Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer.

BACKGROUND: Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up. PATIENTS AND METHODS: Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires. RESULTS: Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) [P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76-1.36 and P = 0.3, HR = 0.87; 95% CI, 0.66-1.15, respectively]. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51-1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3-4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms. CONCLUSIONS: The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.

Analysis of patients' narratives posted on social media websites on benfluorex's (Mediator® ) withdrawal in France.

WHAT IS KNOWN AND OBJECTIVE: Websites and discussion lists on health issues are among the most popular resources on the Web. Use experience reported on social media websites may provide useful information on drugs and their adverse reactions (ADRs). Clear communication on the benefit/harm balance of drugs is important to inform proper use of drugs. Some data have shown that communication (advisories or warnings) is difficult. This study aimed to explore the Internet as a source of data on patients' perception of risk associated with benfluorex and the impact of wider media coverage. METHODS: Three French websites were selected: Doctissimo, Atoute.org considered the best-known and visited website in France for health questions and Vivelesrondes (Long live the Tubbies) for overweight people. Three periods were chosen: (1) before November 2009 (i.e. before benfluorex withdrawal), (2) between November 2009 and November 2010 (when the risk of valvulopathy with benfluorex appeared in social media) and (3) after November 2010. RESULTS AND DISCUSSION: Two hundred twenty initial postings were analysed. These lead to 660 secondary postings which were analysed separately. In period 1, 114 initial postings were analysed, mostly concerning efficacy of the drug (72%). In period 2, 42 initial postings were analysed involving mainly ADRs or warnings (73%). In period 3, 64 initial postings were analysed; most frequent expressing anger directed at the healthcare system (58%) and anxiety about cardiovascular ADRs (30%). Online consumer postings showed that there were drastic changes in consumers' perceptions following media coverage. WHAT IS NEW AND CONCLUSION: This study suggests that analysis of website data can inform on drug ADRs. Social media are important for communicating information on drug ADRs and for assessing consumer behaviour and their risk perception.

Deciphering the immune microenvironment of a tissue by digital imaging and cognition network.

Evidence has highlighted the importance of immune cells in various gut disorders. Both the quantification and localization of these cells are essential to the understanding of the complex mechanisms implicated in these pathologies. Even if quantification can be assessed (e.g., by flow cytometry), simultaneous cell localization and quantification of whole tissues remains technically challenging. Here, we describe the use of a computer learning-based algorithm created in the Tissue Studio interface that allows for a semi-automated, robust and rapid quantitative analysis of immunofluorescence staining on whole colon sections according to their distribution in different tissue areas. Indeed, this algorithm was validated to characterize gut immune microenvironment. Its application to the preclinical colon cancer APCMin/+ mouse model is illustrated by the simultaneous counting of total leucocytes and T cell subpopulations, in the colonic mucosa, lymphoid follicles and tumors. Moreover, we quantify T cells in lymphoid follicles for which quantification is not possible with classical methods. Thus, this algorithm is a new and robust preclinical research tool, for investigating immune contexture exemplified by T cells but it is also applicable to other immune cells such as other myeloid and lymphoid populations or other cellular phenomenon along mouse gut.

Guidelines for postmortem protocol for ocular investigation of sudden unexplained infant death and suspected physical child abuse.

Postmortem examination is a cornerstone in identifying the cause of unexplained sudden death in children. Even in cases of suspected or known abuse, an autopsy may help characterize the nature of the abuse, which is particularly important in the forensic autopsy of children in the first 3 to 4 years of life when inflicted neurotrauma is most common. Forensic examinations are vital in cases that might otherwise be diagnosed as sudden infant death syndrome. The ocular autopsy in particular may demonstrate findings that were not appreciated on antemortem clinical examination. This protocol for postmortem examination of the eyes and orbits was developed to promote more consistent documentation of findings, improved clinical and forensic decision making, and more replicable and coherent research outcomes.

Comparative bioavailability study of cefixime administered as tablets or aqueous solution.

The relative bioavailability of cefixime was studied in 24 healthy male volunteers, with each subject receiving a single 400mg dose of cefixime administered as an aqueous solution, a 400mg tablet and two 200mg tablets, in a randomised crossover sequence. Serum and urine samples were analysed using high-performance liquid chromatography. Peak cefixime levels were achieved 3 hours after administration of the solution vs 4 hours for the 2 tablet formulations; however, the extent of absorption was only slightly improved with the solution (by 14 and 7% compared with the 1 x 400 and 2 x 200mg tablets, respectively). The 400mg and 2 x 200mg tablets were found to be bioequivalent. The pharmacokinetic profile of the 400mg cefixime tablet (mean maximum plasma concentrations of 4.4 mg/L at 4 hours, area under the concentration-time curve of 34.4 mg/L.h, and apparent terminal elimination half-life of 3.7 hours) supports the clinical evaluation of a 400mg once-daily dosage regimen for cefixime.

Negative-configuration electroretinogram in Oregon eye disease. Consistent phenotype in Xp21 deletion syndrome.

OBJECTIVE: To determine whether abnormal configurations on electroretinogram were a consistent finding in patients with Xp21 deletion and to characterize the associated ophthalmologic phenotype. DESIGN: Case series. SETTING: University hospitals and eye institutes. PATIENTS: Five patients with complex glycerol kinase deficiency (Duchenne-type or Becker's muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia) and demonstrated chromosomal deletions at Xp21. Control patients were matched by age. MAIN OUTCOME MEASURES: Clinical information was obtained from medical records. Complete ophthalmologic examinations were performed. Electroretinography was performed using a Ganzfeld technique and chloral hydrate sedation. RESULTS: We report the clinical features and abnormal configurations on electroretinograms of five patients with complex glycerol kinase deficiency, including follow-up studies on a previously described patient. The original patient had ocular hypopigmentation; four, strabismus; two, myopia; three, astigmatism; and one, symptomatic night blindness. All had negative configurations on scotopic electroretinograms showing a reduced-amplitude B wave in the dark-adapted state. CONCLUSIONS: Our original report suggested a diagnosis of Aland Island eye disease, which appears to be an incomplete form of congenital stationary night blindness. Linkage data place Aland Island eye disease and congenital stationary night blindness at Xp11, whereas our patients had deletions at Xp21. The phenotype reported here may represent the effects of a single gene defect or the compound effects of the Xp21 contiguous gene syndrome (complex glycerol kinase deficiency). The phenotype is referred to as Oregon eye disease.

In vitro activity of quinupristin/dalfopristin in comparison with five antibiotics against worldwide clinical isolates of staphylococci.

OBJECTIVE: To evaluate the in vitro activity of quinupristin/dalfopristin (Q/D), a streptogramin combination, in comparison with five antibiotics against worldwide clinical isolates of staphylococci. METHODS: A multicenter in vitro study was performed using the E test during a period of 3 months (April to June) in 1997 on fresh, clinically significant, non repetitive strains of staphylococci from patients hospitalized in 23 different hospitals in 18 countries tested. RESULTS: A total of 2132 staphylococcal isolates including methicillin resistant (MR), methicillin susceptible (MS) S. aureus (1003 MS, 462 MR), S. epidermidis (169 MS, 251 MR), S. haemolyticus (28 MS, 46 MR), S. hominis (28 MS, 16 MR), and coagulase negative staphylococci (86 MS, 43 MR) were analyzed. Q/D was highly active against all species tested. MIC90 (mg/L) ranged from 0.5 to 2 depending on the species. Strains had MIC < or = 1 mg/L in 97.6%. For S. aureus, S. epidermidis, S. hominis and other coagulase-negative staphylococci no differences in MIC90 were observed for MS or MR. One dilution difference was observed for S. haemolyticus, which overall was the less susceptible species. Erythromycin resistance was observed among 57- 87% of MR-strains and was lower among MS-strains (18-56%). Erythromycin resistance had no or little influence on MIC of Q/D. In comparison to vancomycin, Q/D was two to four times more active. CONCLUSIONS: The streptogramin combination Q/D showed an excellent in vitro activity against all staphylococcal species tested regardless of the resistance pattern to other drug classes, particularly resistance to methicillin. Q/D was two to four times more active than vancomycin and MIC values varied from 0.5-2 according to the species. The synergy of Q/D was well conserved in macrolide-resistant strains.

The view of the pharmaceutical industry.

Rhône-Poulenc Rorer has committed itself to the development of artemether because we believe the drug will be of considerable benefit to sufferers from severe falciparum malaria, and because it is a stable, effective and economical compound that can be given by intramuscular injection. The quality of the pharmaceutical product meets international regulatory standards. Artemether is unlikely to yield big profits, but we believe that major pharmaceutical companies have a responsibility to develop such much-needed products. To develop this project further, we will need the assistance of academic institutions, research organizations and international bodies.

[Obstructive mitral vegetations in bacterial endocarditis. Disappearance after migration as an embolism]. / Végétations mitrales obstructives au cours d'une endocardite bactérienne. Disparition après migration embolique.

An unusual form of mitral valve endocarditis was observed on echocardiography. A 49 year old female with well tolerated mitral stenosis and mild aortic incompetence contracted staphylococcal endocarditis. Pulmonary venous hypertension developed and the diastolic murmur increased. The echocardiogramme showed voluminous vegetations obstructing the stenosed mitral orifice in diastole, simulating a left atrial myxoma. An acute ischaemic episode of the lower limb occurred under antibiotic therapy. A voluminous fibrino-cruoric infected embolus was extracted from the iliac artery and a second echocardiogramme showed the intra mitral mass to have disappeared. Concurrently, the diastolic murmur decreased and the signs of intolerance disappeared. When the infective process seemed to have been controlled, the patient died suddenly. Post-mortem examination showed fresh mitral endocardial lesions and renal and splenic infarcts. Five cases of mitral obstruction by vegetations have been previously reported, three of which had echocardiographic studies. The echocardiographic image is stereotyped and resembles a myxoma wedged in the mitral orifice but without the intra atrial mass. This type of mitral obstruction complicated moderate mitral stenosis in all cases. Regression of the echographic appearances of valvular vegetations has been reported in rare cases, but we were unable to find another case of embolism of vegetations reducing the valvular obstruction.

Hyperhomocysteinaemia: a risk factor for extracranial carotid artery atherosclerosis.

Hyperhomocysteinemia arising from impaired methionine metabolism, and usually due to a deficiency of cystathionine beta-synthase is a significant and independent risk factor for symptomatic vascular disease. It is not known if hyperhomocysteinemia in apparently healthy asymptomatic subjects is associated with atherosclerosis and whether such a relationship is independent of conventional risk factors. The prevalence of asymptomatic extracranial carotid artery atherosclerosis was determined by duplex ultrasound examination in 25 obligate heterozygotes with respect for cystathionine beta-synthase deficiency (whose children were known to be homozygous for this genetic defect) and in 21 controls. Hyperhomocysteinemia was determined by a standard methionine-loading test and conventional risk factors were also recorded. Twelve of 25 obligate heterozygotes and 8 of 21 normal controls had evidence of extracranial carotid artery atherosclerosis. Hyperhomocysteinemia as a genetic trait was not a significant risk marker, but the actual homocysteine level was associated with an increased risk of carotid disease. After adjustment for the effects of other significant risk factors, the odds ratio of hyperhomocysteinemia for carotid disease was 1.038 per unit increase in homocysteine level (P = 0.03). Hyperhomocysteinemia is a weak risk factor for asymptomatic extracranial carotid atherosclerosis and the relative risk associated with this genetic trait is less than that observed in a study of patients presenting with clinical manifestations of vascular disease.

Long term therapy of cytomegalovirus retinitis with ganciclovir in a child with acquired immunodeficiency syndrome.

Cytomegalovirus retinitis is the most severe ophthalmological complication of patients with acquired immune deficiency syndrome (aids). Ganciclovir must be given continuously to control progression of the disease or relapse typically occurs. Data in children are limited; this report describes a nine-year-old boy with transfusion-acquired aids who was treated with ganciclovir for 23 months for control of cytomegalovirus retinitis. The retinal disease was exacerbated when ganciclovir was temporarily withheld because of presumed drug toxicity, and improved with re-institution of therapy. When ganciclovir was finally discontinued because of complete loss of vision, the patient rapidly deteriorated and died; widespread cytomegalovirus infection was found at autopsy. Subcapsular cataracts appearing during therapy were thought to be a toxic effect of ganciclovir. Ganciclovir can be effective in controlling cytomegalovirus retinitis in children; however, similarities in laboratory findings may lead to confusion between systemic drug toxicity and disease progression.

[Value of the assay of 4 urinary enzyme activities in the diagnosis of the infectious or toxic (aminoglycosides) origin of a renal disease. Preliminary results]. / Etude de la valeur des dosages de quatre activités enzymatiques urinaires dans le diagnostic de l'origine infectieuse ou toxique (aminosides) d'une atteinte rénale. Résultats préliminaires.

Occurrence of a renal failure in an infected patient may be referred to various causes: infection, renal toxicity of drugs (for instance aminoglycosides), shock . . . Determination of some urinary enzymatic activities might be helpful in unravelling the mechanism involved in such cases. Therefore a prospective study of the specificity of some urinary enzymatic activities was performed. The whole LDH activity, the LDH isoenzyme 5 (LDH 5), and two lysosomal enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and beta-glucuronidase (beta-GLU) were dosed systematically, in several groups of patients: I (n = 34): healthy control, with normal renal function; II (n = 24): renal impairment, without recent upper urinary-tract infection (UTI) or aminoglycoside treatment; III (n = 27): upper UTI without aminoglycoside treatment, IV (n = 22): patients treated with aminoglycosides (without upper UTI); V (n = 16): upper UTI treated with aminoglycosides. Results showed a rather good specificity of whole LDH and LDH 5 for infectious kidney damage, and of NAG for tubular injury due to aminoglycoside treatments. Values of urinary beta-glucuronidase varied over a wide range; they were little increased in group III, without a great discriminative value. No significant difference was noted between group I and group II, for any enzyme whatever.

[Evaluation of the handicap and the quality of life in spinal cord injuries: study in a population of 58 patients living at home]. / Evaluation du handicap et de la qualité de vie chez les blessés médullaires: étude d'un échantillon de population de 58 sujets vivant à domicile.

GOAL: The main purpose of this study was to identify objective factors (social and economic status, impairments, functional limitations) contributing to the subjective quality of life of subjects presenting with residual neurological deficits from a traumatic spinal cord injury (SCI) and living at home. SUBJECTS AND METHOD: This is a cross-sectional descriptive study of a sample of SCI patients followed at a Physical Medicine and Rehabilitation facility. After informed consent was obtained, a clinical and functional examination was conducted and questionnaires were filled out by the subjects. The following parameters were assessed: impairments (sensory and motor ASIA scores), disability (Barthel Index and Functional Independence Measure), and quality of life (Reintegration to Normal Living Index and Nottingham Health Profile). RESULTS: Fifty-eight subjects completed the study (mean age 41.38 +/-13.55 years and mean delay from onset 6.24 +/- 6.06 years). There was a strong significant correlation between the level of quality of life and the current age, the age at the time of the accident and the disability level, particularly for the dimensions of physical independence, social integration and mobility. CONCLUSION: Our results are consistent with published data, which identify age as a determining factor of quality of life after SCI. Our review of the literature indicated that time from onset influences quality of life. Longitudinal studies, taking into account the levels of social participation, are needed to better understand the impact of time on quality of life after SCI.

[Cefixime, the first oral third-generation cephalosporin]. / Le céfixime, première céphalosporine orale de troisième génération.

In the early 1980's parenteral third generation cephalosporins changed the hospital use of antibiotics. The MICs of these cephalosporins are several dozen times lower than those of first or second generation cephalosporins for Enterobacteriaceae and they are much more beta-lactamase stable than second generation cephalosporins. After years of research, is has finally been possible to develop orally active compounds possessing the same antibacterial activity as parenteral third generation cephalosporins, either through the use of prodrugs, or by modifying the molecular structure of drugs. Cefixime is an example of the latter. The vinyl group at the 3-position of the cephem nucleus is responsible for the intestinal absorption of the intact molecule, primarily by a carrier-mediated transport mechanism. The aminothiazole ring and the R-oxyimino group on the side-chain at the 7-position are associated with an antibacterial activity similar to that of third generation cephalosporins. Thousands of adults have been treated by cefixime for lower respiratory tract, ear-nose-throat and urinary tract infections, showing that cefixime is a safe and effective antimicrobial agent. The major clinical indications for cefixime in adults are bronchial and pulmonary infections, acute otitis or sinusitis, acute pyelonephritis with no underlying uropathy, and complicated or uncomplicated lower urinary tract infections excluding prostatitis. In all cases, the dosage is 200 mg b.i.d.

[Comparative study of 2 dosage regimens of cefixime in the treatment of otorhinolaryngeal or bronchial infections]. / Etude comparative de deux schémas d'administration du céfixime dans le traitement des infections otorhinolaryngées ou bronchiques.

A double-blind comparative study of cefixime (400 mg/day), given either as a single daily dose, or in two divided doses, was carried out in collaboration with 54 general practitioners. This study was mainly directed towards tolerance assessment. 431 patients with upper and lower respiratory tract infection were included. In terms of tolerance, 89 per cent of patients showed no side-effect and the tolerance was deemed satisfactory in 90.3 per cent of the cases by the investigators, without any statistically significant difference between both groups. Roughly, the most frequent side-effects were gastrointestinal reactions, such as diarrhea or stool changes (4.0 per cent), gastralgia (1.9 per cent), nausea and/or vomiting (1.6 per cent). In terms of effectiveness, after an average of 8.8 +/- 0.1 days of treatment, 94.4 per cent of assessable patients were improved or cured. Once again, there was no statistical difference between both groups. Cefixime effectiveness and safety are comparable with both modes of administration.

[In vitro comparative bactericidal effect of cefotaxime and cefixime in a kinetic model]. / Activité bactéricide comparée du céfotaxime et du céfixime dans un modèle cinétique in vitro.

The bactericidal activity of cefotaxime against Escherichia coli, Klebsiella pneumoniae and Serratia marcescens, was compared with that of cefixime in an in vitro model simulating the human pharmacokinetics of these antibiotics. Kinetic parameters in this model were T1/2 = 1.3 h and Cmax = 45 mg/l for cefotaxime; T1/2 = 3.5 h and Cmax = 5 or 3.5 mg/l for cefixime. These parameters mimicked those obtained after a 1 g intravenous infusion of cefotaxime and an oral uptake of 0.4 or 0.2 g of cefixime, respectively. Both antibiotics demonstrated a strong bactericidal activity. Against Escherichia coli, the bactericidal effect of cefotaxime was slightly more rapid and more prolonged than that of cefixime: -5 log10 CFU/ml over 4 h vs -3 log10 CFU/ml over 8 h respectively. Against Klebsiella pneumoniae and Serratia marcescens, both drugs exhibited similar bactericidal activity despite different dosages and routes of administration: -2 to -3 log10 CFU/ml over 4 h.

[Pulmonary diffusion of cefixime in man]. / Diffusion pulmonaire du céfixime chez l'homme.

We measured the concentrations of cefixime in the human lung in vivo in order to evaluate indirectly the effectiveness of this antibiotic in the treatment of pulmonary infections. Twenty-three patients undergoing lung surgery entered the study and received cefixime either 200 mg 12-hourly (4 times) or 400 mg every 24 hours (twice). Blood samples and tissue specimens were collected simultaneously during surgery 4 or 8 hours after the last dose. Cefixime concentrations were measured by HPLC. The penetration of cefixime in both normal and neoplastic lung tissue was significant. Four or 8 hours after a 200 or 400 mg oral dose, lung concentrations were higher than the MIC90 values for sensitive strains and therefore consistent with effective therapeutic activity. The pharmacokinetics of cefixime in blood and in lung tissue suggest that pulmonary infections could be treated with a 400 mg dose once a day.

[Pharmacokinetics of cefixime in healthy volunteers after a single oral administration of 200 mg]. / Pharmacocinétique du céfixime chez le volontaire sain après administration orale unique à la dose de 200 mg.

The antibacterial activity of cefixime is identical with that of parenteral third generation cephalosporins. Its kinetics were studied in 24 healthy male volunteers who received one single 200 mg tablet. Cmax was 3.25 mg/l and Tmax was 4 h. After 12 hours, serum concentrations were still as high as 0.70 mg/l. Half-life was 3.3 h and urinary excretion was not predominant. Thus, cefixime was characterized by its relatively long serum half-life as compared with other cephalosporins. Despite some degree of individual variations, serum and urine concentrations of the antibiotic remained for 12 hours above the MIC of susceptible pathogens.

[Effect of hepatic failure upon the pharmacokinetics of cefixime]. / Influence de l'insuffisance hépatique sur la pharmacocinétique du céfixime.

Modifications of cefixime kinetics due to severe impairment of liver function were determined in 9 cirrhotic patients. Cefixime was administered as a single dose of 200 mg and levels were measured by HPLC. Maximum serum concentrations and area-under-the-curves of serum concentrations were not modified. The time for maximum serum concentration was delayed and the cefixime half-life in serum was prolonged, as a reflect of increased volume of distribution resulting from ascites and hypoalbuminemia. Renal clearance increased in these patients, possibly because of reduced extra-renal clearance. No metabolite was detected in serum or urine. Modifications of cefixime kinetics resulting from impaired hepatic function were modest and did not require specific dosage adjustment.