Serum neuron-specific enolase is a useful tumor marker for small cell lung cancer

Small cell lung cancer (SCLC) may be potentially curable. A correct diagnosis of cancer cell type is important and serum markers are of great value. Although several markers have been suggested, they have been of limited value because of insufficient specificity. To assess the value of serum neuron-specific enolase (S-NSE) as a possible marker of SCLC, the serum levels of 81 patients with SCLC (59 patients with extensive disease and 22 patients with limited disease) were compared with the serum levels of patients with non-small cell lung cancer (N-SCLC) and 93 patients with nonmalignant lung diseases. The S-NSE level also was measured in 104 patients with extensive disease of various other malignancies, including 71 solid tumors and 33 malignant hematologic disorders. From 105 healthy control subjects, the upper limit of the normal range (x + 2 standard deviations [SD]) was determined as 12.3 ng/ml. The S-NSE level was elevated in 78% of patients with SCLC, including 11 of 22 (50%) with limited disease and 52 of 59 (88%) with extensive disease. In contrast, the S-NSE level was raised only in 18% of patients with advanced N-SCLC (nine of 50) and 6% of patients with nonmalignant lung diseases (six of 93). Twelve patients (17%) with other solid malignant tumors and two patients (6%) with malignant hematologic disorders had raised S-NSE levels. Serial N-NSE levels were obtained in 13 patients with SCLC. S-NSE levels fell in all patients responding to chemotherapy and increased again with progression of disease. Our results indicate that S-NSE seems to be specific for SCLC (85%), whereas sensitivity seems to be dependent on the stage of disease. Further, S-NSE may be a useful marker for monitoring treatment and predicting relapse in patients with SCLC.     

Serum neuron-specific enolase. A marker for responses to therapy in seminoma

Neuron-specific enolase (NSE) was evaluated as a serum marker in 105 patients with testicular cancer and compared with the established tumor markers alphafetoprotein (AFP) and human chorionic gonadotropin (HCG). Increased serum NSE activity was measured in eight of 11 (73%) patients with metastatic seminoma. Serum NSE concentrations fell to within the normal range following chemotherapy. Localization of NSE in seminoma cells was demonstrated immunohistochemically. Only six of 40 (15%) patients with metastatic nonseminomatous germ cell tumors showed elevated serum NSE levels. AFP and HCG were both positive in 70% of patients in this group, and NSE determination gave no additional information. Serum NSE concentrations were normal in 53 of 54 testicular cancer patients after orchiectomy and there was no evidence of metastatic disease; only one had borderline NSE levels, indicating the specificity of serum NSE determination. NSE is a new marker of seminoma and its measurement may be of clinical value in monitoring chemotherapy in patients with metastatic seminoma.     

Serum neuron-specific enolase in children's cancer

To test its diagnostic potential and sensitivity in paediatric malignancy, serum NSE was measured at diagnosis in 191 children with solid tumours and 25 with acute leukaemia. In stages I + II, III + IV and IVs neuroblastoma median levels were 18.0, 91.0 and 24.0 ng ml-1 respectively. For Wilms' patients, median values for stages I, II, III and IV disease were 16.6, 18.0, 29.0 and 47.0 ng ml-1 respectively. High levels of NSE were also found in patients with other types of tumour. Children in clinical remission after treatment for neuroblastoma invariably had normal NSE levels (mean +/- s.d. = 9.2 +/- 3.0 ng ml-1) even though the majority had radiologically identifiable residual disease. The values rose when relapse was radiologically or clinically obvious. We conclude (a) that, though levels of greater than 100 ng ml-1 are highly suggestive of advanced neuroblastoma, caution should be exercised in using serum NSE as a diagnostic test in children with cancer and (b) that serum NSE levels are not a sensitive index of residual neuroblastoma in patients, with initially elevated levels, that are receiving treatment.     

Establishment and evaluation of a radioimmunoassay for neuron-specific enolase. A marker for small cell lung cancer

Neuron-specific enolase (NSE) was purified from human brain to a specific activity of 91 U/mg with no demonstrable impurities. The enzyme has a molecular weight of 96,000, consists of two subunits of 47,000, and has an isoelectric point at pH 4.5. A radioimmunoassay based on antibody raised in sheep was established. The assay has a sensitivity of 2 micrograms/l, and an interassay coefficient of variation of 6.4% at 10 micrograms/l. The reference limit was defined as 10 micrograms/l, as found in sera from a population of 389 persons. Of 50 untreated patients with small cell lung cancer (SCLC), 70% had NSE levels above 10 micrograms/l. None of 170 patients with non-SCLC neoplasms had elevated enzyme levels.     

Fucosyl-GM1 in small-cell lung cancer. A comparison with the tumour marker neuron-specific enolase

BACKGROUND:: Recently, the ganglioside Fucosyl-GM₁ (FucGM₁) has been describedas a possible new tumour marker for small-cell lung cancer (SCLC).FucGM₁ has been detected in 75% to 90% of SCLC tumours by immunohis-tochemicalanalysis and in about 50% of sera from SCLC patients. Neuron-specificenolase (NSE) is a glycolytic enzyme which is expressed in themajority of SCLC tumours and patient sera. PATIENTS AND METHODS:: Sera from 156 patients with SCLC were analyzed for FucGM₁ witha scintillation proximity assay (SPA), which is a simple andsensitive analysis. Sera were analyzed before the initiationof chemotherapy, and twenty patients were monitored during andafter treatment. The concentration of FucGM₁ was compared tothe tumour marker NSE and related to clinical data and survival. RESULTS:: Sixty-three per cent of the patients were positive for FucGM₁.The concentrations did not correlate with NSE or clinical dataincluding stage of disease, organ site of metastases or ABOblood group status. Nor did the expression of FucGM₁ correlatewith survival. As a monitor of clinical response, a correlationwas found in 8 out of 20 patients. Eighty-four per cent of thepatients were positive for NSE; and 97% were positive for eitherFucGM₁ or NSE. CONCLUSION:: We conclude that FucGM₁ does not have a clinical role as a tumourmarker for patients with SCLC at diagnosis or during treatment. Fucosyl-GM₁, NSE, SCLC, tumour marker     

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.     

Pro-gastrin-releasing peptide (31-98) as a tumour marker of small-cell lung cancer: comparative evaluation with neuron-specific enolase.

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of ''receiver operator characteristics'' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.     

Radioimmunoassay development for human neuron-specific enolase: with some clinical results in lung cancers and neuroblastoma

A double-antibody radioimmunoassay for human neuron-specific enolase (NSE) was developed, using rabbit antiserum against the gamma subunit of enolase purified from human brain. Intra-assay variance was 3.8-5.1% and inter-assay variance 4.3-7.3%, and recovery of NSE added to normal serum was 100.2% on average. Normal serum NSE levels for 451 adults ranged from 3.6 to 10.8 ng/ml (mean 6.6 ng/ml). Antibodies raised against the gamma gamma enolase isozyme did not cross-react with the alpha alpha and beta beta isozymes at concentrations of 1,000 ng/ml, but showed a cross-reactivity of 41.5% (theoretically 50%) with the alpha gamma isozyme. It was also shown that hemolysis of 160 mg/dl hemoglobin can add 5.73 ng/ml of NSE to the true level. The coefficient of correlation between the radioimmunoassay and the sandwich enzyme immunoassay [1] was 0.99 (n = 21), and values determined by the RIA were about twice those obtained by the EIA. Serum NSE was abnormally high in 42 of 52 patients (80.8%) with small cell lung carcinoma, and in all 38 children with neuroblastoma.     

Neuron-specific enolase as a marker for neuroblastoma and small-cell carcinoma of the lung

The use of neuron-specific enolase (NSE, E.C. 4.2.1.11) as a clinical marker for neuroblastoma and small-cell carcinoma of lung (SCCL) is presented. Both tumors have a high content of NSE as demonstrated enzymatically or by immunocytochemistry. Other retroperitoneal tumors in children and other lung tumors had insignificant NSE concentrations. NSE can thus be used in the differential diagnosis of neuroblastoma and SCCL. 73% of patients with SCCL had elevated serum NSE levels. The corresponding figure for patients with other types of lung cancer was 3%. There was a good correlation between serum NSE levels and the clinical course of patients with SCCL.     

Neuron-specific enolase as a new tumor marker

Enolase is a glycolytic enzyme widely distributed in each mammalian tissue and consists of three distinct subunits alpha, beta, and gamma. In the brain enolase exhibits three dimetric isozymic forms: alpha alpha, alpha gamma and gamma gamma. The gamma protein subunit has recently been found to be identical with the nervous system-specific and species-nonspecific protein, 14-3-2; therefore, alpha gamma and gamma gamma types of enolase were characterized as neuron-specific enolase (NSE). NSE has been also detected in the pituitary gland, thyroid gland, adrenal medulla and pancreas, all of which contain neuroendocrine cells. Recently NSE was observed by immunostaining or radioimmunoassay in neuroendocrine tumor such as glucagonomas, insulinomas, gut carcinoids, medullary thyroid carcinomas or neuroblastomas. Furthermore, small cell carcinoma of the lung which has been known to frequently exhibit neuroendocrine properties was found to produce NSE. In this paper NSE as a tumor marker in various cancers was evaluated by immunostaining or enzyme immunoassay which was developed by a co-worker Kato. The data revealed that serum NSE was clinically useful as a tumor marker, especially a monitoring marker of disease extent. NSE productions were also observed in adenocarcinoma of the colon or the lung and large cell carcinoma of the lung as well as small cell carcinoma of the lung and the esophagus, all of which were considered to share the biochemical features of neuroendocrine tumor. The evidence challenges a speculation that small cell carcinoma of the lung has an origin separated from the other histological types of lung carcinoma. In this meaning NSE is an important tumor marker for both clinical medicine and basic research.     

神经元特异性烯醇化酶在非小细胞肺癌中的意义

随着研究的进一步深入,非小细胞肺癌(NSCLC)的神经内分泌化逐步引起人们的重视,现对肿瘤标志物神经元特异性烯醇化酶在非小细胞肺癌鉴别诊断、化疗疗效评估、预后监测等方面的作用作一介绍.     

神经元特异性烯醇化酶在非小细胞肺癌中的意义

随着研究的进一步深入,非小细胞肺癌（NSCLC）的神经内分泌化逐步引起人们的重视,现对肿瘤标志物神经元特异性烯醇化酶在非小细胞肺癌鉴别诊断、化疗疗效评估、预后监测等方面的作用作一介绍.     

Neuron-specific enolase as a marker of brain metastasis in patients with small-cell lung carcinoma

Summary Neuron-specific enolase (NSE) is one of the iso-forms of enolase, a glycolytic enzyme found in the neuroendocrine system. NSE is one of the most widely used tumor markers in small-cell lung carcinoma (SCLC). To assess the value of NSE in discriminating between the sites of metastases in SCLC-patients with and without cerebral involvement, serial NSE determinations were performed.Serum NSE was elevated in 76% of the patients at initial diagnosis. The value did not discriminate between the extent of disease nor between the sites of extrathoracic disease. NSE levels declined significantly at restaging.A persistent, significant rise occurred in patients with relapse of their disease, regardless of the site of relapse. In patients with brain metastases with and without extracranial disease at relapse, the NSE increase was significantly smaller than in patients without intracranial involvement. These findings indicate that serial determination of serum NSE in SCLC-patients may be useful in monitoring tumor activity but not in predicting the site of metastatic disease.     

Immunostaining of neuron-specific enolase as a diagnostic tool for Merkel cell tumors

Conventional histologic examination of Merkel cell tumors may result in misdiagnosis because of the close similarities these tumors bear to either malignant lymphomas or certain undifferentiated carcinomas. The authors have previously reported that neuron-specific enolase (NSE), a specific marker for neuroendocrine cells, is present in normal Merkel cells and can be used as a marker to identify this cell type. In this study, 11 Merkel cell tumors, identified employing electron microscopy, were studied using immunostaining of NSE by the peroxidase-antiperoxidase method. Varying intensities of NSE immunoreactivity were found in the cytoplasm of all the neoplastic cells in the different cases. The uniformly stained cytoplasm formed a small rim surrounding the large, unstained nucleus. Immunostaining of NSE thus provides a simple and reliable method for the differential diagnosis of Merkel cell tumors from other primary skin tumors which, with the exception of some malignant melanomas, have been shown not to contain NSE immunoreactivity.     

Serum neuron-specific enolase in diagnosis and follow-up of gastrointestinal neuroendocrine tumors.

Neuron-specific enolase (NSE), the glycolytic isoenzyme of the enolase gamma-gamma dimer, is a specific marker for the diffuse neuroendocrine system and derivative tumors (NET). Serum levels of NSE were measured in 39 patients with NET of the gastrointestinal tract (including 3 gastric and 13 intestinal carcinoid tumors, 6 gastrinomas, 3 insulinomas, 1 glucagonoma, 2 mixed islet cell tumors, 11 neuroendocrine pancreatic carcinomas), in 15 healthy subjects and in 15 nonendocrine gastric, pancreatic, and intestinal tumors. Thirty-six of the 39 patients had elevated circulating levels of NSE, 2 insulinomas and 1 gastrinoma had values below 12 ng/ml like healthy subjects and nonendocrine tumors. No significant difference of serum NSE was found between 23 'functioning' and 16 'nonfunctioning' NET. Fourteen of the NET were malignant, and NSE circulating values were significantly higher than those of nonmalignant forms. After curative surgery serum NSE decreased significantly. NSE can be considered a reliable marker in the differential diagnosis between endocrine and nonendocrine neoplasms, in the clinical detection of silent endocrine tumors and in the follow-up of NET.     

Serum pseudouridine as a biochemical marker in small cell lung cancer

The serum level of pseudouridine, primarily a degradation product of tRNA, was determined by high-performance liquid chromatography in 24 patients with small cell lung cancer (SCLC), 13 patients with non-SCLC with advanced stages, 15 patients with pulmonary infectious diseases, and 18 healthy controls. The mean serum pseudouridine concentration was significantly higher in the patients with SCLC [4.75 +/- 1.76 (SD) nmol/ml] than that in the patients with pulmonary infectious diseases (3.39 +/- 1.38 nmol/ml) or in healthy controls (2.21 +/- 0.78 nmol/ml). The mean serum pseudouridine concentration in the patients with non-SCLC (4.07 +/- 0.95 nmol/ml) was significantly higher than that in healthy controls but not statistically different from that in the patients with pulmonary infectious diseases. The serum pseudouridine level was elevated above the mean value plus 2 SD for the healthy subjects (3.77 nmol/ml) in 66.7% of all patients with SCLC including 3 of 8 (37.5%) with limited disease and 13 of 16 (81.3%) with extensive disease, and 53.8% of the patients with non-SCLC. Serum carcinoembryonic antigen was elevated (greater than 5 ng/ml) in 29.2% and serum neuron-specific enolase (greater than 10 ng/ml) in 58.3% of the cases with SCLC. In the patients with SCLC followed up during chemotherapy, serum pseudouridine levels changed considerably parallel with the changes in the clinical response. These findings indicate that serum pseudouridine may be a useful biochemical marker in the patients with SCLC.     

Serum neuron-specific enolase (NSE) in patients with small cell lung cancer--comparison with carcinoembryonic antigen (CEA)

Serum neuron-specific enolase (NSE) was determined by RIA in 102 lung cancer patients. Serum NSE was elevated (greater than 10 ng/ml) in 72% (21 of 29 cases) of small cell lung cancer (SCLC) patients, which was a significantly higher positive rate than those in normal adult controls (0%, 0/48), noncancerous lung disease (17%, 4/24), squamous cell carcinoma (19%, 6/31) and adenocarcinoma (16%, 4/25) (p less than 0.05, respectively). There were no NSE-positive cases in stage I-II lung cancer patients. In SCLC, cases of extensive disease had a significantly higher NSE-positive rate (100%, 8/8) than those of limited disease (62%, 13/21) (p less than 0.05), suggesting that NSE levels were related to the bulk of the tumor. There was an excellent correlation between serum NSE and clinical response. Raised NSE levels were identified significantly more frequently than those of CEA in SCLC before chemotherapy and on relapse (or progression) (p less than 0.025, p less than 0.005, respectively). Thus, serum NSE determinations may be more useful than those of CEA for the staging and monitoring of SCLC.