with use of basal impedance.

Background: Oesophageal manometry is the gold standard for accurate positioning of multichannel intraluminal impedance pH (MII-pH) monitoring. The pH step-up method is not as accurate as oesophageal manometry and needs patients to be off proton pump inhibitor (PPI) therapy. Objective: This study aimed to evaluate the feasibility of the impedance step-up method for lower oesophageal sphincter (LOS) localisation. Methods: A total of 100 patients who underwent 24-hour MII-pH monitoring were enrolled. High-resolution manometry (HRM) was performed before MII-pH monitoring in order to locate the LOS by a different operator. The impedance step-up was defined as an increase of ≥50% with respect to gastric baseline. Lin's concordance correlation coefficient (ρc ) with 95% Bland-Altman limits of agreement (LOA) and Spearman's rho correlation coefficient were used when appropriate. Results: The median impedance step-up was on average 0.8 cm caudal to the manometric upper border of the LOS. Agreement between two step-up impedance performances and inter-observer agreement were excellent (ρc = 0.98 and 0.95), although the LOA ranges were wide (-2.4 to 4.0 cm). Impedance step-up performances were similar between patients off and on PPI. Conclusions: We have described an alternative new method for pH impedance probe positioning using impedance step-up. Although less accurate than HRM in locating the LOS, it has excellent intra- and inter-observer agreement.

Jackhammer esophagus with and without esophagogastric junction outflow obstruction demonstrates altered neural control resembling type 3 achalasia.

BACKGROUND: Esophageal hypercontractility can manifest with and without esophagogastric junction (EGJ) outflow obstruction. We investigated clinical presentations and motility patterns in patients with esophageal hypercontractile disorders. METHODS: Esophageal HRM studies fulfilling Chicago Classification 3.0 criteria for jackhammer esophagus (distal contractile integral, DCI >8000 mmHg.cm.s in ≥ 20% swallows) with (n = 30) and without (n = 83) EGJ obstruction (integrated relaxation pressure, IRP > 15 mm Hg) were retrospectively reviewed from five centers (4 in Europe, 1 in US). Single swallows (SS) and multiple rapid swallows (MRS) were analyzed using HRM software tools (IRP, DCI, distal latency, DL); MRS: SS DCI ratio >1 defined contraction reserve. Comparison groups were achalasia type 3 (n = 72, positive control for abnormal inhibition and EGJ obstruction) and healthy controls (n = 18). Symptoms, HRM metrics, and MRS contraction reserve were analyzed within jackhammer subgroups and comparison groups. KEY RESULTS: The esophageal smooth muscle was excessively stimulated at baseline in jackhammer subgroups, with lack of augmentation following MRS identified more often compared with controls (P = .003) and type 3 achalasia (P = .07). Consistently abnormal inhibition was identified in type 3 achalasia (47%), and to a lower extent in jackhammer with obstruction (37%, P = .33), jackhammer esophagus (28%, P = .01), and controls (11%, P < .01 compared with type 3 achalasia). Perceptive symptoms (heartburn, chest pain) were common in jackhammer esophagus (P < .01 compared with type 3 achalasia), while transit symptoms (dysphagia) were more frequent with presence of EGJ obstruction (P ≤ .01 compared with jackhammer without obstruction). CONCLUSIONS AND INFERENCES: The balance of excessive excitation and abnormal inhibition defines clinical and manometric manifestations in esophageal hypercontractile disorders.

Provocative testing in patients with jackhammer esophagus: evidence for altered neural control.

Jackhammer esophagus (JE) is a hypercontractile disorder, the pathogenesis of which is incompletely understood. Multiple rapid swallows (MRS) and rapid drink challenge (RDC) are complementary tests used during high-resolution manometry (HRM) that evaluate inhibitory and excitatory neuromuscular function and latent obstruction, respectively. Our aim was to evaluate esophageal pathophysiology using MRS and RDC in 83 JE patients (28 men; median age: 63 yr; IQR: 54-70 yr). Twenty-one healthy subjects (11 men; median age: 28 yr; range: 26-30 yr) were used as a control group. All patients underwent solid-state HRM with ten 5-ml single swallows (SS) and one to three 10-ml MRS; 34 patients also underwent RDC. Data are shown as median (interquartile range). Abnormal motor inhibition was noted during at least one MRS test in 48% of JE patients compared with 29% of controls ( P = 0.29). Mean distal contractile integral (DCI) after MRS was significantly lower than after SS [6,028 (3,678-9,267) mmHg·cm·s vs. 7,514 (6,238-9,197) mmHg·cm·s, P = 0.02], as was highest DCI ( P < 0.0001). Consequently, 66% of JE patients had no contraction reserve. At least one variable of obstruction during RDC (performed in 34 patients) was outside the normal range in 25 (74%) of JE patients. Both highest DCI after SS and pressure gradient across the esophagogastric junction (EGJ) during RDC were higher in patients with dysphagia versus those without ( P = 0.04 and 0.01, respectively). Our data suggest altered neural control in JE patients with heterogeneity in inhibitory function. Furthermore, some patients had latent EGJ obstruction during RDC, which correlated with the presence of dysphagia. NEW & NOTEWORTHY Presence of abnormal inhibition was observed during multiple rapid swallows (MRS) in some but not all patients with jackhammer esophagus (JE). Unlike healthy subjects, JE patients were more strongly stimulated after single swallows than after MRS. An obstructive pattern was frequently observed during rapid drink challenge (RDC) and was related to presence of dysphagia. MRS and RDC during high-resolution manometry are useful to show individual pathophysiological patterns in JE and may guide optimal therapeutic strategies.

Oesophageal motor function in chronic intestinal idiopathic pseudo-obstruction: A study with high-resolution manometry.

BACKGROUND: Chronic intestinal idiopathic pseudo-obstruction (idiopathic CIPO) is a rare heterogeneous condition for which the different phenotypes are difficult to be established. Oesophageal motility has shown to be impaired in patients with idiopathic CIPO at traditional manometry, whereas no studies have assessed it by high resolution manometry (HRM). AIMS: To evaluate oesophageal motility by HRM in patients with idiopathic CIPO. METHODS: 14 patients with idiopathic CIPO underwent oesophageal HRM. Multiple rapid swallows (MRS) were performed in order to evaluate contraction reserve. The Chicago Classification 3.0 was used to classify the oesophageal motility disorders. RESULTS: One idiopathic CIPO patient had type-II achalasia, one aperistalsis and 12 had minor disorder of peristalsis (11 ineffective oesophageal motility and one fragmented peristalsis). These minor disorders were not significantly different from those of 50 other consecutive patients who underwent HRM for dysphagia or GERD and received the diagnosis of ineffective oesophageal motility. Three of the 12 idiopathic CIPO patients with minor disorder of peristalsis had no contraction reserve after MRS. CONCLUSIONS: HRM is able to identify different grades of oesophageal motor impairment in patients with idiopathic CIPO. Presence of major oesophageal dismotility or absent contraction reserve suggest a more severe and widespread motor disorder.

Yield of prolonged wireless pH monitoring in achalasia patients successfully treated with pneumatic dilation.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a long-term complication of achalasia treatments. The aim of our study was to evaluate the yield of prolonged wireless pH monitoring in patients with successfully treated achalasia and its influence on proton pump inhibitor (PPI) use. METHODS: Twenty-five patients with achalasia who underwent prolonged wireless pH monitoring after a successful treatment with pneumatic dilation were enrolled. pH variables were analysed in the first 24 hours of monitoring to determine if tracings were indicative of GORD; the same variables were analysed in the following 24-hour period in order to obtain a worst-day diagnosis of GORD. PPI therapy before and after the test was recorded. RESULTS: Five out of 25 patients had GORD diagnosis during the first day of monitoring and four of them had oesophagitis at endoscopy. During the following days of monitoring four more patients had a diagnosis of GORD. Out of the 25 patients, PPIs were started after the test in six asymptomatic GORD-positive ones, whereas prescription of PPIs was stopped without detrimental effect on symptoms in three GORD-negative patients. CONCLUSIONS: Prolonged wireless pH monitoring is a useful test to be added to endoscopy in order to evaluate GORD and to optimise antisecretory treatment in successfully treated achalasia patients.

Provocative testing of the esophagus and its future.

Standard tests in clinical practice commonly fail to demonstrate a clear esophageal etiology for symptoms such as heartburn, dysphagia, or chest pain. Over the years, various provocative measures have been developed to provide a better understanding of the origins of such symptoms. Some measures, such as esophageal acid infusion or changing bolus consistency, can be easily incorporated into clinical practice. Others, such as multimodal stimulation systems, are more technically demanding. They have contributed to a better understanding of esophageal physiology in health and disease. Their role in clinical decision making is still evolving. This focused review provides a summary of the esophageal nociceptive pathways and how provocative testing can be used to interrogate their integrity.

Rapid air infusion into the oesophagus: Motor response in patients with achalasia and nonobstructive dysphagia assessed with high-resolution manometry.

BACKGROUND: Achalasia is a neurodegenerative disorder of the oesophagus. Alteration of motor activity induced by oesophageal distension has not been explored. OBJECTIVES: To investigate this function, using high-resolution Manometry. METHODS: This study enrolled 15 healthy subjects, 15 nonobstructive dysphagia (NOD), and 18 achalasia patients successfully treated with pneumatic dilation (six with restored peristalsis). The three groups underwent five rapid (<1 s) intraoesophageal infusions of 20-ml air boluses, followed by eight 5-ml water swallows. RESULTS: WHEREAS THE RESPONSE RATE TO WATER SWALLOWS WAS SIMILAR IN THE THREE GROUPS, AIR INFUSION INDUCED A LOWER RESPONSE RATE IN ACHALASIA (MEDIAN, INTERQUARTILE RANGE: 70%, 40-100%) and, to a lesser extent, in NOD patients (100%, 60-100%) than in healthy subjects (100%, 100-100%; p < 0.001 and p = 0.06, respectively). However, the response rate was highly variable in achalasia patients irrespective of presence of peristalsis. Furthermore, the strength of motor response to air infusion when compared to water swallows was diminished in achalasia patients but not in healthy subjects and NOD. CONCLUSIONS: Motor response to rapid air infusion was variably impaired in achalasia. The role of this alteration in the long-term outcome deserves evaluation.