Invasive Streptococcus pneumoniae in France: antimicrobial resistance, serotype, and molecular epidemiology findings from a monthly national study in 2000 to 2002

A study of 257 French invasive pneumococci isolated between 2000 and 2002 showed high rates of nonsusceptibility to penicillin and macrolides (50%), contrasting with a low frequency of resistance to amoxicillin or levofloxacin (<1%) and tolerance to vancomycin (0%). The genetic homogeneity of some serogroups, including serogroup 1, enhanced the risk of epidemiological changes.     

Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3-year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case-control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow-up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34-89)). The SIR was 113 (95% CI: 62-185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2-125) after chemotherapy alone (1 STS) and 19 (95%CI: 3-60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case-control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended.     

Antineoplastic potency of arylchloroethylurea derivatives in murine colon carcinoma

In a search for new antineoplastic agents the lead compound N-(4-tert-butylphenyl)-N'-(2-chloroethyl)urea (CEU-22) of a series of 1-aryl-3-(2-chloroethyl)ureas and its iodinated bioisostere CEU-98, were previously selected on the basis of their cytotoxicity and the potent tropism for the intestinal tract (evidenced for CEU-22). In this study, we investigated the antitumour profile of these two drugs for the indication of colon cancer. In vitro, we found that micromolar concentrations of both CEU-22 and CEU-98 inhibited proliferation of DLD-1, Caco-2, HT-29, SW-948 and CT-26 lines. In vivo, a high inhibition of tumour growth and a life span increase were observed when BALB/c mice grafted subcutaneously with CT-26 cells received 5 daily intratumoural injections of each drug. When administered by the intraperitoneal route according to an intermittent schedule starting Day 1 or Day 7 post-implant, only CEU-98 demonstrated antitumour activity ( T / C = 29% for the Day-1,5,9-treatment versus 40% for the Day-7,11,15-treatment) and a life span increase around 40% for the two protocols. These results make CEU-98 a candidate for further investigations with a view to developing an efficacious treatment of colorectal cancer.     

Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis

Previous studies have suggested that angiotensinogen (AGT) gene variants are associated with increased plasma AGT levels, and may also contribute towards the inherited component of predisposition to essential hypertension in humans. To explore the potential functionality of several AGT polymorphisms and estimate their effects, together with other sources of familial correlations, on plasma AGT, we undertook a large study involving 545 healthy French volunteers in 130 nuclear families that include 285 offspring. Plasma AGT levels were measured in all participants, and bi-allelic AGT variants were analysed as candidate functional variants at three sites in the 5'-flanking region (C-532T, A-20C, G-6A), two sites in exon 2 (M235T, T174M) and two newly identified variant sites in the untranslated sequence of exon 5 and the 3'-flanking region (C+2054A, C+2127T) of the gene. Analysis with the class D regressive model showed significant effects influencing plasma AGT levels of all AGT polymorphisms tested, with the exception of T174M. The most significant result was found at C-532T (P=0.000001), which accounts for 4.3% of total plasma AGT variability in parents and 5.5% in offspring, with substantial residual familial correlations. Maximum likelihood estimates of haplotype frequencies and tests of linkage disequilibrium between each AGT polymorphism and a putative QTL are in agreement with a complete confounding of C-532T with the QTL, when taking into account sex and generation specific effects of the QTL. However, further combined segregation-linkage analyses showed significant evidence for additional effects of G-6A, M235T and C+2054A polymorphisms after accounting for C-532T, which supports a complex model with at least two functional variants within the AGT gene controlling AGT levels.     

Health outcomes of children fathered by patients treated with radioiodine for thyroid cancer

Context and objectives  Radiation is known to be mutagenic. The present study analyses birth outcomes and the health of offspring from men previously exposed to ¹³¹I treatment for thyroid carcinoma.
Methods  Data on 493 pregnancies (356 from 173 untreated fathers, 23 from 17 patients who have undergone surgery alone and 114 from 63 fathers who received ¹³¹I) were obtained by interviewing male patients treated for thyroid carcinoma who had not received significant external radiation to the testes. Among these pregnancies, 73 were conceived from fathers who had received more than 370 MBq.
Results  The mean activity for the 114 pregnancies fathered by 63 patients was 3993 MBq leading to an estimated radiation dose of 9·2 cGy to the testes (MIRD committee coefficient). No significant differences between untreated and treated fathers were found for any adverse outcome.
Conclusion  There was no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring, whatever the event considered. As our study is underpowered, the question of whether testicular irradiation, fractionated or not, is linked to impaired fertility or consequences on offspring remains to be established.     

Tocilizumab controls bone turnover in early polymyalgia rheumatica

ObjectivesThis study explores changes in the bone homeostasis by testing the N-terminal collagen type I extension propeptide (PINP) marker for osteo-formation and the carboxy-terminal region of collagen type I (CTX-I) marker for osteo-resorption in patients taking tocilizumab for polymyalgia rheumatica (PMR).MethodsTwenty patients were included in the prospective open-label TENOR study (Clinicaltrials.gov NCT01713842) and received three monthly tocilizumab infusions, followed by corticosteroids starting at week (W) 12. PINP and CTX-I were tested at inclusion (W0), after tocilizumab but before steroid initiation (W12), at the end of the protocol (W24) and were compared to healthy controls. Information regarding disease activity, bone mineral density using scanographic bone attenuation correlation (SBAC), inflammatory parameters and interleukin (IL)-6 levels were collected during the follow-up of the patients.ResultsPMR patients were characterised by a reduction in bone mineral density and a higher level of CTX-I relative to healthy controls matched in age and sex at baseline. PINP levels increased at W12 (P < 0.001, versus W0) following tocilizumab introduction and CTX-I levels decreased at W24 and after steroid initiation (P = 0.001, versus W0). Such modifications explain the altered correlation observed between PINP and CTX-I at W0 (r = 0.255 at W0 versus r = 0.641 in healthy controls) and its correction after treatment (r = 0.760 at W12 and r = 0.767 at W24). Finally, greater changes in PINP were observed in patients whose circulating IL-6 levels decreased after tocilizumab therapy.ConclusionsControl of bone turnover, in part through the inhibition of the IL-6 axis, is observed during tocilizumab and subsequent steroid treatment of PMR.     

Identification of responders to a therapy: An example of validation of a predictive model

The general objective of randomized clinical trials is to assess if the treatment effect on a given population is clinically meaningful. In this way, one obtains an average estimate of the treatment effect over the trial population. However, a growing need for medical practitioners is to be able to predict with sufficient precision the efficiency of a given treatment for a given patient. There is little information in the literature about this issue. We have previously proposed a treatment-startified Cox model including interaction between treatment and patient's covariates, to identify and predict the responders to a therapy. In this paper, we focus on the assessment of the predictive power of the model. The performance of the predictive model for a population and for an individual was statistically validated internally and externally from several aspects. The prediction correlates well with the observation. Thus, we suggest that this approach would be useful in identifying and predicting the responders to a therapy, subject to an appropriate and more extensive validation process in real setting.     

Levetiracetam extended release and levetiracetam immediate release as adjunctive treatment for partial-onset seizures: An indirect comparison of treatment-emergent adverse events using meta-analytic techniques

The safety profiles of once-daily adjunctive levetiracetam (LEV) extended release (XR) (1000 mg/day) and adjunctive LEV immediate release (IR) (500 mg twice daily) were compared using data from three randomized, placebo (PBO)-controlled phase III clinical trials in patients with partial-onset seizures. MedDRA 9.0 treatment-emergent adverse events (TEAEs) were indirectly compared using meta-analytic techniques, including calculation of risk difference (RD) and mixed-effects analysis. Statistical significance was set at 10% alpha risk, the normative value for these analyses. Data from 555 patients older than 16 (204 LEV IR, 70 LEV XR, 281 PBO) were analyzed. Following adjustment for incidence of placebo TEAEs, LEV XR showed statistically significantly lower rates of TEAEs than LEV IR across nervous system disorders (RD = −18%, P = 0.03), psychiatric disorders (RD = −11%, P = 0.08), and metabolism and nutrition disorders (RD = −3%, P = 0.08). Among nervous system disorders, the RD for headache favored LEV XR (RD = −11%, P = 0.08). These results suggest that adjunctive LEV XR may be associated with a lower incidence of nervous system, psychiatric, and nutritional and metabolic TEAEs as compared with LEV IR. However, this difference was observed at a broad scale and not at a specific TEAE level except for headache.