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A babygirl, aged six weeks, was hospitalized for rectal prolapse and isolated constipation. The investigation revealed a neuroblastoma (NB) inducing a medullar compression responsible for the sphincter disorders. NB is second among pediatric solid tumors, but is the most frequent cancer among infants. Its diagnosis is difficult because of its rarity and the variety of its symptoms. A new staging, based on imaging, has recently been proposed by the International Neuroblastoma Risk Group. With the exception of its localized, easily resectable forms, NB is best treated by chemotherapy.

The aim of this work is to establish a pre-analytical approach suitable for the neuron-specific enolase (NSE) measurement. This enzyme which is synthesized by neurons and neuroendocrine cells, is a marker useful for the diagnosis and the monitoring of patients with neuroendocrine tumors (neuroblastoma, small cell lung cancer) and during stroke to assess neuronal damage. This NSE measurement is very sensitive to hemolysis due to the abundance of the enzyme in red blood cells. Two methods of evaluation of hemolysis have been compared: the determination of free haemoglobin (Hb) by spectrophotometry and the indirect measurement of an hemolytic index with a multiparameter analyzer, the Modular (Roche Diagnostics). The correlation between these 2 methods on 42 samples is very satisfactory: Y (free Hb) = 12.337 X (index) + 31.743 r = 0.997. The NSE assay is based on TRACE (Time Resolved Amplified Cryptate Emission) technology, on a Kryptor (BRAHMS). The influence of hemolysis on the determination of NSE was confirmed by overloading with hemoglobin (hemolysate) 3 pools of serum with NSE concentrations close to the threeshold decision. The determination of NSE shows an increase in concentration parallely to the hemolytic index (about 150% for an hemolytic index of 10). Consequently, in our laboratory the NSE determination is realized only for samples presenting an hemolytic index < or = 10, this allowing a good monitoring of kinetics of this marker.

Objective: To identify, through a review of the literature, the laboratory variables that would allow a more accurate stratification of unresected non small-cell lung cancer patients who participate in clinical trials., Method: Systematic review, without meta-analysis, following the recommendations of the International Federation of Clinical Chemistry and Laboratory Medicine, and taking into account the Consolidated Standards of Reporting Trials statement., Results: Of 1106 publications retrieved, we were able to include only fourteen studies in our review. Available evidence would support the use of several laboratory variables as prognostic covariables to stratify non resected non small-cell lung cancer patients in clinical trials, but blood haemoglobin would be the only one that could be recommended on a routine basis, and only in patients treated with radiotherapy (three studies out of three). The possible consequences in terms of therapeutic decision of haemoglobin measurements remain however to be clarified., Conclusion: Until better designed studies are published, a number of arguments would support the pre-treatment measurements of the following variables in patients participating in clinical trials: blood haemoglobin, white blood cell count with differential, serum LDH, albumin, calcium, and NSE. Further studies would also be necessary to support the addition to this list, of other tumour markers (including Cyfra 21-1), and/or measurements during or after treatment.

We have examined 82 patients with hormonoresistant prostate cancer in a retrospective study. Bone and lymph node metastases were observed in 94% and 30% of patients respectively. However, the visceral metastases were frequent: liver (17%), lung (7%), bone marrow (4%), meningitis (4%). PSA is constantly high but 28% of the patients have elevated NSE, which is correlated with lymph node or visceral metastases. ACE is elevated in 27% of cases. Objective and palliative effect of chemotherapy is marked for weekly doxorubicin, prednisone with mitoxantrone and etoposide associated with platin-salts for prostatic carcinoma with neuroendocrine differentiation. This study suggests the presence of different subpopulations of patients with specific evolutive patterns, thus further specific therapy should be evaluated.

Objective: To report the results of seric neuron specific enolase in pediatric neuroblastoma., Patients and Methods: Our retrospective study concerns 21 children treated in our institution from 1992 to 1998 for neuroblastoma. Seric NSE was determined by immunoenzymology technique at different stages of the disease and the treatment., Results: Mean value for the 39 dosages of the whole patients was 127.9 ng/ml with a sensitivity of 56%, five patients has presented normal values. Mean value for the 18 patients in stage IV was 132.38 ng/ml. We also observed in 3 patients, an evolution of the seric NSE parallel to this of the disease under chemotherapy., Conclusion: NSE represents a moderate sensitive and specific tumor marker for pediatric neuroblastoma. However, it represents a good value in prognosis and follow-up after chemotherapy.

Pleuropulmonary metastasis occurs in 30 to 50% of all patients with cancer. Certain metastases occur specifically in females: breast and ovary cancer. There are six different clinical presentations of bronchopulmonary metastases: unique or multiple nodular images, mediastinal nodes, carcinomatous lymphangitis, bronchial metastasis, tumoral emboli, and metastatic bronchiolo-alveolar metastatic cancer. When the primary cancer is not known, a minimum number of investigations are needed: thyroid and pelvic ultrasound, mammography, colonscopy for certain cases, alfa-fetoprotein assay, neuron-specific enolase and beta HCG. Metastatic pleurisy accounts for 45% of all cases of pleurisy. In women, neoplastic pleural effusions result from breast cancer (37%), genitourinary tract cancer (20%), and lung cancer (15%).

TUMOR MARKERS: We reviewed the biomedical literature searching for the most well-documented serum markers with prognostic value independent of the usual radioclinical and histological parameters of small cell lung cancer., Relative Prognostic Values: Neuron specific enolase (NSE) would have a pretherapeutic prognostic value better than LDH (lacto-dehydrogenase) and perhaps better than serum sodium, biocarbonates, and uric acid. The superiority of NSE over serum albumin remains to be proven. Although there are only a few reports, TK (thymine kinase), TPA (tissue polypeptide antigen), Cyfra 21-1 and/or IL-2 (interleukin-2) secretion might have better pretherapeutic prognostic value than NSE. We also found that iterative blood assays to follow therapeutic effects in patients with small-cell lung cancer have not been proven to provide independent prognostic information., Conclusion: As medical laboratory resources must be concentrated on priority exploitable assays, the currently available data would suggest that it is not necessary to routinely measure serum tumor markers, and in particular NSE, for the prognostic evaluation of small-cell lung cancer patients.

Rationale: An elevated serum NSE concentration is generally a bad prognostic sign when a diagnosis of small cell lung cancer is made. However, the marker may vary from time to time crossing the discriminant threshold (12.5 ng/ml) in one direction or the other. These variations are presumed to reflect the progress of the disease but it has not been shown that the risk of death from the disease is changed by alterations in the serum concentration of NSE. To resolve this question we have used Markov's mathematical model (homogeneous over time and in three states)., Method: A prospective study has included 52 patients suffering from small cell cancer and treated with chemotherapy based on cisplatin. The NSE was measured following each treatment and three monthly in subsequent follow up. Markov's model was studying the intensities of transition and the risks of death between the two following transient states: living with an NSE concentration of < or = to 12.5 ng/ml, living with an NSE concentration of > 12.5 ng/ml, and an absorbing state: death., Results: When a level of > 12.5 ng/ml was noted the mean time of maintaining in this state was short (123 days). During this time when a transfer was effected in 44 per cent of cases there is turn towards the opposite state (living with a concentration < 12.5 ng/ml) showing the real reversibility between the two transient states. When a patient had an elevated concentration of serum NSE the risk of death was 2.23 times greater than in the opposite state (living with a low NSE; P < 0.01)., Conclusion: The observation of an elevated NSE concentration at any time in the follow up of patients suffering from small cell cancer was strongly associated with an elevated risk of death but a return from this state towards a state of less risk (living with a low NSE level) remains possible. This works suggests that the NSE levels may be useful in the follow up of small cell lung cancer.

Neuroendocrine bladder tumours are exceptional, and the positive diagnosis is only established when they are already large and advanced. We report an original case in view of its small dimensions. We discuss the differential diagnosis (mainly bladder metastases from lung cancer) and pathological specificities, particularly the value of epithelial immunolabelling allowing exclusion of lymphoma. Because of the similarities with bronchial neuroendocrine tumours, the potential value of serum NSE assay should be emphasized. Combined surgery-cisplatin-based adjuvant chemotherapy is recommended.

To evaluate the pronostic value of an elevated seric carcinoembryonic antigen (CEA > 10 ng/ml) at diagnosis, in patients with lung cancer, a pair study was done: couples of patients with same staging and histologic type were established, one patient with high CEA level compared to one patient with normal CEA level (< 5.5 ng/ml). Other markers were measured: neuron specific enolase (NSE), squamous cell carcinoma (SCC) or Cyfra 21-1. Survival was the end point of comparison. For 89 couples created, patients with low CEA level had a better survival rate at one year ( p = 0.02), this prognosis advantage was confirmed by a comparison of survival curves with Mantel-Cox and Breslow test (p = 0.01), but not by the signs test. These differences were also observed for the 71 couples of squamous cell carcinomas and adenocarcinomas, and the apparied signs test was still not significant. The poor prognosis persisted for patients with high CEA level, when one another marker's level (NSE or SCC or Cyfra 21-1) was increased, in comparison with patients with any marker increased. On 29 couples of all histological subtypes or on the 25 couples of non small cell lung cancer, the signs test and the comparison of survival curves were significant, but not the 1 year survival rate. This study shows that a CEA level greater than 10 ng/ml at diagnosis is a poor pronostic factor in patients with lung carcinoma, independent of the stage of disease and of the histologic type.

This study concerns 45 patients group one suffering from broncho-pulmonary cancer, the diagnosis was obtained by bronchial biopsies or by transparietal puncture using a scanner: there were 35 non-small cell bronchial carcinomas (CNPC) and 10 small cell bronchial cancers (CPC). The control patients (99 patients) were divided up as follows: 44 pleuro-pulmonary infections (group two) and 55 with respiratory failure of various causes other than infectious episodes (group three). In group one the level for TPA was positive in 30 cases (the threshold value was 90 units per litre), 9 for CA 19.9, 7 for ACE and 9 for NSE. The overall sensitivity was thus better for TPA. There was no correlation between TPA and type of tumour histology nor between the different markers. Their association did not improve the sensitivity. The NSE however, remained the most sensitive test for the diagnosis of CPC with six positive tests out of ten. In the control population, the specificity of TPA (66%) was less than that of ACE (100%) or of CA 19.9 (94%) and the false positives were significantly more numerous in group two: 21 patients had a positive test compared to only 12 in group three. Finally we noticed an increase in the level of TPA contrary to other markers, as a function of the extent of the disease from the carcinoma (CNPC unique). The TPA is thus the most sensitive and it turns out to be better reflector to the extent of the tumour disease than either ACE, CA 19.9 or NSE but this applies uniquely to non-small cell carcinoma.

Cytokeratins are intermediate filaments of the cytoskeleton that are expressed by bronchial epithelium and its neoplastic counterpart, lung cancer. A new immunoradiometric assay referred to as CYFRA 21-1 makes it possible to titrate in the serum a cytokeratin 19 fragment. This study deals with the sensitivity, specificity and applicability of this serum marker in squamous cell carcinoma. Sera from non malignant pulmonary diseases were taken as controls. In comparison with carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC T-A4) and neuron specific enolase (NSE), CYFRA 21-1 was the most accurate marker. The area under the CYFRA 21-1 ROC curve was significantly greater than those of CEA, SCC T-A4 and NSE. Using a 3.6 ng/ml threshold, as determined by the ROC curve, CYFRA 21-1 was significantly correlated with tumor mass.

Despite its very good specificity, serum neuron-specific enolase (SNE) cannot be relied upon to diagnose small cell carcinoma. However, this marker is of interest owing to the double correlation observed between it and tumoral extension and between its rapid elevation under chemotherapy and clinical response to chemotherapy. Repeated SNE assays help in determining this response when SNE returns to normal level, and in predicting the progression of the disease several weeks in advance when SNE levels increase. Early and later SNE assays therefore have prognostic value.

This study analyses retrospectively the plasma level of neuron-specific enolase (NSE) performed in 236 patients presenting for the diagnosis of a bronchopulmonary disease. Taking a cut off on 15 micrograms/L, 61 (64%) of the 95 patients sharing a small cell lung cancer (SCLC) (45% of those with a limited disease and 90% with an extensive disease) but 8 (13%) of 60 with a non small cell lung cancer patients and 0% of those with a benign bronchopulmonary disease showed an abnormal value of NSE. Therefore in this group of patients, the diagnosis of SCLC could be assessed with a sensitivity of 64% and a specificity of 94% in patients with an NSE plasma level above 15 micrograms/L. In addition, the interest of sequential dosages of NSE for the monitoring of SCLC patients is also stressed.

A serum assay of CA-50, CA-125, CA-19.9, ENOLASE (NSE) and CEA was performed in 65 patients with primary lung cancer, 63% of whom had visceral metastases, with the following histological distribution: squamous carcinoma (40), adenocarcinoma (9), large cell carcinoma (4), oat cell carcinoma (12). A raised CEA level was detected in 37% of cases, compared with 40.6% for CA-50, 44.6% for CA-19.9 and 40.6% for CA-125 and only 26.6% for NSE. Overall, at least one marker was positive in 83% of cases. Statistical analysis of the different markers (correlation analysis and principal component analysis) demonstrated the existence of a strict correlation between the levels of CA-50, CEA and CA-19.9 (p less than 0.01). ENOLASE was more frequently elevated in oat cell carcinomas (42%) than in non-oat cell carcinomas (30%), but the difference was not significant. In contrast, CA-125 appears to be a good marker for non-oat cell carcinomas (51%) (p less than 0.05). The authors also found a correlation between the presence of a raised level of CA-50 (p less than 0.05), CA-125 (p less than 0.02) and especially CEA (p less than 0.001) and the presence of visceral metastases. The initial survey of disseminated lung cancers should include the assay of at least 4 of these markers in order to obtain a reliable serum tracer in more than 2/3 of cases.

In an immunohistochemical study 31 patients with bronchial cancer (squamous cell 9, large cell 4, small intermediate cell 11 and oat cell 7) were investigated for keratin and NSE. Keratin seems to be a valuable marker since only oat cell cancers and 45% of small intermediate cell cancers were negative. In contrast, marking with NSE seems to be non-discriminating. The low value of NSE as marker was confirmed by 133 serum NSE assays performed in 39 bronchial cancer patients. Although NSE values were significantly higher in oat cell cancer, in any given patient serum assays can, at best, detect relapses.

At present we do not possess a specific marker of broncho-pulmonary cancers. We propose to test the specificity of six serum markers labelled by radio-immunological methods (CA-50, CA-19.9, CA-125, CA-15.3, enolase, ACE) in 60 patients suffering from non-tumoural broncho-pulmonary disorders: chronic airflow obstruction = 28, acute infective bronchopulmonary disorders = 23, allergy = 9. We have not found any correlation between the percentage of false positives and sex, age or smoking. On the other hand, the CA-125 was often found to be positive in cases of acute pneumonia. Overall the frequency of false positives with ACE (3.3%) enolase (6.7%) and CA-15.3 (5%) is weak. The threshold of positivity obtained is adequate. This is not the case with CA-50 (33.3%), CA-19.9 (13.3%) and above all CA-125 (53.3%), for these we suggest new thresholds of positivity.