Cerebrospinal Fluid Carcinoembryonic Antigen Research Articles

CMET-08. CEREBROSPINAL FLUID CARCINOEMBRYONIC ANTIGEN PREDICT PROGNOSIS IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicopathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.

1563P - Carcinoembryonic antigen of cerebrospinal fluid predict prognosis of leptomeningeal metastasis from non-small cell lung cancer

BackgroundLeptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. MethodsSeventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. ResultsMedian KPS at diagnosis of LM were 60 (range, 20-90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (>50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. ConclusionsMedian overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

LPTO-07. CARCINOEMBRYONIC ANTIGEN OF CEREBROSPINAL FLUID PREDICT PROGNOSIS OF LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER

BACKGROUND: Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS: Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS: Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION: Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.

Diagnostic Value of CYFRA 21-1 in the Cerebrospinal Fluid for Leptomeningeal Metastasis.

Cerebrospinal fluid (CSF) cytology has low sensitivity for leptomeningeal metastasis (LM); thus, new markers are needed to improve the diagnostic accuracy of LM. We measured carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) in paired samples of CSF and serum from patients with LM and patients with nonmalignant neurological diseases (NMNDs) as controls. Receiver operating curve analysis was performed to assess their diagnostic accuracy for LM. In patients with NMNDs, CEA and CYFRA 21-1 levels in the CSF were significantly lower than the serum levels. In patients with LM, there was no significant difference between the CSF and serum CEA levels, whereas the CYFRA 21-1 levels were significantly higher in the CSF than the serum. CSF/serum quotients of CYFRA 21-1 were higher than those of CEA in patients with LM and patients with NMNDs. CSF CYFRA 21-1 and CSF/serum quotient of CYFRA 21-1 had high accuracy for differentiating LM from NMNDs that was similar to CSF CEA and CSF/serum quotient of CYFRA 21-1, whereas serum CYFRA 21-1 is of poor diagnostic value. Measurement of CSF CYFRA 21-1 should not be overlooked in patients with suspected LM, even if the serum CYFRA 21-1 level is within normal limits.

Diagnostic Value of Cerebrospinal Fluid Level of Carcinoembryonic Antigen in Patients with Leptomeningeal Carcinomatous Metastasis

Background and PurposeMultifocal seeding of the leptomeninges by malignant cells, which is usually referred to as leptomeningeal carcinomatous metastasis, produces substantial morbidity and mortality. The diagnosis of leptomeningeal metastasis is usually established by cerebrospinal fluid (CSF) investigation, including cytology, cell counts, protein, glucose, and a tumor marker such as carcinoembryonic antigen (CEA). This study examined the diagnostic value of CEA in the CSF.MethodsWe measured the CSF CEA level in 32 patients with leptomeningeal metastasis. The control group consisted of 19 cancer patients without leptomeningeal metastasis. CEA was measured by the chemiluminescent emission method.ResultsThe CEA level was significantly higher in patients with leptomeningeal metastasis than in the control group (p<0.005). The level of CSF protein was higher and that of CSF glucose was lower in patients with leptomeningeal metastasis than in the control group (p<0.005).ConclusionsThe CSF CEA level is useful for diagnosing leptomeningeal carcinomatous metastasis. The CSF levels of protein and glucose are also useful in the diagnosis.

Toxicology study of repeat intracerebral administration of a measles virus derivative producing carcinoembryonic antigen in rhesus macaques in support of a phase I/II clinical trial for patients with recurrent gliomas.

Gliomas have a dismal prognosis, with the median survival of patients with the most common histology, glioblastoma multiforme, being only 12-15 months. Development of novel therapeutic agents is urgently needed. We have previously demonstrated that oncolytic measles virus strains derived from the Edmonston vaccine lineage have significant antitumor activity against gliomas [Phuong, L.K., Allen, C., Peng, K.W., Giannini, C., Greiner, S., Teneyck, C.J., Mishra, P.K., Macura, S.I., Russell, S.J., Galanis, E.C. (2003). Cancer. Res. 63, 2462-2469]. MV-CEA is an Edmonston vaccine lineage measles virus strain engineered to express the marker peptide carcinoembryonic antigen (CEA): CEA levels can serve as a correlate of viral gene expression. In support of a phase I clinical trial of intratumoral and resection cavity administration of MV-CEA to patients with recurrent gliomas, we assessed the neurotoxicity of MV-CEA in adult immune male rhesus macaques (Macaca mulatta). The animals ' immune status and administration schedule mimicked the trial population and proposed administration schema. Macaca mulatta represents the prototype animal species for assessment of measles neurotoxicity. The animals were stereotactically administered either vehicle (n = 1) or MV-CEA at 2 x 10(5)or 2 x 10(6) TCID(50) (each, n = 2) in the right frontal lobe in two injections on days 1 and 5. Macaques were closely monitored clinically for neurotoxicity. Body weight, temperature, complete blood count, CEA, clinical chemistries, coagulation, complement levels, immunoglobulin, measles antibody titers, viremia, and shedding (buccal swabs) were tested at multiple time points. Furthermore, cisterna magna spinal taps were performed on day 9 and 1 year after the first viral dose administration, and samples were analyzed for protein, glucose, cell differential, and presence of MV-CEA. Magnetic resonance imaging (MRI) was performed between 4 and 5 months after article administration to assess for subclinical neurotoxicity. To date, 36+ months from study initiation there has been no clinical or biochemical evidence of toxicity, including lack of neurological symptoms, fever, or other systemic symptoms and lack of immunosuppression. Quantitative RT-PCR analysis of blood, buccal swabs, and cerebrospinal fluid (CSF) was negative for MV-CEA at all time points, with the exception of viral genome deletion in the blood of one asymptomatic animal at the 2 x 10(6) TCID(50) dose level on day 85. Vero cell overlays of CSF cells and supernatant were negative for viral recovery. There was no detection of CEA in serum or CSF at any time point. MRI scans were negative for imaging abnormalities and showed no evidence of encephalitis. Our results support the safety of CNS administration of MV-CEA in glioma patients. A clinical trial of intratumoral and resection cavity administration of MV-CEA in patients with recurrent glioblastoma multiforme is currently ongoing.

Immunocytochemical localization of carcinoembryonic antigen in cerebrospinal fluid with metastatic carcinoma of the stomach: Report of four cases

A study was undertaken to evaluate the cellular findings of gastric carcinoma in cerebrospinal fluid (CSF). Immunocytochemical localization of carcinoembryonic antigen (CEA) was performed on four cases of metastatic gastric carcinoma cells in CSF samples. A positive peroxidase-antiperoxidase (PAP) reaction was obtained in all cases, with intense staining for CEA in the CSF samples as well as in the paraffin-embedded tissue sections from the primary gastric tumors. Cellular morphology and the results of immunoperoxidase staining can be studied simultaneously. We believe that the PAP method for CEA increases diagnostic accuracy of cytology in the CSF.

Cerebrospinal fluid carcinoembryonic antigen and alphafetoprotein in patients with central nervous system neoplasia

A solid phase immunoassay was used to evaluate the levels of serum and cerebrospinal fluid of alphafetoprotein and carcinoembryonic antigen in 33 individuals treated for backache and headache with no evidence of organic neurological disease, 19 patients with primary CNS tumor (benign or malignant) and 22 with CNS metastasis from a solid tumor. AFP serum and CSF levels were found in trace amounts or slightly elevated not exceeding normal limits in all groups. Patients with CNS metastasis were found to have statistically significant higher CEA levels (both in serum and CSF) than the control group, and the patients with primary brain tumors. Patients with leptomeningeal dissemination had statistically significantly higher CEA CSF levels than did patients with primary tumors, and patients with parenchymal metastasis.

The clinical relevance of locally produced carcinoembryonic antigen in cerebrospinal fluid.

Sixteen out of eighteen meningeal carcinomas (89%) secreted carcinoembryonic antigen (CEA) into the cerebrospinal fluid, where it could be quantified separately from the portion originating from the circulating blood. The discrimination of both fractions was performed according to an empirical approach analogous to the immunoglobulins. Only 47% of the intraparenchymal carcinomas released CEA into the CSF compartment and it is possible that the extra-cellular space of these tumour sites does not communicate with the free CSF space. Extradural metastases may cause an impairment of the blood-CSF barrier via restrictions of the CSF fluid turnover, but the dura remains impermeable for the tumour marker. Seven out of 54 primary brain tumours (13%) released carcinoembryonic antigen into the cerebrospinal fluid.

Sensitive quantitation of carcinoembryonic antigen in cerebrospinal fluid and its barrier-dependent differentiation

Modification of an enzyme immunoassay using beads as solid phase allows the detection of 3 pg/ml carcinoembryonic antigen (CEA). The beads are shown to be advantageous for the extraction of proteins in highly diluted antigen solutions thus replacing a need for concentration of the sample. The mean concentration of CEA in pooled cerebrospinal fluid (CSF) from 120 control persons was shown to be 2.7 pg/ml. The mean of the CSF/serum concentration quotients of CEA was 0.0015 for normal blood CSF barrier function with a corresponding mean albumin CSF/serum quotient of 0.0048. From the ratio of these two quotients ( Q CEA/ Q A = 0.31) and the corresponding biological variation we constructed the normal range of an evaluation graph. In the range of a blood CSF barrier dysfunction, the discrimination line between values with or without a local CEA synthesis in brain was determined to be Q CEA = 0.7 Q A. Twenty-five out of 383 control persons and 29 out of 45 patients with a tumor metastasis had evaluable quotients. The evaluation graph had a high significance with respect to the identification of tumor metastasis: from a group of patients with a confirmed leptomeningeal metastasis 13 out of 13 and from a group of patients with intraparenchymatous tumor metastasis 10 out of 16 could be identified by CSF analysis. The CEA CSF/serum concentration quotient fits well in the concept of a molecular size-dependent filter function of the blood CSF barrier.

Cerebrospinal fluid carcinoembryonic antigen in patients with metastatic and nonmetastatic neurological diseases.

Cerebrospinal fluid (CSF) carcinoembryonic antigen (CEA) values were determined in 200 patients suffering from various neurological diseases. We found no relationship between CEA levels and age or sex. A positive test was defined as an upper limit of at least 4.0 ng/mL of CEA. We found raised CSF CEA levels in patients with leptomeningeal spread from carcinoma, but not in patients with leptomeningeal metastases from lymphoma. We also found high values of CSF CEA in three of 21 patients with epidural metastases and in two of 28 patients with cerebral metastases from solid tumors. Comparison was made with the CSF levels of total protein, glucose, and lactate dehydrogenase. The sensitivity of the CSF CEA determination in patients for the presence of leptomeningeal involvement of cancer is 31% and the specificity is 90%.

Elevation of Carcinoembryonic Antigen in Cerebrospinal Fluid Among Patients With Meningeal Carcinomatosis

The concentration of carcinoembryonic antigen (CEA) in cerebrospinal fluid (CSF) was determined by using an enzyme immunoassay for 204 patients with various nonneoplastic neurologic disorders, 8 patients with systemic infectious diseases, 19 patients with systemic neoplastic diseases without involvement of the nervous system, and 35 patients with neoplastic neurologic disorders. The highest CEA level in CSF among patients without neoplastic neurologic disorders was 0.6 ng/ml. Of 35 patients with neoplastic neurologic disorders, 10 had CEA levels in CSF that exceeded 0.6 ng/ml, the highest level being 70.5 ng/ml. All 10 patients had carcinomas. Among 14 patients with neoplastic meningitis, 5 of 8 patients with meningeal carcinomatosis had elevated CEA concentrations. Although the efficacy of the assay for CEA in CSF must be compared with that of other laboratory tests such as cytologic examination and the assay for beta-glucuronidase--and any potentially false-positive results should be ruled out by determination of the serum CEA level--the CEA concentration in CSF can be used as an adjunctive diagnostic procedure for detection of meningeal carcinomatosis.

Carcinoembryonic antigen in patients with intracranial tumors.

Carcinoembryonic antigen (CEA) in plasma, cerebrospinal fluid (CSF), and tumor cyst fluid obtained from patients with a variety of intracranial tumors was determined by radioimmunoassay Slightly elevated levels of plasma CEA, ranging from 2.6 to 3.8 ng/ml, were noted in six (4%) of 161 patients with primary brain tumors: in three gliomas, two pineal tumors, and one acoustic neurinoma, respectively. On the other hand, 17 (37%) of 46 patients with metastatic brain tumors showed a definite elevation, and most of them had values higher than 5.0 ng/ml. Of 37 patients with primary brain tumors, only one with a pineal germinoma showed a significant elevation of CEA in CSF, whereas eight (44%) of 18 patients with metastatic brain tumors showed high values of CEA in CSF. All six patients with leptomeningeal carcinomatosis showed elevated CEA in CSF. Levels of CEA in tumor cyst fluid were determined in 17 patients with intracranial tumors, including 12 gliomas, two craniopharyngiomas, two metastatic tumors, and one meningioma; elevation of CEA in tumor fluid was noted in two craniopharyngiomas and one metastatic tumor. Sequential determination of CEA of plasma or CSF revealed that the CEA levels were well correlated with the activity of brain tumors. Consequently, the determination of CEA in plasma or CSF is valuable for the differential diagnosis between primary and metastatic brain tumors and for the management of CEA-producing tumors.

Carcinoembryonic Antigen in Plasma, Cerebrospinal Fluid and Cystic Fluid of Patients with Intracranial Tumors

Carcinoembryonic antigen (CEA) in plasma, cerebrospinal fluid (CSF) and cystic fluid of patients with various intracranial tumors were determined by a radioimmunoassay using Dainabot and Roche CEA Kits. Slightly elevated levels of plasma CEA were noted in 6 (4%) out of 161 (6/161) patients with primary brain tumors: gliomas, 3/67; pituitary adenomas, 0/30; meningiomas, 0/28; acoustic neurinomas, 1/12; pineal tumors, 2/12 (germinomas, 1/8; teratoma, 0/1 ; teratoblastoma, 0/1 ; embryonal carcinoma, 1/1 ; not verified histologically, 0/1); craniopharyngiomas, 0/6; hemangioblastomas, 0/2; epidermoid tumor, 0/1; reticulum cell sarcoma, 0/1; choroid plexus papilloma, 0/1; chondroma, 0/1. The plasma CEA levels of these 6 patients varied from 2.6 to 3.8 ng/ml. On the other hand, 17 (37%) out of 46 patients with metastatic brain tumor showed definite elevation of CEA levels in plasma and most of them showed values higher than 5.1 ng/ml ranging from 3.0 to 2, 317 ng/ml. CEA in CSF of 55 patients with intracranial tumors were determined. Since CEA levels in CSF obtained from 38 control subjects were mostly 0 ng/ml, ranging from 0 to 0.5 ng/ml, an upper limit of normal CEA level in CSF by one step sandwich method was proposed to be 0.5 ng/ml. Significant elevation of CEA levels in CSF was noted in the one of 37 patients with primary brain tumors, a patient with pineal germinoma showing a spinal metastasis, and in 8 (44%) out of 18 patients with metastatic brain tumor. All of 6 patients with leptomeningeal carcinomatosis showed elevated levels of CEA in CSF. CEA in cystic fluid were measured in 17 patients with intracranial tumors, including 12 gliomas, 2 craniopharyngiomas, 2 metastatic brain tumors and 1 meningioma. Elevated levels of the tumor fluid CEA were noted in 2 patients with craniopharyngioma (8.6 ng/ml and 11.0 ng/ml, respectively) and in one with metastatic brain tumor from breast cancer (14300 ng/ml). Mean value of the tumor fluid CEA of 12 glioma patients was 0.6 ± 0.6 ng/ml. A meningioma and one metastatic tumor showed low levels of CEA less than 0.5 ng/ml in the tumor fluids. Study on sequential determination of CEA in plasma or CSF performed on three patients revealed that CEA levels were well-correlated with the activity of the tumors and could be used for evaluation of treatment or foreknowledge of recurrence of tumors. In conclusion, determination of CEA in plasma or CSF is valuable for differential diagnosis between primary and metastatic brain tumors, evaluation of treatments, or fore-knowledge of recurrence of tumors. Determination of CEA in CSF could be very useful especially for diagnosis of leptomeningeal carcinomatosis.