Plasma Carcinoembryonic Antigen Levels Research Articles

Medullary thyroid carcinoma and biomarkers: past, present and future

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Prognostic value of preoperative CEA, CA 19-9, CA 72-4, and AFP levels in gastric cancer

Recent research has suggested that serum tumor markers can give valuable prognostic information in gastric cancer. In this study, we examined the relationship between preoperative serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, CA 72-4, and alfa fetoprotein (AFP) levels on clinicopathologic significance in gastric cancer patients. Preoperative plasma levels of CEA, CA 19-9, CA 72-4, and AFP were retrospectively examined in 95 patients who underwent surgical resection for gastric cancer, and the prognostic value of the tumour markers were estimated. The percentage of CA 19-9, CA 72-4, CEA, and AFP-positive cases were 41%, 32.6%, 24.2%, and 8.4%, respectively. CEA was more frequently positive in the patients with liver metastases (P=0.02). CA 19-9 was more frequently positive in patients with lymph node (P=0.005), peritoneal (P=0.01), and serosal (P=0.03) involvement. CA 72-4 was more frequently positive in patients with lymph node (P=0.01), peritoneal (P=0.03), and liver (P=0.01) involvement. Low 3-year cumulative survival was associated significantly with elevated serum levels of CEA (P=0.001), CA 19-9 (P=0.001), CA 72-4 (P=0.001), and AFP (P=0.01). In multivariate analysis, age, tumor stage, and CA 72-4 were the only independent prognostic factors. Being positive for CA 72-4 was associated with a 3.8-fold higher risk of death (95% confidence intervals: 1.3, 10.9). Our results suggest that high preoperative serum levels of CA 72-4 in gastric cancer patients are associated with a higher risk of death due to gastric cancer.

A phase II trial of ZD6474 in patients with hereditary metastatic medullary thyroid cancer

5533 Background: Medullary thyroid carcinoma (MTC) is the most common cause of death in patients with hereditary syndromes caused by specific mutations in the RET protooncogene. RET activation is the oncogenic event, which results in intrinsic RET receptor tyrosine kinase activity, but other pathways, such as VEGFR- and EGFR-dependent signaling, also participate in tumor growth and development. ZD6474 is a once-daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. The clinical activity of ZD6474 was evaluated in patients with hereditary MTC. Methods: In this open-label Phase II study, patients with unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation received once-daily oral doses of ZD6474 300 mg. The primary objective was to assess the objective tumor response (RECIST). Secondary objectives included assessments of biochemical response (determined by changes in plasma levels of calcitonin [CTN]) and safety/tolerability of ZD6474. An exploratory objective was to measure plasma levels of carcinoembryonic antigen (CEA). Results: As of 30 November 2005, 16 patients (6 male/10 female; median age 50 years, range 22–77) had entered the study and received initial treatment with ZD6474 300mg. The median duration of treatment was 136 days (range 16–353). Fifteen patients were evaluable for tumor response, CTN, and CEA. Objective tumor assessments have demonstrated partial responses in 3 patients (n = 2 confirmed; n = 1 unconfirmed), stable disease in 10 patients (n = 8, ≥8 and <24 weeks; n = 2, ≥24 weeks) and progressive disease in 2 patients. A >50% decrease from baseline in plasma CTN levels has been maintained for at least 4 weeks in 12/15 patients; a decrease in plasma CEA levels of the same magnitude and duration has been observed in 6/15 patients. Common adverse events (AEs) were diarrhea (n = 12) and nausea, rash and fatigue (each n = 11). CTC grade 3 AEs attributable to ZD6474 were QTc interval prolongation (n = 3), and diarrhea, skin rash and hypertension (each n = 2). Conclusions: ZD6474 shows promising evidence of clinical activity in patients with hereditary MTC. These are preliminary data and patients are still being recruited to this ongoing study. [Table: see text]

Dual Therapy of Ovarian Cancer Using Measles Viruses Expressing Carcinoembryonic Antigen and Sodium Iodide Symporter

MV-CEA is an oncolytic measles virus currently being tested in patients with ovarian cancer and whose propagation can be monitored by measuring blood carcinoembryonic antigen (CEA) levels. MV-NIS is an oncolytic measles virus coding for the thyroidal sodium iodide symporter (NIS) whose propagation can be mapped by serial radioiodine imaging. Expression of both CEA and NIS genes from a single virus would combine sensitive, quantitative expression monitoring (CEA) with radioisotopic expression mapping (NIS). Because of the unfavorable replication kinetics of measles viruses expressing both CEA and NIS, we explored the feasibility of combining MV-CEA with MV-NIS for comprehensive virotherapy monitoring in ovarian cancer. Mice implanted with i.p. SKOV3ip.1 ovarian cancer xenografts received MV-CEA alone, MV-NIS alone, or a combination of MV-CEA plus MV-NIS. Viral gene expression was monitored by measuring blood CEA levels, and the location of virus-infected cells was monitored by gamma camera imaging. Surprisingly, mice receiving the combination of MV-CEA plus MV-NIS showed greatly superior responses to therapy, but this was associated with 10-fold lower plasma levels of CEA compared with mice treated with MV-CEA alone. In vitro studies showed superior replication kinetics of MV-NIS relative to MV-CEA. The gamma camera scans were considerably less sensitive than the plasma CEA marker for monitoring virus infection. Dual therapy with MV-CEA and MV-NIS is superior to treatment with either virus alone, and it allows noninvasive monitoring of virotherapy via soluble marker peptide and gamma camera imaging. This has important implications for the clinical development of oncolytic measles viruses.

Pharmacokinetics of oncolytic measles virotherapy: eventual equilibrium between virus and tumor in an ovarian cancer xenograft model

Because of their ability to replicate, the dose-response relationships of oncolytic viruses cannot easily be predicted. To better understand the pharmacokinetics of virotherapy in relation to viral dose and schedule, we administered MV-CEA intraperitoneally in an orthotopic mouse model of ovarian cancer. MV-CEA is an attenuated oncolytic measles virus engineered to express soluble human carcinoembryonic antigen (CEA), and the virus is currently undergoing phase I clinical testing in patients with ovarian cancer. Plasma CEA levels correlate with numbers of virus-infected tumor cells at a given time, and were used as a surrogate to monitor the profiles of viral gene expression over time. The antineoplastic activity of single- or multiple-dose MV-CEA was apparent over a wide range of virus doses (10(3)-10(8) TCID(50)), with little reduction in observed antitumor efficacy, even at the lowest tested dose. However, analysis of CEA profiles of treated mice was highly informative, illustrating the variability in virus kinetics at different dose levels. The highest doses of virus were associated with higher initial levels of tumor cell killing, but the final outcome of MV-CEA therapy at all dose levels was a partial equilibrium between virus and tumor, resulting in significant slowing of tumor growth and enhanced survival of the mice.

A Case of Meningeal Carcinomatosis Presenting with the Primary Symptoms of Facial Palsy and Sensorineural Deafness

We report the case of a 59-year-old man with meningeal carcinomatosis (MC) who presented with peripheral facial palsy and progressive sensorineural deafness. The patient had been operated on for gastric cancer 1 year previously, and no metastases had been detected in the retroperitoneum or thorax at follow-up examination 1 year later. However, he developed headache, deafness, and peripheral facial palsy and was referred to us for further evaluation, as magnetic resonance of the head had shown no abnormalities. Ramsay Hunt syndrome was suspected, but no increase in the cerebrospinal fluid cell count was detected. On the other hand, the balance test suggested a central disorder. In addition, the plasma level of carcinoembryonic antigen suddenly increased, suggesting MC. The cerebrospinal fluid was examined several times; in the end malignant cells and an increase in the cell count were detected, and the diagnosis of MC was established.

Disseminated Medullary Thyroid Carcinoma Despite Early Thyroid Surgery in the Multiple Endocrine Neoplasia-2A Syndrome

A 51/2-year-old boy, with a family history of multiple endocrine neoplasia (MEN)-2A syndrome, was evaluated for presence of MEN-2A and medullary thyroid carcinoma (MTC). DNA diagnostics confirmed MEN-2A. Basal (360 ng/L) and pentagastrin stimulated (430 ng/L) calcitonin (CT) levels were slightly elevated, plasma carcinoembryonic antigen (CEA) was normal. Within a year both tumor markers increased and total thyroidectomy was performed. Histologic examination did not show MTC. In the following years, both tumor markers increased progressively but despite the use of multiple imaging techniques no metastases were localized. After 6 years, biopsy of a palpable lymph node showed MTC. The boy was treated with total cervical, suprahyoidal, and mediastinal lymph node dissection, showing MTC in almost all nodes. Again, the tumor markers remained high. At this point in time, the disadvantages of further medical interventions were outweighed against the chance for cure and it was decided to shift the goal of treatment toward palliation rather than cure. At the last visit the boy was clinically well with persistent extremely high levels of plasma CEA and CT. In conclusion, when prophylactic thyroidectomy in the MEN-2A syndrome has failed, it may be best to withdraw from further interventions to prevent more damage.

Tumor-derived aberrant methylation in plasma of invasive ductal breast cancer patients: Clinical implications

Progressive p16 methylation has been associated with metastasis and invasive phenotypes in many cancers. Loss of E-cadherin (CDH1) function contributes to breast cancer progression by promoting cell proliferation, invasion and metastasis. Using methylation-specific PCR, aberrant hypermethylation of p16 and CDH1 in tumor and plasma was analyzed and correlated with levels of serum protein markers, carcinoembryonic antigen (CEA) and carcinoma antigen 15-3 (CA15.3), in 36 patients with invasive ductal breast cancer. Aberrant p16 methylation was found in 11% (4/36) of primary tumors and 8% (3/36) of plasma samples. Aberrant CDH1 methylation was detected in 25% (9/36) of primary tumors and 20% (7/36) of plasma samples. p16 and/or CDH1 hypermethylation was found in 31% (11/36) of primary breast carcinomas and 82% (9/11) of breast cancer patients with tumoral methylation showing identical epigenetic changes in plasma. The 25 patients without tumoral methylation did not show epigenetic changes in the plasma. Tumoral p16 methylation was significantly associated with advanced tumor stage (p=0.028; Fisher's exact test), tumor size (p=0.017) and nodal metastasis (p=0.002). However, p16 methylation in plasma was only associated with nodal metastasis (p=0.012). Altogether, aberrant p16 methylation in plasma and elevated serum CEA level were associated with advanced tumor stage (p=0.033), tumor size (p=0.022) and extensive nodal metastasis (p=0.003). With clinical implications, p16 hypermethylation in plasma and/or raised serum CEA levels may prove useful as diagnostic and prognostic markers for breast cancer.

Does cardiopulmonary bypass alter plasma level of tumor markers? CA 125 and carcinoembryonic antigen.

In addition to malignant diseases, acute and chronic inflammations may elevate plasma levels of tumor markers CA 125 and carcinoembryonic antigen (CEA). Cardiopulmonary bypass (CPB) causes a generalized inflammatory response. In this study, we have investigated the effect of CPB on plasma levels of CA 125 and CEA. We measured plasma levels of CA 125 and CEA in patients undergoing coronary artery bypass grafting (CABG) with CPB (Group 1, n = 21), and in patients who underwent off-pump CABG, that is, without CPB (Group 2, n = 16). Blood samples were collected preoperatively, and on postoperative days 1, 6, and 12. Within both groups, CEA plasma levels were not significantly influenced in any samples. Comparing with preoperative values, CA 125 values elevated significantly on postoperative days 6 and 12 within both groups. It was observed that the elevation of CA 125 plasma levels in these samples were significantly higher in Group 1. The results indicate that CPB elevated plasma level of CA 125. However, clinical importance of this finding needed further evaluation.

Von Willebrand factor in colorectal cancer.

Von Willebrand factor (vWF) is a protein that mediates adherence of platelets to subendothelium during primary hemostasis. High vWF plasma concentrations have been reported in patients with various types of cancer, such as squamous cell carcinoma of the larynx and the cervix. This effect is associated with tumor-related angiogenesis and the metastatic process. The aim of this study was to determine plasma levels of vWF in a series of patients with colorectal carcinoma and the correlation of these values with specific prognostic predictors for the disease. vWF was measured by quantitative immunoelectrophoresis in 75 patients with colorectal carcinoma at various Dukes' stages and compared with results from 88 healthy controls. Cancer patients had significantly higher vWF concentrations than controls. vWF plasma levels were associated with tumor staging, invasion of adjacent organs by the tumor, and presence of distant metastases. There was no significant correlation between vWF values and tumor size, histological grading, or plasma carcinoembryonic antigen levels. The levels of vWF are elevated in patients with colorectal cancer, and these values tend to increase with tumor progression. Considering that vWF is related to the process of tumor angiogenesis and may contribute to metastatic dissemination of malignant cells, further studies of its potential role as a marker of tumor progression in patients with colorectal cancer are warranted. It should be pointed out, however, that these observations need to be substantiated with additional studies using other methods and, preferably, the determination of vWF levels synthesized in the tumor tissues.

Increased Serum Carcinoembryonic Antigen Levels as An Early Sign of Medullary Thyroid Carcinoma

To emphasize the potential association between increased levels of carcinoembryonic antigen (CEA) and the presence of medullary thyroid carcinoma (MTC). We present two case reports of this association, including long-term serial measurements of CEA in one patient. CEA is a tumor marker often associated with colon cancer. In recent years, increased CEA in plasma has been reported in patients with other cancers. Diagnoses of MTC in two patients were preceded by increased CEA levels (for 6 years in one patient). Because CEA levels returned to normal after thyroidectomy, MTC may have been the cause of the increases. In patients with increased plasma CEA levels, MTC should be considered in the differential diagnosis even if thyroid palpation is nonrevealing and thyroid function is normal.

Anti-carcinoembryonic antigen antibodies versus somatostatin analogs in the detection of metastatic medullary thyroid carcinoma

BACKGROUND Surgery is currently the only potentially curative approach in the treatment of medullary thyroid carcinoma (MTC). In many instances however, postsurgically elevated or rising plasma calcitonin and/or carcinoembryonic antigen (CEA) levels indicate persistent metastatic disease, although conventional diagnostic procedures (computed tomography (CT), magnetic resonance imaging (MRI), and invasive venous catheterization) fail to localize the responsible lesions. Recently, anti-CEA antibodies and somatostatin analogs have shown promising results in the staging of MTC. The aim of this study was to compare the sensitivity of both methodologies, especially for the detection of occult MTC, and to assess whether there may be correlations between the scintigraphic behavior and the patients' prognosis. METHODS A total of 26 patients with medullary thyroid carcinoma were examined at our institution between 1977 and 1996. Ten of them had known disease, 14 had occult metastatic MTC, and 2 were free of disease at the time of presentation. Fourteen patients were investigated with anti-CEA monoclonal antibodies (MAbs) (receiving a total of 35 injections: clones BW431/26, BW431/31, IMACIS, or F023C5, labeled with 99mTc, 111In or 131I), and 8 patients were studied with 111In-labeled octreotide. Two patients received potentially therapeutic doses of 131I-labeled anti-CEA antibodies. All patients underwent conventional radiologic evaluation (ultrasonography, CT, and MRI) and/or biopsy within 4 weeks. Additional imaging was performed with 99mTc-(V)-DMSA, 123I-metaiodobenzylguanidine, 201thallium chloride, 99mTc-methylene diphosphate, and/or 18F-fluorodeoxyglucose-positron emission tomography. Clinical follow-up was obtained. RESULTS All patients with established disease had elevated plasma CEA (range, 6.8-345 ng/mL; calcitonin levels between 92 and 11497 pg/mL), whereas in 9 of 14 occult cases, levels were ≤5 ng/mL (range, 0.6-829 ng/mL; calcitonin, 72-2920 pg/mL). In patients with known disease, the overall lesion-based sensitivity was 86% for the anti-CEA MAbs, whereas octreotide was unable to target any tumor in patients with rapidly progressing disease or distant metastases (overall sensitivity, 47%). In all patients with occult MTC, anti-CEA MAbs and octreotide were able to localize at least one lesion (patient-based sensitivity, virtually 100%). In patients with postsurgically persistent hypercalcitoninemia, cervical lymph nodes were identified as the most frequent site of metastases, whereas in patients with occult and slowly progressing disease several years after primary surgery, anti-CEA MAbs and octreotide showed bilateral involvement of mediastinal lymph nodes; however, tumor to nontumor ratios were usually higher with octreotide in these cases. With anti-CEA Mabs, the highest tumor to nontumor ratios were observed in clinically aggressive, rapidly progressing disease. The sensitivity of all other diagnostic modalities was, at ≤50%, significantly lower. Indication for antitumor effects was observed in a patient receiving 65 mCi of 131I-labeled F(ab')2 fragments of the clone F023C5. CONCLUSIONS. For the detection of occult MTC, anti-CEA MAbs and octreotide seem to have a sensitivity that is superior to conventional diagnostic modalities, especially also when used in combination. Better detectability with anti-CEA antibodies (which may result in higher CEA expression) seems to be associated with more aggressively growing forms of MTC, whereas somatostatin receptor expression at normal CEA plasma levels and weaker MAb targeting may be associated with a more benign clinical course. This is in accordance with the study of Busnardo et al. (Cancer 1984;53:278-85), who showed higher CEA serum levels to be associated with a worse prognosis, as well as with the in vitro findings of Reubi et al. (Lab Invest 1991;64:567-73), who demonstrated lower somatostatin receptor expression in less differentiated MTC. Further studies on a larger patient population are warranted to confirm these observations. Cancer 1997; 80:2436-57. © 1997 American Cancer Society.

Prospects of Radioimmunotherapy in Epithelial Ovarian Cancer: Results with Iodine-131-Labeled Murine and Humanized MN-14 Anti-carcinoembryonic Antigen Monoclonal Antibodies

Objectives.Epithelial ovarian cancer (EOC) is known to produce carcinoembryonic antigen (CEA), and the plasma CEA level is frequently elevated in patients with advanced stage and bulk of tumor. This study reports the results of a phase I therapy trial with intravenously administered 131I-MN-14 anti-CEA monoclonal antibody (MAb) in patients with EOC. Methods.Fourteen patients with advanced refractory EOC were given escalating intravenous doses (two received 30 mCi/m 2, six 40 mCi/m 2, and six 50 mCi/m 2) of 131I-MN-14 IgG. All patients received a diagnostic study with 8 mCi (0.6 mg) of 131I-MN-14 IgG 1 week prior to their therapy infusion. Tumor targeting was assessed by external scintigraphy, toxicity according to the Radiation Therapy Oncology Group criteria, and therapy responses by CT and serum CA-125. Results.The MAb scan was positive in all 14 treated patients. Myelosuppression was the only observed treatment-related toxicity. Dose-limiting toxicity, defined as grade 4 leukopenia or thrombocytopenia of any duration, or grade 3 leukopenia or thrombocytopenia of >2 weeks, was not seen at the 30 or 40 mCi/m 2dose levels. However, 2 of 6 patients treated at 50 mCi/m 2had a grade 4 thrombocytopenia or a grade 3 thrombocytopenia lasting 18 days. Of the 14 patients, 1 with diffuse peritoneal implants of ≤2 cm had a complete clinical remission by CT and CA-125 for 8 months, following an initial partial remission for 10 months, both at the 40 mCi/m 2dose level. Another patient had a mixed response for 1 month. Conclusion.MN-14 anti-CEA MAb is a suitable agent for tumor targeting and may have a therapeutic potential in patients with chemotherapy-refractive EOC, especially those with minimal disease.

Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes ("chimney sign") in occult metastatic medullary thyroid cancer: a typical site of tumour manifestation?

In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 pentetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the "chimney sign" may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis.

Association between preoperative plasma CEA levels and the prognosis of gastric cancer following curative resection

A large-scale retrospective study was undertaken to evaluate the association between preoperative plasma carcinoembryonic antigen (CEA) levels and the prognosis of 2768 gastric cancer patients who underwent curative gastrectomy between 1983 and 1984 at 66 leading medical institutions in Japan Postoperative follow-up was at least 5 years. Preoperative plasma CEA levels were also analysed against other prognostic factors. Preoperative plasma CEA levels showed strong correlations to the degree of lymph node metastasis (P < 0.001), TNM stage (P = 0.004) and the histopathology of the gastric cancer (P < 0.001). Preoperative CEA levels were also evaluated against survival, after being adjusted for the effect of clinically important factors by multivariate analysis. Patients with lower preoperative plasma CEA levels survived significantly longer than patients with higher CEA levels (P = 0.0001). This analysis demonstrates that curatively resected gastric cancer patients with higher preoperative plasma CEA levels have a poorer prognosis than those with lower levels, despite the adjustment for the effects of major prognostic factors.

Resected case of carcinoid tumor of the liver metastatic from the breast

Carcinoid tumor metastatic to the liver from the breast is very unusual. We report a rare case in which the patient underwent curative resection for metastatic lesions to the liver. She had undergone a modified radical mastectomy more than 1 year previously for breast cancer. Recently, it was found that plasma levels of carcinoembryonic antigen (CEA) was elevated, and abdominal ultrasonography detected a liver tumor. The patient underwent a lateral segmentectomy of the liver, resulting in normalization of plasma CEA levels. The resected specimen was diagnosed as carcinoid tumor by histological, immunohistochemical, and ultrastructural microscopic studies. Re-examination of the breast tumor proved it to be the primary carcinoid.

The effect of transfection of the CEA gene on the metastatic behavior of the human colorectal cancer cell line MIP-101.

Carcinoembryonic antigen (CEA) has been shown to increase the metastatic potential of some human colorectal cancer cell lines. To investigate further the mechanisms involved we have produced three clones (6, 8 and 17) from the poorly differentiated human colorectal cancer cell line MIP-101 that have been transfected with the full length cDNA encoding for human carcinoembryonic antigen (CEA). They produce CEA with a mol. wt. of 180000 by Western blotting and secrete it into the culture medium. Clone 6 is a high CEA producer, clones 8 and 17 are intermediate producers. The doubling time for clone 8 was similar to that of the parent cell line while clones 6 and 17 had doubling times nearly twice that of the parent cells. These clones are tumorigenic when injected subcutaneously in nude mice are positive for CEA by immunoperoxidase staining and the mice have elevated blood levels of CEA. Clone 6 formed large aggregates in culture while clone 17 formed smaller aggregates. Clone 8 behaved like the parent cell line with rare cell/cell contact. Clones 6 and 17 also adhered to CEA coated plastic while clone 8, a neo-transfected control and the parent cell line did not. A significant increase in the incidence of hepatic tumors was observed with clone 6 (P < 0.01) and clone 17 (P < 0.02) following intrasplenic injection into nude mice. Immunohistopathology of the hepatic tumors showed strong CEA staining from clones 6 and 17 with weak staining from clone 8. The parent cell line was negative for CEA as were the neo-transfected controls. Of the neo controls none of 10 had liver colonies. Mice injected with clone 6 which developed liver metastasis had the highest plasma levels of CEA (37.3 +/- 8.8 ng/ml). We observed strong CEA staining in Kupffer cells in the normal liver adjacent to the CEA producing tumors. This study provides further evidence for the involvement of CEA in the metastatic process.

Cea tissue staining in colorectal cancer patients - correlation with plasma cea, histology and staging

To study the expression of tissue carcinoembryonic antigen (CEA) by immunoperoxidase staining in colorectal adenocarcinomas and its relation with preoperative serum CEA and clinicopathological parameters, we studied 85 unselected patients who underwent resective surgery for colorectal adenocarcinomas and were followed up for a mean of 66 mths. All tumors except 2 showed positive staining for CEA. The staining pattern was classifiable into 4 types: apical, cytoplasmic, basolateral and stromal, according to the predominant sites of staining. We found a significant positive correlation between tissue CEA staining pattern and preoperative plasma CEA. Plasma CEA levels were higher when tumor cell staining extended to basolateral regions of the cells and into stromal tissues rather than restricted to apical and cytoplasmic regions (p = 0.012). Furthermore, tissue CEA staining also correlated positively with vascular invasion by tumor cells (p = 0.046), with basolateral and stromal types associated with more frequent vascular invasion than apical and cytoplasmic types. This was in contrast to the preoperative CEA which did not correlate with vascular permeation. We speculate that tissue CEA staining is useful in indicating possible vascular invasion even at early stage whereas vascular invasion by a larger tumor bulk or even tumor metastases may be necessary to produce an increased plasma CEA level that is detectable. On the other hand, preoperative plasma CEA had a strong, positive relationship with tumor stage and mortality (p < 0.001 for both). Preoperative CEA was higher in tumors showing moderate and poor differentiation, although it did not reach statistical significance (p = 0.068), whereas tissue CEA staining had no correlation with tumor differention.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukocyte alkaline phosphatase and carcinoembryonic antigen in lung cancer patients.

Leukocyte alkaline phosphatase (LAP) scores in peripheral blood and plasma carcinoembryonic antigen (CEA) levels were determined in 58 lung cancer patients and compared with those of 22 healthy persons, who served as controls. In the control group we found LAP scores of 54 +/- 28 and CEA levels of 4 +/- 3 ng/ml. The 97.7% confidence intervals are: LAP score < 110 and CEA level < 10. In the patients with limited lung cancer we found LAP scores of 152.4 +/- 36.7 and CEA levels of 22.7 +/- 48 ng/ml. The 97.7% confidence intervals are: LAP score > 78.6 and CEA level > 0. In the patients with extensive lung cancer we found LAP scores of 272 +/- 49 and CEA levels of 47.5 +/- 80.4 ng/ml. The 97.7% confidence intervals are: LAP score > 174 and CEA level > 0. The sensitivity of each marker is discussed, here as percent of false-negative results, denoted PFN, and meaning that with a chosen threshold for the marker level, only PFN% of the patients with a given condition (e.g. extensive lung cancer) might have a marker level less than the chosen threshold and could therefore be assumed healthy. The sensitivity of the LAP score is 0.05% PFN for the group of patients with extensive lung cancer, and we conclude that indeed LAP score < 110 indicates a very low probability of having extensive malignancy. The sensitivity of the CEA level is 32% PFN. The sensitivity of the LAP score to limited lung cancer is 12% PFN for the group of patients with that condition compared with 40% of CEA. The specificities of both LAP score and CEA levels, expressed as percent of false-positive results in the control group, are fair (2.3%), provided that the common conditions, other than cancer, that elevate LAP score and/or CEA levels are well known and can be eliminated by the physician. It is concluded that the LAP score is considerably more useful than the CEA level as a marker for extensive lung cancer.

Colorectal cancer. Principles of postoperative follow-up.

Monitoring patients after primary large bowel surgery for malignancy is predicated on the concept that early detection of recurrence may provide salvage treatment for cure. Knowledge of the pathologic site and stage provides important information as to the probability of recurrence and the patterns of failure that are likely to occur. Available methods to detect recurrence include clinical, roentgenographic, and serum tests that are done more frequently during the first 2 years after surgery. Monitoring plasma carcinoembryonic antigen levels can lead to identification of asymptomatic recurrences, but there is controversy about the curability of recurrences outside the liver. Newer techniques (such as computed tomographic portography, intraoperative ultrasonography, and radioimmunoguided surgery) provide greater diagnostic accuracy and lead to more appropriate procedures during "second-look" operations. For example, hepatic resection in properly selected patients offers up to a 30% chance of cure and should be pursued aggressively. A search for metachronous cancers by endoscopy also should be done. Knowledge of the potential and patterns of failure can provide a useful guide during the postoperative follow-up care of the patient with large bowel cancer.