A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy - including photon and proton therapy - for the treatment of radioresistant tumors: the ETOILE trial.

BACKGROUND: Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. METHODS: The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. DISCUSSION: So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02838602 . Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

The European "clinical trial" regulation; relationship with the Jardé Act: a Giens workshop.

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency.

Early effect of hyaluronic acid intra-articular injections on serum and urine biomarkers in patients with knee osteoarthritis: An open-label observational prospective study.

The aim of the study was to investigate the effect of hyaluronic acid (HA) intra articular injections (IA) on osteoarthritis (OA) biomarkers in patients with knee OA. Prospective open label study. Fifty-one patients with unilateral symptomatic K-OA received IA injections of 2mL of HA on days (D) 1, 7, 14 and were followed 3 months. At D-15 patients were examined and X-rays performed, to exclude patients with bilateral K-OA, or those with more than three symptomatic OA joints. From 15 days (D-15) before the first injection to D90 concomitant therapies were unchanged. Walking pain (WP) on VAS was obtained at each visit. Urine (U) and serum (S) samples were obtained at D-15, D1, D30, and D90. S-C2C, S-Cartilage oligomeric matrix protein, S-HA, S-CS 846 epitope, S-type II collagen propeptide, and U-type II collagen C telopeptide (U-CTX II/creatinin) were assayed. Predictive factors of response were analyzed using logistic regression. Correlations between variables were obtained using Spearman test. Forty-five patients were analyzed. Between D-15 and D1 there was no difference for any biomarkers At D1, WP (SD) was correlated with U-CTX II/creat (p = 0.006). Between D1 and D90: U-CTX II/creat decreased significantly. After adjustment for confounding variables there was a significant correlation between clinical response and U-CTX II/creat variation. U-CTX II and S-HA at baseline were independently predictive of clinical response. This study showed that 90 days after HA IA injections, U-CTX II levels significantly decrease compared to baseline, suggesting a slowdown of type II collagen degradation.

Validation of a risk-assessment scale and a risk-adapted monitoring plan for academic clinical research studies--the Pre-Optimon study.

CONTEXT: Good Clinical Practice regulates monitoring activities in clinical research. Due to question and design diversity, and limited resources, on-site monitoring is often less intensive in the academic context, and variable. Standardization is needed, and relies on definition and validation of tools accounting for risk. OBJECTIVE: To define, and validate tools, to implement a risk-based monitoring strategy for academic clinical research. METHODS: Working groups of experienced professionals searched the literature, and built a consensus risk-assessment scale (RAS), and a risk-adapted monitoring plan (RAMP). We allocated 200 protocols to 49 assessors. We assessed the RAS relevance vs. a visual analogue scale (VAS), and its reproducibility through Kraemer's kappa, and intraclass correlation coefficient (ICC) from a random proportional odds model. We identified sources of disagreement through a logistic regression. We described assessors' difficulties during assessment. We applied the RAMP to 10 protocols per risk level, and rated its feasibility (0 = easy to 4 = impossible). RESULTS: RAS and RAMP were defined in 4 levels. RAS relevance was good: RAS-risk levels were evenly distributed on VAS-risk (0.6, 2.6, 5.6, and 7.9). Reproducibility was moderate to good: kappa=0.48, ICC=0.70. Major disagreements (36%) arose from decision-makers, rather than hands-on managers. Most difficulties occurred in ill-written protocols (17%). RAMP was easily feasible for most protocols (mean score: 0.2 to 0.9). We proposed a standard synopsis for evaluation purpose. CONCLUSION: We defined, and validated risk-based tools. This risk-adapted strategy will be compared to an intensive one in a randomized trial, Optimon, to define a standard of practice for academic clinical research.

Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a prospective, randomized controlled trial.

BACKGROUND: Several authors have reported on laparoscopic pyloromyotomy (LP) since the technique was originally described in 1990, but its benefits remain unproven. We performed a randomized controlled trial comparing LP to open circumumbilical pyloromyotomy (OP) for hypertrophic pyloric stenosis. METHODS: In a prospective study, 102 infants with pyloric stenosis were randomly assigned to either LP (n = 50) or OP (n = 52). The primary outcome measure was the incidence of postoperative vomiting; the secondary parameters were the durations of surgery and anesthesia, surgical complications, and postoperative pain. All infants were managed according to standardized procedures regarding general anesthesia, surgical technique, postoperative analgesia, and feeding regimen. Parents, carers, and assessors responsible for the postoperative evaluation were blinded for the technique used. RESULTS: There was no difference in the incidence of postoperative vomiting between the 2 groups. The overall incidence of complications was similar, but the durations of surgery and general anesthesia were significantly longer in the LP group than in the OP group (P = 10(-4) and P = .02, respectively). There were 3 cases of incomplete pyloromyotomy after laparoscopy, requiring a repeat procedure. CONCLUSIONS: Laparoscopic pyloromyotomy does not decrease the incidence of postoperative vomiting, has a similar complication rate compared with the open umbilical approach, but may expose patients to a risk of inadequate pyloromyotomy.

Unstented tubularized incised plate urethroplasty combined with foreskin reconstruction for distal hypospadias.

BACKGROUND AND AIM: Urethral stent has recently been proven to be unnecessary for normal healing in an animal model of tubularized incised plate (TIP) urethroplasty. We report our experience with unstented TIP repair combined with foreskin reconstruction for distal hypospadias in children. PATIENTS AND METHODS: We retrospectively reviewed the records of 162 children consecutively treated by TIP urethroplasty for a distal or mid-shaft hypospadias without urethral stent over a 6 years period. The mean age +/- SEM at surgery was 15.7 +/- 1.2 months. A foreskin reconstruction was performed with the hypospadias repair in 136 boys (84%). One hundred thirty one children (81%) underwent this surgery as an outpatient procedure. RESULTS: With a mean follow-up of 12.4 +/- 1.0 months, urethrocutaneous fistula was observed in 9 children (5.6%), and meatal stenosis in 4 (2.5%). Postoperative urinary retention requiring suprapubic catheter insertion was observed in 4 cases (2.5%) without later complications. Cutaneous dehiscence of the reconstructed foreskin occurred in 6 children (4.4%) and phimosis in 13 (9.5%). CONCLUSIONS: Absence of urethral stent after TIP urethroplasty for distal hypospadias repair does not seem to increase postoperative complication rate. Foreskin reconstruction in distal hypospadias surgery has an acceptable complication rate.