[Ethical principles for the design of a clinical trial in oncology]. / Règles éthiques pour la conception d'un essai clinique en oncologie.

Clinical research in the area of cancer is of utmost importance in order to improve patient care, both in terms of overall survival and quality of life. The implementation of clinical trials on medicinal products, now falling under EU Regulation 536/2014, is conditioned on prior scientific authorisation from the French National Agency for the Safety of Medicines and Health Products and a favorable ethical opinion from a Research Ethics Committee (REC). OBJECTIVE: The objective of this work is to report on the main problematic issues identified during the evaluation of oncology dossiers by the REC in order to present the expected elements and thus optimise the evaluation procedures. METHODS: The National Conference of the Research Ethics Committees analysed the questions raised by the REC during their evaluation of clinical trials of oncology drugs submitted to the European information system in 2022. RESULTS: Out of a total of fourteen dossiers, nine were subject to ethical questions on the protocol and all dossiers required modifications to the information documents. DISCUSSION: The heterogeneous quality of the dossiers reminds the need to submit well-argued, methodologically robust protocols with supervised research procedures that are safe for the participants. The drafting of information documents needs to be thoroughly reconsidered in order to present clear, concise, loyal and respectful documents for patients' rights.

Data Monitoring Committees and clinical trials: From scientific justification to organisation.

Clinical trials often last several months or even several years. As the trial progresses, it can be tempting to find out whether the data obtained already answers the question posed at the start of the trial in order to stop inclusions or monitoring earlier. However, knowing and taking into account interim results can sometimes compromise the integrity of the results, which is counterproductive. To minimise this risk and ensure that the treatments are assessed reliably, safety and/or efficacy criteria are monitored during the study by a Data Monitoring Committee. After receiving the results confidentially, the Data Monitoring Committee assesses the benefit/risk ratio of the study treatment and recommends that the trial be continued, modified or terminated. Data Monitoring Committee members issuing these recommendations have an important responsibility: a hasty decision to end the trial may lead to inconclusive results unable to answer the initial question and, inversely, delaying the decision to end the trial may expose the subjects to potentially ineffective or even harmful interventions. The Data Monitoring Committee's task is therefore particularly complex. With this in mind, the round table discussion at the Giens workshops was a chance to review the scientific justification for creating Data Monitoring Committees and to recall the need for their members to receive comprehensive training on the complexities of multiple analyses, confidentiality requirements applying to the results and the need for them to be aware that recommendations to end a trial must be based on data that is robust enough to assess the benefit/risk ratio of the treatment studied.

Perineal ultrasound in infants with anteriorly displaced anus: A new decision-making tool for the surgeon?

BACKGROUND: Anteriorly displaced anus (ADA) is defined as anterior displacement of the anus toward the perineum. Early radiologic characterization is a crucial step in guiding the first-line management. OBJECTIVE: The objective of this study was to assess the urethra-to-anus distance (UAD) on perineal ultrasound in female infants under the age of 3 months with anteriorly displaced anus and to retrospectively determine a cut-off to guide the indications for surgery. MATERIALS AND METHODS: Perineal ultrasound was performed prospectively in female infants under the age of 3 months with determination of the UAD, during screening for congenital hip dislocation. Determinations of the UAD on perineal ultrasound and pelvic MRI were performed for anteriorly displaced anus in girls between 2011 and 2018. RESULTS: 230 patients were included, of whom 173 were in the control group, with 52 examinations performed for anteriorly displaced anus and 5 examinations performed for vestibular anus. The mean UAD for infants under the age of 3 months was: 22.9 mm (±1.7) in healthy infants, 21.4 mm (±2.4) in infants with non-operated ADA, 17.5 mm (±1.8) in infants with operated ADA, and 10.8 mm (±1.3) in infants with anorectal malformation (ARM). A statistically significant difference was observed between the control group and the ARM group (p = 0.0001) and between the control group and the operated ADA group (p = 0.0001). The mean UAD for infants over the age of 3 months was: 25.5 mm (±4.1) in infants with non-operated ADA and 26 mm (±3) in infants with operated ADA. CONCLUSION: A urethra-to-anus distance of less than 17 mm appears to be a cut-off for anteriorly displaced anus in anorectal malformations.

Transperineal ultrasound to assess anal positioning in female neonates.

AIMS: Anterior anal displacement is a condition that is difficult to define: is it merely an anatomical variation within the range of normality or is it a genuine malformation? In order to improve early diagnosis of anterior displacement of the anus, this study assessed the feasibility of transperineal ultrasound (US) in routine practice for use as first-line management. MATERIALS AND METHODS: Sagittal perineal US was performed on 187 female infants aged between 3 and 9 weeks. The ultrasound was performed randomly, either by a senior or a junior radiologist. The imaging by the senior radiologists defined the sagittal plane quality criteria. Scores to define image quality were established and then validated. The percentage of satisfactory images was then compared according to the planes and the seniority (junior vs. senior) of the radiologists. The junior radiologists were evaluated from the beginning to determine the learning curve for optimal image acquisition. RESULTS: The quality scores for the perineal ultrasounds revealed excellent intra-and inter-operator performances: 84.4% of the sagittal plane images were satisfactory. After the 20th examination, the success rate for the sagittal plane was independent of the seniority of the radiologist. CONCLUSIONS: This preliminary study demonstrates that transperineal sagittal plane US is easy to learn and readily yields reproducible results. The possibility of using this technique provides a solid basis for further studies to evaluate its relevance in regard to clinical data and MRI results, with the aim of providing a reliable early diagnostic tool for routine practice.

School level of children carrying a HNF1B variant or a deletion.

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.

Pain experienced by infants and toddlers at urine collection bag removal: A randomized, controlled, clinical trial.

BACKGROUND: In pre-continent children, collection bags are frequently used as a first-line option to obtain a urine specimen. This practice, acknowledged by several guidelines for the step of UTI screening, is driven by a perception of the technique as being more convenient and less painful. However, our own experience led us to consider bag removal as a painful experience. OBJECTIVE: Our aim was to determine whether the use of an oleo-calcareous liniment to aid bag removal reduced the acute pain expressed by young children. METHODS: This prospective, randomized, controlled, single blind study was carried out in two emergency pediatrics departments. Pre-continent children aged 0-36 months admitted with an indication for urine testing were eligible for the study. Urine for dipstick test screening was obtained using a collection bag. At micturition, the patients were randomized into bag removal with (intervention group) or without (control group) liniment. Bag removal was recorded on video in such a manner as to permit independent assessments of pain by two evaluators blinded to group allocation. Pain was assessed using the FLACC scale. FINDINGS: 135 patients were analyzed: 70 in the intervention group and 65 in the control group. The median FLACC scores [interquartile range] for the intervention and control groups, respectively 4.0 [2.0-7.0] and 4.0 [3.0-7.0], did not differ significantly (p = 0.5). A FLACC score ≥4 was obtained for 56% of the patients and a score ≥7 for 28%. CONCLUSION: Removal of urine collection bags caused moderate to severe pain in half of the children included. The use of an oleo-calcareous liniment did not reduce this induced pain.

Antibiotic Resistance Acquisition in the First Week of Life.

Objectives: The fetus is considered sterile but recent studies have suggested that gut colonization could start before birth. Scarce data are available for the acquisition of resistant Gram-negative bacteria (GNB) during the first days of life. Several studies have shown that integrons play a major role in antibiotic resistance acquisition. In this work, we studied the dynamics of human intestinal acquisition of GNB and integrons during the first days of life. Methods: Meconium was collected at birth and a stool sample before hospital discharge (days 2 or 3) on 185 term neonates. GNB were searched by culture on each sample and class 1, 2, and 3 integrons from each GNB or directly from samples. Eight risk factors for integron and GNB acquisition were studied. Results: We isolated 228 GNB, 46 from meconium and the remainder from stools. No link was found between GNB isolation and antibiotic exposure during delivery, but antibiotic exposure during labor significantly selected blaTEM-positive amoxicillin-resistant Enterobacteria. Two-thirds of GNB were antibiotic-susceptible and most of the resistant isolates were acquired after birth. Integrons were detected in 18 of the 228 GNB isolates from 3 meconium and 20 stools. Antibiotic administration during delivery and vaginal carriage of Streptococcus agalactiae appeared as risk factors for integron acquisition. Conclusion: Gram-negative bacteria and integrons are mostly acquired after birth during the first days of life even if for some term neonates, meconium was not sterile. Antibiotic administration during delivery is a major risk for integron acquisition and for selection of amoxicillin-resistant Enterobacteria.

Comparison of 8 and 5 mm robotic instruments in small cavities : 5 or 8 mm robotic instruments for small cavities?

INTRODUCTION: Robotic surgery has seen increasing use in the field of pediatric surgery. Our clinical experience suggested instrument size can impact on the surgical ability. This study aimed to compare the performance of robot-assisted laparoscopic skills in confined spaces using either 5 or 8 mm instruments. METHODS: A preclinical randomized crossover study design was implemented. 24 assessors performed three different reproducible drill procedures (M1: peg transfer, M2: circle cutting, M3: intracorporeal suturing). To assess surgical proficiency in confined working spaces, these exercises were performed with 5 and 8 mm instruments of the da Vinci® Surgical Systems Si in a cubic box with 60 mm-sized edges. Each performance was recorded and evaluated by two reviewers using both objective structured assessment of technical skills (OSATS) and global evaluative assessment of robotic skills (GEARS) scores. Parietal iatrogenic impacts and instrument collisions were specifically analyzed using a dedicated scoring system. RESULTS: Regardless of their experience, trainees performed significantly better when using 8 mm instruments in terms of OSATS scores (20.5 vs. 18.4; p < 0.01) and GEARS scores (23.4 vs. 21.9; p < 0.01) for most items, except for "depth perception" and "autonomy." The 8 mm performances involved significantly less parietal box damage (4.1 vs. 3.4; p < 0.01), and tool collisions (4.1 vs. 3.2; p < 0.01). CONCLUSIONS: In light of the better performances with 8 mm tools for specific tasks and parietal sparing constraints in restricted spaces, this study indicates that 5 mm instruments can be deemed to be less effective for reconstructive procedures in small children.

Urine Contamination in Nontoilet-trained and Uncircumcised Boys.

OBJECTIVE: To assess any differences between the initial and midstream urine samples from nontoilet-trained, uncircumcised boys. Contamination during urine collection makes the diagnosis of urinary tract infections (UTIs) difficult in nontoilet-trained children, especially in uncircumcised boys. Whether the contamination comes mainly from the initial stream or the contact between urine and perineal skin is not known in this population. MATERIALS AND METHODS: A prospective diagnostic study between early and midstream urine samples was conducted on asymptomatic patients with no suspicion of UTI. The clean void method was performed in nontoilet-trained boys under general anesthesia. The exclusion criteria were circumcision, older than 3 years of age, recent antibiotics treatment, and recent UTI. Urinalysis and urine culture were performed, allowing a comparison between early and midstream urine samples. RESULTS: Forty-four patients were enrolled in the study, and 31 satisfactory samples were obtained. A higher contamination rate was found in the early stream (n = 16; 51%) than in the midstream (n = 5; 16%) (P < .01). The positive culture from the early stream sample was statistically associated with a lower age (P = .02). The contamination rate of the first stream is 3-fold higher than for the midstream when collecting urine for urine culture. CONCLUSION: The clean void method in nontoilet-trained, uncircumcised boys provides low-quality urine samples for both early and midstream urine samples. The benefit of catching midstream urine samples for the diagnosis of UTI in this population is even more important when the children are young.

Differential learning processes for laparoscopic and open supraumbilical pyloromyotomy.

PURPOSE: To compare the learning curves for mastering OP and LP surgical techniques, in terms of effects on completion times and postoperative outcomes/complications. METHODS: A retrospective analysis was performed for 198 patients with hypertrophic pyloric stenosis. The learning curves were in regard to two groups of surgeons: three of whom performed 106 OPs while three others performed 92 LPs. Treatment-related complications were divided into two categories: specific complications relating to the pyloromyotomy and non-specific complications. A logistic regression model with repeated data was used to explore the occurrence of complications. RESULTS: The overall postoperative complication rates were not significantly different between the OP (15.1 %) and the LP (11.8 %) groups. Specific complications were more frequent in the LP group (6.4 versus 2.8 %), while non-specific complications were more frequent in the OP group (12.1 versus 5.3 %). The occurrence of complications exhibited a statistically decreasing risk with each supplementary procedure that was performed (p = 0.0067) in the LP group, but not in the OP group (p = 0.9665). CONCLUSION: From a learning process perspective, laparoscopy is mainly associated with a significantly higher risk of specific complications. This risk decreases in line with the surgeon's level of experience, whereas non-specific complications remain stable in open procedures.

Topical Sodium Thiosulfate: A Treatment for Calcifications in Hyperphosphatemic Familial Tumoral Calcinosis?

CONTEXT: Hyperphosphatemic familial tumoral calcinosis (HFTC) and hyperphosphatemia hyperostosis syndrome (HHS) are rare diseases characterized by hyperphosphatemia and ectopic calcifications or recurrent episodes of diaphysitis. In the setting of metabolic or inflammatory diseases, recent data suggest that systemic administration of sodium thiosulfate (STS) could be effective in the treatment of ectopic calcifications but may also be poorly tolerated (digestive symptoms, metabolic acidosis). Our group developed a topical formulation of STS to treat ectopic calcifications locally, therefore limiting patient exposure to the drug and its adverse effects. OBJECTIVE: We aimed at describing efficacy and tolerance for a topical formulation of STS in treated patients. DESIGN: We performed a retrospective study wherein clinical, radiological, and biological data before and after the application of the topical STS treatment were collected and analyzed. PATIENTS OR OTHER PARTICIPANTS: Three patients admitted to 3 different hospitals with an ectopic calcification secondary to HFTC or HHS were treated with topical STS. INTERVENTION: The topical STS was applied daily by the patients. RESULTS: A significant clinical and radiological decrease of ectopic calcifications was observed after at least 5 months of treatment. The STS treatment was well tolerated and no clinical or biological side effects were observed. CONCLUSION: Topical STS appears to be a promising treatment for ectopic calcifications secondary to HFTC or HHS.

Towards a new point of view on the phenotype of patients with a 17q12 microdeletion syndrome.

OBJECTIVE: 17q12 microdeletion syndrome involves 15 genes, including HNF1B, and is considered to confer a high risk of neuropsychiatric disorders. Patients with HNF1B gene deletion diagnosed secondary to renal disorders are only very rarely reported to have neuropsychiatric disorders. Interestingly, however, when tested, patients with HNF1B gene deletion are found to have 17q12 deletion. This brings into question the extent to which 17q12 deletion is genuinely associated with severe neuropsychological disorders and in which patients. In this study, we sought to confirm 17q12 microdeletion in kidney patients initially diagnosed with HNF1B gene deletion and evaluate neuropsychological disorders in these patients compared with those with HNF1B point mutation. PATIENTS AND DESIGN: Thirty-nine children with HNF1B disorders (26 with deletions) diagnosed secondary to renal abnormalities were included in this prospective study and tested for 17q12 microdeletion and neuropsychological disorders. RESULTS: The same 17q12 microdeletion found in patients with neuropsychological disorders was identified in all of our patients with HNF1B deletion. Neurological examinations found no severe impairments except for one patient with autism. No significant differences were found between patients with deletions and those with point mutations as concerns learning abilities and schooling. Nevertheless, patients with deletions tended to have lower developmental quotients and more difficulties at school. CONCLUSIONS: Complete deletion of the HNF1B gene and 17q12 microdeletion syndrome are actually the same genetic disorder. The neuropsychological phenotype of patients appears less severe when 17q12 deletion is diagnosed secondary to kidney rather than neuropsychological abnormalities. These data may influence antenatal counselling.

Moving from bag to catheter for urine collection in non-toilet-trained children suspected of having urinary tract infection: a paired comparison of urine cultures.

OBJECTIVE: To compare, in the same children, urine culture results from bag- versus catheter-obtained specimens with catheter culture as the reference. STUDY DESIGN: A total of 192 non-toilet-trained children <3 years of age from 2 emergency departments were recruited for this prospective cross-sectional study. All had positive urinalysis results from bag-obtained specimens that were systematically checked with a catheter-obtained specimen before treatment. Results of comparison of urine cultures obtained with these 2 collecting methods are presented. RESULTS: A total of 7.5% of bag-obtained specimen positive cultures had false-positive results. Twenty-nine percent of bag-obtained specimen cultures with negative results were false negative. Altogether, bag-obtained specimens led to either a misdiagnosis or an impossible diagnosis in 40% of cases versus 5.7% when urethral catheterization was used. CONCLUSION: Every bag-obtained positive-result urinalysis should be confirmed with a more reliable method before therapy.