Neuron-Specific Enolase-What Are We Measuring?

Since the discovery of the neuron-specific protein by Moore and McGregor in 1965, tens of thousands of studies have investigated the basic and applied significance of neuron-specific enolase (NSE). This promising biomarker, according to many researchers, has not found widespread use in clinical practice, particularly in acute cerebrovascular accidents. Moreover, the several studies refuting the usefulness of serum NSE measurement in critically ill patients leads us to consider the reasons for such contradictory conclusions. In this article, we have analyzed the main directions in the study of NSE and expressed our perspective on the reasons for the contradictory results and the difficulties in implementing the results of these studies in clinical practice. In our opinion, the method of the enzyme-linked immunosorbent assay (ELISA) used in the majority of the studies is inappropriate for the evaluation of NSE as a marker of central nervous system damage, because it does not allow for the differentiation of heterodimers of enolases and the assessment of the enzymatic activity of this group of enzymatic proteins. Therefore, the methodological approach for the evaluation of NSE (γγ-enolase) as a biomarker needs to be elaborated and improved. Furthermore, the specificity of the applied research methods and the appropriateness of the continued use of the term "neuron-specific enolase" must be addressed.

Can serum NSE predict and evaluate sepsis-associated encephalopathy: A protocol for a systematic review and meta-analysis.

INTRODUCTION: Brain dysfunction in sepsis is known as sepsis-associated encephalopathy (SAE), which often results in severe cognitive and neurological sequelae and increases the risk of death. Neuron specific enolase (NSE) may serve as an important neurocritical biomarker for detection and longitudinal monitoring in SAE patients. Our systematic review and meta-analysis will aim to explore the diagnostic and prognostic value of serum NSE in SAE patients. Currently, no systematic review and meta-analysis have been assessed that NSE as a biomarker of SAE. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of serum NSE for the diagnostic and prognostic value of SAE patients. The primary objective is to evaluate the diagnostic accuracy of serum NSE as an independent biomarker for SAE. The secondary objective is to determine the prognostic strength of serum NSE as an independent biomarker of mortality in septic patients determine. We will perform a systematic search and descriptive review using the MEDLINE database and the PubMed interface. We will assign two independent reviewers to review all collected titles and associated abstracts, review full articles, and extract study data. We will use the Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2) assessment tool according to the recommendation by the Cochrane Collaboration to evaluate quality and risk of bias of the selected studies. Subgroup and sensitivity analyses will also be used to assess heterogeneity. Review Manager version 5.4 and Stata16.0. will be used for statistical analysis. ETHICS AND DISSEMINATION: The meta-analysis will provide ICU physicians with the most current information to predict which patients are at risk of SAE and take corresponding intervention measures to reduce morbidity and ameliorate neurological outcomes. There is no need for ethics approval for this review. The findings will be disseminated in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: CRD42023398736.

Limited prognostic role of routine serum markers (AP, CEA, LDH and NSE) in oligorecurrent prostate cancer patients undergoing PSMA-radioguided surgery.

INTRODUCTION: We evaluated the prognostic role of pre-salvage prostate-specific membrane antigen-radioguided surgery (PSMA-RGS) serum levels of alkaline phosphatase (AP), carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), and neuron-specific enolase (NSE). MATERIALS AND METHODS: Patients who consecutively underwent PSMA-RGS for prostate cancer (PCa) oligorecurrence between January 2019 and January 2022 were selected. Biomarkers were assessed one day before surgery. Cox regression and logistic regression models tested the relationship between biochemical recurrence-free survival (BFS), 6- and 12-month biochemical recurrence (BCR), and several independent variables, including biomarkers. RESULTS: 153 consecutive patients were analyzed. In the univariable Cox regression analysis, none of the biomarkers achieved predictor status (AP: hazard ratio [HR] = 1.03, 95% CI 0.99, 1.01; p = 0.19; CEA: HR = 1.73, 95% CI 0.94, 1.21; p = 0.34; LDH: HR = 1.01, 95% CI 1.00, 1.01; p = 0.05; NSE: HR = 1.02, 95% CI 0.98, 1.06; p = 0.39). The only independent predictor of BFS was the number of positive lesions on PSMA PET (HR = 1.17, 95% CI 1.02, 1.30; p = 0.03). The number of positive lesions was confirmed as independent predictor for BCR within 6 and 12 months (BCR < 6 months: odds ratio [OR] = 1.1, 95% CI 1.0, 1.3; p = 0.04; BCR < 12 months: OR = 1.1, 95% CI 1.0, 1.3; p = 0.04). CONCLUSION: The assessment of AP, CEA, LDH, and NSE before salvage PSMA-RGS showed no prognostic impact. Further studies are needed to identify possible predictors that will optimize patient selection for salvage PSMA-RGS.

Plasma neurological biomarkers as a measure of neurotoxicity in pediatric dental general anesthesia: a prospective observational feasibility study.

PURPOSE: Neurotoxicity concerns have been raised over general anesthesia and sedation medication use in children. Such concerns are largely based on animal studies, historical anesthetic agents, and assessment tools, thus warranting further investigations. Blood biomarkers in detecting neuronal inflammation and apoptosis are novel methods for detecting neuronal damage. Therefore, the aim of this feasibility study was to assess the usefulness of the levels of four plasma biomarkers in dental general anesthesia (DGA) as surrogate markers of neurotoxicity in children. The secondary aim was to compare changes in motor manipulative skills pre- and post-anesthetic exposure. METHODS: This single-center prospective observational study included 22 healthy children aged between 3 and 6 years old who underwent DGA. Subclinical neurotoxicity was measured with a panel of four plasma biomarkers: Caspase-3, neuron-specific enolase (NSE), neurofilament light chain, and S100B at three time points (1; at start, 2; end and 3; on recovery from DGA). The Skillings-Mack test was used to identify the difference in the biomarker levels at three time points. Motor manipulative score assessment, prior and two weeks after DGA was also performed. RESULTS: A total of 22 study participants (mean age = 5 ± 1 years) were included with a median DGA duration of 106 ± 28 min. A reduction in Caspase-3 levels was recorded, with pairwise comparison over three time points, reporting a statistical significance between time point 2 vs. 1 and time point 3 vs. 1. Although fluctuations in NSE levels were recorded, no significant changes were found following pairwise comparison analysis. Among other biomarkers, no significant changes over the three periods were recorded. Furthermore, no significant changes in manipulative motor scores were reported. CONCLUSION: Caspase-3 reduced significantly in the short time frames during day-care DGA; this might be due to the relatively short anesthesia duration associated with dental treatment as compared with more extensive medical-related treatments. Therefore, further studies on Caspase-3 as a potential biomarker in pediatric DGA neurotoxicity are required to further ascertain results of this study.

Analysis of the relationship between MYCN gene and serum NSE and urinary VMA levels and neuroblastoma pathological features and prognosis.

The purpose of this study was to explore the relationship between the MYCN gene, serum neuron-specific enolase (NSE), urinary vanillylmandelic acid (VMA) levels, and neuroblastoma pathological features and prognosis. Ninety-four children with neuroblastoma treated in the hospital were selected to compare the differences in MYCN gene amplification, serum NSE, and urinary VMA levels in children with different clinicopathological features and prognoses. The proportion of children with MYCN gene copy number ≥10 in INSS stage 3-4 was higher than that of children with INSS stage 1-2 (P < 0.05); the proportion of children with MYCN gene copy number ≥10 in high-risk children in the COG risk stratification was higher than that of children with intermediate and low risk (P < 0.05); the serum NSE of children aged >12 months higher than that of children aged ≤12 months (P < 0.05); serum NSE of children with tumors >500 cm3 higher than that of children with tumors ≤500 cm3 (P < 0.05); serum NSE and urinary VMA of children with INSS staging of stages 3-4 were higher than that of children with stages 1 to 2 (P < 0.05); serum NSE and urinary VMA in children with lymph node metastasis were higher than that of children without lymph node metastasis (P < 0.05); serum NSE of children with MYCN gene copy number ≥10 was higher than that of children without lymph node metastasis (P < 0.05); the proportion of children with MYCN gene copy number ≥10 who died, and the percentages of serum NSE and urinary VMA were higher than those of the surviving children (P < 0.05). MYCN gene amplification and serum NSE and urinary VMA levels were related to the age, tumor size, INSS stage, COG stage, lymph node metastasis, and prognosis of the children with neuroblastoma.

Serum Neuron-Specific Enolase as a Biomarker of Neonatal Brain Injury-New Perspectives for the Identification of Preterm Neonates at High Risk for Severe Intraventricular Hemorrhage.

Neonatal brain injury (NBI) is a critical condition for preterm neonates with potential long-term adverse neurodevelopmental outcomes. This prospective longitudinal case-control study aimed at investigating the levels and prognostic value of serum neuron-specific enolase (NSE) during the first 3 days of life in preterm neonates (<34 weeks) that later developed brain injury in the form of either periventricular leukomalacia (PVL) or intraventricular hemorrhage (IVH) during their hospitalization. Participants were recruited from one neonatal intensive care unit, and on the basis of birth weight and gestational age, we matched each case (n = 29) with a neonate who had a normal head ultrasound scan (n = 29). We report that serum NSE levels during the first three days of life do not differ significantly between control and preterm neonates with NBI. Nevertheless, subgroup analysis revealed that neonates with IVH had significantly higher concentrations of serum NSE in comparison to controls and neonates with PVL on the third day of life (p = 0.014 and p = 0.033, respectively). The same pattern on the levels of NSE on the third day of life was also observed between (a) neonates with IVH and all other neonates (PVL and control; p = 0.003), (b) neonates with II-IV degree IVH and all other neonates (p = 0.003), and (c) between control and the five (n = 5) neonates that died from the case group (p = 0.023). We conclude that NSE could be an effective and useful biomarker on the third day of life for the identification of preterm neonates at high risk of developing severe forms of IVH.

Minor head injury in anticoagulated patients: performance of biomarkers S100B, NSE, GFAP, UCH-L1 and Alinity TBI in the detection of intracranial injury. A prospective observational study.

OBJECTIVES: Data in literature indicate that in patients suffering a minor head injury (MHI), biomarkers serum levels could be effective to predict the absence of intracranial injury (ICI) on head CT scan. Use of these biomarkers in case of patients taking oral anticoagulants who experience MHI is very limited. We investigated biomarkers as predictors of ICI in anticoagulated patients managed in an ED. METHODS: We conducted a single-cohort, prospective, observational study in an ED. Our structured clinical pathway included a first head CT scan, 24 h observation and a second CT scan. The outcome was delayed ICI (dICI), defined as ICI on the second CT scan after a first negative CT scan. We assessed the sensitivity (SE), specificity (SP), negative predictive value (NNV) and positive predictive value (PPV) of the biomarkers S100B, NSE, GFAP, UCH-L1 and Alinity TBI in order to identify dICI. RESULTS: Our study population was of 234 patients with a negative first CT scan who underwent a second CT scan. The rate of dICI was 4.7 %. The NPV for the detection of dICI were respectively (IC 95 %): S100B 92.7 % (86.0-96.8 %,); ubiquitin C-terminal hydrolase-L1 (UCH-L1) 91.8 % (83.8-96.6 %); glial fibrillary protein (GFP) 100 % (83.2-100 %); TBI 100 % (66.4-100 %). The AUC for the detection of dICI was 0.407 for S100B, 0.563 for neuron-specific enolase (NSE), 0.510 for UCH-L1 and 0.720 for glial fibrillary acidic protein (GFAP), respectively. CONCLUSIONS: The NPV of the analyzed biomarkers were high and they potentially could limit the number of head CT scan for detecting dICI in anticoagulated patients suffering MHI. GFAP and Alinity TBI seem to be effective to rule out a dCI, but future trials are needed.

COMPARATIVE EVALUATION AND PROGNOSTIC UTILITY OF NEURONAL INJURY BIOMARKERS IN COVID-19 PATIENTS: A PROSPECTIVE STUDY.

ABSTRACT: Background : COVID-19 disease severity markers include mostly molecules related to not only tissue perfusion, inflammation, and thrombosis, but also biomarkers of neural injury. Clinical and basic research has demonstrated that SARS-COV-2 affects the central nervous system. The aims of the present study were to investigate the role of neural injury biomarkers and to compare them with inflammatory markers in their predictive ability of mortality. Methods : We conducted a prospective observational study in critically ill patients with COVID-19 and in a cohort of patients with moderate/severe disease. S100b, neuron-specific enolase (NSE), and inflammatory markers, including soluble urokinase plasminogen activator receptor (suPAR), were measured on intensive care unit or ward admission, respectively. Statistical comparisons between patient groups were performed for all biomarkers under investigation. Correlations between different biomarkers were tested with Spearman correlation coefficient. Receiver operating characteristic curves were plotted using mortality as the classification variable and the biomarker levels on admission as the prognostic variables. Results : A total of 70 patients with COVID-19 were included in the final analysis. Of all studied biomarkers, s100b had the best predictive ability for death in the intensive care unit, with an area under the curve of 0.73 (0.61-0.83), P = 0.0003. S100b levels correlated with NSE, interleukin (IL)-8, and IL-10 (0.27 < rs < 0.37, P < 0.05), and tended to correlate with suPAR ( rs = 0.26, P = 0.05), but not with the vasopressor dose ( P = 0.62). Conclusion : Among the investigated biomarkers, s100b demonstrated the best predictive ability for death in COVID-19 patients. The overall biomarker profile of the patients implies direct involvement of the nervous system by the novel coronavirus.

Development of a strategy for assessing blood-brain barrier disruption using serum S100 calcium-binding protein B and neuron-specific enolase in early stage of neuroemergencies: A preliminary study.

BACKGROUND: Rapid disease progression in neuroemergencies is associated with blood-brain barrier (BBB) disruption. We investigated a less invasive strategy for assessing BBB status by evaluating S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) at early stages of the hypoxic-ischemic brain injury (HIBI) cascade. METHODS: This retrospective study used prospectively collected data from patients with out-of-hospital cardiac arrest (August 2019-July 2021). Albumin specimens obtained from serum and cerebrospinal fluid via arterial catheter and lumbar puncture were used to measure the albumin quotient (Qa), which is widely accepted as the gold standard method for detecting BBB disruption. Serum S100B and NSE levels were measured simultaneously following the return of spontaneous circulation. We conducted linear regression to evaluate the relationship between S100B and Qa and the predictive performance of S100B for abnormal Qa. The primary study outcome was abnormal Qa (>0.007). RESULTS: Forty-one patients were enrolled; 30 showed an abnormal Qa suggestive of BBB disruption. S100B levels were significantly higher than in those with a normal Qa (0.244 µg/L [interquartile range [IQR], 0.146-0.823 vs 0.754 µg/L [IQR, 0.317-2.228], P = .03). We report a positive correlation between serum S100B and Qa (R2 = 0.110; P = .04). The area under the receiver operating characteristics curve (AUROC) evaluating the predictive performance of S100B with respect to abnormal Qa was 0.718 (95% confidence interval, 0.556-0.847). The cutoff value for S100B (with respect to BBB disruption) in the total cohort was 0.283 µg/L (sensitivity, 80.0%; specificity, 72.7%). Subgroup analyses in patients with serum neuron-specific enolase (NSE) levels of <40.8 ng/mL (excluding those with established neuronal cell injury) showed an improved correlation coefficient (R2 = 0.382; P < .01) and predictive performance (AUROC, 0.836 [95% confidence interval, 0.629-0.954]) compared with the total cohort. CONCLUSIONS: Serum S100B obtained at an early stage of the HIBI cascade is associated with abnormal Qa, suggesting BBB disruption. The predictive performance of S100B and the correlation between serum S100B and Qa can be improved using a complementary strategy (i.e., evaluations of S100B and NSE levels) that combines considerations of cell damage in astrocytes and neurons.

Pro-Gastrin-Releasing Peptide as a Marker of Small Cell Lung Cancer.

The serum levels of pro-gastrin-releasing peptide (proGRP), neuron-specific enolase (NSE), and chromogranin A (CgA) were studied in 69 patients with small cell lung cancer and 50 apparently healthy donors. A significant increase of all studied biochemical markers was revealed in small cell lung cancer patients, while the highest diagnostic efficiency was demonstrated by proGRP compared to NSE and CgA. ProGRP is a promising biochemical marker of small cell lung cancer, especially sensitive in patients with distant metastases (in the brain, liver, and bones).

Clinical Value of Serum Neuron-Specific Enolase Combined with Serum S100B Protein in the Diagnosis of Systemic Lupus Erythematosus.

Objective: To investigate the clinical value of serum neuron-specific enolase (NSE) combined with serum S100B protein in the diagnosis of systemic lupus erythematosus (SLE). Methods: Sixty patients with SLE treated in our hospital from January 2019 to April 2021 were enrolled as the study group. According to the degree of activity, the study group was assigned into three groups: mild activity group (n = 20), moderate activity group (n = 20), and severe activity group (n = 20). A total of 60 healthy people who underwent physical examination in our hospital in the same period were enrolled as the control group. The NSE and serum S100B protein were detected in the two groups, and the correlation between serum nerve-specific enolase and serum S100B protein and the clinical value in the diagnosis of SLE were analyzed. Results: First of all, we compared the general data of the two groups. There was no significant difference in sex, age, marital status, and education level, and no significant difference was exhibited (p > 0.05). There was no significant difference in sex, age, marital status, and education level among mild activity group, moderate activity group, and severe activity group, and no significant difference in data was exhibited (p > 0.05). Secondly, we compared the levels of serum S100B protein and NSE. The levels of serum S100B protein and NSE in the study group were higher compared to the control group (p < 0.05). The levels of serum S100B protein and NSE in patients with different activity levels of SLE were compared. The levels of serum S100B protein and NSE in mild activity group < moderate activity group < severe activity group were significantly different (p < 0.05). Correlation analysis between serum S100B, NSE levels, and SLE activity indicated that serum S100B and NSE levels were positively correlated with SLE activity. With the increase of SLE activity, serum S100B and NSE levels gradually increased, and the data difference was statistically significant (r = 0.855, 0.844, p < 0.05). Finally, we established the logistic prediction model, take the probability of generating prediction as the analysis index, and draw the ROC curve to evaluate the diagnostic value of different combinations to SLE. The highest AUC and sensitivity of the two indexes in the diagnosis of SLE were 0.773 and 0.836, respectively. The levels of serum S100B protein and NSE have a certain value in the diagnosis of SLE, while the combined diagnosis is of higher value, sensitivity, and specificity in the diagnosis of SLE. Conclusion: Serum S100B protein and NSE are very sensitive indexes to judge the damage of central nervous system. However, due to the small number of cases in this study, there were as many as 19 kinds of NPSLE classification, so the relationship between serum S100B protein, NSE levels, and various NPSLE and their exact application value in diagnosing the disease and judging the prognosis needs to be confirmed by expanding the number of cases.

Blood-brain barrier disruption as a cause of various serum neuron-specific enolase cut-off values for neurological prognosis in cardiac arrest patients.

We compared the cut-off and prognostic value of serum neuron-specific enolase (NSE) between groups with and without severe blood-brain barrier (BBB) disruption to reveal that a cause of various serum NSE cut-off value for neurological prognosis is severe BBB disruption in out-of-hospital cardiac arrest (OHCA) patients underwent target temperature management (TTM). This was a prospective, single-centre study conducted from January 2019 to June 2021. Severe BBB disruption was indicated using cerebrospinal fluid-serum albumin quotient values > 0.02. The area under the receiver operating characteristic curve of serum NSE obtained on day 3 of hospitalisation to predict poor outcomes was used. In patients with poor neurologic outcomes, serum NSE in those with severe BBB disruption was higher than in those without (P = 0.006). A serum NSE cut-off value of 40.4 µg/L for poor outcomes in patients without severe BBB disruption had a sensitivity of 41.7% and a specificity of 96.0%, whereas a cut-off value of 34.6 µg/L in those with severe BBB disruption had a sensitivity of 86.4% and a specificity of 100.0%. We demonstrated that the cut-off and prognostic value of serum NSE were heterogeneous, depending on severe BBB disruption in OHCA patients treated with TTM.

Distinct expression and clinical value of aquaporin 4 in children with hand, foot and mouth disease caused by enterovirus 71.

Brain dysfunction is a prerequisite for critical complications in children with hand, foot, and mouth disease (HFMD). Aquaporin 4 (AQP-4) may be involved in the pathological process of cerebral oedema and injury in children with severe and critical HFMD. This study aimed to assess the association of AQP-4 with the severity of enterovirus 71 (EV71)-associated HFMD. Children with EV71-infected HFMD were divided into a common group (clinical stage 1), a severe group (clinical stage 2), and a critical group (clinical stage 3) according to Chinese guidelines. The levels of AQP-4, interleukin-6 (IL-6), norepinephrine (NE), and neuron-specific enolase (NSE) before and after treatment were tested. Serum AQP-4, IL-6, NE, and NSE levels showed significant differences among the critical, severe, and common groups before and after treatment (P < 0.01). No significant differences in AQP-4 levels in cerebrospinal fluid (CSF) were observed between the critical and severe groups before and after treatment, but the CSF AQP-4 levels in these two groups were higher than those in the common group before treatment (P < 0.01). Serum AQP-4 levels, but not CSF AQP-4 levels, closely correlated with serum IL-6, NE, and NSE levels. These results suggest that the level of AQP-4 in serum, but not in CSF, is a candidate biomarker for evaluating the severity and prognosis of EV71-associated HFMD.

Establishing prognostic significance of hypoxia predictors in patients with acute cerebral pathology.

OBJECTIVES: This research aims to study the prognostic role of serum S100 as a predictor of mortality in vascular and traumatic brain injuries. METHODS: This prospective cohort study involved 219 patients. In the blood serum, neuron-specific markers (S100, NSE) and glucose, acid-base state and gas composition of arterial blood were obtained at admission, on the 3rd, 5th and 7th days of patients' stay in the intensive care unit. RESULTS: The most significant risk factor for an unfavorable outcome is the marker S100 with a cut-off point of 0.2 mcg/l. The analysis results indicate a statistically significant direct relationship between S100 > 0.2 mcg/l and NSE ≥ 18.9 ng/ml compared to other variables, while the chance ratio (OR) is 11.9 (95%CI:3.2927-1.6693;). With blood sugar increase above 7.4 mmol/l, the OR is 3.82 (95% CI: 2.1289-0.5539;); with a Glasgow scale below 13 points, the OR is 3.69 (95% CI: 2.1316-0.4819;); with an increase in pCO2 < 43.5 mm Hg, the OR was 3.15 (95% CI: 1.8916- 0.4062;). The obtained model certainty measure according to pseudo R2 Nagelkerke criterion is 263.5, showing the excellent quality of the mathematical model's predictive ability. The developed prognostic model, including the dependent variable S100 and independent variables as predictors of a poor outcome of NSE, pCO2, GCS and Hb, reached a cut-off point of 84.51%, AUC - 0.88 with high levels of sensitivity and specificity: 91.89% and 64.14%, respectively. NOVELTY: This model can be used to predict the outcome in patients with acute cerebral pathology.

Elevated neuron-specific enolase level is associated with postoperative delirium and detection of phosphorylated neurofilament heavy subunit: A prospective observational study.

BACKGROUND: Delirium is the most common central nervous system complication after surgery. Detection of phosphorylated neurofilament heavy subunit in the serum reflects axonal damage within the central cervous system and is associated with the severity of postoperative delirium. Neuron-specific enolase and S100 calcium-binding protein ß have been identified as possible serum biomarkers of postoperative delirium. This study examined the association of the levels of these markers with incidence of postoperative delirium and detection of phosphorylated neurofilament heavy subunit. METHODS: This study represents a post hoc analysis of 117 patients who participated in a prospective observational study of postoperative delirium in patients undergoing cancer surgery. Patients were clinically assessed for development of postoperative delirium within the first five days of surgery. Serum levels of phosphorylated neurofilament heavy subunit, neuron-specific enolase, and S100 calcium-binding protein ß levels were measured on postoperative day 3. RESULTS: Forty-one patients (35%) were clinically diagnosed with postoperative delirium. Neuron-specific enolase level (P < 0.0001) and the proportion of patients positive for phosphorylated neurofilament heavy subunit (P < 0.0001) were significantly higher in the group of patients with postoperative delirium. Neuron-specific enolase level discriminated between patients with and without clinically diagnosed postoperative delirium with significantly high accuracy (area under the curve [AUC], 0.87; 95% confidence interval [CI], 0.79-0.95; P < 0.0001). Neuron-specific enolase level was associated with incidence of postoperative delirium independently of age (adjusted odds ratio, 8.291; 95% Cl, 3.506-33.286; P < 0.0001). The AUC for the serum neuron-specific enolase level in detecting phosphorylated neurofilament heavy subunit was significant (AUC, 0.78; 95% CI, 0.66-0.90; P < 0.0001). CONCLUSION: Elevated serum neuron-specific enolase was associated with postoperative delirium independent of age as well as detection of phosphorylated neurofilament heavy subunit in serum. Serum neuron-specific enolase and phosphorylated neurofilament heavy subunit might be useful as biomarkers of postoperative delirium. TRIAL REGISTRATION: University Medical Information Network (UMIN) trial ID: UMIN000010329; https://clinicaltrials.gov/.

Mixed neuroendocrine non-neuroendocrine neoplasm of the gallbladder complicated by a pancreaticobiliary maljunction of a non-dilated biliary duct: A case report.

RATIONALE: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare tumor. MiNEN of the gallbladder (GB) with pancreaticobiliary maljunction (PMJ) is extremely rare. The origin of MiNEN of the GB remains unknown; the biliary tract normally lacks neuroendocrine cells. MiNEN of the GB has a poor prognosis; because of its rarity, no treatment or management guidelines have been established yet. PATIENT CONCERNS: A 47-year-old male presenting with right hypochondrial pain and malaise for 3 months was referred to our hospital for further management. DIAGNOSIS: The neuron-specific enolase level was increased. Contrast-enhanced computed tomography revealed a mass of 70 mm in size with unclear boundaries in the liver. The GB was surrounded by this mass, narrowing the lumen of the GB. Many swollen lymph nodes were observed in the hepatoduodenal ligament. Endoscopic retrograde cholangiopancreatography revealed a PMJ with a non-dilated biliary duct. A percutaneous biopsy was performed on the liver mass, and the pathological findings were neuroendocrine carcinoma (NEC) (small cell type). We diagnosed a NEC of the GB, T3N1M0, stage IIIB (Union for International Cancer Control, 7th edition). INTERVENTIONS: Because of advanced lymph node metastasis, we considered this tumor difficult to cure solely by surgical intervention. After initial chemotherapy consisting of cisplatin and irinotecan, a marked reduction in both tumor and lymph node sizes enabled conversion surgery. The pathological diagnosis of the resected tumor was MiNEN consisting of NEC and adenocarcinoma. The primary lesion was the adenocarcinoma occupying the luminal side of the GB. As a postsurgical treatment, the patient received additional irradiation therapy to the common hepatic duct and liver stump because of positive surgical margins. OUTCOMES: At 13 months postoperatively, computed tomography findings revealed the appearance of a hypervascular liver tumor, and laboratory data showed increased serum neuron-specific enolase levels. Chemotherapy was unsuccessful, leading to the death of the patient 36 months from the date of diagnosis. LESSONS: There are several reports on the development of MiNEN of the GB. In our case, a PMJ-related adenocarcinoma of the GB transdifferentiated into NEC. Further accumulation of cases is necessary to establish a treatment strategy for MiNEN of the GB.

Prognostic role of serum neutrophil gelatinase-associated lipocalin in cardiac arrest patients: A prospective observational study.

ABSTRACT: Accurate neurological prognostication is of the utmost importance to avoid futile treatments in patients treated with targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA). This study aimed to investigate the prognostic value of serum neutrophil gelatinase-associated lipocalin (NGAL) by comparing with neuron-specific enolase (NSE), which is currently recommended by international guidelines in patients treated with TTM after OHCA.The study included 85 comatose adult patients with OHCA who underwent TTM between May 2018 and December 2020. Serum NGAL and NSE were measured at 24-hour intervals until 72 hours after return of spontaneous circulation (ROSC). The primary outcome was their prognostic performance for poor neurological outcome at 3 months after OHCA.Forty-nine patients (57.6%) had a poor neurological outcome; NGAL levels at all time points measured were significantly higher in these patients than in those with a good outcome (P < .01). NGAL showed lower maximal sensitivity (95% confidence interval [CI]) under a false-positive rate of 0% for the primary outcome compared with NSE (18.2% [95% CI 8.2-32.7] vs 66.7% [95% CI 50.5-80.4]). The combination of NGAL with NSE at 48 h showed the highest sensitivity (69.1% [95% CI 52.9-82.4]) and had the highest area under the curve (0.91 [95% CI 0.81-0.96]) for a poor outcome. The prognostic performance of NGAL alone was inadequate at all time points. However, NGAL combined with NSE at 24 and 28 hours after ROSC showed improved sensitivity compared to NGAL alone.NGAL should be considered a supplementary biomarker in combination with NSE for prognostication in patients with OHCA treated with TTM.

Prediction of delayed neuropsychiatric sequelae after carbon monoxide poisoning via serial determination of serum neuron-specific enolase levels.

BACKGROUND: Neuron-specific enolase (NSE) is released into serum when nerve cells are damaged, and the levels thereof are used to determine neurological prognosis in patients who have suffered cardiac arrest or stroke. Delayed neuropsychiatric sequelae (DNS), a major complication of carbon monoxide poisoning (COP), can be caused by inflammatory response which is a mechanism of neuronal injury in cardiac arrest and stroke. NSE is known as a predictor of neurological prognosis in ischemic brain injury after cardiac arrest, and it is also reported as a predictor of DNS in acute COP. When serum NSE is measured serially in cardiac arrest patients, the best time to predict neurological prognosis is known at 48-72 h, but there are no studies analyzing serial serum NSE in acute COP. Thus, we explored whether serum NSE levels measured three times at 24 h intervals after COP predicted the development of DNS. METHODS: This prospective observational study was conducted on patients treated for COP from May 2018 to April 2020 in a tertiary care hospital in Korea. Neuron-specific enolase levels were assessed 24, 48, and 72 h after presentation at hospital. We used logistic regression to explore the association between NSE levels and DNS development. RESULTS: The NSE level was highest at 48 h, and the difference between the DNS group and the non-DNS group was greatest on the same time point. On multivariable logistic regression analysis, the NSE level at 48 h of >20.98 ng/mL (odds ratio [OR], 3.570; 95% confidence interval [CI], 1.412-9.026; P = .007) and the initial Glasgow Coma Scale (GCS) score of <9 (OR, 4.559; 95% CI, 1.658-0.12.540; P = .003) was statistically significant for DNS development. CONCLUSION: Early identification of those who will experience DNS in acute COP patients is clinically important for deciding treatment. In this study, we revealed that NSE level of >20.98 ng/mL at 48 h time point can be used as an independent predictor of DNS (OR, 3.570; 95% CI, 1.412-9.026; P = .007; AUC, 0.648).