Validation of UBE2C protein as a prognostic marker in node-positive breast cancer.

BACKGROUND: We recently identified and validated UBE2C RNA as a prognostic marker in 252 node-positive (N+) breast cancers by means of a microarray study. The aim of this study was to validate UBE2C protein as a prognostic marker in N+ breast cancer by immunohistochemistry (IHC). METHODS: To this end, 92 paraffin-embedded blocks were used. The impact of UBE2C IHC value on metastasis-free survival (MFS) and overall survival (OS) was evaluated and compared with Ki-67 and Nottingham prognostic index (NPI) performances. RESULTS: In accordance with genomic data, UBE2C IHC had a significant impact both on MFS and OS (hazard ratio=6.79 - P=0.002; hazard ratio=7.14 - P=0.009, respectively). Akaike information criterion proved that the prognostic power of UBE2C IHC was stronger than that of Ki-67 (and close to that of NPI). Furthermore, multivariate analyses with NPI showed that, contrary to Ki-67 IHC, UBE2C IHC remained an independent factor, both for MFS (adjusted P=0.02) and OS (adjusted P=0.04). CONCLUSION: We confirmed that UBE2C protein measured by IHC could be used as a prognostic marker in N+ breast cancer. The potential predictive interest of UBE2C as a marker of proteasome activity needs further investigations.

Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome.

BACKGROUND: CA 125 assays enable treatment response monitoring in ovarian cancer. PATIENTS AND METHODS: This multicentric study was carried out to assess the prognostic value of the CA 125 change after the first and the second courses of induction chemotherapy (CT). Of the 494 stage IIc-IV patients, 194 had a surgical second look, 397 (80.4%) relapsed and 382 (77.3%) died from cancer. Median (range) follow-up time was 34 months (3-215 months). RESULTS: In Cox models, CA 125 change after the first course (P < 0.0001), residual tumour (P = 0.003), CA 125 before the second course (P = 0.025) and patients' age (P = 0.048) were independent prognostic factors for overall survival (OS). A normal CA 125 before each of the two first CT courses or a CA 125 decrease >50% after the first course with a normal CA 125 before the second course identify patients with good prognosis. Both criteria retained a significant value in predicting second-look findings by univariate and multivariate analysis (P < 0.0001). CONCLUSION: Among well-established prognostic factors in ovarian cancers, the CA 125 change after first course of CT was independent prognostic factors for both achievement of pathological complete response and OS.

CA 125 half-life and CA 125 nadir during induction chemotherapy are independent predictors of epithelial ovarian cancer outcome: results of a French multicentric study.

BACKGROUND: CA 125 assays enable treatment-response monitoring in ovarian cancer. PATIENTS AND METHODS: A multicentric study of CA 125 kinetics under induction chemotherapy was performed in 631 patients. CA 125 half-life was calculated by mono-compartmental logarithmic regression. Nadir CA 125 concentration and time to nadir were also studied. Survival analyses for disease-free survival (DFS) and overall survival (OS) used univariate (Kaplan-Meier) and multivariate (Cox) models. RESULTS: For 553 stage IIC-IV patients, 459 (83.0%) relapsed and 444 (80.3%) died from cancer. Median (range) follow up time was 32 months (2-214 months). Median (range) for CA 125 kinetics were: 263 kU/l (5-52000 kU/l) before 1st course, 15.8 days (4.5-417.9 days) for CA 125 half-life, 16 kU/l (3-2610 kU/l) for nadir and 85 days (0-361 days) for time to nadir. Pre-chemotherapy CA 125, its half-life, nadir concentration and time to nadir all had a univariate prognostic value for DFS and OS (P<0.0001). In Cox models, CA 125 half-life, residual tumour (P<0.0001 for both), nadir concentration (P=0.0002) and stage (P=0.0118) were the most powerful prognostic factors for DFS. For OS, the significant variables were similar, with age ranking last (P=0.0319). CONCLUSION: Among well-established prognostic factors in ovarian cancers, CA 125 half-life and nadir concentration bear a strong and independent prognostic value.

[Manufacture of DNA chips in a laboratory for internal use: legislation and quality assurance]. / Fabrication de puces à ADN par un laboratoire pour sa propre utilisation: réglementation et assurance qualité

Manufacturing and using DNA chips in a laboratory, while respecting legality and good practices, require a review of the regulatory framework and relevant documentation for implementing a quality assurance system. Using DNA chips, either as a research tool, or as an in vitro diagnostic medical device, does not come within the same regulations: none in the first case, and european directive 98/79/CE in the second one. It is the same for research practice, for which the law to be enforced has been primarily conditioned to ethics, while carrying out medical analyses has been framed in France by the GBEA. The regulatory approach laid down in the GBEA is a first step for implementing a quality assurance system, but this must be extended to the manufacturing process of DNA chips. International standards (ISO 9001: 2000, ISO/IEC 15189...) provide documentation to meet this last requirement, but also enable one to carry on the quality approach up to the certification of the laboratory or its accreditation.

G388R mutation of the FGFR4 gene is not relevant to breast cancer prognosis.

This study screened large cohorts of node-positive and node-negative breast cancer patients to determine whether the G388R mutation of the FGFR4 gene is a useful prognostic marker for breast cancer as reported by Bange et al in 2002. Node-positive (n=139) and node-negative (n=95) breast cancer cohorts selected for mutation screening were followed up for median periods of 89 and 87 months, respectively. PCR - RFLP analysis was modified to facilitate molecular screening. Curves for disease-free survival were plotted according to the Kaplan - Meier method, and a log-rank test was used for comparisons between groups. Three other nonparametric linear rank-tests particularly suitable for investigating possible relations between G388R mutation and early cancer progression were also used. Kaplan - Meier analysis based on any of the four nonparametric linear rank tests performed for node-positive and node-negative patients was not indicative of disease-free survival time. G388R mutation of the FGFR4 gene is not relevant for breast cancer prognosis.

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.

Prognostic value of uPA and p53 accumulation measured by quantitative biochemical assays in 1245 primary breast cancer patients: a multicentre study.

The purpose of this retrospective multicentre study was to assess the prognostic value of urokinase plasminogen activator (uPA) and p53 levels in a large series of primary breast cancer, using an automatic quantitative luminometric method. Samples of 1245 operable breast tumours were collected from seven French institutions and patients were followed for a median of 75 months. The median uPA and p53 levels assayed in cytosols by means of the immunoluminometric technique (LIA) were 0.31 and 0.20 ng mg(-1) of protein respectively. In univariate analysis, high levels of uPA and p53 were associated with shorter disease-specific survival, disease-free interval, and distant recurrence-free interval. The 5-year survival rates were 95.5% among patients with uPA values below the 20th percentile, and 77.5% in those with values above the 80th percentile. The 5-year survival rates were 91.0% in patients with p53 values below the 20th percentile, and 77.6% in those with values above the 80th percentile. In multivariate analysis, the risk of disease-related death increased with uPA levels after adjustment for tumour size, histological grade, lymph node involvement, and estrogen receptor status. A high level of uPA was also related to a shorter disease-free interval and distant recurrence-free interval. In node-negative patients, a high level of uPA remained strongly related to the three outcomes. When adjusted for other prognostic factors, p53 was no longer significantly related to the outcomes. Given its rapidity and simple application to routinely prepared cytosols, this LIA may be useful for evaluating the prognostic impact of uPA in primary breast cancer, particularly in node-negative patients. According to our results, the prognostic value of p53 accumulation is limited when uPA is included in multivariate analysis.

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.

Clinical validation of the new ELSA-CA 125 II assay: report of a European multicentre evaluation.

The ELSA-CA 125 II is a second-generation radioimmunoassay for the quantification of CA 125 in serum. In a multicentre study involving 49 follow-ups of patients with ovarian cancers, and 880 other patients, 2.8% of healthy persons, 25% of 149 patients with benign gynaecological diseases and 39% of 82 patients with benign non-gynaecological diseases had CA 125 levels above 35 U/ml. Using the 35 U/ml cut-off, sensitivities among epithelial ovarian cancers were found to be 85% in serous tumors, 41% in mucinous tumors and 83% in other types. During follow-up of patients with serous ovarian cancers, we observed an equivalent behaviour of both assays--first- and second-generation--with the clinical evolution. We also compared results obtained with other assays commercially available; these were significantly different when a polyclonal antibody was used in the sandwich assay.

[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%).

[Methodological problems in the determination of microalbuminuria]. / Problèmes méthodologiques posés pour la détermination de la microalbuminurie.

We have performed 7 different urinary collections to assess albumin excretion rate in insulin-dependent diabetics. The night and the 24 hours urine collections were more accepted than the others. For albumin excretion rate there was no correlation among the different collections. So, the albumin excretion rate must be done always on the same sample for one patient and be repeated to confirm pathological values.

Radioimmunoassay of the CA 12 5 antigen in ovarian carcinomas: advantages compared with CA 19-9 and CEA.

Antigen CA 12 5, associated with ovarian carcinomas, was assayed in the serum by an immunoradiometric method using monoclonal antibody OC 125. In a control group of 67 women in apparent good health, CA 12 5 serum levels in 64 cases (96%) were lower than 35 U/ml, the value arbitrarily considered as the upper normal limit. Using this limit, in benign lesions excluding cirrhosis, 19% (5/27) had raised levels. None of 10 cases with benign ovarian lesions had elevated values. However, in cirrhosis 86% of cases were positive being very high in 43% of cases (greater than 500 U/ml). In 38 cases of ovarian carcinomas, the overall positivity was 92% (35/38); in serous carcinomas it was 96% (26/27). For other non-ovarian cancers, particularly colonic and mammary adenocarcinomas at advanced stages, the positive rate was 43% (19/44). Finally, for 20 patients treated by chemotherapy for ovarian carcinomas and followed up by repeated CA 12 5 assays over a 2 to 8 month period, an increase or decrease in CA 12 5 levels correlated with progression or regression of the disease in 18 cases (90%).

[Effects of chronic administration of lithium on thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3) free thyroxine ratio (FTR) and thyreostimuline (TSH) in thyrotoxicosis (author's transl)]. / Effet chronique du lithium sur la thyroxine (T4), la triiodothyronine (T3), la T3 inverse (rT3), l'index de thyroxie libre (ITL) et le thyréostimuline (TSH) chez l'hyperthyroïdien.

Fourteen hyperthyroid subjects were studied between 3 and 141 days. The reduction of thyrotoxicosis is rarely obtained (2 cases), mainly because on the one hand, correct plasma lithium level (0.7-1.2 mEq/L) is rarely obtained (3 cases only), on the other hand because a high dose of lithium is required, perhaps owing to high clearance of lithium in thyrotoxicosis. The indications of lithium use in thyrotoxicosis are reviewed.