High Neuron-specific Enolase Levels Research Articles

Autophagy sensitivity of neuroendocrine lung tumor cells

Neuroendocrine (NE) phenotypes characterize a spectrum of lung tumors, including low-grade typical and intermediate-grade atypical carcinoid, high-grade large-cell NE carcinoma and small cell lung carcinoma. Currently, no effective treatments are available to cure NE lung tumors, demanding identification of biological features specific to these tumors. Here, we report that autophagy has an important role for NE lung tumor cell proliferation and survival. We found that the expression levels of the autophagy marker LC3 are relatively high in a panel of lung tumor cell lines expressing high levels of neuron-specific enolase (NSE), a key NE marker in lung tumors. In response to bafilomycin A1 and chloroquine, NE lung tumor cells exhibited cytotoxicity whereas non-NE lung tumor cells exhibited cytostasis, indicating a distinct role of autophagy for NE lung tumor cell survival. Intriguingly, in certain NE lung tumor cell lines, the levels of processed LC3 (LC3-II) were inversely correlated with AKT activity. When AKT activity was inhibited using AKTi or MK2206, the levels of LC3-II and SQSTM1/p62 were increased. In contrast, torin 1, rapamycin or mTOR knockdown increased p62 levels, suggesting that these two pathways have opposing effects on autophagy in certain NE lung tumors. Moreover, inhibition of one pathway resulted in reduced activity of the other, suggesting that these two pathways crosstalk in the tumors. These results suggest that NE lung tumor cells share a common feature of autophagy and are more sensitive to autophagy inhibition than non-NE lung tumor cells.

Neuron-specific enolase serum levels predict severe neuronal injury after extracorporeal life support in resuscitation†

Extracorporeal life support (ECLS) is a rescue option in critically ill patients. Since fast available and appropriate for respiratory and circulatory failure, it is frequently applied in resuscitation scenarios. Neurological injury is a complication common in ECLS patients limiting outcome, particularly after resuscitation. In this study, the institutional ECLS database was used to correlate neuron-specific enolase (NSE) serum peak values with outcome of patients supported with venoarterial (VA) ECLS during cardiopulmonary resuscitation (CPR). From January 2011 to August 2012, 31 patients were provided with a VA ECLS during CPR (external cardiac massage). Serum NSE peaks were monitored and correlated with neurological outcome and hospital mortality. Patients were divided into two groups with mild-to-moderate and high NSE levels (cut-off value 100 μg/l). High NSE levels were seen in 7 patients (mean 218 ± 155 μg/l) and mild-to-moderate levels in 24 patients (50 ± 23 μg/l, P = 0.0001). Duration of extracoporeal support was comparable in both groups (6.3 ± 7.5 vs 5.0 ± 4.5 days, P = n.s.). Patients with mild-to-moderate NSE levels were significantly older than those with high NSE levels (58 ± 16 vs 44 ± 15 years, P = 0.02). Six patients with high NSE levels (86%) developed severe neurological complications. Though 4 patients could be weaned from extracorporeal support, hospital mortality was 86% (6 patients). In contrast, patients with mild-to-moderate NSE levels had a hospital mortality of 46% (11 patients). Eighteen patients (75%) could be weaned from the device, and incidence of major neurological events was 29% (6 patients) only. Serum pH and lactate levels before ECLS implantation were significantly lower in patients with mild-to-moderate NSE values (pH: 7.23 ± 0.04 vs 6.93 ± 0.12, P = 0.039; lactate: 106 ± 11 vs 161 ± 16 mg/l, P = 0.023). High NSE serum levels after ECLS correspond to poor neurological outcome and considerable mortality. Therefore, early neuroimaging is reasonable for determining therapeutic strategies in patients with high NSE peaks after resuscitation and extracorporeal support.

Changes of serum neuron-specific enolase and serum ferritin levels in patients with pneumoconiosis

To investigate the changes in serum neuron-specific enolase (NSE) and serum ferritin (SF) in patients with pneumoconiosis and their relationship with the onset of pneumoconiosis. The serum NSE and SF levels in the peripheral blood of patients with pneumoconiosis were measured by electrochemical fluorescence immunoassay. The patients with first-stage pneumoconiosis and second-stage pneumoconiosis had significantly higher serum NSE and SF levels than the control group (23.0264±14.0410 and 44.9776±26.5208 ng/ml vs 8.1480±3.7512 ng/ml, P < 0.05; 267.2515±186.5809 and 579.1371±433.9326 ng/ml vs 120.8613±74.2809 ng/ml, P < 0.05), and the patients with second-stage pneumoconiosis had significantly higher serum NSE and SF levels than those with first-stage pneumoconiosis (P < 0.05). After treatment, the serum NSE level decreased significantly in the patients with pneumoconiosis (21.1675±17.5942 ng/ml vs 33.4490±21.6948 ng/ml, P < 0.05), but it was still significantly higher than that in the control group (P < 0.05). The treatment did not produce significant changes in SF level among these patients (P > 0.05). Patients with pneumoconiosis have elevated serum NSE and SF levels, which may be related to the onset and progression of this disease.

Neuroendocrine neoplasms of the stomach

Gastric neuroendocrine neoplasms of type 1 and type 3 are different entities and as such require different therapeutical strategies. The aim of this study was to define and distinguish these two tumour subtypes with clearly different biological properties and patient survival. As shown, serum gastrin is an important diagnostic tool for differentiating the less malignant type 1 "hypergastrinemia non-related" tumor from malignant type 3, along with other parameters of malignant potential such as proliferation index and depth of invasion. The biological behaviour, tumour marker status, symptomatology, survival and therapeutical strategy were assessed and compared in 18 consecutive patients with type 1 and 7 with type 3 gastric neuroendocrine tumours. All 18 patients with type 1 gastric carcinoids survived long-term. 17/18 patients were treated with endoscopic tumour removal. The prognosis for patients with generalized type 3 neuroendocrine neoplasms was poor, with short-term survival. No statistically significant differences between the types were found in urine 5-hydroxyindolacetic acid concentration or serum chromogranin A concentration. Significant differences were found in serum gastrin with high levels even in localized type 1 tumors and normal levels in generalized type 3 neoplasm. Further, high neuron-specific enolase levels were found in type 3. Type 1 tumour should be preferably treated with endoscopic tumour removal. Recently, favourable tumoristatic effects have been reported in somatostatin analogs. Surgery is a treatment option for type 3 neuroendocrine carcinoma with normal gastrinemia. Serum gastrin is suitable for assessment of the biological properties of both neuroendocrine neoplasm types. It serves, among other factors, as a predictor of prognosis and an indicator for the selection of optimal therapeutical strategy.

Serum neuron-specific enolase levels were associated with the prognosis of small cell lung cancer: a meta-analysis

This study aims to evaluate the association of serum neuron-specific enolase (NSE) levels with the prognosis of small cell lung cancer (SCLC). Literature retrieval, trials selection and assessment, data collection, and statistical analysis were performed according to the Revman 5.0 guidelines. Literature-based searching was guided to gather data and either fixed-effect or random-effect model was used to pool the hazard ratio (HR) according to the test of heterogeneity. A total of 11 eligible studies that included 3,497 SCLC patients and 3,344 control subjects were analyzed. About 68.6 % of patients had high serum levels of NSE, according to the cutoff value defined by the authors. The HR of high levels of NSE for overall survival (OS) was 1.74 times that of low levels of NSE in SCLC patients (95 % CI, 1.14 to 2.65; P = 0.01). Patients with high levels of NSE appear to have a poorer OS compared with those with low levels of NSE.

Prognostic Value of Tumor Markers, NSE, CA125 and SCC, in Operable NSCLC Patients

The aim of this study was to investigate the prognostic value of tumor markers in operable non-small cell lung cancer (NSCLC) patients. A total of 481 NSCLC patients were enrolled in the present study. High levels of neuron-specific enolase (NSE), carbohydrate antigen 125 (CA125) and squamous cell carcinoma antigen (SCC) were detected in 306 (63.6%), 89 (18.5%) and 125 (26.0%) patients, respectively. Seventy-eight of 481 patients died of disease progression, and the median disease-free survival (DFS) and overall survival (OS) were 16.0 and 21.0 months, respectively. The three-year DFS rate was 56.7%, and the OS rate was 75.3%. For serum NSE, the three-year cumulative DFS rate for the normal and elevated group was 67.7% and 51.8% (p = 0.007). The OS in patients with high and normal levels of NSE was 34.0 months and 48.0 months, respectively. The median DFS was 46.0 months versus 32.0 months (p = 0.001), and the OS was 48.0 months versus 44.0 months (p = 0.001) in patients with normal and high levels of CA125. For patients with squamous cell carcinoma, the overall survival was significantly shorter in patients with elevated levels of SCC (p = 0.041). In the multivariate analysis high levels of NSE, CA125 and clinical stage were significantly correlated with worse prognosis (p < 0.05). Patients with all three tumor markers elevated presented the worst prognosis (p < 0.05). In our analysis, high levels of preoperative serum NSE and CA125 are correlated with worse survival in operable NSCLC patients.

The impact of S100b and persistent high levels of neuron-specific enolase on cognitive performance in elderly patients after cardiopulmonary bypass

Primary objectives: The primary aim was to investigate the impact of neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100b) on cognitive functioning after cardiopulmonary bypass (CPB).Research design: Prospective exploratory study.Setting: Psychiatric Consultation-Liaison Service, Ludwig-Maximilians-University Medical School, Munich, Germany.Participants: Thirty-four patients who underwent elective CPB.Measurements: Before the CPB and on the day before discharge neurocognitive tests based on the Syndrom Kurztest (SKT) were carried out. During the ICU stay and shortly after discharge from the ICU, the delirious state was evaluated daily using the Delirium-Rating-Scale. NSE and S100b levels were assayed before CPB, 24 hours and 48 hours post-operatively and on the day before discharge.Results: After the CPB, 1 day before discharge, six (17.6%) participants had sub-threshold cognitive deficits and seven (20.6%) had clinically significant cognitive deficits. A trend toward persistently high NSE levels at discharge indicates greater cognitive impairment at the time of discharge. After surgical intervention S100b is elevated in all patients, independent of cognitive status.Conclusions: Persistently high levels of NSE might be a useful biomarker to identify patients with cognitive performance impairments, while no significant correlation between levels of S100b and impaired cognitive function were found.

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Introduction: Neuron Specific Enolase (NSE) and astroglial protein S-100b have been proposed as serum biomarkers to predict outcome following resuscitation from cardiac arrest. Hypothesis: We hypothesize that NSE and S-100b levels are associated with depth of coma on hospital arrival and are associated with survival to hospital discharge. Methods: Prospective cohort of subjects successfully resuscitated from cardiac arrest. Levels of NSE and S-100b were obtained at arrival and 24 hours after cardiac arrest. The change in these levels was determined. Data included demographic information, category of post-cardiac arrest illness severity ((I) awake, (II) coma (not following commands but intact brainstem responses) + mild cardiopulmonary dysfunction (SOFA [Sequential Organ FailureAssessment] cardiac + respiratory score <4), (III) coma + moderate-severe cardiopulmonary dysfunction (SOFA cardiac + respiratory score >=4), and (IV)coma without brainstem reflexes) and survival to hospital discharge. Non-normal data were log-transformed. Levels of NSE and S-100b at each time interval were compared by category of post-cardiac arrest illness severity using ANOVA. Single variable logistic regression was used to determine predictors of survival using a cut-off of p<0.1. Multivariable logistic regression was used to create a final parsimonious model. Hosmer-Lemeshow value was used to determine goodness of fit. Results: Of 86 subjects, 9 were awake and excluded. Mean age was 59 (SD 16) years and most were male (N=44, 57%). Out of hospital cardiac arrest made up 69% (N=53), with VF/VT and PEA the majority of rhythm at arrest (47% and 25%). Most (N=71, 93%) received TH. Grouped by arrest categories: category II comprised 30 (39%); category III, 15 (19%), and category IV, 32 (42%). Survival was 39% (N=30). Category IV illness severity was associated with higher levels of NSE at 24 hours (1.22, SD=0.51;1.03, SD=0.53; 1.63, SD=0.35; p=0.001). Category IV illness severity was associated with higher levels of s100b at arrival (-0.83, SD=0.75) and 24 hours (-0.92, SD=0.78). In the multivariate analysis, only change in NSE between arrival and 24 hours was associated with survival (OR=0.96, CI: 0.92 - 0.99). Category II illness severity (OR=1.64, CI: 0.30 - 9.05) Category IV illness severity (OR=0.30, CI: 0.05 – 1.86) and VF (OR=2.46, CI: 0.62-9.81) were not associated with survival. Conclusions: More severe neurologic injury on initial examination is associated with higher levels of NSE and S-100b 24 hours following resuscitation. The change in NSE between arrival and 24 hours after resuscitation is associated with survival.

Research of the serum level of neuron⁃specific enolase in children with various types of seizure

Objective To explore the relevance between the level changes of serum neuron⁃specific enolase (NSE) and neuronal damage in various seizure types of children with epilepsy. Methods According to the classification criteria of seizure types formulated by International League Against Epilepsy (ILAE) in 1981, 190 children with epilepsy were enrolled including tonic⁃clonic seizure group (41 cases), tonic seizure group (34 cases), clonic seizure group (22 cases), myoclonic seizure group (12 cases), atonic seizure group (17 cases), absence seizure group (22 cases), simple partial seizure group (21 cases) and complex partial seizure group (21 cases), and 64 healthy children were enrolled as control group. The long⁃ range vedio⁃electroencephalogram (VEEG) was operated and the blood samples were collected from these cases within 72 h after their seizures. Results The serum NSE levels of epileptic children were significantly higher than control group (P = 0.000). Among these seizure groups, serum NSE in myoclonic seizure group [(32.42 ± 6.62) ng/ml] was significantly higher than the other types, except for tonic⁃clonic seizure group (P = 0.062). There was no significant difference among the other types (P > 0.05, for all). According to rank correlation analysis, there was positive corrlation between serum NSE levels and VEEG abnormal intensity (rs = 0.613, P = 0.000). Conclusion The serum NSE were markedly increased in children with epilepsy after seizures, suggesting that a certain degree of neuronal damage may result from seizures; the higher NSE levels were, the more serious neuronal damage caused by epileptiform discharges was. The serum NSE levels in myoclonic seizure group and tonic⁃clonic seizure group were significantly higher than other seizure types, indicating the two kinds of seizures may result in greater neuronal damage. DOI：10.3969/j.issn.1672⁃6731.2012.05.013

The value of EEG monitoring after cardiac arrest treated with hypothermia

The prognostic value of EEG in comatose patients after cardiac arrest (CA) has been an important clinical issue for decades. Research started in the 1960s with the classic study by Hockaday et al.1 in which EEG predicted outcome with a not-so-great reliability of about 80%. At present, the management of post-CA patients often involves the induction of therapeutic hypothermia (TH). TH, a neuroprotective strategy, improves clinical outcomes in comatose patients after witnessed out-of-hospital CA from ventricular fibrillation in randomized controlled trials,2 and it is standard of care for these patients. How to prognosticate outcome in post-CA patients treated with hypothermia has become a very active area of research, in particular regarding the value of EEG monitoring. In this issue of Neurology ®, Rossetti et al.3 add valuable information to this growing body of literature. Rossetti et al. evaluated the prognostic value of EEG findings during TH. They used elevated serum levels of neuron-specific enolase (NSE) as a surrogate marker of irreversible brain damage. They hypothesized that “malignant” EEG patterns were indicative of neuronal damage or death and sought support for this idea by correlating EEG with high NSE levels. The results of their study confirm …

Influence of Methylprednisolone on Levels of Neuron-Specific Enolase in Cardiac Surgery: A Corticosteroid Derivative to Decrease Possible Neuronal Damage

Cerebral injury is a well-known complication after cardiac surgery with cardiopulmonary bypass (CPB), especially in adult patients. Specific biochemical markers like neuron-specific enolase (NSE) and S-100beta protein were developed previously for early detecting neuronal damage after CPB. Corticosteroids are shown to reduce multisystemic deleterious effects of cardiopulmonary bypass due to their anti-inflammatory characteristics. The aim of this study is to demonstrate the decrease of serum neuron-specific enolase levels in patients who received corticosteroids before CPB. Thirty patients scheduled for elective coronary bypass surgery were included in the study. Patients were divided randomly into two groups as the control group (n = 15) who underwent a standard coronary bypass surgery without any additional medication and the study group (n = 15) who received 1 gm of methylprednisolone before CPB. Blood samples for analysis of serum NSE, interleukin-6 (IL-6), and IL-10 were drawn before CPB, 4 and 24 hours after the end of extracorporeal circulation. Serum cytokine and NSE levels were significantly increased after CPB above their normal range in both groups. In the study group, IL-6 and NSE levels were significantly reduced while IL-10 levels were much higher after CPB. High NSE levels significantly correlated with IL-6 levels in the control group. The lower levels of NSE in patients who received methylprednisolone may suggest that corticosteroids might be useful in decreasing possible neuronal damage during heart surgery. However, we were not able to demonstrate an adverse neurological outcome.

Abstract 2054: Neuron-specific Enolase as a Prognostic Parameter in Patients Treated with Mild Hypothermia After Cardiopulmonary Resuscitation for Out-of-hospital Cardiac Arrest

Background: Overall prognosis in comatose survivors of Cardiopulmonary resuscitation is poor and the degree of hypoxic brain damage is usually the most important prognostic factor. Elevation of the neuron-specific enolase (NSE) as measured with 72 hours after admission has been identified as a predictor of neurologic outcome, and a threshold level of 33 ng/ml has been proposed as a highly specific cut-off value, above which neurologic outcome will be unfavourable. Therapeutic hypothermia is a new concept to improve neurologic outcome in patients after resuscitation, and the prognostic relevance of elevated NSE levels in patients treated by hypothermia has not yet been assessed. Methods: Mild therapeutic hypothermia (33–34°C) was applied via an intravenous cooling catheter for 24 hours in 38 consecutive patients admitted after successful on-site resuscitation following out-of-hospital cardiac arrest (28 male, 10 female, age 38 – 83 years, mean age 64.4±12.7 years). 72 hours after admission, NSE level was measured. Clinical and neurologic outcome was assessed at 1 and 4 weeks. Results: Out of 38 patients, 4 patients died within the first 72 hours. In 2 additional patients, NSE measurement was impossible because of haemolytic serum. NSE levels displayed a wide range (9.8 ng/ml − 720 ng/ml). Of the 32 patients available for analysis, 17 patients suffered severe ischemic brain damage or died during the further course (NSE 11.0 –720 ng/ml, mean 150.4±185.9 ng/ml). 15 patients recovered and had favourable neurologic outcome (NSE 9.8 – 47.9 ng/ml, mean 21.1±11.9 ng/ml). Using the recommended threshold value of 33 ng/ml, the sensitivity for ischemic brain damage was 76.5%, specificity was 80.0%, and the positive predictive value was 81.3%. Conclusions: Based on prior experience in patients without therapeutic hypothermia, a cut-off level of 33 ng/ml has been recommended as a highly specific threshold above which neurologic outcome in patients resuscitated for out-of-hospital cardiac arrest will be poor. Our data demonstrate, however, that favourable outcome can be achieved even for higher NSE levels in patients who are treated with therapeutic hypothermia. Thus, the prognostic value of NSE in these patients must be reconsidered.

Optimizing neurologic prognosis after cardiac arrest

Neurologic disability is a feared outcome of resuscitation from cardiac arrest. The study by Rech and colleagues in the previous issue of Critical Care describes the use of neuron-specific enolase to inform an early prognosis in patients who survived in-hospital cardiac arrest. In their study 'none of the patients had a DNR order and there was no limitation of life support.' As a result, 10% of patients remained in a vegetative state at 6 months, a higher percentage than in other recent studies. The existence of a population of patients in which all are fully supported without withholding care or withdrawal of care may represent an important research opportunity. High neuron-specific enolase levels have been reported in patients that awoke and seem to occur in studies with a higher percentage of patients in a vegetative state at follow-up (more uniform support). If a comprehensive set of clinical, electrophysiological, biochemical and imaging measures could be obtained in a uniform manner in a cohort of patients without limitations in care, a more objective set of comprehensive prognostic indicators could be obtained. A focused international consortium is called for.

Neuron-Specific enolase as a marker for acute ischemic stroke: A systematic review

Study objectives: Neuron-specific enolase (NSE) is a glycolytic enzyme that is found mainly in the cytoplasm of neurons and cells of neuroendocrine origin. To date, the majority of the work delineating the usefulness of NSE as a marker for acute ischemic stroke has been inconclusive and on a limited number of patients. We determine whether serum NSE correlates with time of onset of stroke symptoms, volume of infarct, stroke severity, functional outcome, or hospital length of stay. We determine whether serial NSE levels are useful as a marker for ongoing brain ischemia. We determine if NSE levels are significantly higher for patients with stroke compared with controls at various intervals. Methods: All abstracts and published full reports identified as potentially relevant by the literature search were independently assessed for inclusion in the review by each of the reviewers. This was a qualitative analysis. Results: Twelve studies satisfying the entry criteria were identified. Four studies examined time of onset of stroke symptoms versus earliest time NSE levels were detectable. NSE levels were found to be higher ranging from 4 to 8 hours postinfarct. Seven studies found increased NSE levels to be associated with increased size of stroke. Two studies found no correlation. Two studies examined stroke severity versus NSE levels. Higher NSE levels generally indicated worse outcome, but with low NSE levels, the results were equivocal. Seven of the 12 included studies examined functional outcome at discharge and follow-up versus NSE levels. Four of these 7 studies found no correlation between serum NSE and functional outcome. No correlation was found when using the Scandinavian Stroke Scale, Activities of Daily Living Scale, or the Glasgow Outcome Score. There was a correlation with Barthel index, modified Rankin Score at 90 days, admission and day 7 National Institutes of Health Stroke Scale, and a trend with the Lindley score. No trial correlated hospital length of stay with NSE levels without the confounding influence of increased volume of infarct leading to increased length of stay. Three studies found a relationship between NSE levels and time; however, 3 studies did not. Seven studies reported statistically significant differences between NSE levels in patients with stroke compared with control groups. One study reported that patients with total anterior cerebral strokes had statistically elevated levels of NSE compared with controls. However, patients with partial anterior cerebral stroke did not reach statistical significance with regard to NSE levels. Conclusion: Overall, according to the data for these 597 patients, it is possible to state that serum NSE level does in fact seem to be higher in stroke patients compared with controls and does appear to correlate with volume of infarct. However, it does not appear to correlate with functional outcome, and its relationship to stroke severity is unclear.

Auditory neuropathy in hyperbilirubinemia: is there a correlation between serum bilirubin, neuron-specific enolase levels and auditory neuropathy?

This study evaluated whether a correlation exists between increased serum bilirubin and neuron-specific enolase (NSE) assays (a biochemical index of neuronal damage) and auditory neuropathy. Nineteen term neonates without hemolysis whose serum bilirubin levels were above 20 mg/dl and 27 healthy term newborns with bilirubin levels <13 mg/dl were included in the study. Auditory brainstem responses (ABRs) and transient evoked otoacoustic emissions (TEOAEs) of patients with hyperbilirubinemia were obtained before discharge. This preliminary study did not show any correlation between the serum NSE and bilirubin values. However, infants who had auditory neuropathy had significantly higher NSE levels, and thus these patients, being in the high-risk group, need close follow-up.

Cytosolic levels of neuron-specific enolase in squamous cell carcinomas of the lung.

To study the behavior and possible correlations of neuron-specific enolase (NSE) with other clinicobiological parameters, we measured the cytosolic levels of this marker by means of an immunoradiometric assay (IRMA) in 95 squamous cell lung carcinoma samples. We also analyzed the levels of pS2, tissue-type plasminogen activator (t-PA), hyaluronic acid (HA), free beta subunit of human chorionic gonadotropin (beta-HCG), CYFRA 21.1 and CA 125 in cytosol. On the cell surface we analyzed the concentrations of epidermal growth factor receptor (EGFR), HA, erbB-2 oncoprotein, CD44s, CD44v5 and CD44v6. Other parameters considered were clinical stage, lymph node involvement, histological grade (HG), ploidy and the cellular S-phase fraction measured by flow cytometry on nuclei obtained from fresh tissues. In the 95 squamous cell carcinomas the cytosolic levels of NSE varied from 4.5 to 2235 ng/mg protein (median: 267) and were significantly higher (p < 0.001) than those observed in 38 samples of normal pulmonary tissue obtained from the same patients (range: 56-657; median: 141.5). When classifying tumors according to the different parameters analyzed, we observed that the levels of NSE were higher in aneuploid than in diploid cases (p = 0.046) and in those that were HG3 than in those that were HG2 (p < 0.001). Tumors with high NSE levels (> 422 ng/mg protein; 75th percentile) were more likely to have high S-phase values (p = 0.012) and were more frequently aneuploid (p = 0.038) and HG3 (p < 0.001) than those with low levels of NSE (< 180 ng/mg protein; 25th percentile). These results lead us to the following conclusions: 1) the cytosolic concentrations of NSE are significantly higher in squamous cell carcinomas than in healthy pulmonary tissue, and 2) the cytosolic concentrations of NSE are not correlated with clinical stage or nodal involvement. However, in our study higher levels of the enzyme were statistically correlated with aneuploidy, histological grade 3 and S-phase. This may explain its association with poorer outcome and progression, but also the more favorable response of tumors with elevated NSE to chemotherapy, as suggested by other groups.

Cytosolic levels of neuron-specific enolase in squamous cell carcinomas of the lung

To study the behavior and possible correlations of neuron-specific enolase (NSE) with other clinicobiological parameters, we measured the cytosolic levels of this marker by means of an immunoradiometric assay (IRMA) in 95 squamous cell lung carcinoma samples. We also analyzed the levels of pS2, tissue-type plasminogen activator (t-PA), hyaluronic acid (HA), free beta subunit of human chorionic gonadotropin (beta-HCG), CYFRA 21.1 and CA 125 in cytosol. On the cell surface we analyzed the concentrations of epidermal growth factor receptor (EGFR), HA, erbB-2 oncoprotein, CD44s, CD44v5 and CD44v6. Other parameters considered were clinical stage, lymph node involvement, histological grade (HG), ploidy and the cellular S-phase fraction measured by flow cytometry on nuclei obtained from fresh tissues. In the 95 squamous cell carcinomas the cytosolic levels of NSE varied from 4.5 to 2235 ng/mg protein (median: 267) and were significantly higher (p < 0.001) than those observed in 38 samples of normal pulmonary tissue obtained from the same patients (range: 56-657; median: 141.5). When classifying tumors according to the different parameters analyzed, we observed that the levels of NSE were higher in aneuploid than in diploid cases (p = 0.046) and in those that were HG3 than in those that were HG2 (p < 0.001). Tumors with high NSE levels (> 422 ng/mg protein; 75th percentile) were more likely to have high S-phase values (p = 0.012) and were more frequently aneuploid (p = 0.038) and HG3 (p < 0.001) than those with low levels of NSE (< 180 ng/mg protein; 25th percentile). These results lead us to the following conclusions: 1) the cytosolic concentrations of NSE are significantly higher in squamous cell carcinomas than in healthy pulmonary tissue, and 2) the cytosolic concentrations of NSE are not correlated with clinical stage or nodal involvement. However, in our study higher levels of the enzyme were statistically correlated with aneuploidy, histological grade 3 and S-phase. This may explain its association with poorer outcome and progression, but also the more favorable response of tumors with elevated NSE to chemotherapy, as suggested by other groups.

Serum neuron-specific enolase predicts outcome in post-anoxic coma: a prospective cohort study.

The aim of this study was to investigate whether serial serum neuron-specific enolase (NSE) can be used to predict neurological prognosis in patients remaining comatose after cardiopulmonary resuscitation (CPR). DESIGN. Observational cohort study. Clinicians were blinded to NSE results. Eighteen-bed general ICU. Comatose patients admitted to the ICU after CPR. Serum NSE was measured at admission and daily for 5 days. Patients received full intensive treatment until recovery or until absence of cortical response to somatosensory evoked potentials more than 48 h after CPR proved irreversible coma. Of the 110 patients included (mean GCS at ICU admission 3, range 3--9), 34 regained consciousness, five of whom died in hospital. Seventy-six patients did not regain consciousness, 72 of whom died in hospital. Serum NSE at 24 h and at 48 h after CPR was significantly higher in patients who did not regain consciousness than in patients who regained consciousness (at 24 h: median NSE 29.9 microg/l, range 1.8-250 vs 9.9 microg/l, range 4.5-21.5, P<0.001; at 48 h: median 37.8 microg/l, range 4.4-411 vs 9.5 microg/l, range 6.2-22.4, P= 0.001). No patient with a serum NSE level >25.0 microg/l at any time regained consciousness. Addition of NSE to GCS and somatosensory evoked potentials increased predictability of poor neurological outcome from 64% to 76%. High serum NSE levels in comatose patients at 24 h and 48 h after CPR predict a poor neurological outcome. Addition of NSE to GCS and somatosensory evoked potentials increases predictability of neurological outcome.

Brain metastases at the time of presentation of non-small cell lung cancer: a multi-centric AERIO* analysis of prognostic factors

A multi-centre retrospective study involving 4 French university institutions has been conducted in order to identify routine pre-therapeutic prognostic factors of survival in patients with previously untreated non-small cell lung cancer and brain metastases at the time of presentation. A total of 231 patients were recorded regarding their clinical, radiological and biological characteristics at presentation. The accrual period was January 1991 to December 1998. Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The median survival of the whole population was 28 weeks. Univariate analysis (log-rank), showed that patients affected by one of the following characteristics proved to have a shorter survival in comparison with the opposite status of each variable: male gender, age over 63 years, poor performance status, neurological symptoms, serum neuron-specific enolase (NSE) level higher than 12.5 ng ml−1, high serum alkaline phosphatase level, high serum LDH level and serum sodium level below 132 mmol l−1. In the Cox's model, the following variables were independent determinants of a poor outcome: male gender: hazard ratio (95% confidence interval): 2.29 (1.26–4.16), poor performance status: 1.73 (1.15–2.62), age: 1.02 (1.003–1.043), a high serum NSE level: 1.72 (1.11–2.68), neurological symptoms: 1.63 (1.05–2.54), and a low serum sodium level: 2.99 (1.17–7.62). Apart from 4 prognostic factors shared in common with other stage IV NSCLC patients, whatever the metastatic site (namely sex, age, gender, performance status and serum sodium level) this study discloses 2 determinants specifically resulting from brain metastasis: i.e. the presence of neurological symptoms and a high serum NSE level. The latter factor could be in relationship with the extent of normal brain tissue damage caused by the tumour as has been demonstrated after strokes. Additionally, the observation of a high NSE level as a prognostic determinant in NSCLC might reflect tumour heterogeneity and understimated neuroendocrine differentiation. © 2001 Cancer Research Campaignhttp://www.bjcancer.com

Cyfra 21-1, neuron specific enolase and prognosis of non-small cell lung cancer: prospective study in 621 patients

Background: CYFRA 21-1, a serum cytokeratin 19 fragment, and neuron specific enolase (NSE), the γ-subunit of enolase, are putative markers of lung cancer. Their clinical applicability as prognostic factors in non-small cell lung cancer (NSCLC) would need an appraisal by simultaneous evaluation of other known survival determinants in a large population followed over a long period. Aim: To determine the prognostic value of different clinical and routine biological variables at presentation with particular attention paid to the above-mentioned markers. Methods: 621 histologically proven and previously untreated NSCLC patients have been prospectively studied (seven were lost to follow-up). Median follow-up was 4 years and 2 months. At presentation, 16 clinical and biological variables were recorded. Serum NSE and CYFRA 21-1 were assayed blind without any clinical information given. Results: The serum CYFRA 21-1 distribution differed significantly according to histology, disease stage and performance status, with the highest levels observed in squamous cell carcinomas, metastatic stage, positive mediastinal nodal status and poor performance status. However, the respective ‘receiver operating characteristic’ curves showed that the CYFRA 21-1 serum level did not accurately predict tumour stage. Serum NSE distribution correlated neither with tumour stage nor with performance index and its sensitivity in the whole NSCLC was low. In the Cox proportional hazard model, the following variables were independent determinants of a poor outcome: performance status 2 or 3, hazard ratio (HR): 2.25; Nodal status N2–3, HR: 1.84; Metastatic disease, HR: 1.73; NSE>12.5 ng/ml, HR: 1.52; CYFRA 21-1>3.6 ng/ml, HR: 1.41 and Tumour status T3–4, HR: 1.31. When the survival analysis was restricted to the 274 patients affected by a metastatic stage, we observed that performance status, nodal status, NSE and CYFRA 21-1 remained prognostic determinants with similar hazard ratios. Conclusion: The prognostic information given by a high serum CYFRA 21-1 level is independent from other well-known variables such as performance status and disease stage and is perennial throughout extended follow-up period. A high NSE level also prognosticates a poor outcome probably by reflecting tumour heterogeneity and underestimated neuroendocrine differentiation.