18F-FDOPA PET for the diagnosis of parkinsonian syndromes.

18F-FDOPA PET has been historically used for the evaluation of parkinsonian syndromes in research settings. With the wider availability of PET cameras and 18F-DOPA this method can be used as a clinical diagnostic tool. Current acquisition protocols are simple with a 10 minute static acquisition performed 90 minutes post injection. Criteria for precise visual analysis of the images are defined. The performances of the method are reviewed throughout the literature. The method is very sensitive for detection of IPD versus normal patients. Few studies comparing 18F-FDOPA PET and DAT SPECT did not show any difference in diagnostic accuracy. 18F-FDOPA PET is reliable for evaluation of IPD progression. In general, atypical Parkinson's syndromes cannot be reliably differentiated from IPD since they share a similar nigro-striatal degeneration process. However, some patterns such as the asymmetrical faint homogeneous striatal uptake reduction pattern of CBD can be recognized. The short acquisition protocol, the various indications in oncology of 18F-FDOPA and the high quality of PET images are in favor of this technique in daily clinical practice for the improvement of diagnosis of parkinsonian syndromes.

Evidence for biological roots in the transgenerational transmission of intimate partner violence.

Intimate partner violence is a ubiquitous and devastating phenomenon for which effective interventions and a clear etiological understanding are still lacking. A major risk factor for violence perpetration is childhood exposure to violence, prompting the proposal that social learning is a major contributor to the transgenerational transmission of violence. Using an animal model devoid of human cultural factors, we showed that male rats became highly aggressive against their female partners as adults after exposure to non-social stressful experiences in their youth. Their offspring also showed increased aggression toward females in the absence of postnatal father-offspring interaction or any other exposure to violence. Both the females that cohabited with the stressed males and those that cohabited with their male offspring showed behavioral (including anxiety- and depression-like behaviors), physiological (decreased body weight and basal corticosterone levels) and neurobiological symptoms (increased activity in dorsal raphe serotonergic neurons in response to an unfamiliar male) resembling the alterations described in abused and depressed women. With the caution required when translating animal work to humans, our findings extend current psychosocial explanations of the transgenerational transmission of intimate partner violence by strongly suggesting an important role for biological factors.

Aromatase inhibition in male breast cancer patients: biological and clinical implications.

BACKGROUND: The role of aromatase inhibitors (AIs) and their impact on estradiol (E(2)) levels remain unknown in male breast cancer (MBC) patients. PATIENTS AND METHODS: MBC patients with metastatic disease and those treated with AIs were selected from the breast cancer database of the Centre Antoine-Lacassagne (Nice, France). Sex hormone levels were retrospectively assessed on serum samples from our institutional serum bank. RESULTS: Fifteen patients entered the study. Two patients (13%) had complete response, four patients (27%) had partial response, two patients (13%) had stable disease and seven patients (47%) had progressive disease. The median progression-free survival and overall survival were 4.4 months [95% confidence interval (CI) 0.1-8.6] and 33 months (95% CI 18.4-47.6), respectively. All assessable patients (n = 6) had E(2) levels less than the lower limit of the assay during AI treatment. Among them, three had partial response, one had stable disease and two had progressive disease. A large increase in follicle-stimulating hormone, luteinizing hormone and E(2) levels was observed in one responding patient at progression. CONCLUSIONS: AIs are active in MBC patients. This activity is correlated with a significant reduction in E(2) levels. Secondary resistance is in part related to a deleterious feedback loop resulting in a significant increase in substrate for aromatization.

Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) gene in head and neck cancer patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck cancer. The first intron of EGFR gene is polymorphic (9-23 CA repeats) and transcription declines when the number of repeats increases. PATIENTS AND METHODS: EGFR polymorphism (fluorescent genotyping) and expression (ligand-binding assay) were analyzed in tumors and normal tissues from 112 patients (100 men, 12 women; mean age 60 years). RESULTS: The number of CA repeats varied from 15 to 22. Allelic distribution was trimodal (predominance of 16, 20 and 18 CA repeats). EGFR concentrations were significantly higher (P=0.02) in homozygous tumors as compared with heterozygous. Considering homozygous tumors, or classifying genotypes as short/long/intermediary (two alleles <17 versus two alleles > or =17 versus others), no relationship was observed between tumoral EGFR genotype and expression. In the 76 tumors exhibiting at least one 16-CA allele, the length of the remaining allele was inversely correlated to EGFR expression (P=0.047). Tumoral EGFR expression, performance status (WHO criteria) and node involvement were independent predictors of specific survival (P <0.01). Tumoral or normal tissue EGFR genotype did not influence survival. CONCLUSIONS: Intron 1 EGFR polymorphism may be implicated in the regulation of EGFR expression in head and neck tumors.

Comparison of Cyfra 21-1 and SCC assays in head and neck tumours.

Patients with head and neck tumours (HNT) have a high risk of early locoregional relapse that is difficult to diagnose. This study evaluated the usefulness of the serum Cyfra 21-1 assay compared to squamous cell carcinoma antigen (SCC) assay for monitoring such patients. Three hundred and twelve HNT patients, including 204 newly diagnosed patients, were followed up for a median of 446 days with serial serum assays for SCC and Cyfra 21-1. Untreated patients showed SCC and Cyfra 21-1 serum levels correlated with each other: concentration was correlated to clinical stage, tumour size (as T1 + T2 vs. T3 + T4) and nodal status. Cyfra 21-1, but not SCC, was related to the presence of metastases and the primary tumour site, with a univariate prognostic value for disease-free survival (p = 0.015). Cox's regression analysis showed that only Cyfra 21-1 was associated with a risk of relapse (p = 0.027). The random coefficient growth curve model applied to serial SCC and Cyfra 21-1 measurements of 111 patients showed that only Cyfra 21-1 exhibited a significant difference between patients with and without relapses. We found Cyfra 21-1 to be more closely related to initial clinical data and disease evolution than SCC, and therefore propose the use of Cyfra 21-1 for monitoring head and neck cancers.

A multifactorial approach including tumoural epidermal growth factor receptor, p53, thymidylate synthase and dihydropyrimidine dehydrogenase to predict treatment outcome in head and neck cancer patients receiving 5-fluorouracil.

The prognostic value of tumoural epidermal growth factor receptor (EGFR), p53, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) was analysed on 82 advanced head and neck cancer patients (71 men, 11 women; mean age 59). Induction treatment was cisplatin-5-FU +/- folinic acid (61 patients, Chem group) or concomitant cisplatin-5-FU-radiotherapy (21 patients, RChem group). EGFR (binding assay), p53 protein (Sangtec immunoluminometric assay), TS and DPD activities (radioenzymatic assays) were measured on biopsies obtained at time of diagnosis. Significant positive correlation was demonstrated between p53 and EGFR. In the RChem group, p53 was higher in non-complete responders (median 1.03 ng mg(-1)) than in complete responders (median 0.08 ng mg(-1)) (P = 0.057). Univariate Cox analyses stratified on treatment group showed that specific survival (33 events) was significantly related to T staging, p53 taken as continuous or categorial (below vs over 0.80 ng mg(-1)) variable, and EGFR (below vs over 220 fmol mg(-1)); survival increased when EGFR and p53 were below thresholds. Multivariate stepwise analysis including T staging, EGFR and p53 revealed that T staging and EGFR were independent predictors of survival; relative risks were 3.68 for T staging and 2.65 for EGFR. Overall, EGFR remained an independent prognostic factor when response to treatment and T staging were considered in the multivariate analysis.

Study of the frequencies of CYP1A1 gene polymorphisms and glutathione S-transferase mu1 gene in primary breast cancers: an update with an additional 114 cases.

We studied the polymorphisms m1 (Msp1 restriction site) and m2 (codon Val substitution) of CYP1A1 gene and the copy number of glutathione S-transferase mu1 (GSTM1) gene on 487 DNA of breast cancer primary tumours from Caucasian group. Tumours of patients aged 55 years and under at diagnosis presented a great proportion of wild m1 (-/-) genotype; 83.6% vs. 69.5% (p < 0.0006), and a higher percentage of copy number of GSTM1 equal or under one copy; 65.2% vs. 53.4% (p < 0.011) for older patients m1 and m2 variants are closely linked (p < 0.0000). Tumour with a low copy number of GSTM1 is correlated with high histological grading (p < 0.01) and high Cathepsin D concentrations (p < 0.02). The combinations of different genotypes showed that association wild m1 (-/-) genotype and copy number of GSTM1 inferior or equal to one copy is correlated with an early onset of breast cancer primary tumour 44% vs. 6.4% for m1 (-/+) or (+/+) genotype and copy number of GSTM1 superior to one (p < 0.0000). The CYP1A1 gene wild form seems to be associated with early cancer development in Caucasian patients.

[Glutathione S-transferase mu 1 (GSTM1): susceptibility gene of breast cancer]. / Glutathion S-transférase mu 1 (GSTM1): gène de susceptibilité du cancer du sein.

Glutathione S-transferases mu (GSTM) are dimeric cytosolic isoenzymes. They catalyze glutathione conjugation upon a large variety of electrophiles as carcinogens, trans-stilbene peroxide or benzo(a)pyrene. The gene GSTM1 is localized on chromosome 1p13, it has drawn attention because it is absent approximately in 50% of the white population. GSTM1 null genotype seems linked with susceptibility to cancers as lung, colon and bladder cancers. We have studied GSTM1 genotype from 373 primary breast tumours. The GSTM1 null genotype was found in 50% of the cases (185/373). The incidence study of GSTM1 copy number on clinical and biological variables displayed a significant difference (p < 0.01) of the GSTM1 genotype, showed by the tumour, according to the patient age at diagnosis. The patients younger than 55 years had a percentage more important of primary tumours (65%) with a copy number of GSTM1 gene, inferior or equal at one, compared to the patients older than 55 years (52%). The tumours, whose cathepsin D level was high, presented few copies of GSTM1 gene (p < 0.03). There was no other relationship, particularly, with tumour size, node status, histological type, hormonal receptors, pS2 cytosolic level GSTM1 gene seems protect the mammary gland from cancerogenesis with its detoxification role. This results had not, pointed out in breast cancer, yet.

C-erb-B2 gene amplification and serum level of c-erb-B2 oncoprotein at primary breast cancer diagnosis.

We studied c-erb-B2 gene amplification of DNA of primary breast tumours without distant metastasis from 236 women admitted to our institute during 1992. For 125 of them, we had a serum sample at diagnosis, before any treatment. C-erb-B2 gene amplification (> or = 2 copies) was observed in 26% (62/236) of the cases. There was a correlation with higher histological grades (p < 0.03) and with absence of hormone receptors: ER-(p < 0.0001). PgR-(p < 0.0001), association ER- and PgR-(p < 0.0000). Large tumours T3 and T4 taken together tended to present more c-erb B2 gene amplifications (p < 0.08). There was no correlation with age, histological type or nodal status. At diagnosis, mean concentration of serum c-erb-B2 oncoprotein was 8.5 +/- 18 U/ml with a median of 4 U/ml (4-150). Choosing a cut-off value of 8 U/ml gave a sensitivity of 21% (26/125). Serum levels of c-erb-B2 oncoprotein were correlated with tumour spread: large tumours T3-T4 (p < 0.001), nodal involvement (N+) (p < 0.01), association T3-T4 and N+(p < 0.0005), high levels of CA 15:3 (normal value < 25 IU/ml) (p < 0.05). There was no other correlation, particularly with age, histological type, hormone receptors or c-erb-B2 gene amplification. c-erb-B2 oncoprotein serum levels could be helpful to detect recurrences. Assessment of c-erb-B2 oncoprotein serum concentration, before treatment, as an independent prognostic factor is necessary.

[Study of mdm2 gene amplification in primary breast tumors]. / Etude de l'amplification du gène mdm2 dans les tumeurs primitives du sein.

mdm2 (mouse double minute) protein seems lead to p53 inactivation and therefore might potentially play a role in carcinogenesis. We have studied mdm2 gene amplification from 239 primary breast cancer tissues. mdm2 gene was amplified in 10% of cases (25/239). mdm2 amplification was associated with c-erbB2 amplification (P < 10(-3)). No other correlation was found. However there was inverse correlation between c-erbB2 gene amplification and hormonal receptors (P < 10(-4)), only from patients without mdm2 gene amplification.

Analysis of C-myc amplification by the differential polymerase chain-reaction (d-PCR), study in breast-cancer.

c-myc proto-oncogene amplification seems to have a prognostic value in breast cancer. In this study, quantitative analysis of c-myc amplification was carried out by differential polymerase chain reaction technique (d-PCR) using beta-globin as the reference gene. d-PCR assessment showed coampIification products of c-myc and beta-globin depend on variations in reaction factors such as the genomic DNA concentration, the relative concentrations of the various amplimers, the thermostable DNA polymerase concentration and the number of cycles. However, amplification of c-myc can be estimated quantitatively. In addition, results of individual sets of d-PCR can be expressed on a standard reference scale. A clinical study of 309 patients with breast cancer found c-myc amplification, respectively in 19% (45/236) of primary tumour tissues, 21% (4/19) of subsequent second primary cancers, 36% (4/11) of tumours of patients with bilateral lesions, 40% (8/20) of local recurrence tumours and 22% (5/23) of metastatic lesions. Amplification of c-myc was observed more frequently in histological grades 2-3 (p<0.02), in ER negative (p<0.01) and PgR negative tumours (p<0.02), but was not associated with age, tumour size, nodal status, histology, cytosolic cathepsin D or pS2. d-PCR appears amenable to automation and should facilitate large scale, inter laboratory gene amplification studies.

Sedimentation rate and serum thymidine kinase activity: prognostic factors in squamous cell head and neck cancer.

Identification of prognostic factors in squamous cell head and neck cancers involves analysis of highly diverse clinical and biological parameters. This study analyzed the prognostic value of clinical variables (age, sex, tumor site, stage) and biologic parameters (squamous cell carcinoma antigen [SCC], serum thymidine kinase activity [TK], fibrin, sedimentation rate [SR]) at the time of diagnosis of squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx) in 189 patients. Among the clinical variables investigated, UICC stage III-IV disease (p < .0002), a hypopharyngeal site (p < .02), and age over 60 years (p < .01) were all associated with a poor prognosis. Similarly, analysis of biological blood variables allowed definition of cut-off values above which the prognosis was poor: SCC 2.5 ng/mL (p < .01), fibrin 3.5 g/L (p < .01), TK 7 IU/L (p < .0005), and SR 15 mm per first hour (p < .0000). Cox regression analysis of overall survival identified the UICC stage (p < .000), the SR (p < .001), and serum TK (p < .02) as the main independent prognostic factors. A separate study on a small number of head and neck cancer patients revealed higher TK levels in malignant squamous cell carcinoma tissue than in adjacent healthy tissue.

Phase I and pharmacokinetic study of brequinar (DUP 785; NSC 368390) in cancer patients.

Brequinar (DUP 785, NSC 368390) is a 4-quinoline carboxylic acid derivative with broad spectrum antitumour activity in experimental models that acts as an antimetabolite by specific inhibition of de novo pyrimidine synthesis. We performed a phase I study of brequinar administered as a 10 min intravenous (i.v.) infusion for 5 consecutive days, every 4 weeks. 67 evaluable patients were entered in this study and a total of 130 courses were administered at doses ranging from 2 to 350 mg/m2. The dose-limiting toxicity was myelosuppression with predominant thrombocytopenia. Myelosuppression was dose-related and non-cumulative, with considerable interpatient variability depending on haematological risk factors. The maximum tolerated dose of brequinar was 210 mg/m2/day in poor risk patients whereas patients with good risk haematological profile tolerated higher doses (up to 350 mg/m2/day). Other non-limiting toxicities included nausea and vomiting, mucositis and skin reactions. Brequinar plasma pharmacokinetic profiles were biphasic with alpha half-life ranging from 0.1 to 0.7 h, and beta half-life ranging from 1.5 to 8.2 h. Increase in brequinar area under the plasma concentration versus time curves (AUC) was nonlinear. Day 5 brequinar pharmacokinetics obtained in 21 patients indicated a significant increase in AUC (47%) and half-life beta (133%) compared to day 1 pharmacokinetics in the same patient. Brequinar plasma AUC and the per cent change in platelet count at nadir were correlated (P < 0.001). Although no objective response was observed in this study, one minor response was noted in cervical lymph nodes of a Hodgkin's disease patient.

[Evaluation of the "squamous cell carcinoma antigen" as marker of epidermoid cancer of the anal canal]. / Evaluation du "Squamous Cell Carcinoma Antigen" comme marqueur du cancer epidermoïde du canal anal.

The authors studied the value of Squamous Cell Carcinoma Antigen (SCC) in squamous carcinoma of the anal canal in 66 patients. Assays were made at the time of diagnosis, before any treatment and during follow-up. A total of 353 assays were made. The positive threshold was selected at 2 ng/ml. At the time of diagnosis, sensitivity of the marker was 44 per cent and its specificity 92 per cent. In our series, pre-treatment SCC levels were not correlated with T by the Papillon classification, but were correlated with lymph node involvement (p less than 0.05). They had no prognostic value at the time of the initial diagnosis. During follow-up, at the time of recurrence, SCC levels were 20.3 +/- 43 ng/ml. This rise was significant (p less than 0.01), the sensitivity of the marker being 77 per cent. In patients who had a recurrence, the outcome was correlated with SCC levels and the latter were of prognostic value (p less than 0.01). In conclusion, SCC levels should form part of the clinical monitoring of patients with a squamous carcinoma of the anal canal.

Prognostic value of total cathepsin D in breast tumors. A possible role in selection of chemoresistant patients.

Evaluation of prognostic factors for breast cancers is important for therapeutic decisions both at the time of surgery and during postoperative surveillance. In 1979, H. Rochefort described an induced protein with a molecular weight of 52,000 Daltons identified as procathepsin D. Total cathepsin D (TCD) (52K + 48K + 34K), expressed in pmol/mg protein, can be measured by an immunoradiometric method commercialized by Cis-Biointernational. Total cathepsin D was assayed in 413 breast cancer tumors from patients who underwent surgery between January 1, 1978, and December 31, 1985. Using a cut-off of 35 pmol/mg protein, patients with an elevated level had a significantly poorer survival than those with a low level (p = 0.03). This difference was not found for node-negative patients but was very significant for node-positive patients (p less than 0.008). The survival of node-positive patients with a low total cathepsin level was not statistically different from that of node-negative patients. Analysis of the N+ subgroup of patients who did not receive adjuvant chemotherapy revealed that TCD no longer had any prognostic value, whereas it was still important for the N+ subgroup who received an adjuvant treatment. Cox multivariate analysis of prognostic value for survival placed total cathepsin D in third position, after nodal invasion and progesterone receptor status, for the entire population, and in first position before progesterone receptor status for the node-positive population. The association of a low cathepsin level and positive progesterone receptors characterized the subgroup of patients with the longest survival. TCD levels played the same role for prediction of the outcome of metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of "squamous cell carcinoma antigen" (SCC) as a marker of epidermoid carcinoma of the anal canal.

We measured squamous cell carcinoma antigen (SCC) in epidermoid carcinoma of the anal canal in 66 patients. Samples were taken at diagnosis, before treatment, and during follow-up; 353 samples were analyzed. The positive threshold was taken as 2 ng/ml. At diagnosis, the sensitivity of the marker was 44 percent and its specificity 92 percent. In our series, the pretherapeutic level of SCC does not correlate with T as in Papillons' Clinical Staging System, but it does correlate with nodal invasion (P less than 0.05). It is of no prognostic value at the time of diagnosis. During follow-up, at relapse the level of SCC is 20.3 +/- 43 ng/ml. This increase is significant (P less than 0.01): the sensitivity of the marker is 77 percent. In patients who have relapsed, development of the illness correlates with the level of SCC, which is of prognostic value (P less than 0.01). In conclusion, the level of SCC should be associated with the clinical follow-up of patients with epidermoid carcinoma of the anal canal.

Pharmacokinetics of cisplatin given at a daily low dose as a radiosensitiser.

A total of 25 patients with inoperable cervical cancer were treated by daily radiotherapy (2 Gy); sensitisation was obtained by administration of 5 mg cisplatin 30 min before each irradiation session. The total cumulative dose of cisplatin varied between 50 and 150 mg. A complete kinetic profile (0-24 h) of platinum (Pt) was established after the first dose and at the end of treatment for 22 patients. Pt was quantified by atomic absorption spectrophotometry using Zeeman-effect background correction for trace analysis. The total Pt AUC0-24h increased from 1.53 +/- 0.77 to 7 +/- 3.55 micrograms.h.ml-1 between the start and the end of treatment (P less than 0.001). Ultrafilterable Pt (Pt UF) rose from 0.079 +/- 0.038 to 0.138 +/- 0.095 microgram.h.ml-1 (P less than 0.01). Elimination half-lives were unchanged for total Pt but rose for Pt UF; these kinetic modifications in Pt UF did not correlate with any significant change in individual serum creatinine levels. No clear correlation was found between the cumulative cisplatin dose and tumor levels measured in 13 patients, and the tumor cisplatin dose did not correlate with response to treatment. Patients with hematological toxicity were characterised by an increase in their residual Pt UF level during treatment. Overall, our findings strengthen the notion of Pt UF kinetic variability during repeated treatment.

Phase II study of mitozolomide (M & B 39,565) in head and neck cancer.

Nineteen patients with advanced head and neck cancer were given mitozolomide (MTZ), i.v. infusion, every 6 weeks. The starting dose was 100 mg m-2. When it was well tolerated, dose escalation was performed up to 110-115 mg m-2. The limiting toxicity was thrombocytopenia, often mild, but occasionally severe, with hemorrhage and the need for platelet transfusions in two patients. The platelet nadir was 85 x 10(9) l-1 (11-225). No response was observed in 14 evaluable patients. MTZ, according to this schedule and dosage does not show significant activity in human squamous cell head and neck cancer.