Serum fragment of cytokeratin subunit 19 measured by CYFRA 21-1 immunoradiometric assay as a marker of lung cancer.

Cytokeratin 19 is a subunit of cytokeratin intermediate filament expressed in simple epithelia and their malignant counterparts. Therefore, it is expressed by respiratory epithelium cells and has been detected in lung cancer specimens. An immunoradiometric assay was used to detect a fragment of the cytokeratin 19, referred to as CYFRA 21-1, in the serum of 165 patients with histologically proved lung cancer (128 non-small cell and 37 small cell lung cancers). This prospective study was conducted to evaluate the reliability of this immunoradiometric assay and to identify the relationship between serum CYFRA 21-1 and different features of lung cancer including prognosis. The minimal detectable concentration detected by this assay was 0.06 ng/ml. The reliability of the immunoradiometric assay was demonstrated by the linear relationship between CYFRA 21-1 measurement and dilution of the serum, the reproducibility of the dosage in intraassay and interassay, and the high sensitivity of the method in discriminating low CYFRA 21-1 concentrations. Using a threshold of 3.6 ng/ml, sensitivity and specificity were 0.52 and 0.87, respectively. The sensitivity of the marker was highest in squamous cell carcinoma and lowest in small cell carcinoma. In non-small cell lung cancer patients, the marker varied significantly according to both stage of the disease (Kruskal-Wallis, 13.7; P < 0.005) and performance status (Kruskal-Wallis, 9.16; P < 0.05) inasmuch as a high serum CYFRA 21-1 level was associated with advanced stages, mediastinal lymph nodes, and poor performance status. Consequently, the marker was significantly lower in patients who were operated upon when compared with unresectable ones. Lung cancer patients with serum CYFRA 21-1 over 3.6 ng/ml proved to have a significantly shorter overall survival than those with a normal serum level (log rank, P = 0.007; Wilcoxon, P = 0.001). The negative prognostic effect of CYFRA 21-1 was highly significant in squamous cell carcinomas whereas it was nonsignificant for the other histologies. In Cox's model analysis, performance status, stage grouping, and CYFRA 21-1 were the only significant determinants of survival. This study supports the use of the serum fragment of cytokeratin subunit 19 CYFRA 21-1 as an independent prognostic marker of squamous cell carcinoma of the lung.

Thymidine kinase as a proliferative marker: clinical relevance in 1,692 primary breast cancer patients.

PURPOSE: To assess the prognostic value of thymidine kinase (TK), an enzyme involved in the DNA synthesis salvage pathway, relative to other prognostic factors in primary breast cancer. PATIENTS AND METHODS: This retrospective study involved 1,692 patients with operable breast cancer treated in six institutions (median follow-up, 82 months). Among the 857 node-negative patients, 135 received adjuvant chemotherapy (fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, etoposide, and cisplatin [FEC]). TK was assayed in cytosol with a quantitative radioenzymatic technique. Disease-specific survival (DSS), local recurrence-free interval (LRI), and distant-relapse-free interval (DRI) were investigated. RESULTS: High TK levels were associated with large tumor size, high histologic grade, and steroid hormone receptor negativity. Univariate analysis of the entire data set showed that high TK levels were related to shorter DSS (P < 10(-5)), LRI (P < 10(-3)), and DRI (P < 10(-5)). In time-dependent Cox models, high TK levels remained an independent predictor of the three outcomes, both in the overall population and in node-negative patients, although its prognostic value decreased over time. In node-negative patients, the introduction of an interaction term in multivariate analysis suggested that chemotherapy was more efficacious for patients who had tumors with high TK contents. In node-positive patients, high TK levels were related only to an increased risk of LRI. CONCLUSION: High TK values are an important risk factor in node-negative patients and seem to be associated with a beneficial effect of adjuvant FAC or FEC in patients who received adjuvant chemotherapy. The rationale of chemotherapy for patients with slowly proliferating tumors has to be discussed from a risk-benefit point of view.

Quantitative analysis of BRCA1, BRCA2 and Hmsh2 mRNA expression in colorectal Lieberkühnien adenocarcinomas and matched normal mucosa: relationship with cellular proliferation.

The human DNA mismatch repair gene hMSH2 is involved in the development of sporadic and hereditary nonpolyposis colorectal cancer. An increased risk of colorectal cancer has also been suggested in BRCA1 and BRCA2 mutation carriers. To address the relationship between the expression level of these genes and colorectal tumorigenesis, we studied BRCA1, BRCA2 and hMSH2 mRNA expression by real-time quantitative RT-PCR in 72 colorectal Lieberkühnien adenocarcinomas and matched normal mucosa. We investigated the relationship between mRNA levels and various clinicopathological parameters. The mean expression of BRCA1 3' and BRCA2 3' (mRNA pool), BRCA1 ex11 (with exon 11), BRCA2 ex12 (with exon 12) and hMSH2 mRNAs were increased in tumor samples. BRCA1 and BRCA2 mRNAs expressions were altered according to colon tumor site: BRCA1 3' and BRCA2 3' mRNAs levels were highest, respectively, in the right colon and left colon. No difference in hMSH2 mRNA levels was detected in relation to clinicopathological parameters. The mean SPF value was significantly higher in tumor than in non-tumor colonic tissue, and a high SPF value was correlated with high BRCA2 mRNA levels. BRCA2 3' mRNA levels tended to decrease as the Dukes' stage increased. In conclusion, the mechanisms of colorectal carcinogenesis seem to differ according to the right or left position of the tumor.

Plasma sialic acid as a marker of the effect of the treatment on metastatic colorectal cancer.

The concentration of total sialic acid (TSA) is increased in the plasma of patients with many types of cancer. The purpose of this study was to assess the usefulness of the TSA marker in predicting the efficacy of the treatment, and to compare TSA with two common markers, carcinoembryonic antigen (CEA) and the carbohydrate antigen 19-9 (CA 19-9). The study was performed on 44 patients treated for advanced colorectal carcinoma by a weekly 8 h continuous infusion of 5-fluorouracil (1300 mg/m2) plus bolus injection of L-folinic acid (100 mg/m2). TSA, CEA and CA 19-9 levels were measured before and after 3 months of treatment and their variations analysed as a function of the response to the treatment. TSA levels of patients with metastatic colorectal carcinoma before treatment (959 +/- 265 mg/l) were significantly higher than those of 32 healthy people (584 +/- 99 mg/l). The percentage of patients with TSA concentration above the cut-off level (782 mg/l) was 73% before treatment and 23% after. All patients who experienced an objective response to the treatment (complete, partial or minor response) (n = 29) had a significant decrease of TSA levels (t = 5.96; P < 0.001). When the disease was considered as stabilised (n = 10), TSA changed slightly, but it increased with progressive disease (4 out of 5 patients). Changes in CEA and CA 19-9 did not correlate as well as TSA to the treatment efficacy. Initial levels of TSA did not permit prediction of the efficacy of the treatment since they were not significantly different between the five response groups. TSA seems to be more likely involved in tumour changes than in tumour volume. Its determination could provide useful information about the spreading and metastatic properties of the tumour. TSA normalisation is an indicator of probable tumour growth arrest and its elevation could be a marker of relapse.

Quantitative determination of c-erbB-2 in human breast tumours: potential prognostic significance of low values.

The purpose of this prospective multicentric study was to quantify the c-erbB-2 protein and investigate its relationship with DNA amplification and with various prognostic parameters of breast cancer. A total of 1062 primary operable human breast tumours were collected from six French anticancer centres. The c-erbB-2 protein was measured using an enzymoimmunoassay using two monoclonal antibodies directed against the extracellular domain of the protein. The results were expressed in arbitrary units/mg membrane protein (AU) after adjustment for the anticancer centre. A significant association was found between the dosage of the protein and DNA amplification (P = 0.0001). A value of 200 AU was found to maximise sensibility and specificity and was chosen as a cut-off for over-expression. Significant associations were found between c-erbB-2 values and oestrogen receptor (ER) (P = 0.01), progesterone receptor (PgR) (P = 0.0001) and histological grading (P = 0.01). The extreme high values (above the mean plus one standard deviation, S.D.) were significantly more numerous in ER- (P = 10(-16)), PgR- (P = 10(-14)) and grade III (P = 10(-8)) tumours. The extreme low values (below the mean minus one S.D.) were significantly more numerous in ER- (P = 10(-9)) and PgR- (P = 0.02) tumours. This prospective study confirms that high c-erbB-2 protein values are linked to poor prognostic factors and shows for the first time that low values are also linked to hormone receptor negative tumours, suggesting that these low values might also have a negative prognostic significance.

Influence of scanning doses of iodine-131 on subsequent first ablative treatment outcome in patients operated on for differentiated thyroid carcinoma.

UNLABELLED: The therapeutic outcome after (131)I first ablative treatment in patients operated on for nonmedullary differentiated thyroid carcinoma was compared after both the currently used scanning dose of 111 MBq (131)I and a scanning dose of 37 MBq (131)I. METHODS: Two-hundred twenty-nine consecutive patients with no known metastases were retrospectively studied. They were divided in two populations according to the scanning dose (127 patients with 111 MBq and 102 patients with 37 MBq). All patients received 111 or 37 MBq (131)I for diagnostic purposes and 3.7 GBq (131)I for ablative therapy 9 days later. To assess the efficacy of the treatment, all patients were studied with (131)I and with thyroglobulin plasma assays 6-17 mo later. RESULTS: Successful outcome was significantly more frequent after a scanning dose of 37 MBq (131)I than after a scanning dose of 111 MBq (76% versus 50%, p < 0.001). The treatment efficacy was particularly enhanced after 37 MBq in patients with associated lymphocytic thyroiditis. CONCLUSION: In patients with no known metastases, our data suggest that the impairment of the treatment efficacy observed after a scanning dose of 111 MBq (131)I is related to a stunning effect on the thyroid remnants. The threshold amount above which this effect begins to occur in thyroid remnants could be between 37 and 111 MBq (131)I. Consequently, a scanning dose of only 37 MBq (131)I could be recommended before first ablative treatment. The absence of metastatic patients in our study prevents any conclusion about the possible stunning of the neoplastic tissue. Nevertheless, we must suspect such an effect and try to avoid it, especially during follow-up after first radioiodine therapy. For instance, one may consider postponing radioiodine treatment several weeks or even months after scanning dose administration or using only thyroglobulin measurement for patients who are likely to receive a subsequent radioiodine treatment.

Predicting the efficacy of first iodine-131 treatment in differentiated thyroid carcinoma.

UNLABELLED: The purpose of this study was to search for predictors of (131)I first ablative treatment efficacy in patients with postsurgical remnants after total thyroidectomy for nonmedullary differentiated thyroid carcinoma with no known metastasis. METHODS: Thirty-seven patients were retrospectively studied. None presented antithyroglobulin antibodies. All patients received 111 MBq of (131)I for diagnostic purpose and, 9 days later, 3.7 GBq of (131)I for ablative therapy (IAT). To assess the efficacy of treatment, all patients were studied with (131)I and with thyroglobulin (Tg) plasma assays 6-15 mo later. Treatment was considered successful if no abnormal uptake was seen on whole-body scan and if the Tg plasma level was lower than 1 ng/ml. RESULTS: Ablative treatment was found to be successful in 17 patients [IAT(+)] and unsuccessful in 20 [IAT(-)]. There was no significant difference between the two groups for clinical and histological data, size of thyroid remnants on a 1:1 dot scan and TSH level just before treatment. Although Tg levels were not different in the two groups before scanning dose administration (D0), Tg levels were higher in IAT(-) group 9 days later, just before radioiodine treatment administration (D9) and, in contrast, Tg levels were higher in the IAT(+) group 5 days after treatment administration (D14). Tg percentage change between D9 and D14 was significantly higher in the IAT(+) group and, with an optimal cutoff value of 750%, this parameter would have been able to predict successful treatment in 9 of 10 cases and unsuccessful treatment in 18 of 21 cases. Conversely, Tg percentage change between D0 and D9 was significantly higher in the IAT(-) group and of 11 patients with more than 100% change, 10 belonged to this group. CONCLUSION: The increase in Tg during the first (131)I ablative treatment could be a good predictor of treatment efficacy for patients with nonmetastatic differentiated thyroid carcinoma. Conversely, the increase in Tg observed after the administration of the scanning dose of (131)I just before ablative therapy is associated with a more frequent incomplete ablation, perhaps reflecting a stunning effect on the thyroid remnants.

Evaluation of the automated fluorescent analysis of the H-ras minisatellite after optimized PCR amplification in comparison with a standardized Southern blot technique.

Determination of allele sizes? loss of heterozygosity or genetic instability at minisatellite VNTR loci, are routinely performed by the conventional Southern technique. We have investigated the potential use of automated DNA sequencer for the analysis of the H-ras minisatellite. We report the modifications of amplification parameters and electrophoresis conditions on the sequencer. Seventy-one colorectal carcinomas and the corresponding normal tissues were amplified with fluorescent-labeled primers, analyzed on sequencer, and concurrently controlled by Southern blotting. The results on sequencer showed that a Hydrolink matrix used in non-denaturing conditions and a specific analysis software facilitate a more accurate fragment size calculation.

Allelic imbalance at NBS1 is frequent in both proximal and distal colorectal carcinoma.

Nijmegen breakage syndrome (NBS) is a hereditary disorder involving chromosomal instability, cancer risk and radiosensitivity. NBS carriers have an increased risk of cancer, though the significance of mutations in the NBS1 gene in sporadic cancer has not yet been investigated. Because the loss of NBS1 is associated with increased chromosomal re-arrangements, and tumors of the colon are particularly prone to chromosomal anomalies, we have begun to study the NBS1 locus in colorectal cancer (CRC). DNA was isolated from 99 microdissected colorectal tumors, and microsatellite markers flanking the NBS1 locus at 8q21.3 as well as elsewhere on 8q were analyzed. Normal lymphocyte DNA from each patient served to normalize the amplification of each allele, and a reduction of at least 35% in the intensity of one allele was taken as evidence of allelic imbalance (AI). In proximal and distal CRCs we found 25.9 and 36.2% with AI at 8q21.3, respectively. AI in proximal CRC tended not to extend to marker D8S555 at 8q24.1, whereas in distal CRC the region of AI frequently included all the informative markers. AI of 8q21.3 was not associated with any clinical variable. These results suggest that 8q21.3 contains a tumor suppressor gene involved in proximal CRC, possibly NBS1. The large regions of AI make it difficult to determine the importance of AI at the NBS1 locus in distal CRC.

Loss of heterozygosity at the ATM locus in colorectal carcinoma.

Patients homozygous for mutation of the ATM gene exhibit constitutional genetic instability and have a high risk of cancer. A-T heterozygotes also have an increased tendency to develop adenocarcinomas. Colorectal cancer (CRC) is the second most common cancer in western populations, and tumors of the right colon are typically highly genetically unstable. The DNA mismatch repair genes mutated in most familial and some sporadic CRCs account for one route by which cells acquire additional oncogenic mutations during the progression of malignancy. Mismatch repair defects, however, do not seem to account for the majority of CRCs. Because of its role in maintaining genomic stability, and the high risk of cancer to homozygotes, ATM is a candidate gene for inactivation in the evolution of chromosomal instability in tumor cells. We have examined 114 CRC patients for loss of heterozygosity (LOH) using six microsatellite markers tightly linked to the ATM locus. Our data suggest that LOH of this region is not associated with cancer of the proximal colon. In the distal colon, LOH was found in 23-31% of cases, which is moderately elevated above the non-specific LOH reported in tumors of this tissue. No correlations were found with regard to clinicopathological variables aside from tumor location.

p185 overexpression in 220 samples of breast cancer undergoing primary surgery: comparison with c-erbB-2 gene amplification.

In breast cancer, DNA amplification of the oncogene c-erbB-2, encoding for the p185 protein, is associated with a poor prognosis. A retrospective study on a population of 220 cases of primary breast cancer permitted a quantitative measure of p185 oncoprotein overexpression by an immunoenzymetric assay and the determination of c-erbB-2 amplification by the Southern blot method. A correlation existed between the two measurements (r=0.85) using the double cut-off: DNA 2 copies and p185 400 U/mg protein, and only 2.7% of the cases were discordant. 13.2% of the tumors showed p185 overexpression. The percentage of tumors overexpressing p185 was significantly different between the groups with amplified and non-amplified c-erbB-2. We observed a significant correlation between p185 levels and tumor grade (p=0.03), and an inverse correlation with hormonal receptors (p=0.0001). The p185 assay could be an additional prognostic factor to better define patient subgroups with node negative, grade II, and positive or negative hormonal receptors.

Cytosolic p53 protein and serum p53 autoantibody evaluation in breast cancer. Comparison with prognostic factors.

Mutations of the TP53 gene induce the production of an abnormal protein (p53) with a prolonged half-life allowing its detection by monoclonal antibodies and leading to a development of serum p53 autoantibodies. We have quantified the protein p53 in 196 cytosols of primary breast cancer tissues, by an immunoluminometric method and searched for p53 autoantibodies in the sera of 101 patients, by an immunoenzymatic assay. The median value has been chosen as cut-off (0.26 ng/mg protein). 18.4% of tumors had a p53 level < 0.10 ng/mg protein, and 8.2% had a p53 level > or = 2.5 ng/mg protein (range: 0.43.37). We found a significant difference between p53 distribution (p = 0.003) and median level (p = 0.001) in ductal and lobular carcinomas. The p53 median levels were significantly different between the grade III versus the grade I tumors (p = 0.01) and versus the grade II tumors (p = 0.008). An inverse correlation was obtained between p53 levels and ER (p = 0.003) alone or with PR (p = 0.006). p53 autoantibodies were detected in 7.9% of cases (8/101). This p53 study shows correlations with some poor prognostic factors, but would require further evaluation to better define the patient groups with poor prognosis. The p53 detection autoantibodies is neither correlated with the p53 cytosolic assay nor with prognostic factors of breast cancer, and should therefore not be used for patient the selection of the patient groups with poor prognosis.

Immunostaining of colorectal cancer with monoclonal anti-CEA antibodies compared to serum and tumor CEA content.

Carcinoembryonic antigen was measured in serum and in extracts from 37 colorectal tumors and we found a poor correlation between circulating and tumor CEA. Monoclonal antiCEA antibodies were used in indirect immunoperoxidase staining of the corresponding formalin fixed tissue sections. We found that serum CEA measurement had a sensitivity of only 41.9% as compared to 90.3% for the immunohistochemical staining. The positive and negative predictive values for immunostaining were respectively 96.6% and 72.7%. Immunohistochemical staining of tissue sections with monoclonal anti CEA coupled to other biochemical or immunological assays could be a useful adjunct for the diagnosis of premalignant or slightly modified tissues.

Flow cytometric studies of colorectal tumors using fine needle aspiration.

The results are reported of cytofluorometric DNA analyses of colorectal tumors using cells obtained by mechanical disruption and fine needle aspiration. The latter method does not lower the level of debris or cell aggregates. We found a significantly higher proportion of aneuploid cells by needle aspiration. There was a good correlation between the data obtained by both methods, but for large heterogeneous tumors multiple site aspirations are needed to obtain representative specimens. Fine needle aspiration was found particularly useful for small tumors and polyps.

Association between H-ras minisatellite and colorectal cancer risk.

BACKGROUND: The H-ras locus has been suggested to play an important role in susceptibility to cancer. However, the results remain controversial. METHODS: In order to elucidate the potential role of the H-ras locus in colorectal carcinogenesis, 142 colorectal tumors with matched normal samples were studied for genomic instability and loss of heterozygosity (LOH), and 143 healthy samples of white blood cell DNA were examined by PCR, for H-ras allelic polymorphism. RESULTS: Nine percent of colorectal cancer patients constitutionally presented at least one rare allele versus 1.4% of healthy individuals (P = 0.0034). The risk of developing colorectal cancer increased significantly with the presence of rare H-ras alleles (odds ratio = 7.10 and 95% confidence interval = 1.92-26.35). The genotype associating one common allele and one rare allele was overrepresented in cancer patients (P < 0.01). No associations were observed between the rare alleles and tumor site or with the aggressiveness of cancer. Low frequencies of LOH (5%) and genetic instability (0.7%) at the H-ras locus were found in our colorectal cancer set. CONCLUSIONS: Consequently, the presence of uncommon alleles at the H-ras locus appeared to be an informative genetic marker.

Specific H-Ras minisatellite alleles in breast cancer susceptibility.

Mutations in BRCA1 and BRCA2 genes account for the majority of familial aggregation of breast and ovarian cancers but other common genes in the population with low penetrance should be also involved in susceptibility to breast cancer. The H-ras minisatellite, located downstream of H-ras oncogene, is considered to be a likely candidate. Previous findings have estimated that as many as 1 in 11 cancers of the breast might be attributed to this region, but other studies observed inconsistent results. We propose to elucidate the potential role of H-ras locus in breast cancer, by looking at somatic alterations occurring in tumor DNAs such as the instability or the loss of heterozygosity (LOH) and by determining a potential correlation between constitutional specific H-ras alleles and clinical and/or pathological characteristics. DNA was extracted from 123 sporadic breast tumors and matched peripheral blood lymphocytes. 143 DNA samples from of peripheral blood lymphocytes from healthy donors served as a control population. The allelic diversity was determined by polymerase chain reaction analysis. Rare H-ras alleles were found to be present in about 9% of breast cancer patients while they were detected in only 1.4% of lymphocytes from healthy donors (P = 0.0044). Therefore, the risk of breast cancer is increased in patients with one or two rare alleles (odd ratio = 7.14 and 95% confidence interval = 1.94-22.27). Analyses of somatic alterations in tumor DNA have shown the lost of one allele, in general the longest, in 6.7% informative cases and an instability to H-ras locus in 6.5% tumors that appeared as a size increase of one of the two alleles. No correlation of rare H-ras alleles with clinicopathological parameters was found. Our results demonstrated an association of rare H-ras alleles with breast cancer and suggest that minisatellite H-ras may be considered as an informative marker for the breast cancer risk.

The usefulness of prostate-specific antigen and prostatic acid phosphatase in clinical practice.

A comparative study was performed on the usefulness of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) in control subjects (69), benign prostatic hypertrophy (BPH) patients (150), and patients with prostatic carcinoma (113) in a urology department. We establish, as others, the greater clinical sensitivity of PSA and its effectiveness as a prognostic tool in the evaluation of prostatic cancer therapy and in the early detection of residual tumor following radical prostatectomy. However, patients are admitted to our department with more severe and complicated benign prostatic pathology and urinary dysfunctions, which decreases the specificity of the PSA test to 30% (N = 2.7 ng/ml). A cutoff threshold of 50 ng/ml becomes necessary to maintain a 90% positive predictive value. The combination of PSA sensitivity (96%) and PAP specificity (95%) enabled a better definition of the high-risk subpopulation among noncancer patients and, in addition, was a help for differential diagnosis, confirmation of advanced stages of prostatic cancer, and selection of low-stage prostatic cancer candidates undergoing radical prostatectomy. Routine serum PSA measurements in the population of patients consulting a urology department will no doubt bring about a new approach to the management of prostate cancer.

[Diagnostic value of SCC-TA4 determination in 4 localizations of epidermoid cancers. An experience of the FNCLCC subgroup of radio-analysis]. / Intéret diagnostique du dosage du SCC-TA4 dans quatre localisations de cancers épidermoïdes. Expérience du sous-groupe de radio-analyse de la FNCLCC.

A multicenter and retrospective study of the diagnosis value of SCC-TA4 in squamous cell carcinomas of 4 localisations was made with the 2 thresholds of 2 and 2.5 ng/ml. However, 3.1% of controls have a SCC value above 2.5 ng/ml. Sixteen benign gynecologic pathologies had no positive level. The benign digestive (N = 73), bronchial (N = 345) pathologies and no squamous cell carcinomas (N = 93, N = 220 respectively), had SCC-TA4 mean levels significantly lower than corresponding squamous cell carcinomas (N = 153, N = 128 respectively). Sensitivity of the test varied from 40% in the squamous cell carcinomas of the lung, to 72% in the squamous cell carcinomas of the uterine cervix. Specificity was always very high and varied from 91% in the SCC of lung, to 100% in the SCC of uterine cervix. For the SCC of uterine cervix, oesophagus and head and neck, the mean values and incidence of positive levels increased significantly with increasing tumor size and advancing disease stage. For the SCC of uterine cervix, mean SCC-TA4 levels and percentages of positive levels above 2 ng/ml were significantly higher for the patients with recurrence (22.5 +/- 4.6 ng/ml; 76%) or with metastasis appearance (23.6 +/- 5.4 ng/ml; 77%) than for the patients in remission (less than 1.5 ng/ml; 0%). In the SCC of oesophagus, we report levels before treatment that are significantly higher for the patients with metastasis at the first attempt (4.2 +/- 5.1 ng/ml; 59%), and an elevated SCC level at the diagnosis evoked a SCC of lung already disseminated (8.8 +/- 12.1 ng/ml; 50%) that will fail to respond to treatment (4.0 +/- 4.2 ng/ml; 48%).

Flow cytometric analysis of DNA abnormalities in colorectal carcinomas.

We report a flow cytometric study on ploidy in 117 colorectal cancers. An aneuploid cell population was found in more than 70% of adenocarcinomas. Ploidy was found to be stage-related; aneuploid tumors with DNA index greater than or equal to 1.4 were found mainly in Dukes' C and Dukes' D stages (P less than 0.02). Tumors of the caecum and of the ascending colon were more often found to be diploid than those of the other sites. There was a progressive increase in the proportion of cells in S-phase depending on whether they were from normal tissue, inflammatory mucosa or adenocarcinomas. The proportion of cells in S-phase was significantly larger in aneuploid tumors (P less than 0.001). The data presented above suggest that aneuploidy and the proportion of non-resting cells could be important prognostic factors for colorectal cancers. The latter are independent of the stage of the disease and histological differentiation.

[Standardization and quality control in the evaluation of proliferation parameters in T1T2, N0N1, M0 breast cancer : multicentric retrospective study I. DNA synthesis enzyme activities]. / Standardisation et mise en place d'une assurance qualité dans l'évaluation des paramètres de prolifération de 1,003 cancers du sein T1T2, N0N1, M0: étude multicentrique I. Enzymes de réplication et de transduction du signal.

As part of a clinical research project co-ordinated in Grenoble, six French institutions (CRLCC Angers, CHU Grenoble, Hospices civils Lyon, AP Marseille, CRLCC St-Cloud, CHU Tours) grouped together in order to study the following proliferative parameters in primary breast cancer: DNA synthesis enzymes [thymidine kinase (TK), thymidylate synthase (TS)], signal transduction enzyme [protein tyrosine kinase (PTK)] and S-phase fraction (%S). TK, TS and PTK were measured in cytosols using radio-enzymatic biochemical methods. S-phase was estimated using flow cytometry. The first step consisted in standardization and technical validation of the measurements. The second step consisted in the clinical validation by using a retrospective series of 1,003 breast cancers T1T2, N0N1, M0. We report the results of the first step, together with the distributions of the variables and their relationship with classical clinical variables: 1) Using standardized methods and a cytosolic control, a good reproducibility of measurements was obtained, whether assays were performed in one (TS, PTK) or in several laboratories (TK). 2) Significantly different distributions of TK and TS were observed between the different centres mainly due to different conditions of storage of tumours and cytosols. 3) A highly significant correlation was observed between TK, TS and PTK. Highest TK, TS and PTK levels were observed in tumours with high histological grade or receptor negative tumors. This study clearly illustrates the importance of quality assurance of multicentre studies.