Nonpublication and Selective Outcome Reporting of Oral Health Trials.

Less than one-quarter of oral health trials are registered in a public registry. However, no study has assessed the extent of study publication and selective outcome reporting bias in the field of oral health. We identified oral health trials registered between 2006 and 2016 in ClinicalTrials.gov. We assessed whether results of early discontinued trials, trials having an unknown status, and completed trials had been published and, among published trials, whether outcomes differed between the registered record and the corresponding publication. We included 1,399 trials, of which 81 (5.8%) were discontinued, 247 (17.7%) had an unknown status, and 1,071 (76.6%) were completed. The registration was prospective for 719 (51.9%) trials. Over half the registered trials were unpublished (n = 793, 56.7%). To explore the association between trials publication and characteristics of trials, we performed a multivariate logistic regression analysis. Trials conducted in the United States (P = 0.003) or Brazil (P < 0.001) were associated with increased odds of publication, whereas trials registered prospectively (P = 0.001) and industry-sponsored trials (P = 0.02) were associated with decreased odds. Among the 479 published trials with completed status, the primary outcomes of 215 (44.9%) articles differed from that registered. Major discrepancies consisted of the introduction of a new primary outcome in the published article (196 [91.2%]) and the transformation of a registered secondary outcome into a primary outcome (112 [52.1%]). In the remaining 264 (55.1%) trials, primary outcomes did not differ from that registered, but 141 (53.4%) had been registered retrospectively. Our study highlights the high rate of nonpublication and selective outcome reporting in the field of oral health. These results could alert sponsors, funders, authors of systematic reviews, and the oral health research community at large to combat the nondisclosure of trial results.

Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Population Pharmacokinetics of Intravenous Ganciclovir and Oral Valganciclovir in a Pediatric Population To Optimize Dosing Regimens.

Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, to optimize dosing schemes. All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using nonlinear mixed-effect modeling. Monte Carlo simulations were used to optimize the dosing regimen to maintain the area under the concentration-time curve (AUC) in the preventive or therapeutic target. Among the 105 children (374 concentration-time observations) included, 78 received intravenous (i.v.) ganciclovir, 19 received oral valganciclovir, and 6 received both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe the bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and medical status of critically ill children were significantly associated with ganciclovir elimination. Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg of body weight/day oral or 15 to 20 mg/kg/day i.v. in children with normal eGFR and to 56 mg/kg/day oral or 20 to 25 mg/kg/day i.v. in children with augmented eGFR. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.).

Population pharmacokinetics of cefazolin in critically ill children infected with methicillin-sensitive Staphylococcus aureus.

OBJECTIVES: Cefazolin is one of curative treatments for infections due to methicillin-sensitive Staphylococcus aureus (MSSA). Both growth and critical illness may impact the pharmacokinetic (PK) parameters. We aimed to build a population PK model for cefazolin in critically ill children in order to optimize individual dosing regimens. METHODS: We included all children (age < 18 years, body weight (BW) > 2.5 kg) receiving cefazolin for MSSA infection. Cefazolin total plasma concentrations were quantified by high-performance liquid chromatography. A data modelling process was performed with the software MONOLIX. Monte Carlo simulations were used in order to attain the PK target of 100% fT > 4 ×MIC. RESULTS: Thirty-nine patients with a median (range) age of 7 (0.1-17) years and a BW of 21 (2.8-79) kg were included. The PK was ascribed to a one-compartment model, where typical clearance and volume of distribution estimations were 1.4 L/h and 3.3 L respectively. BW, according to the allometric rules, and estimated glomerular filtration rate (eGFR) on clearance were the two influential covariates. Continuous infusion with a dosing of 100 mg/kg/day to increase to 150 mg/kg/day for children with a BW < 10 kg or eGFR >200 mL/min/1.73m2 were the best schemes to reach the PK target of 100% fT> 4 ×MIC. CONCLUSIONS: In critically ill children infected with MSSA, continuous infusion seems to be the most appropriate scheme to reach the PK target of 100 % fT > 4 ×MIC in children with normal and augmented renal function.

Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens.

Acyclovir is an antiviral currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. This study aimed to characterize the pharmacokinetics (PK) of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Children receiving acyclovir or valacyclovir were included in this study. PK were described using nonlinear mixed-effect modeling. Dosing simulations were used to obtain trough concentrations above a 50% inhibitory concentration for HSV or VZV (0.56 mg/liter and 1.125 mg/liter, respectively) and maximal peak concentrations below 25 mg/liter. A total of 79 children (212 concentration-time observations) were included: 50 were taking intravenous (i.v.) acyclovir, 22 were taking oral acyclovir, and 7 were taking both i.v. and oral acyclovir, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect, and the estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination. To obtain target maximal and trough concentrations, the more suitable initial acyclovir i.v. dose was 10 mg/kg of body weight/6 h for children with normal renal function (eGFR ≤ 250 ml/min/1.73 m2) and 15 to 20 mg/kg/6 h for children with augmented renal clearance (ARC) (eGFR > 250 ml/min/1.73 m2). The 20-mg/kg/8 h dose for oral acyclovir and valacyclovir produced effective concentrations in more than 75% of children; however, a 15-mg/kg/6 h dose, if possible, is preferred. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.).

A meropenem pharmacokinetics model in patients with haematological malignancies.

BACKGROUND: Optimal dosing of antibiotics is critical in immunocompromised patients suspected to have an infection. Data on pharmacokinetics (PK) of meropenem in patients with haematological malignancies are scarce. OBJECTIVES: To optimize dosing regimens, we aimed to develop a PK population model for meropenem in this population. METHODS: Patients aged ≥18 years, hospitalized in the haematology department of our 1500 bed university hospital for a malignant haematological disease and who had received at least one dose of meropenem were eligible. Meropenem was quantified by HPLC. PK were described using a non-linear mixed-effect model and external validation performed on a distinct database. Monte Carlo simulations estimated the PTA, depending on renal function, duration of infusion and MIC. Target for free trough concentration was set at >4× MIC. RESULTS: Overall, 88 patients (181 samples) were included, 66 patients (75%) were in aplasia and median Modification of Diet in Renal Disease (MDRD) CLCR was 117 mL/min/1.73 m2 (range: 35-359). Initial meropenem dosing regimen ranged from 1 g q8h to 2 g q8h over 30 to 60 min. A one-compartment model with first-order elimination adequately described the data. Only MDRD CLCR was found to be significantly associated with CL. Only continuous infusion achieved a PTA of 100% whatever the MIC and MDRD CLCR. Short duration of infusion (<60 min) failed to reach an acceptable PTA, except for bacteria with MIC < 0.25 mg/L in patients with MDRD CLCR below 90 mL/min/1.73 m2. CONCLUSIONS: In patients with malignant haematological diseases, meropenem should be administered at high dose (6 g/day) and on continuous infusion to reach acceptable trough concentrations.

Guidelines of the French Society of Otorhinolaryngology (SFORL): Nonsteroidal anti-inflammatory drugs (NSAIDs) and pediatric ENT infections. Short version.

OBJECTIVES: To present the guidelines of the French Society of Otolaryngology-Head and Neck Surgery concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) in pediatric ENT infections. METHODS: Based on a critical analysis of the medical literature up to November 2016, a multidisciplinary workgroup of 11 practitioners wrote clinical practice guidelines. Levels of evidence were classified according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system: GRADE A, B, C or "expert opinion". The first version of the text was reworked by the workgroup following comments by the 22 members of the reading group. RESULTS: The main recommendations are: NSAIDs are indicated at analgesic doses (e.g. 20-30 mg/kg/day for ibuprofen) in combination with paracetamol (acetaminophen) in uncomplicated pediatric ENT infections (acute otitis media, tonsillitis, upper respiratory infections, and maxillary sinusitis) if: o pain is of medium intensity (visual analogue scale (VAS) score 3-5 or "Evaluation Enfant Douleur" (EVENDOL) child pain score 4-7) and insufficiently relieved by first-line paracetamol (residual VAS≥3 or EVENDOL≥4); o pain is moderate to intense (VAS 5-7 or EVENDOL 7-10). When combined, paracetamol and ibuprofen are ideally taken simultaneously every 6h. It is recommended: (1) o not to prescribe NSAIDs in severe or complicated pediatric ENT infections; (2) o to suspend NSAIDs treatment in case of unusual clinical presentation of the infection (duration or symptoms); (3) o not to prescribe NSAIDs for more than 72h.

Addition of droperidol to prophylactic ondansetron and dexamethasone in children at high risk for postoperative vomiting. A randomized, controlled, double-blind study.

BACKGROUND: : The combination of dexamethasone (DEX), ondansetron (OND) and droperidol (DRO) is efficacious in preventing postoperative nausea and vomiting in adults, but has not been well assessed in children. METHODS: : Children undergoing elective surgery under general anaesthesia and considered at high risk for postoperative vomiting (POV) were randomly assigned to receive a combination of DEX, OND and placebo (Group A) or a combination of DEX, OND and DRO (Group B). The primary outcome was the incidence of POV during the first 24 hours after surgery. We hypothesized that the addition of DRO to the standard antiemetic prophylaxis would provide a further 15% reduction in the residual risk for POV. The secondary outcome considered was any adverse event occurring during the study. RESULTS: : One hundred and fifty-three children, aged three to 16 years, were randomized to Group A and 162 to Group B. The overall incidence of POV did not differ significantly between the two groups, with 16 patients in Group A (10.5%) and 18 in Group B (11.1%) presenting with one or more episodes of POV, P =0.86. Fewer patients presented with adverse events in Group A (2%) compared with Group B (8%), P =0.01. Drowsiness and headache were the principal adverse events reported. CONCLUSIONS: : The addition of DRO to a combination of OND and DEX did not decrease POV frequency below that obtained with the two-drug combination in children at high risk of POV, but increased the risk of drowsiness. The combination of DEX and OND should be recommended in children with a high risk of POV. CLINICAL TRIAL REGISTRATION.: NCT01739985.

Development and validation of a LC-MS/MS method for the quantification of tenofovir and emtricitabine in seminal plasma.

Accurate and sensitive liquid-chromatography tandem mass spectrometry method for the quantification of tenofovir and emtricitabine in seminal plasma has been developed and full validated. Molecules were separated by high-performance liquid chromatography on an Atlantis T3 C18 column using a gradient of deionized water and methanol, including 0.05% formic acid (250µl/min) and detected by electrospray ionisation/tandem mass spectrometry in positive ion mode. The method was validated over a clinical range of 3.13-1000ng/mL for tenofovir and 6.25-2000ng/mL for emtricitabine. Inter and intra-assay precisions were <9.37% for tenofovir and<10.88% for emtricitabine, and accuracies were between 0.48% and 8.43% for tenofovir, and between 0.64% and 13.87% for emtricitabine. The developed method was successfully applied for analysing tenofovir and emtricitabine concentrations in seminal plasma samples from a clinical study. The use of tandem mass spectrometry can be a suitable method for the analysis of this kind of matrices, providing high sensitivity and specificity to the analysis.

How to replace codeine after tonsillectomy in children under 12 years of age? Guidelines of the French Oto-Rhino-Laryngology--Head and Neck Surgery Society (SFORL).

The authors present the guidelines of the French Oto-rhino-laryngology--Head and Neck Surgery Society (SFORL) regarding pain management in children and adults following tonsillectomy. A multidisciplinary work group was entrusted with a literature review. Guidelines were drawn up based on the articles retrieved and the group members' experience. They were read over by an editorial group independent of the work group. A coordination meeting drew up the final version. Guidelines were graded A, B or C or as professional agreement in decreasing order of level of evidence. At home, non-steroid anti-inflammatory drugs (NSAIDs) are recommended in association with paracetamol in elevated respiratory risk and especially obstructive sleep apnea syndrome; in elevated hemorrhagic risk (hemostasis disorder, surgical problems, etc.), tramadol is recommended. Two other treatment schedules (modified NSAIDs and corticosteroids) have not undergone dedicated study and should be assessed. Management of post-tonsillectomy pain in children is founded on individual risk/benefit analysis.

Guidelines (short version) of the French Oto-Rhino-Laryngology--Head and Neck Surgery Society (SFORL) for the management of post-tonsillectomy pain in adults.

OBJECTIVES: The present clinical practice guidelines cover the entire field of management of post-tonsillectomy pain. Given the French and European regulatory restrictions on the use of codeine, an update appears necessary to clarify the management of post-tonsillectomy pain in adults. METHOD: A work group approached the issue of pain management, following the chronological pathway from initial consultation to postoperative period. As exhaustive a study of the literature as possible assessed the pain impact of the various surgical techniques and the efficacy of the various analgesia schedules. RESULTS: Guidelines on the management of post-tonsillectomy pain in adults were drawn up and graded, based on the levels of evidence of selected articles and on work group consensus. The guidelines stress the importance of patient information and seek to harmonize practice, reduce the risk of postoperative complications and above all improve control of post-tonsillectomy pain in adults.

Determination of total and unbound concentrations of lopinavir in plasma using liquid chromatography-tandem mass spectrometry and ultrafiltration methods.

Lopinavir is an HIV protease inhibitor with high protein binding (98-99%) in human plasma. This study was designed to develop an ultrafiltration method to measure the unbound concentrations of lopinavir overcoming the non-specific binding issue. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of total concentrations of lopinavir in plasma was developed and validated, and an adaptation was also optimized and validated for the determination of unbound concentrations. The chromatographic separation was performed with a C18 column (100 mm × 2.1mm i.d., 5 µm particle size) using a mobile phase containing deionized water with formic acid, and acetonitrile, with gradient elution at a flow-rate of 350 µL min(-1). Identification of the compounds was performed by multiple reaction monitoring, using electrospray ionization in positive ion mode. The method was validated over a clinical range of 0.01-1 µg/mL for human plasma ultrafiltrate and 0.1-15 µg/mL in human plasma. The inter and intra-assay accuracies and precisions were between 0.23% and 11.37% for total lopinavir concentrations, and between 3.50% and 13.30% for plasma ultrafiltrate (unbound concentration). The ultrafiltration method described allows an accurate separation of the unbound fraction of lopinavir, circumscribing the loss of drug by nonspecific binding (NSB), and the validated LC-MS/MS methodology proposed is suitable for the determination of total and unbound concentrations of lopinavir in clinical practice.

Dental caries and enamelin haplotype.

In the literature, the enamelin gene ENAM has been repeatedly designated as a possible candidate for caries susceptibility. Here, we checked whether ENAM variants could increase caries susceptibility. To this aim, we sequenced coding exons and exon-intron boundaries of ENAM in 250 children with a severe caries phenotype and in 149 caries-free patients from 9 French hospital groups. In total, 23 single-nucleotide polymorphisms (SNPs) were found, but none appeared to be responsible for a direct change of ENAM function. Six SNPs had a high minor allele frequency (MAF) and 6 others were identified for the first time. Statistical and evolutionary analyses showed that none of these SNPs was associated with caries susceptibility or caries protection when studied separately and challenged with environmental factors. However, haplotype interaction analysis showed that the presence, in a same variant, of 2 exonic SNPs (rs7671281 and rs3796704; MAF 0.12 and 0.10, respectively), both changing an amino acid in the protein region encoded by exon 10 (p.I648T and p.R763Q, respectively), increased caries susceptibility 2.66-fold independent of the environmental risk factors. These findings support ENAM as a gene candidate for caries susceptibility in the studied population.

Common SNPs of AmelogeninX (AMELX) and dental caries susceptibility.

Genetic approaches have shown that several genes could modify caries susceptibility; AmelogeninX (AMELX) has been repeatedly designated. Here, we hypothesized that AMELX mutations resulting in discrete changes of enamel microstructure may be found in children with a severe caries phenotype. In parallel, possible AMELX mutations that could explain resistance to caries may be found in caries-free patients. In this study, coding exons of AMELX and exon-intron boundaries were sequenced in 399 individuals with extensive caries (250) or caries-free (149) individuals from nine French hospital groups. No mutation responsible for a direct change of amelogenin function was identified. Seven single-nucleotide polymorphisms (SNPs) were found, 3 presenting a high allele frequency, and 1 being detected for the first time. Three SNPs were located in coding regions, 2 of them being non-synonymous. Both evolutionary and statistical analyses showed that none of these SNPs was associated with caries susceptibility, suggesting that AMELX is not a gene candidate in our studied population.

Placental transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of ABC transporter expression.

Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding placental transfer. Besides, various factors may modulate this transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc placental transfer and the influence of ABC transporter expression on this transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (n = 10 placentas) or fetal-to-maternal (n = 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc placental transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.

ABC drug transporter and nuclear receptor expression in human cytotrophoblasts: influence of spontaneous syncytialization and induction by glucocorticoids.

OBJECTIVES: ABC transporters in the human placenta play a major role in protecting the fetus against potential toxic drugs. The glucocorticoid dexamethasone has been shown to induce ABCB1 expression in enterocytes and hepatocytes. However, in placental cells, little data exists either for dexamethasone, betamethasone or prednisone while these three glucocorticoids may be used during pregnancy. We investigated the modulation of placental ABC transporter and nuclear receptor expression by these drugs. METHODS: Cytotrophoblasts were isolated from normal full-term placentas. We first assessed the influence of spontaneous syncytialization on transporter and nuclear receptor gene expression by taking samples of cytotrophoblasts after 24, 48 and 72 h of cell culture (n = 7 placentas). Incubations were then conducted with dexamethasone (50 nM-1 µM), betamethasone (20-400 nM) and prednisone (50 nM-1 µM) versus no drug for 24 h (n = 6). mRNA expression was determined by qRT-PCR. RESULTS: Influence of syncytialization was observed only for ABCB1, ABCC2 and ABCC5 gene expression between t = 24 and 48 h (p < 0.05). Therefore, the following induction studies were conducted between t = 48 h and 72 h. Dexamethasone and betamethasone significantly induced ABCB1 gene expression by around 4-fold (p < 0.01 and 0.001, respectively). In parallel, 100 nM betamethasone decreased the glucocorticoid receptor gene expression by 22% (p < 0.01). Prednisone showed no effect on transporter or receptor expression. CONCLUSIONS: These results suggest that dexamethasone or betamethasone administration may decrease the maternal-fetal transfer of an associated treatment being ABCB1 substrate, which may be either protective or deleterious for the fetus depending on the treatment's therapeutic aim.

Joint population pharmacokinetic analysis of zidovudine, lamivudine, and their active intracellular metabolites in HIV patients.

The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.

Pregnancy-associated breast cancer is as chemosensitive as non-pregnancy-associated breast cancer in the neoadjuvant setting.

BACKGROUND: The aim of this study was to determine the chemosensitivity of pregnancy-associated breast cancer (PABC) in the neoadjuvant setting by comparing the observed pathological complete response (pCR) rate with the rate predicted by a validated nomogram. METHODS: Data from 48 PABC patients who received neoadjuvant chemotherapy (NACT) were collected. To predict the response rate to chemotherapy, we used well-calibrated logistic regression-based nomograms to calculate individual probability of pCR. RESULTS: Observed rates of pCR were concordant with predictions in the whole sample and in the analyzed subgroups. For the whole sample, the area under the receiver-operated curve (AUC) was 0.77 (95% CI 0.66-0.87). The calibration of predicted and observed probabilities was excellent. In the subgroup analyses (NACT initiated during pregnancy or postpartum, NACT with only anthracycline or both anthracycline and taxanes), discriminations assessed by AUC were significantly above 0.5, except for patients treated with anthracycline only. The interpretation was limited by a lack of power. CONCLUSION: Through the use of nomograms, our study demonstrates that PABC is as chemosensitive as non-PABC and suggests that taxanes should be part of the NACT regimen for PABC. Further studies are warranted to increase the power of the presented data.

Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia.

OBJECTIVE: To evaluate the extent to which parents are satisfied with and understand the information they are given when their consent is sought for their child to participate in a phase III randomised clinical trial and the reasons for their decision. PATIENTS AND METHOD: The authors carried out a prospective study. The authors included all parents whose consent was sought for their child to participate in the FRALLE 2000A protocol (acute lymphoblastic leukaemia) at two centres. The parents were questioned twice by a qualified psychologist using a semidirected interview, 1 and 6 months after consent was sought. RESULTS: 43 first interviews were carried out. All the parents declared they were satisfied with the explanations provided by the physician. 35 (81%) parents felt that the information provided with the request for consent was appropriate. Eight (19%) parents did not realise that their child had been included in a research protocol. 16 (39%) parents did not understand the concept of randomisation. Half the parents could explain neither the aim of the clinical trial nor the potential benefit of inclusion to their child. Only one third of the parents were aware that they had an alternative. The principal factor underlying their decision, as stated by 29 parents (67%), was confidence in the medical team. CONCLUSIONS: The parents signed consent forms without having fully understood all the elements specific to the experimental protocol. Rather, the parents based their decision on their confidence in the medical team, even when their child's life was at risk.