CHRU de Strasbourg

Breast cancer is the most common female cancer in the world. Numerous studies have shown that the risk of metastatic disease increases with tumor volume. In this context, it is useful to assess whether the regular practice of formal breast self-examination (BSE) as opposed to breast awareness has an impact on the number of cancers diagnosed, their stage, the treatments used and mortality. Design The Commission of Senology (CS) of the Collège National de Gynécologie et Obstétrique Français (CNGOF) respected and followed the Grading of Recommendations Assessment, Development and Evaluation method to assess the quality of the evidence on which the recommendations were based. Methods The CS studied 16 questions individualizing four groups of women (general population, women aged over 75, high-risk women, and women previously treated for breast cancer). For each situation, it was determined whether the practice of BSE versus abstention from this examination led to detection of more breast cancers and/or recurrences and/or reduced treatment and/or increased survival. Results BSE should not be recommended for women in the general population, who otherwise benefit from clinical breast examination by practitioners from the age of 25, and from organized screening from 50 to 74 (strong recommendation). In the absence of data on the benefits of BSE in patients aged over 75, for those at high risk and those previously treated for breast cancer, the CS was unable to issue recommendations. Thus, if women in these categories wish to undergo BSE, information on the benefits and risks observed in the general population must be given, notably that BSE is associated with a higher number of referrals, biopsies, and a reduced quality of life.

Background and hypothesis Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. Methods We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. Results We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT + group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT + group, P = 0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P = 0.48). Conclusion Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

In the realm of ophthalmology, precise measurement of tear film break-up time (TBUT) plays a crucial role in diagnosing dry eye disease (DED). This study aims to introduce an automated approach utilizing artificial intelligence (AI) to mitigate subjectivity and enhance the reliability of TBUT measurement. We employed a dataset of 47 slit lamp videos for development, while a test dataset of 20 slit lamp videos was used for evaluating the proposed approach. The multistep approach for TBUT estimation involves the utilization of a Dual-Task Siamese Network for classifying video frames into tear film breakup or non-breakup categories. Subsequently, a postprocessing step incorporates a Gaussian filter to smooth the instant breakup/non-breakup predictions effectively. Applying a threshold to the smoothed predictions identifies the initiation of tear film breakup. Our proposed method demonstrates on the evaluation dataset a precise breakup/non-breakup classification of video frames, achieving an Area Under the Curve of 0.870. At the video level, we observed a strong Pearson correlation coefficient (r) of 0.81 between TBUT assessments conducted using our approach and the ground truth. These findings underscore the potential of AI-based approaches in quantifying TBUT, presenting a promising avenue for advancing diagnostic methodologies in ophthalmology.

Purpose Utility of prostate-specific antigen density (PSAd) for risk-stratification to avoid unnecessary biopsy remains unclear due to the lack of standardization of prostate volume estimation. We evaluated the impact of ellipsoidal formula using multiparametric magnetic resonance (MRI) and semi-automated segmentation using tridimensional ultrasound (3D-US) on prostate volume and PSAd estimations as well as the distribution of patients in a risk-adapted table of clinically significant prostate cancer (csPCa). Methods In a prospectively maintained database of 4841 patients who underwent MRI-targeted and systematic biopsies, 971 met inclusions criteria. Correlation of volume estimation was assessed by Kendall’s correlation coefficient and graphically represented by scatter and Bland–Altman plots. Distribution of csPCa was presented using the Schoots risk-adapted table based on PSAd and PI-RADS score. The model was evaluated using discrimination, calibration plots and decision curve analysis (DCA). Results Median prostate volume estimation using 3D-US was higher compared to MRI (49cc[IQR 37–68] vs 47cc[IQR 35–66], p < 0.001). Significant correlation between imaging modalities was observed (τ = 0.73[CI 0.7–0.75], p < 0.001). Bland–Altman plot emphasizes the differences in prostate volume estimation. Using the Schoots risk-adapted table, a high risk of csPCa was observed in PI-RADS 2 combined with high PSAd, and in all PI-RADS 4–5. The risk of csPCa was proportional to the PSAd for PI-RADS 3 patients. Good accuracy (AUC of 0.69 and 0.68 using 3D-US and MRI, respectively), adequate calibration and a higher net benefit when using 3D-US for probability thresholds above 25% on DCA. Conclusions Prostate volume estimation with semi-automated segmentation using 3D-US should be preferred to the ellipsoidal formula (MRI) when evaluating PSAd and the risk of csPCa.

Purpose Accurate prediction of extraprostatic extension (EPE) is crucial for decision-making in radical prostatectomy (RP), especially in nerve-sparing strategies. Martini et al. introduced a three-tier algorithm for predicting contralateral EPE in unilateral high-risk prostate cancer (PCa). The aim of the study is to externally validate this model in a multicentric European cohort of patients. Methods The data from 208 unilateral high-risk PCa patients diagnosed through magnetic resonance imaging (MRI)-targeted and systematic biopsies, treated with RP between January 2016 and November 2021 at eight referral centers were collected. The evaluation of model performance involved measures such as discrimination (AUC), calibration, and decision-curve analysis (DCA) following TRIPOD guidelines. In addition, a comparison was made with two established multivariable logistic regression models predicting the risk of side specific EPE for assessment purposes. Results Overall, 38%, 48%, and 14% of patients were categorized as low, intermediate, and high-risk groups according to Martini et al.’s model, respectively. At final pathology, EPE on the contralateral prostatic lobe occurred in 6.3%, 12%, and 34% of patients in the respective risk groups. The algorithm demonstrated acceptable discrimination (AUC 0.68), comparable to other multivariable logistic regression models (p = 0.3), adequate calibration and the highest net benefit in DCA. The limitations include the modest sample size, retrospective design, and lack of central revision. Conclusion Our findings endorse the algorithm's commendable performance, supporting its utility in guiding treatment decisions for unilateral high-risk PCa patients.

OBJECTIVE Bilateral spheno-orbital meningiomas (bSOMs) are a rare entity among meningiomas. These tumors are benign and predominantly affect women. They represent 4% of spheno-orbital meningiomas (SOMs) and are poorly described in the literature. This study aimed to describe the characteristics, risk factors, evolution, and management of bSOMs. METHODS Twenty patients with bSOMs were enrolled in a multicentric descriptive study including 15 neurosurgical departments. RESULTS In this study, the authors found that bSOMs affected exclusively women, with a mean age of 50 years. Approximately 65% of patients were on progestin therapy. The mean follow-up in this series was 55 months. Clinically, visual symptoms were predominant: proptosis was present in 17 of 20 patients (85%; 7 unilateral, 10 bilateral), and a decrease in visual acuity was observed in 11 of 20 patients (55%; 6/10 to 9/10 in 6 patients, 3/10 to 5/10 in 1 patient, and < 3/10 in 4 patients). Contrary to unilateral SOMs, the authors identified that intracranial hypertension was a common presentation (25%) of bSOMs. Surgical management with gross-total resection was the gold standard treatment. Recurrences only occurred following subtotal resection in 36% to 60% of patients, with a median time of 50 to 54 months after surgery. Visual improvement or stability was observed in 75% of cases postoperatively. Progesterone receptor expression levels were 70% to 100% in 10 of 11 (91%) cases. CONCLUSIONS Bilateral SOMs are usually found in female patients and are strongly associated with hormone replacement therapy. Early surgical management with gross-total resection is the most effective treatment in terms of recurrence and improves visual acuity. Given the slow progressive nature of bSOMs and their time to recurrence, which can be up to 10 years, long-term follow-up of patients is essential.

Simple Summary The quality of resection after unplanned excision of soft tissue sarcoma (STS) performed outside of a reference center or at second resection potentially impacts local and metastatic recurrence and survival. The French cohort NETSARC prospectively collected data from patients with unplanned excision outside reference centers from 2010 to 2019 and reported survival in patients reexcised (RE) or not (No-RE). Patients who would most benefit from RE need to be identified. A total of 2371 patients had unplanned excision for STS outside reference centers, including 1692 patients with no multidisciplinary board review (RE: 913; No-RE: 779). Discrepancies in RE/No-RE subgroups were observed regarding age, tumor site, size, depth, grade and histotype. R0 final resection associated with better MFS; R1 initial resection showed better MFS than R0 initial resection. The study identified RE as an independent favorable factor for MFS (HR 0.7, 95% CI 0.53–0.93; p = 0.013). All subgroups except patients > 70 years, and patients with large tumors (>10 cm) showed better MFS with RE. RE in patients with STS of limb or trunk after macroscopic complete resection out of NETSARC reference center, and also in R0 resections to improve LRFS and MFS. Systematic RE should not be advocated for patients ≥ 70 years, or tumor size ≥ 10 cm. Abstract Background: Whether re-excision (RE) of a soft tissue sarcoma (STS) of limb or trunk should be systematized as adjuvant care and if it would improve metastatic free survival (MFS) are still debated. The impact of resection margins after unplanned macroscopically complete excision (UE) performed out of a NETSARC reference center or after second resection was further investigated. Methods: This large nationwide series used data from patients having experienced UE outside of a reference center from 2010 to 2019, collected in a French nationwide exhaustive prospective cohort NETSARC. Patient characteristics and survival distributions in patients reexcised (RE) or not (No-RE) are reported. Multivariate Cox proportional hazard model was conducted to adjust for classical prognosis factors. Subgroup analysis were performed to identify which patients may benefit from RE. Results: Out of 2371 patients with UE for STS performed outside NETSARC reference centers, 1692 patients were not reviewed by multidisciplinary board before treatment decision and had a second operation documented. Among them, 913 patients experienced re-excision, and 779 were not re-excised. Characteristics were significantly different regarding patient age, tumor site, size, depth, grade and histotype in patients re-excised (RE) or not (No-RE). In univariate analysis, final R0 margins are associated with a better MFS, patients with R1 margins documented at first surgery had a better MFS as compared to patients with first R0 resection. The study identified RE as an independent favorable factor for MFS (HR 0.7, 95% CI 0.53–0.93; p = 0.013). All subgroups except older patients (>70 years) and patients with large tumors (>10 cm) had superior MFS with RE. Conclusions: RE might be considered in patients with STS of limb or trunk, with UE with macroscopic complete resection performed out of a reference center, and also in originally defined R0 margin resections, to improve LRFS and MFS. Systematic RE should not be advocated for patients older than 70 years, or with tumors greater than 10 cm.

Background: We aimed to evaluate the value of the Fibrosis-4 (FIB-4) score as a prognostic factor in RA in the prospective ESPOIR cohort. Methods: We included patients from the ESPOIR cohort with a diagnosis of RA according to ACR/EULAR criteria. The formula for the FIB-4 score is as follows: [age (years) × aspartate transaminase level (U/L)]/[platelet count (10⁹/L) × alanine aminotransferase level (U/L)1/2]. We used a linear mixed-effects model with a random effect of patient to account for repeated measures over time. Results: Overall, 647 of the 813 patients included met the ACR/EULAR criteria for RA, with no differential diagnosis during the first 10 years of follow-up. Of these patients, at baseline, 633 had a calculable FIB-4 score. Median FIB-4 score was 0.75 (interquartile range 0.53–0.99). On multivariate analysis, FIB-4 score was not independently associated with progression of Disease Activity Score in 28 joints over 10 years of follow-up, unlike baseline C-reactive protein level and SJC. Baseline FIB-4 score was not associated with the modified Sharp score at 5-year follow-up, unlike age and ACPAs. FIB-4 score was not associated with mortality (hazard ratio 1.1 [95% CI 0.46; 2.8], p = 0.77) or major adverse cardiovascular events (0.46 [0.13; 1.6], p = 0.22) over the 10-year follow-up. No significant change in FIB-4 score over time was related to treatments. Conclusions: The present prospective cohort study did not find a prognostic role of FIB-4 score in RA. Reassuringly, FIB-4 score was not increased with DMARD treatment after 10 years of follow-up.

This study aimed to identify the risk factors for placenta accreta spectrum (PAS) in women who had at least one previous cesarean delivery and a placenta previa or low-lying. The PACCRETA prospective population-based study took place in 12 regional perinatal networks from 2013 through 2015. All women with one or more prior cesareans and a placenta previa or low lying were included. Placenta accreta spectrum (PAS) was diagnosed at delivery according to standardized clinical and histological criteria. Of the 520,114 deliveries, 396 fulfilled inclusion criteria; 108 were classified with PAS at delivery. Combining the number of prior cesareans and the placental location yielded a rate ranging from 5% for one prior cesarean combined with a posterior low-lying placenta to 63% for three or more prior cesareans combined with placenta previa. The factors independently associated with PAS disorders were BMI ≥ 30, previous uterine surgery, previous postpartum hemorrhage, a higher number of prior cesareans, and a placenta previa. Finally, in this high-risk population, the rate of PAS disorders varies greatly, not only with the number of prior cesareans but also with the exact placental location and some of the women's individual characteristics. Risk stratification is thus possible in this population.

Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients’ hemodynamics, it might also be harmful, supporting the need for adjuvant treatment. We therefore investigated whether NButGT, enhancing O-GlcNAcylation and showing beneficial effects in acute heart failure might improve AS therapy. Ovalbumin-sensitized rats were randomly allocated to six groups: control (CON), shock (AS), shock treated with NButGT alone before (AS+pre-Nbut) or after (AS+post-Nbut) AS onset, shock treated with epinephrine alone (AS+EPI) and shock group treated with combination of epinephrine and NButGT (AS+EPI+preNBut). Induction of shock was performed with an intravenous (IV) ovalbumin. Cardiac protein and cycling enzymes O-GlcNAcylation levels, mean arterial pressure (MAP), heart rate, cardiac output (CO), left ventricle shortening fraction (LVSF), mitochondrial respiration, and lactatemia were evaluated using Western blotting experiments, invasive arterial monitoring, echocardiography, mitochondrial oximetry and arterial blood samples. AS decreased MAP (−77%, p < 0.001), CO (−90%, p < 0.001) and LVSF (−30%, p < 0.05). Epinephrine improved these parameters and, in particular, rats did not die in 15 min. But, cardiac mitochondrial respiration remained impaired (complexes I + II −29%, p < 0.05 and II −40%, p < 0.001) with hyperlactatemia. NButGT pretreatment (AS+pre-Nbut) efficiently increased cardiac O-GlcNAcylation level as compared to the AS+post-Nbut group. Compared to epinephrine alone, the adjunction of NButGT significantly improved CO, LVSF and mitochondrial respiration. MAP was not significantly increased but lactatemia decreased more markedly. Pretreatment with NButGT increases O-GlcNAcylation of cardiac proteins and has an additive effect on epinephrine, improving cardiac output and mitochondrial respiration and decreasing blood lactate levels. This new therapy might be useful when the risk of AS cannot be avoided.

Objective: Our objective was to study the efficacy of GLP-1 analogs compared to placebo in adults with craniopharyngioma-related obesity (CRO). Design: We conducted a double-blind multicenter superiority randomized clinical trial in eleven French University hospital Centers. Methods: After a 4-week run-in period, 40 adults with CRO (BMI > 30 kg/m²) without sign of recurrence in the past year patients were randomized to receive exenatide (n=20) or placebo (n=20) injected subcutaneously twice a day. All participants were maintained on lifestyle intervention.The primary outcome was mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life and the tolerance profile. Results: At week 26, weight decreased from baseline by a mean of - 3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. Adjusted mean treatment difference was -3.1 kg (95% CI -7.0 to 0.7, p = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared to placebo (estimated treatment difference in change from baseline to week 26: -2.3, (95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in respectively 19 (95%) participants (108 events) and 14 (70%) participants (54 events). Conclusion: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.

Aims Lower respiratory tract infections (LRTI) are common worldwide. Patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high risk of developing LRTI. Prior studies were able to show that sodium–glucose cotransporter 2 inhibitors may reduce the incidence of LRTI in patients with type 2 diabetes. The aim of this study was to evaluate patient characteristics and prognosis according to LRTI status and to assess the effect of empagliflozin on LRTI in 5988 patients with HFmrEF/HFpEF enrolled in the EMPEROR-Preserved trial randomized to either empagliflozin or placebo over a median follow-up of 26 months. Methods and results Time-updated models were used to study the mortality risk after a LRTI. Cox regression was used to study the effect of empagliflozin on incident LRTI. Throughout the follow-up, 699 of 5988 (11.7%) patients developed LRTI: these were older, were more frequently hospitalized within the previous year, had type 2 diabetes, chronic kidney disease, and had higher N-terminal pro-B-type natriuretic peptide levels than patients without incident LRTI. Patients who developed LRTI had a 2.7-fold higher risk of subsequent mortality compared to patients without LRTI. The incidence of LRTI was 5.2 (95% confidence interval [CI] 4.6–5.8) events per 100 person-years in the empagliflozin group and 6.2 (95% CI 5.6–6.9) events per 100 person-years in the placebo group (hazard ratio 0.83, 95% CI 0.71–0.96, p = 0.014). The total number of LRTI events was reduced in the empagliflozin group (incidence rate ratio 0.80, 95% CI 0.68–0.94, p = 0.008). No effect of empagliflozin was observed on COVID-19 incidence. Conclusion In EMPEROR-Preserved, LRTI was frequent and associated with a poor prognosis. Empagliflozin was associated with a reduced risk of LRTI compared to placebo.

Background Single-nucleotide variants (SNVs) within gene coding sequences can significantly impact pre-mRNA splicing, bearing profound implications for pathogenic mechanisms and precision medicine. In this study, we aim to harness the well-established full-length gene splicing assay (FLGSA) in conjunction with SpliceAI to prospectively interpret the splicing effects of all potential coding SNVs within the four-exon SPINK1 gene, a gene associated with chronic pancreatitis. Results Our study began with a retrospective analysis of 27 SPINK1 coding SNVs previously assessed using FLGSA, proceeded with a prospective analysis of 35 new FLGSA-tested SPINK1 coding SNVs, followed by data extrapolation, and ended with further validation. In total, we analyzed 67 SPINK1 coding SNVs, which account for 9.3% of the 720 possible coding SNVs. Among these 67 FLGSA-analyzed SNVs, 12 were found to impact splicing. Through detailed comparison of FLGSA results and SpliceAI predictions, we inferred that the remaining 653 untested coding SNVs in the SPINK1 gene are unlikely to significantly affect splicing. Of the 12 splice-altering events, nine produced both normally spliced and aberrantly spliced transcripts, while the remaining three only generated aberrantly spliced transcripts. These splice-impacting SNVs were found solely in exons 1 and 2, notably at the first and/or last coding nucleotides of these exons. Among the 12 splice-altering events, 11 were missense variants (2.17% of 506 potential missense variants), and one was synonymous (0.61% of 164 potential synonymous variants). Notably, adjusting the SpliceAI cut-off to 0.30 instead of the conventional 0.20 would improve specificity without reducing sensitivity. Conclusions By integrating FLGSA with SpliceAI, we have determined that less than 2% (1.67%) of all possible coding SNVs in SPINK1 significantly influence splicing outcomes. Our findings emphasize the critical importance of conducting splicing analysis within the broader genomic sequence context of the study gene and highlight the inherent uncertainties associated with intermediate SpliceAI scores (0.20 to 0.80). This study contributes to the field by being the first to prospectively interpret all potential coding SNVs in a disease-associated gene with a high degree of accuracy, representing a meaningful attempt at shifting from retrospective to prospective variant analysis in the era of exome and genome sequencing.

A low allele burden (i.e., <20%) of the CALR driver mutation is found in 10.8% of CALR‐mutated MPNs, mostly in essential thrombocythemia, and correlates with a milder phenotype and a more indolent evolution compared to patients with an allele burden ≥20%. image