Classification of human colorectal adenocarcinoma cell lines. (1/2094)

Eleven human colorectal adenocarcinoma cell lines established in this laboratory were classified into three groups based on morphological features (light and electron microscopy), modal chromosome number, and ability to synthesize carcinoembryonic antigen (CEA). Group 1 cell lines contained both dedifferentiated and differentiating cells growing in tight clusters or islands of epithelium-like cells; their modal chromosome number was about 47, and they synthesized small to moderate amounts of CEA. Group 2 cell lines were more dedifferentiated, were hyperdiploid, and synthesized small amounts of CEA. Group 3 cell lines were morphologically similar to those of Group 1 by light microscopy. They differed ultrastructurally by containing microvesicular bodies; the modal chromosome number varied from hyperdiploid to hypertriploid or they had bimodal populations of hypodiploid and hypertriploid cells, and they synthesized relatively large amounts of CEA. No correlation could be found between Broder's grade or Duke's classification of the original tumor and modal chromosome number or ability to synthesize CEA. These findings support Nowell's hypothesis that the stem line is different for each solid tumor, which makes it difficult to relate chromosomal changes to the initiation of the neoplastic state.  (+info)

Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen. (2/2094)

Marimastat is a specific inhibitor of matrix metalloproteinases that has been shown to be effective in cancer models. A pilot, escalating-dose study of oral marimastat was performed in patients with recurrent colorectal cancer, in whom evaluation of serological response was made by measurement of carcinoembryonic antigen (CEA) levels. The study assessed the safety and tolerability of 4 weeks administration of marimastat, and determined a dose range producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered into a continuation protocol if a serological response or clinical benefit was observed. Pharmacokinetic and safety data determined that groups of patients were recruited sequentially at 25 mg and 50 mg twice daily, and, thereafter, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no greater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients recruited, 63 completed the 28-day treatment period, and 55 were eligible for cancer antigen analysis. Examination of the dose-effect relationships provides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice daily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 37%) (P = 0.043, chi2 test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patients receiving twice daily marimastat (P<0.0001), but not for patients receiving marimastat once daily (P = 0.25). Musculoskeletal adverse events emerged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. It was concluded that marimastat was associated with dose-dependent biological effects in cancer patients. The occurrence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points and describe the long-term tolerability of this novel agent.  (+info)

Detection of occult lymph node metastases in esophageal cancer by minimally invasive staging combined with molecular diagnostic techniques. (3/2094)

BACKGROUND AND OBJECTIVES: Lymph node metastases are the most important prognostic factor in patients with esophageal cancer. Histologic examination misses micrometastases in up to 20% of lymph nodes evaluated. In addition, non-invasive imaging modalities are not sensitive enough to detect small lymph nodes metastases. The objective of this study was to investigate the use of reverse transcriptase-polymerase chain reaction (RT-PCR) of messenger RNA (mRNA) for carcinoembryonic antigen (CEA) to increase the detection of micrometastases in lymph nodes from patients with esophageal cancer. METHODS: RT-PCR of CEA mRNA was performed in lymph nodes from patients with malignant and benign esophageal disease. Each specimen was examined histopathologically and by RT-PCR and the results were compared. RESULTS: Metastases were present in 29 of 60 (48%) lymph nodes sample by minimally invasive staging from 13 patients with esophageal cancer when examined histopathologically. RT-PCR identified nodal metastases in 46 of these 60 (77%) samples. RT-PCR detected CEA mRNA in all 29 histologically positive samples and in 17 histologically negative lymph nodes. All lymph nodes from patients with benign disease (n = 15) were negative both histopathologically and by RT-PCR. The stage of two patients was reclassified based on the RT-PCR results, which identified lymph node spread undetected histopathologically. Both of these patients developed recurrent disease after resection of the primary tumor. CONCLUSIONS: RT-PCR is more sensitive than histologic examination in the detection of lymph node metastases in esophageal cancer and can lead to diagnosis of a more advanced stage in some patients. The combination of minimally invasive surgical techniques in combination with new molecular diagnostic techniques may improve our ability to stage cancer patients.  (+info)

The role of tumour markers in predicting skeletal metastases in breast cancer patients with equivocal bone scintigraphy. (4/2094)

Bone scintigraphy (BS) is commonly performed in the staging and postoperative monitoring of breast cancer. Nevertheless, due to low specificity it often demonstrates hot spots with equivocal interpretation, which may be misleading in the management of these patients. The aim of this study was to assess the value of a serum tumour marker panel in selecting among the patients with equivocal BS those with bone metastases. Between January 1986 and December 1995, 297 breast cancer patients were followed-up after mastectomy with serial determinations of a CEA-TPA-CA15.3 tumour marker panel, BS and liver echography. The tumour marker panel was used to select patients with equivocal BS for examination of suspicious bone areas by further imaging techniques. Up to December 1995, 158 (53%) patients showed an equivocal BS and 47 patients developed bone metastases. In the 158 patients with equivocal BS, prolonged clinical and imaging follow-up over 45 months (mean; range 12-120) was used to ascertain the presence or absence of bone metastases. In these 158 patients the negative predictive value and positive predictive value of the tumour marker panel to predict bone metastases was 97% and 75% respectively. This study shows that in breast cancer patients the CEA-TPA-CA15.3 tumour marker panel has a high value in selecting those patients with bone metastases, or at high risk of developing clinically-evident bone metastases, among the large number of subjects with equivocal BS.  (+info)

Serum YKL-40 and colorectal cancer. (5/2094)

YKL-40 is a mammalian member of the chitinase protein family. Although the function of YKL-40 is unknown, the pattern of its expression suggests a function in remodelling or degradation of extracellular matrix. High serum YKL-40 has been found in patients with recurrent breast cancer and has been related to short survival. In the present study we analysed YKL-40 in preoperative sera from patients with colorectal cancer and evaluated its relation to survival. Serum YKL-40 was determined by RIA in 603 patients. Survival after operation was registered, and median follow-up time was 61 months. Three hundred and forty patients died. Sixteen per cent of the patients with Dukes' A, 26% with Dukes' B, 19% with Dukes' C and 39% with Dukes' D had high serum YKL-40 levels (adjusted for age). Analysis of serum YKL-40 as a continuous variable showed an association between increased serum YKL-40 and short survival (P < 0.0001). Patients with high preoperative serum YKL-40 concentration had significantly shorter survival than patients with normal YKL-40 (HR = 1.7; 95% CI: 1.3-2.1, P < 0.0001). Multivariate Cox analysis including serum YKL-40, serum CEA, Dukes' stage, age and gender showed that high YKL-40 was an independent prognostic variable for short survival (HR = 1.4; 95% CI: 1.1-1.8, P = 0.007). These results suggest that YKL-40 may play an important role in tumour invasion.  (+info)

Intratumoral distribution of radiolabeled antibody and radioimmunotherapy in experimental liver metastases model of nude mouse. (6/2094)

The biodistribution and intratumoral distribution of radiolabeled anticarcinoembryonic antigen (CEA) monoclonal antibody in experimental liver metastases and the therapeutic effect of 131I-labeled anti-CEA antibody on the metastases were studied. METHODS: Three weeks after an intrasplenic injection of human colon cancer cells, mice received an intravenous injection of 125I- or 111In-labeled anti-CEA antibody F33-104. The biodistribution and tumor penetration of radiolabeled antibody were examined by using quantitative autoradiography. To evaluate the therapeutic effect, 5.55, 9.25 or 11.1 MBq (150, 250 or 300 microCi) 131I-labeled F33-104 were injected into groups of mice that had micrometastases smaller than 1 mm. Control groups were injected with phosphate-buffered saline or 131I-labeled control antibody. Mice were killed 3 wk later to determine the size of liver metastases. RESULTS: 1251-labeled F33-104 showed a high accumulation in the liver metastases (percentage of injected dose per gram of metastases [%ID/g] >24%, metastasis-to-liver ratio >9.8, metastasis-to-blood ratio >2.1); however, its accumulation was heterogeneous or peripheral in the nodules more than 1 mm in diameter. When the antibody dose was increased, antibody penetration was improved, but tumor uptake of radioactivity and specificity ratios decreased. In mice with large metastases, radioactivity in the normal tissue was lower than that in mice with small metastases, resulting in higher metastasis-to-background ratios. 111In-labeled antibody showed even higher tumor uptake than 125I-labeled antibody (>51 %ID/g). Metastases formation was suppressed in a dose-dependent manner by 131I-labeled F33-104 injection (5 of 8 mice had no macroscopic tumor after an injection of 5.55 MBq (150 microCi), and all mice had no visible metastasis after an injection of 9.25 or 11.1 MBq [250 or 300 microCi]), whereas tumor progression was seen in the control groups. CONCLUSION: Liver metastases had easy accessibility to the antibody. Micrometastases of less than 0.5 mm in diameter showed homogeneous intratumoral distribution of injected antibody and were successfully treated with 131I-labeled antibody. Very high uptake and satisfactory metastasis-to-liver ratios with 111In-labeled antibody suggest that the use of a radiometal with high beta-energy, such as 90Y or 188Re, is preferable for the successful radioimmunotherapy of metastases larger than 1 mm.  (+info)

Gastroenteropancreatic neuroendocrine tumor metastases to the thyroid gland: differential diagnosis with medullary thyroid carcinoma. (7/2094)

Neuroendocrine tumors (NET) of the thyroid gland are rare. Apart from medullary thyroid carcinoma (MTC), metastases of gastroenteropancreatic (GEP) NET may also occur. Features of six patients (five men, one female: age range, 39-67 years) with thyroid metastases from a GEP-NET are described. Thyroid metastases were bilateral in all patients and were associated with enlarged neck lymph nodes in five. In four cases, the thyroid tumor was either the first sign of the disease (n = 2) or was an isolated site of recurrence (n = 2). The tumors were well (n = 3) or poorly differentiated (n = 3). Five tumors for which the primary site could be determined corresponded to foregut-derived tumors (3 lungs, 1 thymus and 1 pancreatic NET). One tumor demonstrated calcitonin (CT) production as shown by immunohistochemistry and elevated plasma CT levels. However, the disease history and the clinical features strongly favored a metastasizing GEP-NET. No tumoral RET proto-oncogene mutation was found in this patient. The differential diagnosis between metastatic GEP-NET and MTC is crucial because prognosis, work-up, and treatment differ greatly.  (+info)

Roles of circulating carcinoembryonic antigen and calcitonin in diagnosis of medullary thyroid carcinoma: a comparative study. (8/2094)

Carcinoembryonic antigen (CEA) and calcitonin (CT) were simultaneously determined in sera and tumor tissues from 15 patients with medullary carcinoma of the thyroid (MCT). Serum CEA was increased in all but one patient, and CT did in all of them. Both levels were significantly related to the weight of excised tumor, but not to the presence of metastasis. Furthermore, a significant correlation was noted between the basal levels of CT and CEA. Both levels fell to normal after a radical operation had been performed. Tissue concentrations of CEA and CT in the MCT were more than 100 times those in hyperthyroidism, and the ratios of tissue over serum levels averaged 770 in CEA and 1000 in CT. In the calcium infusion test, CEA levels were not significantly changed in contrast with a distinct increase in CT levels. The results indicate that CEA and CT represent separate activities of the tumor cells, and that circulating CEA together with CT is a useful indicator in the diagnosis and follow-up of the disease.  (+info)