Role of cyclosporine metabolites and clinical toxicity in organ transplantation.
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Biomedical subjects
Publications and source records attributed to M Brunet.
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1. Clinical response to treatment with haloperidol was studied in 20 schizophrenic inpatients with acute exacerbation (DSM-IIIR). 2. Patients were assigned to fixed doses of haloperidol (10, 20 or 30 mg/day) for three weeks. Clinical assessment was made using scales SAPS, SANS, BPRS and Simpson-Angus Scale for rating of extrapyramidal side effects. 3. Sixteen patients showed forty per cent or more decrease in positive symptoms assessed by SAPS, being considered the group of responders. Six out of the twenty patients showed improvement in negative symptoms assessed by SANS (improvement above 30%). 4. Clinical predictors of response were only identified for SAPS. The group of responders showed higher basal scores in total scale and formal thought disorder. 5. Negative symptoms responsive to treatment were affective flattening and alogia. Improvement in negative symptoms was independent from that in positive ones. 6. Socio-demographic predictors of clinical response were not found. No differences in clinical response were found in relation to the dose administered. 7. The results of our study suggest that negative symptomatology improves in a scheduled treatment with haloperidol. Assessment of negative symptoms may be useful in the evaluation of treatment of acute schizophrenia.
The increased incidence of primary central nervous system malignant non-Hodgkin's lymphomas (PCNSL) in HIV- and non-HIV-infected patients and the demonstration of Epstein-Barr virus (EBV) in these tumours may indicate relationships between PCNSL and EBV. Consequently expression of EBV-induced antigens and cellular markers were studied in 11 HIV-infected and seven non-infected patients by in situ hybridization (ISH) and immunocytochemistry in monoclonal B cell PCNSL. In HIV-infected patients EBV genome was present in 9/11 cases, LMP in 11/11 cases and EBNA2 in 10/11 cases. The expression of adhesion and activation molecules was low or absent. In HIV non-infected patients, EBV genome was present in 5/7 cases, with LMP in 4/7 cases. EBNA2 was never detected. All these lymphomas expressed LFA1beta. Whatever the population, no lytic cycle EBV markers were detected. Compared with other types of EBV lymphomas, our results suggest a different EBV latency state in primary B cell lymphomas of the CNS from HIV-infected or non-infected patients.
Twenty-two schizophrenic inpatients were treated for 3 weeks with three randomly fixed oral doses of haloperidol (10, 20, or 30 mg). Analysis of the results by a nonlinear regression model revealed a curvilinear relationship between haloperidol levels in plasma and clinical response, as assessed on the Brief Psychiatric Rating Scale (pseudo-R2 = 0.85, F = 17.7, p < 0.001, correlation between coefficients ranged from 0.99 to -0.52). This curve defines roughly three drug level ranges (low, < 5.5 ng/ml; optimal, 5.5 to 14.4 ng/ml; and high or toxic, > 14.4 ng/ml), which are significant for clinical practice. Patients with high levels improve to a lesser extent or even worsen in negative symptoms, showing a nonstatistically significant trend to present more extrapyramidal symptoms. Our data thus support the existence of a therapeutic window for haloperidol. Schizophrenic patients with acute exacerbation and drug levels in this range would have a greater probability of global clinical improvement.
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BACKGROUND AND METHODS: Predictors of distant relapse following conservative surgery for breast cancer were studied in a review of 425 women. Five steps of breast cancer patient management were defined in which increasing amounts of information, potentially relevant to prognosis for metastasis-free survival (MFS), were available: (1) clinical, (2) biopsy, (3) tumorectomy, (4) axillary dissection, and (5) adjuvant treatment. At each step, a prognosis study based on the Cox model was carried out using all acquired information from the first step. RESULTS: Among the 21 studied variables, 5 were independent stable risk factors in predicting MFS: (1) clinical node status, (2) modified Scarff-Bloom-Richardson (MSBR) histoprognostic grade, (3) progesterone receptor (PR), (4) anatomic tumor size, and (5) histologic lymph node status. These factors were progressively identified throughout the successive prognostic analyses and kept their significance at the reference step (axillary dissection step where all information is acquired). According to the prognostic score based on the significant variables, a stratification of the patients had been built at each step, identifying three risk groups (low, moderate, high). Even at biopsy step, the mere knowledge of clinical information, such as clinical node status, and biopsy information, such as MSBR grade and PR status, would enable 68% of the patient to be well classified according to the stratification of reference. Knowledge of an additional factor, such as anatomic tumor size, would bring the rate up to 88%. Some subsets of patients with stable prognosis throughout the steps were identified and their profiles were described. It is noticeable that 95% of the patients, classified low risk at the biopsy step, were patients that were stable. CONCLUSIONS: The early recognition of patients, highly curable by local therapy alone, would obviate aleatoric neoadjuvant treatment.
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BACKGROUND: An array of biological features related to tumor cell differentiation status, growth rate, and invasive potential have been identified as potential prognostic factors in breast cancer. We were interested in determining their relative importance in predicting patient survival. PURPOSE: We evaluated the relative weight of the following four biological factors in predicting survival of patients with breast cancer: tumor cell DNA content (determined by flow cytometry), tumor cell proliferation rate (determined by thymidine kinase activity), expression levels of cathepsin D and urokinase plasminogen activator, and several "classical" clinical and histological factors. METHODS: Selected from a prospectively updated database, the study population consisted of 319 primary breast cancer patients who received treatment and follow-up care (median, 6 years) in the Centre René Huguenin. To determine the profile of biological factors for each patient, we used frozen tumor specimens and (except for the flow cytometric DNA content assay) commercially available assay kits. We determined by Cox multivariate analysis the relationships of the biological factors to each other, to classical prognostic factors, and to disease-free and metastasis-free survival. RESULTS: In the overall population, disease-free survival was best predicted by node status (P = .004), clinical tumor size (P = .02), and cathepsin D expression (P = .01), whereas metastasis-free survival was best predicted by node status (P = .0004), clinical tumor size (P = .009), and urokinase plasminogen activator expression (P = .04). In node-negative patients, thymidine kinase activity was the only factor selected for disease-free (P = .04) and metastasis-free (P = .05) survival. In node-positive patients, the number of positive axillary lymph nodes was the only factor selected for disease-free (P = .0008) and metastasis-free (P = .00017) survival. CONCLUSIONS: Our retrospective analysis has identified protease expression and tumor cell proliferation rate as important biological prognostic factors in breast cancer. Prospective clinical trials should be undertaken to confirm these results.
An enzyme-linked immunosorbent assay using monoclonal and polyclonal antibodies against recombinant pS2 was devised. It was used to measure pS2 concentration in the cytosol of 339 breast cancer, 15 fibroadenomas, 16 cases of benign breast disease, and 6 normal breast tissues. The mean value of pS2 concentration was higher in cancer, but the protein could be detected readily in benign tumors and even in normal breast. The concentration of pS2 was significantly lower in postmenopausal women and tumors of differentiation Grade 3. The pS2 concentration was correlated strongly with the presence of estrogen receptors (ER) and progesterone receptors (PR). No correlation was observed with the size, histologic type of the tumor, and lymph node status. The prognostic value of pS2 appeared relatively limited. It was clear cut only for a relatively small group of patients (approximately 15%), who had low concentrations of pS2 (less than or equal to 0.32 ng/mg of protein). These patients had a shorter disease-free interval and overall survival time. The most striking correlation was observed with the outcome of adjuvant hormone therapy. pS2 concentration was shown to be the most potent prognostic factor, preceding even ER.
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Forty-five patients who had primary cancer of the breast had a laparotomy when a second cancer appeared in the ovaries. There were no other peritoneal metastases to suggest that it was disseminated breast cancer. Twenty-eight had primary ovarian cancer and 17 metastases from breast cancer. The study comparing the two groups shows that: there are few clinical or paraclinical features that make it possible to arrive at a differential diagnosis; ovarian metastases occurring in patients who have primary breast cancer carry a more serious prognosis; if the cancer is a primary ovarian cancer (and not a secondary) the chances of survival are less poor; in primary ovarian cancer the results justify our attitude for carrying out surgery; screening systematically for ovarian involvement by using CA 125 or by routine ultrasound does not seem to us to be effective.
Risk factors for distant metastases following mastectomy and axillary node dissection for breast cancer were analyzed in a review of 1022 women. From diagnosis until the end of the adjuvant treatment, six stages were identified that corresponded well to patient data acquisition. At each stage, a prognosis study based on the Cox model was carried out using all acquired information from the first stage. The results demonstrated that tumor size, nuclear pleomorphism, mitotic index, and nodal status at the top of axilla were stable independent risk factors in predicting metastasis-free survival (MFS). These analyses also revealed those factors that were significantly related to MFS at one or several stages and losing their significance at a subsequent stage. This was the case with clinical node status, age, and vascular tumor emboli. Other factors such as estrogen, progesterone, histologic grade, and clinical stage were never identified as independent factors at any stage. The four major stable risk factors were used to define a stratification of reference. The results demonstrated that the mere knowledge of clinical information such as tumor size, clinical node status, and age would enable 51% of the patients to be universally well classified according to that stratification. Knowledge of additional factors, such as nuclear pleomorphism and mitotic index, would bring the rate up to 61%, and then to 64% if supplementary information such as vascular tumor emboli were acquired. These percentages did not appear high enough to claim that the physician may make a reliable prognosis of operable breast cancer patients before acquiring information from the axillary node dissection. However, it was proven that there exist some subsets of patients with stable prognosis, i.e., subsets of patients who will belong permanently to the same risk group through the stages.
Breast cancer is the most common of all cancers affecting women in France; its frequency increases in countries with a high standard of living. A family history and certain types of mastosis are unquestionable risk factors, although their weight has not yet been well established, but there is no absolute proof that feeding habits (notably fats and alcohol), which have been blamed by some authors, play a role in the genesis of breast cancer. Among the classical prognostic factors, which are necessary for surgical decisions, the size of the tumour, its histological grade and above all the number of axillary lymph nodes involved are the most important. However, a better knowledge of breast cancer biology has yielded factors that seem to be more promising than hormonal receptors, notably the DNA content of tumoral cells and the presence or absence of a protease, procathepsin 52 K, which reflects tumoral aggressiveness. As for the study of oncogens described elsewhere in this monograph, it will provide a better definition of high risk subjects and more precise information on the progress of the cancer.
A retrospective study was performed on 109 human breast tumors stored in liquid nitrogen in order to assess the prognostic value of epidermal growth factor receptor (EGF-R) (median patient follow-up 5 years). A significant inverse relationship was observed between EGF-R and both estrogen (ER) and progesterone receptors (PR). Univariate analysis showed a trend towards a shorter metastasis-free survival both in the overall population and in node-negative patients with EGF-R positive tumors. Multivariate analysis of the overall population showed that lymph-node involvement and PR status were the only significant variables in predicting metastasis-free survival. However, in patients receiving no adjuvant treatment (hormone therapy or chemotherapy). EGF was the only significant variable in the multivariate Cox analysis. No c-erbB-1 amplification was detected in these tumors.