Neuron-specific enolase (NSE) as a tumour marker and comparative evaluation with carcinoembryonic antigen (CEA) in small-cell lung cancer

Serum neuron-specific enolase (NSE) was evaluated in a number of malignant tumours. It was elevated (greater than 12.5 micrograms l-1) in 13/17 (76.5%) patients with extensive small-cell lung carcinoma and in none of the three patients with limited disease. Of patients with carcinoma of the breast 4/12 (33.3%) had elevated concentrations. Normal concentrations were found in patients with non-Hodgkin's lymphoma (19) and Hodgkin's disease (15), carcinoma of the cervix (2), CSF and serum (5) of patients with gestational trophoblastic disease (with definite nervous system involvement). Comparative serial studies of NSE and carcinoembryonic antigen (CEA) concentrations were done in 15 patients with small-cell lung cancer (SCLC). Of these 7/15 (46.7%) had elevated pre-treatment concentrations of both CEA and NSE, 1/15 (6.7%) had CEA elevated only, while 2/15 (13.3%) had NSE alone elevated. Of those patients with normal pre-treatment marker concentrations 3/5 (60%) had elevated markers on recurrence. The mean survival period was 61.9 weeks; 66.8 weeks for the marker-negative group and 44.6 weeks for the marker-positive (both NSE and CEA) group. Combined NSE and CEA evaluation provide additional means of monitoring SCLC.     

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 as a marker of lung cancers

Neuron-specific enolase (NSE) in sera of lung cancer patients was studied in order to evaluate its clinical significance as a tumor marker. The subjects included 15 normal volunteers, 13 cases without malignant neoplasms or neuronal diseases and 42 lung cancer cases. NSE was quantified by a double antibody radioimmunoassay. As one of the sera from normal volunteers and control patients showed an NSE content 10 ng/ml or more, values of 10 ng/ml or over were considered to be positive. Seventeen of 42 sera from lung cancer patients showed positive NSE levels. Histological evaluation revealed that the degrees of NSE positiveness for small cell carcinoma, large cell carcinoma, squamous cell carcinoma and adenocarcinoma were 73%, 50%, 33%, and 21%, respectively, and that all the positive cases except for one were confined to disease stages III or IV. The level of NSE in patients with 10 ng/ml or more before surgery decreased to within normal limits 1-2 weeks after surgery Localization of NSE could be confirmed immunohistologically in small cell carcinoma cells. In conclusion, NSE was considered to be very useful as a tumor marker of the lung, especially in small cell carcinoma for diagnosis and determination of disease extent and response to therapy, and also in non-small cell carcinoma for the evaluation of treatment effectiveness.     

Significance of serum pro-gastrin-releasing peptide as a predictor of relapse of small cell lung cancer: comparative evaluation with neuron-specific enolase and carcinoembryonic antigen

Neuron-specific enolase (NSE) and carcinoembryonic antigen (CEA) have been reported to be useful markers for staging, monitoring treatment, and predicting relapse in patients with small cell lung cancer (SCLC). Recently, pro-gastrin-releasing peptide (Pro-GRP) became available as a sensitive, specific, and reliable tumor marker for patients with SCLC. The aim of this study is to determine the most useful tumor marker to detect the relapse of SCLC. Furthermore, we analyzed the relationship between tumor markers at relapse and survival from relapse or response to salvage chemotherapy. Medical records were reviewed to obtain serum levels of Pro-GRP, NSE, and CEA before and after the initial chemotherapy, and at relapse. Consecutive 66 patients with SCLC, with an objective response and confirmed relapse treated at the National Cancer Center Hospital East, were analyzed in this study. The percentages of patients whose tumor marker level were elevated before treatment, decreased after the treatment, and increased again at relapse were 67% (95% CI, 55-78) for Pro-GRP, 20% (10-29) for NSE, and 38% (26-50) for CEA. Multivariate analysis indicated that poor performance status before initial treatment and elevated serum levels of lactate dehydrogenase at relapse were poor prognostic factors for patients with recurrent SCLC (P<0.005). None of the serum levels of Pro-GRP, NSE, and CEA at relapse was a significant prognostic factor and associated with an objective response to salvage chemotherapy. The present study demonstrated that serum levels of Pro-GRP reflect the disease course of patients with SCLC most accurately.     

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.     

小细胞肺癌血清ProGRP（31—98）与神经元性烯醇化酶同步检测的临床价值及其相关性

目的探讨小细胞肺癌（SCLC）患者血清神经元性烯醇化酶（NSE）与ProGRP（31-98）水平同步检测的临床价值及其相关性。方法采用酶联免疫吸附法（ELISA）对159例SCLC患者、97例肺部良性疾病患者、100名健康人进行血中ProGRP（31—98）与NSE水平的检测。结果SCLC治疗前NSE与ProGRP（31—98）的中位值分别为21．33μg／L和323．70pg／ml,肺部良性疾病分别为4．24μg／L和11．94Pg／ml,健康人分别为5．82μg／L和8．54Pg／ml,3组间比较差异均有统计学意义（均P〈0．001）;以NSE10．35ng／L和ProGRP（31-98）47．98Pg／ml为界值,敏感度分别为71．1％和88．7％,特异度分别为95．5％和96．9％,两项联合检测的敏感度和特异度分别为95．6％和96．8％。SCLC局限期和广泛期NSE中位值分别为14．75μg／L和34．10μg／L,敏感度分别为51．14％和93．44％,ProGRP（31—98）中位值分别为143．14Pg／ml和1061．14Pg／ml,敏感度分别为80．61％和98．61％。治疗后缓解和部分缓解的患者两项血清水平较治疗前明显下降,差异有统计学意义（P〈0．001）,未缓解和进展期的患者治疗前后无明显变化。SCLC患者NSE和ProGRP（31-98）血清水平的检测有显著相关性（r=0．379,P〈0．01）。结论NSE和ProGRP（31—98）血清水平有明显的相关性,作为SCLC治疗前诊断和疗效观察均有一定的指导意义,但ProGRP（31．98）,特别是对早期SCLC的诊断有更好的敏感性和准确度,两项联合可进一步提高检测的阳性率和有效性。     

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.     

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.     

Pro-gastrin-releasing peptide, neuron specific enolase and chromogranin A as serum markers of small cell lung cancer

BACKGROUND: Small cell lung cancer (SCLC) yields neuroendocrine properties. Pro-gastrin-releasing peptide (ProGRP), neuron specific enolase (NSE) and chromogranin A (CGA) are therefore putative serum markers in this disease. AIM: To assess any difference in the sensitivity-specificity relationship between these neuroendocrine markers regarding various control populations and disease extent. METHOD: A total of 146 patients were prospectively assessed clinically and biologically. Serum marker titrations were performed using commercial immunoradiometric assays (NSE, CGA) or ELISA (ProGRP). Areas under receiver operating characteristic curves (AUC-ROC) were calculated in order to assess the sensitivity-specificity relationship of each marker and to compare marker accuracy. Maximum Youden indices were used to determine marker thresholds able to produce the best overall diagnostic information. RESULTS: Assessing the sensitivity in the SCLC population and the specificity in benign lung disease, ProGRP demonstrated the best sensitivity relationship in as much as its AUC-ROC was significantly greater than the ones calculated using NSE and CGA (respective values, 0.95, 0.89, 0.70; two-tailed Z-test <0.05). The ProGRP threshold value, which offered the best sensitivity-specificity relationship was 53 pg/ml corresponding to a 0.80 sensitivity and a 0.96 specificity. In addition, when specificity was assessed in NSCLC and again the sensitivity in the whole SCLC population, ProGRP continued to demonstrate a greater AUC-ROC in comparison with other markers. Using the 53 pg/ml threshold the specificity of this marker was excellent with no false positives in NSCLC. On the other hand, none of the markers were able to discriminate limited from extensive SCLC as suggested by the fact that AUC-ROC, constructed when sensitivity was defined as a positive test in extensive disease and specificity as a true negative test in limited disease, did not reach the upper left octant (AUC 0.65, 0.71 and 0.63 for ProGRP, NSE and CGA, respectively). CONCLUSION: ProGRP yields the best sensitivity-specificity feature in SCLC, a result deserving further studies designed to evaluate the clinical applicability of this marker.     

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.     

Serum neuron-specific enolase (S-NSE) and the prognosis in small-cell lung cancer (SCLC): a combined multivariable analysis on data from nine centres.

The influence of pretreatment serum neuron-specific enolase (S-NSE) in addition to more conventional prognostic factors on survival duration in small-cell lung cancer (SCLC) was investigated in 770 patients from nine centres in six countries. The other variables included stage of disease, performance status (PS), age, sex, serum lactate dehydrogenase (S-LDH), serum alkaline phosphatase (S-AP), and serum carcinoembryonic antigen (S-CEA). Increased values of S-NSE (> 12.5 micrograms-1 l) were observed in 81% of the patients, whereas S-LDH, S-AP and S-CEA were elevated in only half of the patients or less. Multivariable analysis by Cox''s proportional hazard model disclosed S-NSE as the most powerful prognostic factor followed by poor PS and extensive stage disease. If PS was ignored, S-LDH came up as a significant prognostic factor. S-AP, S-CEA, age and sex had no significant influence on the prognosis. The three prognostic factors, S-NSE, PS and stage of disease, enabled establishment of a prognostic index (PI) based on a simple algorithm PI = zNSE + z(stage) + 2zPS. This segregated the patients into four groups with clearly different prognosis. The median survival and 95% confidence intervals of the four groups were: 468 days (540-408), 362 days (405-328), 256 days (270-241) and 125 days (179-58). Based on the present results we recommend S-NSE and PS, in addition to stage, for prognostic stratification in treatment trials on SCLC.     

Distinction of two different classes of small-cell lung cancer cell lines by enzymatically inactive neuron-specific enolase.

Neuron specific enolase (NSE) is widely used as a neuro-endocrine marker. However the presence of NSE in many non-neuroendocrine tissues has raised questions on the specificity of NSE. We have investigated NSE immunoreactivity (NSA-ag), gamma-enolase activity and total enolase activity in small cell lung cancer (SCLC) cell lines. During well-controlled exponential growth comparison of NSE-ag content and gamma-enolase activity with the doubling-time (Td) and NSE-ag content with gamma-enolase and total enolase activity led to a clear distinction of two types of cell line: variant cell lines plus part of the classic cell lines (type I) and the remaining classic cell lines (type II). The distinction was based upon both an abrupt 6-fold increase of gamma-enolase activity and an 18-fold increase of NSE-ag, which for the larger part was enzymatically inactive. Within each group the increase of NSE-ag content was significantly correlated with the increase of gamma-enolase activity and both NSE-ag content and gamma-enolase activity increased linearly with Td. It is concluded that gamma-enolase seems to be associated with the regulation of growth rate and that a compound with the gamma-enolase antigen but without enzyme activity can distinguish two different classes of SCLC cell lines. Furthermore the demonstration that NSE-ag can represent the active enzyme as well as an enzymatically inactive compound may explain why a controversy about neuron- or non-specificity of NSE exists.     

Neurone specific enolase (NSE) in small cell lung cancer: a tumour marker of prognostic significance?

Pretreatment serum levels of neurone specific enolase (NSE) were measured in patients with small cell lung cancer (SCLC). Median values were significantly higher in patients with extensive compared with limited stage disease (48 ng ml-1 v. 17 ng ml-1: P less than 0.001). Serial NSE levels paralleled the clinical response to treatment. In 37 patients with limited SCLC, receiving identical chemotherapy, the pretreatment NSE level was of prognostic significance: with an approximate reduction in median survival of 10% for each 5 ng ml-1 incremental rise in NSE (P = 0.004).     

Neuron-specific enolase is an effective tumour marker in non-small cell lung cancer (NSCLC)

BACKGROUND: Neuron-specific enolase (NSE) is a well known marker of small cell lung cancer. The present study was designed to assess the clinical value of NSE in non-small cell lung cancer (NSCLC), as compared to that of carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA). METHODS: The study comprised 448 new consecutive NSCLC patients seen from 1996 to 2001. A set of 30 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was prospectively recorded for all patients. Patients were carefully followed-up, and their subsequent clinical course recorded. RESULTS: Increased values of NSE were present in 32% of the patients. Bivariate analyses showed that NSE, TPA and CEA were significantly correlated with each other, lactate dehydrogenase, tumour diameter, and disease extent. Univariate analyses showed that patients with elevated concentration of both NSE and TPA had significantly shorter survivals than patients with low values (30 [95% CI: 25-35] vs. 61 weeks [46-76], and 30 [CI: 24-36] vs. 59 weeks [40-79], respectively, P=0.0000). The Cox proportional hazards model including all the 22 variables significant in univariate analysis selected, in decreasing order of significance, the following variables: (1) N factor; (2) main treatment; (3) ECOG PS; (4) CNS metastasis; (5) age; (6) tumour cavitation; (7) NSE; (8) T factor; and (9) adrenal gland metastasis. CONCLUSIONS: This data indicates that serum assay of NSE is a useful marker also in NSCLC and a significant predictor of survival, independently of the other prognostic factors.     

Comparative prognostic value of lactate dehydrogenase and neuron-specific enolase in small-cell lung cancer patients treated with platinum-based chemotherapy

The influence of pretreatment serum levels of lactate dehydrogenase (LDH) and neuron-specific enolase (NSE) on survival was investigated in a series of 263 consecutive patients with small-cell lung cancer. LDH was elevated in one-half of the patients, NSE in 79%. Both were significantly higher when the disease was considered extensive than when it was limited. The markers were significantly correlated (r= 0.54, P=1.03 x 10(-20)), and both had a significant impact on survival in the univariate analysis. The multivariate survival analysis of the entire population showed that LDH, along with performance status, extent of disease, and albumin, was a more important prognostic factor than NSE. Only when LDH was removed from the model did NSE become an independent prognostic factor. In the separate multivariate survival analyses of limited and extensive disease, LDH remained an independent prognostic factor. For extensive disease, NSE did not even appear in the model when LDH was excluded; for limited stage disease, NSE did become a weak independent prognostic factor when LDH was excluded. In conclusion, LDH, which is less expensive to assay than NSE, is also a stronger independent prognostic factor for small-cell lung cancer and should be part of the initial work-up. In clinical trials, stratification for LDH levels should be considered because of its prognostic weight.     

Ca125 and neuron-specific enolase (NSE) as tumour markers for intra-abdominal desmoplastic small round-cell tumours.

Seven consecutive patients with intra-abdominal desmoplastic small round-cell tumours were screened at presentation for carcinoembryonic antigen (CEA), Ca19-9, Ca15-3, Ca125, alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and neuron-specific enolase (NSE). Initially elevated tumour markers were used to monitor therapy and follow-up. Tumour marker assays were all in the normal range, with the exception of Ca125 and NSE. The Ca125 level was initially high in six of the seven patients (86%) with a median value of 200 U ml-1 and a range of 22-735 U ml-1. The NSE value was elevated before therapy in three of the five patients (60%) for whom assay results were available, with a median of 19 ng ml-1 and a range of 6.8-37.5 ng ml-1 . Ca1 25 normalized in five out of six cases and NSE always normalized during chemotherapy, but neither of these two tumour markers correlated specifically with response, as only one patient experienced a partial response, five tumour stabilization and the remaining patient tumour progression. At progression, Ca125 was again elevated in two out of four cases several weeks before clinical relapse and NSE in only one out of three cases. Ca125 and NSE are frequently raised in the serum of patients with intra-abdominal desmoplastic small round-cell tumours before therapy, but are not reliable monitors of the course of the disease. However, normalization is frequently associated with an improvement of symptoms or a moderate clinical response.