SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients.

PURPOSE: To determine incidence of non-AIDS-defining cancers (NADC) in HIV-infected patients before (P1) and during (P2) the use of highly active antiretroviral therapy (HAART) relative to that observed in the French general population (FGP) of the same age and sex. PATIENTS AND METHODS: Sex- and age-adjusted NADC standardized incidence ratios (SIR), with FGP as reference, were estimated in 1992 to 1995 (P1) and in 1996 to 1999 (P2) in a French Hospital Database on HIV prospective hospital cohort study. RESULTS: NADCs were diagnosed in 260 patients during P1 and 391 patients during P2 among the 77,025 patients included in the database between January 1, 1992, and December 31, 1999. Estimated incidence of all cancers was higher in HIV-infected men than in FGP during both periods (P1 SIR = 2.36 and P2 SIR = 1.91). No excess of cancers was observed among HIV-infected women in either period. Incidence of all cancers did not change from P1 to P2 in either sex (SIR = 0.96 for men and 1.00 for women). In contrast, incidence of Hodgkin's disease (HD) was higher than in FGP in both sexes and both periods and increased in P2 as compared with P1; incidence of lung cancer was higher in both sexes during P2. CONCLUSION: Relative to FGP, the overall incidence of NADCs was increased in HIV-infected men but not in women and did not differ between P1 and P2. Only HD was much more common in HIV infection, and the potential role of HAART on HD cannot be excluded.     

Hepatocyte growth factor and c-Met in cervical intraepithelial neoplasia: overexpression of proteins associated with oncogenic human papillomavirus and human immunodeficiency virus.

PURPOSE: High prevalence of squamous cervical intraepithelial neoplasia (CIN) linked to oncogenic human papillomavirus (HPV) exits in HIV-infected women. Hepatocyte growth factor (HGF) and its receptor, c-Met, promote cell proliferation and are involved in tumor progression. Nothing is yet known about their expression in low- and high-grade CIN. Therefore, the expression, localization, and behavior of HGF and c-Met in normal and dysplastic cervical epithelium were investigated. EXPERIMENTAL DESIGN: We studied normal cervical mucosa from 10 healthy women, and low- and high-grade cervical lesions, uninfected (condyloma acuminata) or infected with oncogenic HPVs, from 40 HIV-negative and 48 HIV-positive women, using in situ molecular techniques, immunocytochemistry and morphoquantitative methods. RESULTS: In 154 oncogenic HPV-infected CIN encountered in biopsy samples, the total number of epithelial cell layers increased significantly during lesion progression. This number was significantly higher in HIV-positive than in HIV-negative women for CIN1 and CIN2 (P < 0.025 to P < 0.01). In HIV-negative women, the number and percentage of HGF and c-Met immunostained cell layers, and the intensity of immunostaining were enhanced in oncogenic HPV-infected lesions as compared with normal mucosa and condyloma acuminata. The latter parameters were significantly higher in tissues of HIV-positive women (oncogenic HPV-infected CIN1 and CIN2, normal-appearing mucosa contiguous to CIN, condyloma acuminata) than in the corresponding tissues of HIV-negative women (P < 0.025 to P < 0.0001). CONCLUSIONS: Overexpression of HGF/c-Met complex strongly correlates with oncogenic HPV and HIV infection. This overexpressed complex may stimulate cell proliferation in condyloma acuminata and participate in tumor progression in oncogenic HPV-infected lesions.     

Predictive factors of acute urinary morbidity after iodine-125 brachytherapy for localised prostate cancer: a phase 2 study.

PURPOSE: To analyse predictive factors of acute urinary morbidity after transperineal permanent prostate brachytherapy. METHODS AND MATERIALS: Sixty patients treated in a phase 2 study with iodine-125 brachytherapy (9/1998 to 2/2000) for localised prostate adenocarcinoma were analysed after at least 1-year follow-up. Prescribed dose was 144 Gy and all patients had a pre-planning and a post-implant dosimetry. Urinary morbidity was evaluated prospectively using the Radiation Therapy Oncology Group (RTOG) scale. We examined the relationship between pre-implant ultrasound prostate volume, post-implant CT-scan prostate volume, neoadjuvant hormonotherapy, total number of needles and seeds, post-implant dosimetry variables, first 30 vs. last 30 treated patients and post-implant urinary morbidity. RESULTS: All patients experienced some degree of urinary distress symptoms after treatment. Symptoms were generally mild grade 1 in 56% and grade 2 in 10% lasting less than 6 months. Eight patients (13%) required bladder catheter for acute urinary obstruction. At 1-year follow-up, nine patients (15%) complained from persistent dysuria requiring in three cases endoscopic prostate resection. The percentage of urethra volume receiving 216 Gy (cut-off 40%) and the pre-implant prostate volume (cut-off 31 ml) were the only statistically significant predictor of grade 2-3 or persistent urinary morbidity on multivariate analysis. CONCLUSION: Our short-term data suggest that both pre-implant prostate volume value and post-implant V.U. 150 value might be predictors for urinary morbidity after prostate brachytherapy.     

Accelerated fractionation in esophageal cancers: A multivariate analysis on 88 patients

: Accelerated fractionation was used to shorten overall treatment time to increase locoregional control and cause-specific survival.

: Eighty-eight patients with cancer of the esophagus ineligible for surgery were entered in the study between 1986 and 1993. Neoadjuvant chemotherapy was given to 64% of patients. Accelerated radiotherapy using the concomitant boost technique delivered a median dose of 65 Gy in a median overall treatment time of 32 days.

: The 3-year acturial local control rate in patients with T1, T2, and T3 tumors was 71%, 42%,and 33%, respectively. The 3-year cause-specific survival rates were 40%, 22%, and 6%, respectively. Sixteen percent of patients experienced Grafe 3 esophagitis. Late toxicity included esophageal stenosis and pulmonary fibrosis in 8% and 9% of the patients, respectively. Multivariate analysis demonstrated that T stage and overall treatment time were prognostic factors for cause-specific survival. T stage and neoadjuvant chemotherapy were independent prognostic factors for locoregional control.

: These findings suggest that accelerated giben in an overall treatment time of <35 days might be beneficial for easy-stage cancer of the esophagus. Neoadjuvant chemotherapy is not recommended, as it was a significant adverse prognostic factor in the multivariate analysis for local control. Accelerated fractionation can be carried out with modeate acure and late toxicity.     

Recommendations for medical management of hereditary breast and ovarian cancer: The French National Ad Hoc Committee

Background and purpose: Almost 10% of breast and ovarian cancers are familial, and the majority are linked to BRCA1 and BRCA2 germline mutations. Despite uncertainty about the management of female gene carriers, consensus guidelines have been established to assist practitioners and consultees in making health care decisions.Methodology: The Ad Hoc Committee was composed of 14 experts appointed by the French National Institute for Health and Medical Research, all of whom attended eleven workshops at which more than 3500 articles were systematically analyzed. Five additional experts critically analysed the first version of the report.Criteria and decision process: On a probability scale of the risk of developing breast or ovarian cancers, two thresholds were defined for use in determining whether an intervention would be worthwhile. The first is the threshold above which an intervention can be envisaged or recommended, and the second is the one below which an intervention can be ruled out; between the two, the decision has to be made on a case-by-case basis.Screening and preventive strategies analyzed: With respect to breast cancer: 1) hormonal interventions; 2) primary prevention (diet, family planning and chemoprevention); 3) screening (breast self-examination, clinician breast examination, tumor markers, imaging); 4) prophylactic mastectomy. With respect to ovarian cancer: 1) hormonal stimulation; 2) screening (clinical screening, ultrasound and tumor markers); 3) prophylactic oophorectomy.Main conclusions: For each strategy the following points were addressed: the information to be given to the consultee, the procedure and the indications. In addition, the committee's opinion about BRCA1 and BRCA2 mutation screening is that population-based, or even large-scale, implementation are not justified. Although no scientific evidence is available, the committee feels that specific management is indispensable and advocates the use of defined and evaluated procedures, and participation in clinical trials.     

Impact of medical practice guidelines on the assessment of patients with acute coronary syndrome without persistent ST segment elevation.

OBJECTIVE: To assess the impact of introducing clinical practice guidelines on acute coronary syndrome without persistent ST segment elevation (ACS) on patient initial assessment. DESIGN: Prospective before-after evaluation over a 3-month period. SETTING: The emergency ward of a tertiary teaching hospital. PATIENTS: All consecutive patients with ACS evaluated in the emergency ward over the two 3-month periods. INTERVENTION: Implementation of the practice guidelines, and the addition of a cardiology consultant to the emergency team. MAIN OUTCOME MEASURES: Diagnosis, electrocardiogram interpretation, and risk stratification after the initial evaluation. RESULTS: The clinical characteristics of the 328 and 364 patients evaluated in the emergency ward for suspicion of ACS before and after guideline implementation were similar. Significantly more patients were classified as suffering from atypical chest pain (39.6% versus 47.0%; P = 0.006) after guideline implementation. Guidelines availability was associated with significantly more formal diagnoses (79.9% versus 92.9%; P < 0.0001) and risk stratification (53.7% versus 65.4%, P < 0.0001) at the end of initial assessment. CONCLUSION: Guidelines implementation, along with availability of a cardiology consultant in the emergency room had a positive impact on initial assessment of patients evaluated for suspicion of ACS. It led to increased confidence in diagnosis and stratification by risk, which are the first steps in initiating effective treatment for this common condition.     

Factors associated with liver biopsy performance in HCV-HIV coinfected injecting drug users with HCV viremia: Results from a five-year longitudinal assessment

The last international consensus conference about hepatitis C virus (HCV) treatment emphasized the importance of treatment for persons coinfected with HCV and human immunodeficiency virus (HIV). As liver biopsy precedes treatment, we aimed to identify factors associated with the performance of liver biopsy among HIV-HCV coinfected drug users during a 5-year follow-up to study their access to HCV treatment. Of the 296 patients followed in the HIV hospital departments of Nice and Marseilles and with retrievable records about HCV diagnosis and care, 166 were eligible for analysis having had detectable HCV RNA at least once during the study period. Overall, 45.2% of patients underwent liver biopsy during follow-up. Using proportional hazard models, predictors of having had a liver biopsy were high social support, complete abstinence from drug injection, and lack of immunosuppression as well as male gender, no history of multiple incarcerations, more recent onset of drug use, and an increase of liver enzyme levels. These results suggest that specific efforts should be devoted to HIV-HCV coinfected drug users to assist with stabilizing these patients to optimize their access to HCV care whenever possible. The MANIF 2000 study group includes C. Boirot, A. D. Bouhnik, M. P. Carrieri, J. P. Cassuto, M. Chesney, P. Dellamonica, P. Dujardin, S. Duran, J. G. Fuzibet, H. Gallais, J. A. Gastaut, G. Lepeu, D. A. Loundou, C. Marimoutou, D. Mechali, J. P. Moatti, J. Moreau, M. Nègre, Y. Obadia, I. Poizot-Martin, C. Pradier, D. Rey, C. Rouzioux, A. Sobel, B. Spire, F. Trémolières, and D. Vlahov.     

Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis.

PURPOSE: To investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non-small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis. PATIENTS AND METHODS: Ninety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses. RESULTS: Forty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNFalpha, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011). CONCLUSION: Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.