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XRCC4-related microcephalic primordial dwarfism: description of a clinical series of 7 cases, phenotype expansion and new diagnostic approaches
No full textInternational audienceThe non-homologous end joining (NHEJ) pathway is essential to repair DNA double-strand breaks. XRCC4 acts as a stabilizer of the DNA ligase LIG4 in the NHEJ process. In humans, XRCC4 pathogenic variants are responsible for a microcephalic primordial dwarfism syndrome (MPD). Currently, 17 patients have been reported with XRCC4-related MPD and we report 7 new patients from 6 different families, including one fetus. The patients present with short stature, severe microcephaly, neurodevelopmental disorder and additional features, such as transient increase in nuchal translucency, congenital glaucoma, thumb anomalies, hepatic steatosis, seizures, essential tremor and oligodontia which have not been previously described. Hyper-and hypopigmented skin macules, dermatofibrosarcoma, mandibular osteoid osteoma and pancytopenia are also new features, reminiscent of cancer susceptibility syndromes. Functional studies were performed on two patients carrying the known pathogenic p.(Trp43Arg) variant in homozygous state, using a fast, cost-effective and non-invasive approach on PBMCs: (1) Survival analyses after ionizing radiation confirm important radiosensitivity. (2) Flow cytometry showed the lack of TCR-Va7+ T-lymphocytes, suggesting recombination defect of V(D)J coding segments. (3) This was confirmed by multiplexed RT-PCR (PROMIDISα biomarker), analyzing the diversity of V(D)J coding segments in a subset of the TCRα repertoire. We therefore extend the phenotype of XRCC4-related MPD and suggest a combination of three functional assays, based on radiosensitivity and V(D)J recombination defect, to improve the interpretation of XRCC4 variants in fast, cost-effective and non-invasive manner. These findings will improve the diagnosis, genetic counselling, follow-up and management of these patients.</div
Impact of the intronic RFC1 expansion size in CANVAS phenotype: an oculomotor study
No full textInternational audienceThe identification of the RFC1 homozygous intronic expansion in cerebellar ataxia neuropathy and vestibular areflexia syndrome (CANVAS) highlighted that genetically determined CANVAS patients exhibit a wide range of clinical presentations and natural course. Previous studies suggested a link between disease severity and the size of the intronic expansion. The aim of our study was to obtain quantitative data related to vestibular and cerebellar impairments using oculomotor recordings to provide further evidence of a link between RFC1 intronic expansion size and the phenotype. This study recruited 26 genetically determined CANVAS patients in whom the size of the pathological intronic expansion was measured on both alleles. In addition to clinical data, we also recorded the Overall Neuropathy Limitation Scale (ONLS) and conducted objective oculomotor testing. According to the median expansion length on one allele, the patients were divided in a longer intronic repeat subgroup and a shorter intronic repeat subgroup. Given the homozygous nature of this disease, this analysis was carried out for the smallest and for the longest allele. We found for the smallest allele that vestibular deficit and cerebellar impairment were significantly more frequent and mean ONLS, smooth pursuit, pendular visually enhanced vestibulo-ocular reflex, and head impulse vestibulo-ocular reflex gains were significantly more impaired in the subgroup of patients with the long intronic repeat. This work provides objective evidence for a functional impact of the pathological intronic expansion size in CANVAS and highlights the interest of oculomotor assessment in research and clinical practice both for diagnostic and potentially prognostic purposes
Pre-emptive TIPS for gastric variceal bleeding in patients with cirrhosis (GAVAPROSEC): an open-label randomised clinical trial
No full textInternational audienceBackgroundIn patients with cirrhosis, variceal glue obliteration is recommended for the treatment of acute fundal variceal bleeding, and for the prevention of rebleeding in combination with non-selective β blockers (NSBB). We evaluated the efficacy of pre-emptive transjugular intrahepatic portosystemic shunt (p-TIPS) in this setting.MethodsThis open-label randomised trial was conducted at 17 tertiary centres in France. Patients with cirrhosis and acute fundal variceal bleeding (excluding type 1 gastro-oesophageal varices), who achieved initial haemostasis with endoscopic glue injection and vasoactive therapy, and remained stable for at least 12 h, were randomly assigned to receive either a covered p-TIPS within 72 h or to continue with on-demand glue obliteration sessions combined with NSBB. Randomisation was centralised, stratified by centre, and performed in blocks of four (1:1 ratio). The primary composite endpoint was all-cause mortality or clinically significant rebleeding within 1 year. Analyses were conducted in the modified intention-to-treat (mITT) population. This completed study was registered on ClinicalTrials.gov(NCT03705078).FindingsBetween Jan 3, 2019, and Feb 25, 2023, 292 patients were screened, of whom 105 were enrolled and randomly assigned. After excluding two patients who were randomly assigned by error and two who withdrew consent, 101 patients were included in the mITT population (mean age 58·2 years [SD 9·7], 81 [80%] male, 91 [90%] alcohol-related cirrhosis, mean MELD score 14·3 [SD 5·0]). Of these 101 patients, 47 were allocated to p-TIPS and 54 to glue obliteration and NSBB. The 1-year probability of being free from death or rebleeding was 77% (95% CI 62–87) in the p-TIPS group versus 37% (24–50) in the glue obliteration and NSBB group (hazard ratio 0·25 [95% CI 0·12–0·51]; p<0·0001). Rescue TIPS was required in 20 (37%) patients in the control group. Glue migration was reported in eight patients (three [6%] in the p-TIPS group and five [9%] in the control group). One case of cardiac decompensation occurred in the p-TIPS group. The 1-year cumulative incidence of hepatic encephalopathy was similar between groups (35% [95% CI 21–49] vs 32% [19–45]).InterpretationIn patients with cirrhosis and acute bleeding from fundal varices, p-TIPS significantly reduced the risk of rebleeding or death at 1 year and should be considered as first-line therapy
Data linkage between the French multiple sclerosis cohort (OFSEP) and the French national health insurance database (SNDS)
No full textInternational audienceBackground: Linking disease registries to nationwide healthcare administrative databases increases the research opportunities. Recent guidelines emphasize the need of transparency in this process.Objective: Our aims were to describe the process of record linkage between the French multiple sclerosis (MS) cohort (OFSEP) and the national health insurance database (SNDS) and to evaluate the linkage quality.Methods: As no unique identifier was available in the two databases, the OFSEP-SNDS data linkage was performed by indirect matching using the following sixteen patient variables to create a unique key: sex, dates of birth and death, of visits to a neurologist, of MS-related hospitalizations, of MRI, and use of disease-modifying therapies. Three indicators were computed to assess the linkage quality.Results: Among the 52,034 eligible patients in the OFSEP registry, 42,603 (81.9%) were matched with patients in the SNDS database, with good overall quality (robustness=3.19; this is the number of linkage variables that can be removed without losing the uniqueness of the linked pair; 87.8% of common information). Comparison of the linked and unlinked populations revealed no major selection bias regarding age and sex distributions.Conclusion: The successful linkage of more than 40,000 patients with MS broadens the research perspectives by allowing access to a wide range of clinical and administrative data (e.g., comorbidities, care pathways) over a long mean disease duration (> 15 years)
Functional positioning in robotic patello-femoral arthroplasty: a step-by-step technique
No full textInternational audiencePatello-femoral arthroplasty (PFA) is an effective treatment option for isolated patello-femoral osteoarthritis. However, challenges remain regarding implant positioning and patellar tracking. Recent advances in implant design and robotic-assisted techniques have contributed to more personalized and reproducible procedures. Functional positioning (FP), a three-dimensional alignment concept, introduces a customized approach to optimize trochlear resurfacing and restore joint kinematics of the anterior compartment. This article presents a step-by-step surgical technique for PFA using FP principles in combination with an image-based robotic system. The technique ensures accurate preoperative planning, real-time intraoperative adjustments, and precise component placement. The key steps of this surgical technique include trochlear resurfacing assisted by an image-based robotic system and the restoration of patellar tracking, following a step-by-step approach that is both effective and reproducible. The use of FP enables personalized anterior compartment restoration, avoiding overstuffing and improving patellar tracking. Future studies will help refine FP strategies and further optimize outcomes in these patients
Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Chemotherapy in Advanced Metastatic Gastroesophageal Adenocarcinoma: The Phase III, Randomized LEAP-015 Study
No full textInternational audiencePURPOSE The phase III randomized open-label LEAP-015 study (ClinicalTrials.gov identifier: NCT04662710 ) evaluated first-line lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy for advanced metastatic gastroesophageal adenocarcinoma. METHODS Eligible participants 18 years and older with untreated human epidermal growth factor receptor 2–negative locally advanced unresectable or metastatic gastroesophageal adenocarcinoma were randomly assigned 1:1 to induction with oral lenvatinib 8 mg once daily plus pembrolizumab 400 mg intravenously once every 6 weeks (×2) and investigators’ choice of capecitabine and oxaliplatin once every 3 weeks (×4) or fluorouracil, leucovorin, and oxaliplatin once every 2 weeks (×6) and consolidation with lenvatinib plus pembrolizumab, or chemotherapy. Dual primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 combined positive score (CPS) ≥1 and all participants. Secondary end points included objective response rate (ORR) and duration of response. RESULTS Of 880 participants randomly assigned, 443 received lenvatinib plus pembrolizumab and 437 received chemotherapy. The median follow-ups were 32.2 months (range, 19.0-41.7) in participants with PD-L1 CPS ≥1 and 31.8 months (19.0-41.7) in all participants. At interim analysis, PFS was statistically significant with lenvatinib plus pembrolizumab versus chemotherapy in participants with PD-L1 CPS ≥1 (median, 7.3 v 6.9 months; hazard ratio [HR], 0.75 [95% CI, 0.62 to 0.9]; P = .0012) and all participants (median, 7.2 v 7.0 months; HR, 0.78 [95% CI, 0.66 to 0.92]; P = .0019). The ORR was 59.5% versus 45.4% in participants with PD-L1 CPS ≥1 and 58.0% versus 43.9% in all participants, P < .0001 for both. At final analysis, OS was not statistically significant in participants with PD-L1 CPS ≥1 (median, 12.6 v 12.9 months; HR, 0.84 [95% CI, 0.71 to 1.00]; P = .0244; P value boundary = .0204). Grade ≥3 drug-related adverse event rates were 65% versus 49%. CONCLUSION Lenvatinib plus pembrolizumab and chemotherapy versus chemotherapy provided a statistically significant improvement in PFS in advanced unresectable or metastatic gastroesophageal carcinoma at interim analysis although the clinical significance of this difference seems to be limited. No significant improvement occurred in OS in participants with PD-L1 CPS ≥1
Long-term outcomes of a 3D printed cementless fixed bearing unicompartmental knee arthroplasty
No full textInternational audienceIntroductionCementless fixation of medial unicompartmental knee arthroplasty (UKA) is attracting growing interest as a way to improve implant survival. This study aimed to evaluate the near-decade results, survivorship, and revision causes for a fixed-bearing cementless fully 3D printed UKA.Materials and methodsFrom 2011 to 2014, 168 consecutive cementless UKA implants on 165 patients had been performed in our hospital using a fixed bearing implant with a 3D printed Hydroxyapatite coated ingrowth surface both on the femoral and tibia components. At a mean follow-up of 8.73 years, 132 patients were retrospectively available for long-term assessment. Clinical outcomes and survivorship were analyzed using validated Patient Reported Outcome Measures (PROMs) such as the Oxford Knee Score (OKS), the International Knee Society (IKS) Score and the Numeric Rating Scale (NRS). The Hip-Knee-Ankle (HKA) angle was measured preoperatively and postoperatively at the last follow-up. Kaplan-Meier survival analysis was conducted with revision for any reason as primary endpoint and UKA failure as secondary endpoint.ResultsSignificant reductions were observed in terms of mean NRS from 6.90 to 1.49 points (p < 0.0001), OKS from 34.82 to 19.05 points (p < 0.0001), and IKS Score, in particular clinical knee score from 59.13 to 85.61 points (p < 0.0001) and functional knee score from 58.70 to 88.94 points (p < 0.0001). The 10-year survival rate for revision for any reason was 93.6% (95% CI: 89.5–97.8). For revision specifically due to implant mechanical failure, the 10-year survival rate was 94.9% (95% CI: 91.3–98.8). The primary revision cause was aseptic loosening of the tibial component. Factors such as age, BMI, and sex were not significantly associated with an increased risk of revision.ConclusionsThe present study shows good clinical results and long-term implant survivorship, compared to literature data, confirming the effectiveness of cementless UKA
Parkinson's Disease, Speech and Neurosurgery
No full textInternational audienceBackground: Speech impairment is a recognized but unpredictable adverse effect of sub-thalamic nucleus deep brain stimulation (STN-DBS) for Parkinson's disease (PD).Objectives: To evaluate the prevalence of speech impairment 1 year after STN-DBS in PD patients and to determine the predictive factors for speech outcome following STN-DBS.Methods: Data for 417 patients from the French national PREDISTIM study were collected preoperatively. The combined effect of medical treatment and surgery on speech was compared using specific items from dedicated clinical scales (MDS-UPDRS III.1: primary endpoint) and patient self-assessment questionnaires (items 34 and 35 of the PDQ39: secondary endpoints). For each variable, three patient groups were generated according to speech outcome at 1 year: worsening, stability, and improvement. In the second step analysis, the three groups were compared for demographic and clinical variables at baseline and STN-DBS parameters.Results: There was a significant deterioration in speech of all considered items 1 year after combined STN-DBS and dopaminergic treatment. Four predictive factors for speech deterioration were detected: (i) the absence of preoperative speech impairment (p < 0.001); (ii) severity of motor activity of daily living (MDS-UPDRS II off total score) (p = 0.037); (iii) high-intensity stimulation of the left electrode (i.e., above 3.6 V) (p = 0.046); and (iv) the absence of any change in non-motor experiences of daily life (MDS-UPDRS I total score) (p = 0.048).Conclusions: Speech outcome should be carefully monitored after STN-DBS, especially in PD patients without preoperative speech impairment, with motor difficulties in daily-living activities, and with increased left electrode intensity.Trial registration: ClinicalTrials.gov identifier: NCT02360683
Association of phenylacetylglutamine and cognitive impairment in chronic kidney disease
No full textInternational audienceBackgroundChronic kidney disease (CKD) leads to the accumulation of uremic toxins (UTs). Studies have suggested that UTs are associated with cognitive impairment (CI) in CKD patients. Recently studies reported that phenylacetylglutamine (PAG) contributes to the association between CKD and CI. However, this association has not been investigated in adult non-dialysis-dependent with CKD.MethodsThe CKD-REIN cohort study included 3033 patients with CKD stages 2-5. This cross-sectional analysis included those with a PAG measurement and a Mini-Mental State Examination (MMSE) score within 3 months of each other. CI was defined as an MMSE score ≤26/30. Logistic regression were used to assess the association between PAG and CI.ResultsOf the 2590 patients included (mean (standard deviation (SD)) age: 67 (13); mean (SD) estimated glomerular filtration rate (eGFR): 34 (13) mL/min/1.73m2; median [interquartile range] PAG level: 2.1 [1.2-3.6] mg/L), 908 (35%) presented an MMSE score ≤26/30. After adjustment for sociodemographic factors (age, sex, educational level), cardiovascular risk factors, cerebrovascular disease, current depression, eGFR, urinary albumin to creatinine ratio and UTs known to be associated with CI risk, a two-fold increase in the PAG level was associated with CI (odds ratio [95% confidence interval]: 1.13 [1.01, 1.28]).ConclusionsThis study shows that a higher serum PAG level was associated with CI in adult non-dialysis-dependent with CKD and highlight a new UT associated with CI in patients with CKD. Further studies are needed to confirm the causal nature of the association and to explore strategies for reducing serum PAG levels to protect cognition
Characteristics of SARS-CoV-2-associated severe episodes of monoclonal gammopathy-associated capillary leak syndrome (Clarkson disease)
No full textInternational audienceBackground Monoclonal gammopathy-associated capillary leak syndrome (MG-CLS) is a rare condition characterized by recurrent episodes of hypovolemic shock caused by a sudden increase in capillary permeability. The COVID-19 pandemic has been associated with a rise in MG-CLS episodes and increased mortality. We aimed to explore the association between MG-CLS and SARS-CoV-2 infection. We conducted a multicenter retrospective observational study involving MG-CLS patients who were admitted to the intensive care unit (ICU). The primary endpoint was 28-day mortality according to whether SARS-CoV-2 was identified as a trigger. Results The study included 84 patients (44% women) with a median age of 55 years [IQR 46–62], accounting for 127 ICU admissions. Most patients (88%) had monoclonal gammopathy, predominantly with an IgG heavy chain (98%). A trigger was identified in 63% of cases, primarily suspected or confirmed viral infections, including 26 episodes of SARS-CoV-2 infection. Within 28 days of ICU admission, 32% of patients died. Episodes triggered by SARS-CoV-2 were associated with a higher need for mechanical ventilation (69% vs. 38%, p = 0.004), renal replacement therapy (54% vs. 31%, p = 0.03), and increased 28-day mortality (42% vs. 17%, p = 0.005). Multivariable analysis revealed that SARS-CoV-2 infection was independently associated with 28-day mortality (OR 4.67 [1.08–20.1], p = 0.04). The use of intravenous immunoglobulins did not improve 28-day survival. Conclusion In this large cohort of MG-CLS episodes requiring ICU admission, SARS-CoV-2as a trigger was associated with significantly higher 28-day mortality compared to other triggers. Further research is essential to elucidate the specific mechanisms by which SARS-CoV-2 impacts MG-CLS patients. Graphical abstrac