Centre Hospitalier Universitaire de Caen

Background Lipohypertrophy is a common skin complication in people with insulin-treated diabetes. Despite its high prevalence and potential impact on diabetes management and outcomes, published data regarding the risk factors for the development of this complication are contradictory. The study aimed to determine risk factors for lipohypertrophy related to patient characteristics and insulin therapy. Method Medical databases (MEDLINE/PubMed, Embase, CENTRAL) were searched from 1990 to August 21, 2023. All relevant studies describing potential risk factors for lipohypertrophy in people with insulin-treated diabetes (eg, sex, age, body mass index [BMI], type of diabetes, and injection technique) were included. Data enabling calculations of prevalence odds ratios (pOR) and mean differences (MD) with 95% confidence intervals [95% CI] were extracted and pooled in meta-analyses. Results Fifty-one studies of risk factors for lipohypertrophy were identified. Performed meta-analyses indicate that the strongest contributor to lipohypertrophy was incorrect injection site rotation (pOR = 8.85 [95% CI: 5.10-15.33]), followed by needle reuse (3.20 [1.99-5.13]), duration of insulin therapy >5 years (2.62 [1.70-4.04]) and >2 daily injections per day (2.27 [1.58-3.25]). Those with type 1 diabetes and obese/overweight individuals also had significantly higher odds of developing lipohypertrophy. Sex, age, and insulin device (pen, syringes) were not significant risk factors for lipohypertrophy. Conclusions This systematic review with meta-analysis revealed that incorrect injection site rotation and needle reuse are the most substantial factors in developing lipohypertrophy. Notably, both factors are modifiable through patient education, emphasizing the importance of teaching proper injection techniques for better diabetes management.

Introduction: Gorlin-Goltz syndrome or nevoid basal cell carcinoma syndrome is a rare hereditary disease with autosomal dominant transmission. Multiple basal cell carcinomas, keratocysts located in the jaw, and developmental abnormalities are common clinical manifestations. Observation: The article reports the case of a 10-year-old patient addressed for the diagnostic and therapeutic management of a mandibular cystic lesion. Keratocysts can be the inaugural manifestation of Gorlin-Goltz syndrome. The originality of this case lies in the conservative approach adopted in this disease to treat a wide-ranging cystic lesion, using a cystic decompression method. Clinically, the patient had macrocephaly and hypertelorism, clinical signs frequently associated with Gorlin-Goltz syndrome, confirmed by the discovery of a mutation of the PTCH1 gene through genetic testing. Conclusion: This case highlights the importance of a multidisciplinary approach in the management of Gorlin-Goltz syndrome, by integrating innovative surgical techniques such as cystic decompression.

Aims/Background Recent agents have profoundly reshaped the multiple myeloma (MM) landscape. Their real‐world impacts need to be assessed over the long term. Methods EMMY is a non‐interventional, prospective dynamic cohort, conducted in France, since 2017, with 900 patients enrolled each year. Newly diagnosed MM (NDMM) who initiated a treatment from 2017 to 2020 are here described. Results A total of 1036 non‐transplant eligible (NTE) patients (median age: 74.9 years) and 561 patients who received autologous stem cell transplantation (ASCT) (median age: 60.6 years) were enrolled. For ASCT patients, a shift in induction treatment from bortezomib‐thalidomide‐dexamethasone (VTd) (29.1%) to bortezomib‐lenalidomide‐dexamethasone (VRd) (55.1%) marked the period. Maintenance treatment with R after ASCT became a standard (75% of patients). In NTE patients, R‐based regimens were increasingly used from 29.4% in 2017 (of whom Rd.: 17.0%, VRd: 10.6%) to 73.3% in 2020 (of whom Rd.: 21.8%, VRd: 48.5%). Median progression‐free survival (mPFS) was 46.5 months (95% CI: 37.8–50.6) and 18.7 months (95% CI: 16.3–20.8) in ASCT and NTE patients, respectively. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The estimated 48‐month overall survival rates were 89% (95% CI: 84.5–92.2) and 63% (95% CI: 58.5–67.1) for ASCT and NTE patients, respectively. Conclusions The 2017–2020 period was marked by the expansion of R use in both NDMM ASCT and NTE patients.

Importance Vitamin D deficiency is a risk factor for multiple sclerosis (MS) and is associated with the risk of disease activity, but data on the benefits of supplementation are conflicting. Objective To evaluate the efficacy of high-dose cholecalciferol as monotherapy in reducing disease activity in patients with clinically isolated syndrome (CIS) typical for MS. Design, Setting, and Participants The D-Lay MS trial was a parallel, double-blind, randomized placebo-controlled clinical trial in 36 MS centers in France. Patients were enrolled from July 2013 to December 2020 (final follow-up on January 18, 2023). Untreated patients with CIS aged 18 to 55 years with CIS duration less than 90 days, serum vitamin D concentration less than 100 nmol/L, and diagnostic magnetic resonance imaging (MRI) meeting 2010 criteria for dissemination in space or 2 or more lesions and presence of oligoclonal bands were recruited. Intervention Patients were randomized 1:1 to receive oral cholecalciferol 100 000 IU (n = 163) or placebo (n = 153) every 2 weeks for 24 months. Main Outcomes and Measures The primary outcome measure was disease activity, defined as occurrence of a relapse and/or MRI activity (new and/or contrast-enhancing lesions) over 24 months of follow-up, also analyzed as separate secondary outcomes. Results Of the 316 participants enrolled and randomized (median [IQR] age, 34 [28-42] years; 70% women), the primary analysis included 303 patients (95.9%) who took at least 1 dose of the study drug and 288 (91.1%) ultimately completed the 24-month trial. Disease activity was observed in 94 patients (60.3%) in the vitamin D group and 109 patients (74.1%) in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; P = .004), and median time to disease activity was longer in the vitamin D group (432 vs 224 days; log-rank P = .003). All 3 secondary MRI outcomes reported significant differences favoring the vitamin D group vs the placebo group: MRI activity (89 patients [57.1%] vs 96 patients [65.3%]; HR, 0.71 [95% CI, 0.53-0.95]; P = .02), new lesions (72 patients [46.2%] vs 87 patients [59.2%]; HR, 0.61 [95% CI, 0.44-0.84]; P = .003), and contrast-enhancing lesions (29 patients [18.6%] vs 50 patients [34.0%]; HR, 0.47 [95% CI, 0.30-0.75]; P = .001). All 10 secondary clinical outcomes showed no significant difference, including relapse, which occurred in 28 patients (17.9%) in the vitamin D group vs 32 (21.8%) in the placebo group (HR, 0.69 [95% CI, 0.42-1.16]; P = .16). Results were similar in a subset of 247 patients meeting updated 2017 diagnostic criteria for relapsing-remitting MS at treatment initiation. Severe adverse events occurred in 17 patients in the vitamin D group and 13 in the placebo group, none of which were related to cholecalciferol. Conclusions and Relevance Oral cholecalciferol 100 000 IU every 2 weeks significantly reduced disease activity in CIS and early relapsing-remitting MS. These results warrant further investigation, including the potential role of pulse high-dose vitamin D as add-on therapy. Trial Registration ClinicalTrials.gov Identifier: NCT01817166

Introduction Recent literature has reported instances of drug associated with hypertension with serotonin reuptake inhibitors (SRIs). Nonetheless, the association between SRIs and hypertension development is the subject of ongoing debate. It remains uncertain whether this is indicative of a class effect, and if dose-effect exist. To investigate the potential class effect associating SRIs with hypertension reporting, we utilized real-world data from VigiBase®, the World Health Organization (WHO) pharmacovigilance database. Methods We conducted an updated disproportionality analysis within VigiBase® to identify a signal of hypertension reporting with individual SRIs by calculating adjusted reporting odds ratios (aRORs) within a multivariate case/non-case study design. Additionally, we explored the presence of a dose-effect relationship. Results The database contained 13,682 reports of SRI associated with hypertension (2.2%), predominantly in women (70.0%). Hypertension was most reported in the 45-64 years old age group (44.8%). A total of 3,879 cases were associated with sertraline, 2,862 with fluoxetine, 2,516 with citalopram, 2,586 with escitalopram, 2,441 with paroxetine, 201 with fluvoxamine and 8 with zimeldine. A significant ROR was observed for all SRIs in both univariate (RORs ranging from 1.39 to 1.54) and multivariable analyses (aRORs ranging from 1.16 to 1.40) after adjustments for age group, sex, concurrent antihypertensive medication and drugs knowns to induce hypertension, except for fluvoxamine and zimeldine. No dose-response relationship was identified. Conclusion This investigation, conducted under real life conditions, unveils a notable pharmacovigilance safety signal associating SRI usage with hypertension reporting. No dose-response effect was detectable. Further longitudinal studies are warranted.

In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (<70, ≥70 to <75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45–0.67; P < 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P < 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.

Objective Carbohydrate intake remains one of the most influential factors affecting post-meal glucose levels in type 1 diabetes (T1D). To individualize and optimize patient education on carbohydrate counting, it is essential to assess their knowledge of carbohydrate counting. For this purpose, we aimed to produce and validate a questionnaire for French-speaking individuals based on the American AdultCarbQuiz questionnaire (43 items). Design The translation and cross-cultural adaptation of the American questionnaire were followed by an analysis conducted by patient and diabetologist expert groups. Participants 190 participants living with T1D, Diabetologist expert group. Main outcome measure(s) Internal consistency and reliability were verified by administering the adapted French version of the questionnaire to 190 participants living with T1D. Analysis Clinical validity was verified by examining the correlation between the questionnaire score and the time in range (TIR) of these participants. Results Translation and back-translation demonstrated good consistency with the original questionnaire. Typical American food items were replaced with foods commonly consumed in France. All items were validated by both patient and diabetologist experts. After analyzing the responses of 190 participant, seven items were considered non-discriminatory and were therefore removed. Internal consistency, assessed by Cronbach’s α, was high, with α = 0.785, 95 CI [0.738–0.826]. Finally, we produced a 36 item French questionnaire named GluciQuizz. TIR correlated with the GluciQuizz score (r = 0.3; p < 0.0001). Conclusions and implications This study validates a French-language self-administered questionnaire (GluciQuizz), which evaluates different domains of carbohydrate knowledge in a 15-minute quiz for people living with T1D.

This study compares various surgical approaches for treating congenital diaphragmatic eventration (CDE) in children to identify the most effective and safest method. We conducted a retrospective analysis of a multicentric cohort of pediatric patients operated on for CDE between 2010 and 2021. The different surgical approaches, including robot-assisted thoracoscopic surgery (RATS), and their outcomes were compared (Clinical Trials NCT04862494). One hundred and twelve patients, aged 12 (5–21) months, underwent diaphragmatic plication. Thoracoscopy or RATS was performed in 69 (62%) cases, posterolateral thoracotomy (PLT) in 15 (13%), and an abdominal approach in 28 (25%), based on surgeons' choice. Symptom relief was achieved in 88% of patients, and 90% showed radiographic improvement. There were 31 peri- or early postoperative complications (28%), mainly including pleural effusions, infections, and lobar atelectasis, and 8 recurrences of eventration (7%), with no significant correlation between these complications and the surgical approach. Compared to other approaches, thoracotomy multiplied the duration of intravenous analgesia by three (96 h vs. 36 h, p < 0.0001) and hospital stay length by two (8 vs. 4 days, p = 0.002). RATS, although comparable to thoracoscopy in short-term outcomes, had a higher incidence of perioperative hepatic injuries and long-term complications, including persistent symptoms in all five patients and chest wall deformities in two. Diaphragmatic plication via a minimally invasive thoracic approach may be the best treatment option for cases of symptomatic CDE. Further research is required to establish potential added risks of RATS as compared to thoracoscopy in this indication.

Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern, and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex, or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy (dHMN). Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score ≤ 1). One fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies (NCS) were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in one fourth of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.

Aims Shear Wave Elastography (SWE) is a new promising ultrasound modality that enables non-invasive measurement of the dynamic myocardial stiffness. The impact of varying physiological conditions on SWE measurement of left ventricular (LV) myocardial stiffness remains poorly investigated. Methods and results Nineteen sheep were evaluated during open-chest surgery. Epicardial multiframe SWE acquisitions were performed in short axis view simultaneously with hemodynamic acquisitions during inferior vena cava occlusion, aortic clamping, atrial pacing and ischaemia-reperfusion. The cyclic variation in the median value of LV myocardial stiffness ranged from 1.1 m/s in diastole (Cmin) to 2.4 m/s in systole (Cmax). At steady state, intra-animal reproducibility was good for Cmin (intraclass correlation coefficient ICC= 0.77 [0.54, 0.90], p < 0.001) and Cmax (ICC= 0.92 [0.84, 0.96], p < 0.001). Cmin was independent of loading conditions, heart rate and short 15-minute episodes of ischaemia and reperfusion. Cmax was independent of loading conditions and moderate increase in heart rate but decreased significantly during ischaemia and reperfusion. Compared to baseline, percentage changes in Cmax was correlated to percentage changes in dP/dtmax (R=0.47, p = 0.001) and in LV systolic pressure (R=0.35, p=0.013) and SW (R=0.31, p=0.026). Conclusion In this study, LV diastolic myocardial stiffness Cmin assessed using SWE demonstrated the characteristics of a potentially useful clinical marker of LV diastolic function linked to the intrinsic elastic properties of the myocardium, whereas Cmax was an indicator of LV contractility.

442 Background: In the U.S., racial disparities in renal cell carcinoma (RCC) are documented for common histologies, highlighting differences in incidence and outcomes between Black and non-Black patients. Such disparities are underexplored in European populations, especially across a broader histology spectrum within a universal healthcare system. We aim to investigate racial disparities in RCC histologies and their outcomes among Black and non-Black patients in France. Methods: We conducted a retrospective cohort study utilizing the UroCCR database, spanning from March 1957 to May 2024. This multicenter study, referred as UroCCR-191, involved 30 tertiary centers in France, analyzing 9,404 patients (338 Black and 9,066 non-Black) with confirmed histology. Patients with unknown racial background or unidentified/multiple histologies were excluded. Histological distribution, demographics, clinical presentations, tumor features, and outcomes were compared. Results: Clear cell RCC (ccRCC) was more prevalent among non-Black patients (68.8% vs 47.6%; odds ratio [OR]: 2.4, p < 0.001). Non-clear cell histologies were more common in Black patients, including papillary RCC (23.1% vs 11.8%, p < 0.001), the rare clear cell papillary renal cell tumor (1.5% vs 0.5%, p = 0.044), and other rare molecularly-defined histologies such as translocation RCC (2.1% vs 0.6%, p = 0.005), FH-deficient RCC (0.6% vs 0.1%, p = 0.067) and renal medullary carcinoma (0.3% vs 0, p = 0.001); all with OR ≥2 and a false discovery rate <0.15. Black patients were younger at diagnosis, with earlier-stage tumors and higher rates of partial nephrectomy. No significant differences were observed in cancer-specific survival; however, Black patients showed better distant recurrence-free survival (hazard ratio [HR]: 0.55, p = 0.020). Race was not an independent prognostic factor when accounting for other clinical variables (Table). Conclusions: Black patients in France exhibit higher incidences of non-clear cell RCC and are diagnosed at earlier stages compared to non-Black patients. The absence of race as an independent prognostic factor, unlike U.S. data, highlights the potential influence of healthcare systems in modulating racial disparities. This underscores the need for tailored RCC management that considers racial backgrounds to refine diagnosis and outcomes. Hazard ratios using multivariate Cox regression for predictors of distant recurrence-free survival. Variable Reference group Comparison group HR 95% CI p -value Race non-Black Black 0.96 0.51-1.79 0.889 Age (years) ≤63 >63 1.25 1.07-1.47 0.005 Sex Female Male 1.29 1.09-1.53 0.004 Nephrectomy type Partial Radical 2.98 2.46-3.61 <0.001 T stage T1 + T2 T3 + T4 2.36 1.96-2.85 <0.001 N stage N0 N1 + N2 2.84 2.25-3.58 <0.001 Fuhrman grade 1 + 2 3 + 4 2.39 1.97-2.91 <0.001 Histology ccRCC non-ccRCC 0.81 0.65-1.01 0.062

Introduction: Peritonitis occurring within the first months on peritoneal dialysis (PD) has been associated with poorer PD outcomes. Whether early peritonitis is a risk factor for transfer to haemodialysis in the long term is a matter of investigation. Methods: This retrospective study was conducted using data from the French Language PD Registry of incident PD patients between 2002 and 2018. Early-onset peritonitis (EOP) was defined as peritonitis occurring during the first 3 months on PD. Our hypothesis was that EOP was associated with an increased risk of transfer to haemodialysis during the first months on PD but that it was no longer associated with an increased risk of transfer to haemodialysis several months after the start of PD. The associations between EOP and the different outcomes were explored via time-dependent coefficient Cox regression and Fine and Gray regression. Results: EOP was associated with an increased risk of PD cessation by transfer to haemodialysis within the first 12 months of PD and beyond (<12 months cs-HR 1.50, 95% CI: 1.36-1.66 and >12 months cs-HR 1.17, 95% CI: 1.06-1.28, respectively). Conclusion: EOP is associated with a greater risk of PD cessation due to transfer to haemodialysis, especially within the first year after peritonitis occurrence, and with a persistent effect in the long term. Reducing or delaying EOP, notably through its systematic reporting and monitoring as a KPI to help in the implementation of QIPs, could have a favourable impact on patient-level outcomes.