Hôpital Cochin (Hôpitaux Universitaires Paris Centre)

Background This narrative review aims to examine the biological mechanisms of toxicity in patients with benign prostatic hyperplasia (BPH) receiving prostate cancer (PCa) external beam radiotherapy (RT), as well as possible strategies to prevent genitourinary (GU) toxicity following PCa RT in men with BPH, through the adaptation of both medical, surgical, and irradiation strategies. Methods A broad literature search was performed in November 2024 in the PubMed database with the terms “prostate cancer”, “prostate epithelial cells”, “prostate stromal cells”, “radiation therapy”, “lower urinary tract symptoms”, “stereotactic body radiotherapy”, “transurethral resection of the prostate”, “enucleation”. Results RT affects several pathophysiological contributors to LUTS, such as urothelial dysfunction, prostatic inflammation and bladder fibrosis. While preexisting LUTS appear to be a risk factor to develop severe GU toxicity following PCa RT, the development of strategies reducing the incidental dose delivered to urinary structures appears to be particularly relevant. Urethra-sparing strategies holds the potential to reduce the onset of severe GU toxicity following PCa RT. The relationship between the highest doses delivered to the bladder and the onset of severe GU toxicity highlight the pivotal role of image-guided radiotherapy (IGRT) for PCa RT. Aggressive margin reduction from 4 mm to 2 mm demonstrated its ability to halve the risk to develop severe GU toxicity 2 years following SBRT. De-escalation in either dose or target volume represent appealing strategies, currently assessed within prospective trials. Both assessment and optimization of urinary function through medical or surgical approaches is mandatory before RT. Conclusion Strategies designed to reduce the planned and delivered dose to functional structures hold promise for the limitation of urinary toxicity after PCa RT. Further efforts should be made to adapt surgical and irradiation techniques in men with BPH, with the development of studies dedicated to this population of patients.

MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC). MET exon 14 mutations affect splice sites and are highly heterogeneous which makes them difficult to detect. Because of the approval of capmatinib for patients with MET exon 14 mutated tumors and the related poor response to immunotherapy (ICI) for a subset of patients with MET mutated tumors, MET screening has become mandatory for first line treatment decision. Here we report our testing experience based on 1143 consecutive NSCLC addressed for molecular diagnosis. Two strategies using either DNA sequencing (NGS) and fragment analysis or DNA-RNA sequencing (NGS) were developed and validated to accurately detect MET exon 14 alterations including large deletions. For patients with MET tumors (n = 46), demographic characteristics, treatments and outcomes were obtained from medical records and discussed. 46 MET exon 14 alterations were identified, 4 were not called by DNA sequencing and rescued by fragment analysis or RNA sequencing. Sixty-seven percent tumors had a high PD-L1 expression > 50 and 42% of cases had co-occurring alterations, mainly TP53 mutations (24%) and PIK3CA mutations (9%). Response to MET inhibitors (Crizotinib and Capmatinib) was evaluated for 15 patients. The ORR (Objective Response Rate) and the median of PFS (Progression Free Survival) were 44% and 5.5 months [1.6–18.2 months] respectively. Thirteen patients were treated by immunotherapy, ORR and median PFS (Progression Free Survival) median were 30% and 4 months [0.7–55.5 months] respectively. The response to immunotherapy was not correlated with PD-L1 status but smokers seemed to better respond to ICIs. This study highlights that a multimodal approach may be necessary to detect MET exon 14 mutations as large deletions may not be detected by DNA sequencing. Targeted DNA-ARN sequencing strategies broadly interrogate the diverse druggable genomic variations and permits direct detection of altered splicing or gene fusions. Because patients with MET exon 14 mutated tumors, demonstrate low response to immunotherapy despite high PDL1 and because MET exon 14 is druggable the detection of MET mutations is mandatory to optimize treatment.

In this special issue, 5 articles will delve into hypothesis around fibromyalgia's pathophysiology and 3 articles will explore how to tackle fibromyalgia.

VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is a severe monogenic disorder caused by somatic UBA1 mutations, characterized by inflammation, cytopenias and frequent association with myelodysplastic neoplasms (MDS). Steroid dependence is common, and targeted therapies have demonstrated limited efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS but data remain limited. This multicenter retrospective study assessed AZA efficacy and safety in 88 genetically confirmed VEXAS patients from the FRENVEX (French VEXAS) group, 80% meeting WHO 2022 MDS criteria. Inflammatory response rates were 41% at 6 months and 54% at 12 months, regardless of MDS status. A total of 50 (61%) patients achieved inflammatory response, with 70% occurring at 6 months, suggesting a delayed median response. Among responders, relapse-free survival on AZA was 90% at 1 year and 85% at 5 years. Of the 12 responders who discontinued AZA, 9 relapsed after a median of 3.1 years (range: 0.4-5.6), with effective re-exposure in 4 of 5 patients. Hematological responses included red blood cell transfusion independence in 65% and platelet improvement in 77% of patients. Molecular response, defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was observed in 65% of patients, all of whom achieved inflammatory and hematological responses; and VAF dropped below 2% in 43% of cases. Infections (34%) and cytopenias (36%) were common, particularly during the first three cycles. This study establishes AZA as an effective therapy for VEXAS, improving inflammation, cytopenias, and UBA1 clonal burden, warranting larger prospective trials.

Objective Individual patients' data sharing requires interoperability, security, ethical, and legal compliance. The aim was to assess the landscape and sharing capacities between endocrine researchers. Design A standardized survey (SurveyMonkey®) with 67 questions was sent to European Network for the Study of Adrenal Tumors centers. Methods Answers were counted as absolute numbers and percentages. Comparisons between inclusiveness target countries (ITC) and non-ITC (defined by Cooperation in Science & Technology Action) were performed using Fisher's exact test. Results Seventy-three centers from 34 countries answered the survey. Electronic health record (EHR) systems are now the main source of data (90%). However, significant variability was reported, entailing >35 EHR providers, and variable data collected. Variable stakeholders' implication for enabling data sharing was reported, with more lawyers (P = .023), patient representatives (P < .001), ethicists (P = .002), methodologists (P = .023), and information technology experts (P < .001) in non-ITC centers. Implication of information technologies experts for data collection and sharing was underwhelming (33%). Funding for clinical research was higher in non-ITC than in ITC for clinical trials (P = .01) and for registry-based and cohort studies (P = .05). However, for retrospective studies addressing a specific clinical question, the funding was either very low (<10%) or nonexistent for both ITC and non-ITC (37% and 46%, respectively), with no dedicated funding for information technology (86%) and ethical and regulatory aspects (88%). Conclusions In the absence of dedicated funding for retrospective research, current requirements for data sharing are obstacles.

Ibuprofen arginine (IBA) combines well-established analgesic and anti-inflammatory properties with enhanced pharmacokinetics. The addition of arginine significantly improves solubility and absorption, leading to a faster onset of action compared to conventional ibu-profen. Clinical studies consistently demonstrate that IBA achieves meaningful pain relief within a shorter timeframe while maintaining a favorable safety profile. IBA's rapid action is particularly valuable in managing acute exacer-bations of chronic pain and preventing central sensitization, thus improving patient comfort, adherence, and overall quality of life. By addressing both the inflammatory and nociceptive components of pain, IBA offers an effective and well-tolerated alternative in multimodal pain management strategies. This review explores the clinical benefits of IBA in pain management among various clinical settings.

Background Prognostic markers of good neurological outcome after cardiac arrest (CA) remain limited. We aimed to evaluate the prognostic value of neuron-specific enolase (NSE), electroencephalogram (EEG) and somatosensory evoked potentials (SSEP) in predicting good outcome, assessed separately and in combination. Methods A retrospective study was conducted in a tertiary CA center, using a prospective registry. We included all patients comatose after discontinuation of sedation and with one EEG and NSE blood measurement at 24, 48 or/and 72 h after CA. The primary outcome was favorable neurological outcome at three months, a Cerebral Performance Categories (CPC) scale 1–2 defining a good outcome. Results Between January 2017 and April 2024, 215 patients were included. Participants were 63 years old (IQR [52–73]), and 73% were male. At 3 months, 54 patients (25.1%) had a good outcome. Compared to the poor outcome group, NSE blood levels were significantly lower in the good outcome group at 24 h (39 IQR[27–45] vs 54 IQR[37–82]µg/L, p < 0.001), 48 h (26 [18–43] vs 107 [54–227]µg/L, p < 0.001) and 72 h (20 µg/L IQR [15–30] vs 184 µg/l IQR [60–300], p < 0,001). Normal NSE (i.e., < 17 µg/L) at 24 h was highly predictive of good outcome, with a predictive positive value (PPV) of 71% despite a sensitivity (Se) of 9%. The best cut-off values for NSE at 24, 48 and 72 h were below 45.5, 51.5 and 41.5 µg/L, yielding PPV of 64%, 80% and 83% and sensitivities of 74%, 93% and 90%, respectively. A decreasing trend in NSE levels between 24 and 72 h was also highly predictive of good outcome (PPV 82%, Se 81%). A benign EEG pattern was more frequently observed in the good outcome group (87.1 vs 14.9%, p < 0.001) and predicted a good outcome with a PPV of 72% and a Se of 94%. Regarding SSEPs, a bilateral N20-baseline amplitude > 0.85 µV was predictive of good outcome (PPV 75%, Se 100%). The combination of NSE < 51.5 µg/l at 48 h, a decreasing NSE trend between 24 and 72 h and a benign EEG showed the best predictive value (PPV 96%, Se 76%). Conclusion In comatose patients after CA, a low NSE levels at 24, 48 h or 72 h, a decreasing trend in NSE over time, a benign EEG and a high N20 amplitude are robust markers of favorable outcome, reducing prognosis uncertainty. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13054-025-05378-8.

Chronic histiocytic intervillositis (CHI) is an inflammatory condition of the placenta, characterised by an abnormal, mainly macrophagic infiltrate within the intervillous space. Recent research suggests that CHI results from a ‘maternal‐foetal rejection’ mechanism, because at least some CHI cases fulfil the criteria for antibody‐mediated rejection (AMR) of kidney allografts according to the Banff classification [i.e. presence of anti‐human leukocyte antigen (HLA) paternal antibodies activating the complement or foetal‐specific antibodies (FSA), a macrophage‐rich infiltrate, and positive C4d immunostaining]. To gain further insights into CHI pathogenesis, we aimed to refine the phenotype of the inflammatory infiltrate using a multiplex immunofluorescence technique and to compare the mRNA signatures between CHI and AMR of kidney allografts. Twelve patients with C4d + FSA+ CHI were included in the study and compared to a control group of 5 patients without inflammatory lesions on placental examination. We developed a multiplex immunofluorescence panel to identify CD4+ and CD8+ T lymphocytes, CD68+/CD206− and CD68+/CD206+ macrophages, and NK cells in the villi and intervillous space. Molecular signatures were studied using NanoString® technology and the B‐HOT panel recommended by the Banff classification for kidney allografts. Multiplex immunofluorescence revealed that the infiltrate in the intervillous space was mainly composed of CD68+/CD206− macrophages as well as a higher proportion of CD8+ lymphocytes in patients with CHI compared to controls. Densities of NK cells and CD4 T cells were very low. Molecular signatures showed an overexpression of HLA class II genes, an IFN‐γ signature, and cytokine gene sets in C4d + FSA+ CHI patients, also involved in kidney AMR. These results reinforce the paradigm of maternal‐foetal rejection. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Limb–girdle muscular dystrophy Type 2A/R1 or calpain-3 deficiency is the most common autosomal recessive limb–girdle muscular dystrophy. However, in recent years, autosomal dominant cases and families with calpain-3 deficiency have been reported, and there is an emerging interest in looking for single variants in the calpain-3 gene in mildly to moderately affected patients with limb–girdle muscular dystrophy without biallelic gene variants in CAPN3. Here, we report four cases with creatine kinase levels above 1500 U/L, mild-to-moderate proximal weakness, waddling gait, and scapular winging. Two patients, a son and his father, are heterozygous for the CAPN3 variant c.304C>T; p.(Pro102Ser), which has previously been reported in patients with compound heterozygous variants in CAPN3. The third and fourth patients were heterozygous for c.1371C>G; p.(Asn457Lys) and c.1490C>T; p.Ala497_Glu508del, respectively, neither of which has been reported before. All four patients had a near-complete loss of calpain-3 as determined by western blotting. While inherited autosomal dominant calpainopathy has now been firmly established, additional single cases of dominant calpainopathy are likely to emerge; some will be associated with clinical findings from parents or siblings, while others will arise from spontaneous mutations, but nevertheless with similar clinical findings of mild-to-moderate proximal weakness, increased level of creatine kinase, and nearcomplete loss of calpain-3 protein in affected individuals. This report expands the known number of variants causing dominant calpainopathy from 8 to 11 that appears to exclusively reside in two out of four domains that make up calpain-3. This information could aid in determining whether a CAPN3 variant of unknown significance is pathological.

Immune evasion is a hallmark of cancer progression but the role of steroid hormones in this evasion has long been underrated. This oversight is particularly notable for glucocorticoids given that exogenous glucocorticoids remain a cornerstone therapy in various oncological treatment regimens, supportive care and treatment of immune-related adverse events caused by immune-checkpoint inhibitors. Cortisol, the main endogenous glucocorticoid in humans, is secreted by the adrenal cortex in response to stress. Additionally, cortisol and its inactive metabolite cortisone can be interconverted to further modulate tissue-dependent glucocorticoid action. In the past 5 years, intratumoural production of glucocorticoids, by both immune and tumour cells, has been shown to support tumour immune evasion. Here, we summarize current progress at the crossroads of endocrinology and immuno-oncology. We outline the known effects of steroid hormones on different immune cell types with a focus on glucocorticoids and androgens. We conclude with options for pharmaceutical intervention, including the engineering of cell-based therapies that resist the immunosuppressive action of steroid hormones. Overall, local steroid production and metabolism are emerging elements of tumour immune suppression that are potentially amenable to therapeutic intervention. Targeting steroid hormones to enhance anticancer therapies could increase their efficacy but will require expertise in endocrine care.

Introduction Current bronchiectasis guidelines advise against the use of inhaled corticosteroids (ICS) except in patients with associated asthma, allergic bronchopulmonary aspergillosis (ABPA) and/or chronic obstructive pulmonary disease (COPD). This study aimed to describe the use of ICS in patients with bronchiectasis across Europe. Methods Patients with bronchiectasis were enrolled into the European Bronchiectasis Registry from 2015 to 2022. Patients were grouped into ICS users and non-users at baseline and clinical characteristics associated with ICS use were investigated. Patients were followed up for clinical outcomes of exacerbation, hospitalisation and mortality for up to 5 years. We evaluated if elevated blood eosinophil counts (above the laboratory upper limit of normal) modified the effect of ICS on exacerbations. Results 19 324 patients were included for analysis and 10 109 (52.3%) were recorded as being prescribed ICS at baseline. After exclusion of patients with a history of asthma, COPD and/or ABPA, 3174/9715 (32.7%) patients with bronchiectasis were prescribed ICS. Frequency of ICS use varied across countries, ranging from 17% to 85% of included patients. ICS users had more severe disease, with significantly worse lung function, higher Bronchiectasis Severity Index scores and more frequent exacerbations at baseline (p<0.0001). Overall, ICS users did not have a reduced risk of exacerbation or hospitalisation during follow-up, but a significant reduction in exacerbation frequency was observed in the subgroup of ICS users with elevated blood eosinophil counts (relative risk 0.70, 95% CI 0.59 to 0.84, p<0.001). Conclusion ICS use is common in bronchiectasis, including in those not currently recommended ICS according to bronchiectasis guidelines. ICS use may be associated with reduced exacerbation frequency in patients with elevated blood eosinophils.

Introduction Acute encephalopathy in the ICU poses significant diagnostic, therapeutic, and prognostic challenges. Standardized expert guidelines on acute encephalopathy are needed to improve diagnostic methods, therapeutic decisions, and prognostication. Methods The experts conducted a review of the literature, analysed it according to the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) methodology and made proposals for guidelines, which were rated by other experts. Only expert opinions with strong agreement were selected. Results The synthesis of expert work and the application of the GRADE method resulted in 39 recommendations. Among the 39 formalized recommendations, 1 had a high level of evidence (GRADE 1 +) and 10 had a low level of evidence (GRADE 2 + or 2-). These recommendations describe indication for ICU admission, use of clinical scores and EEG for diagnosis, detection of complications, and prognostication. The remaining 28 recommendations were based on expert consensus. These recomandations describe common indications for blood and CSF studies, neuroimaging, use of neuromonitoring, and provide guidelines for management in the acute phase. Conclusion This expert consensus statement aims to provide a structured framework to enhance the consistency and quality of care for ICU patients presenting with acute encephalopathy. By integrating high-quality evidence with expert opinion, it offers a pragmatic approach to addressing the complex nature of acute encephalopathy in the ICU, promoting best practices in patient care and facilitating future research in the field.

Background Pregnancy may have a beneficial effect on disease activity in rheumatoid arthritis (RA) but the evidence is more conflicting in spondyloarthritis (SpA). The aim of this study was to analyse disease activity and relapse during pregnancy in women with RA and SpA. Methods Consecutive pregnant women with RA or SpA were enrolled in this French multicentre observational cohort from 2014 to 2022. Women who had at least two prenatal visits (including one in the first trimester) were included in the analysis. Disease relapse was defined as treatment intensification (initiation or switch of a DMARD) or increase in disease activity scores (DAS28-CRP for RA patients; ASDAS-CRP and/or BASDAI for SpA patients). Results Of the 124 pregnant women included, 53 had RA and 71 had SpA. A total of 18 (35%) RA and 44 (62%) SPA received a TNF inhibitor during pregnancy. At the group level, disease activity indexes remained stable in the 1st, 2nd and 3rd trimesters. Disease relapse during pregnancy occurred in 17 (32%) RA patients and 28 (39%) SpA patients, among whom 30 (24%) requiring a treatment intensification. In multivariable analysis, factors associated with disease relapse were nulliparity (odds ratio, OR: 6.5, 95%CI: 1.1 to 37.9) and a disease flare in the 12 months prior to conception (OR: 8.2, 95%CI: 1.6 to 42.7) for RA patients, and a history of bDMARD use (OR: 5.4, 95%CI: 1.1 to 27.3) for SpA patients. Conclusion Disease activity remained stable during pregnancy in women with RA and SpA but almost a quarter required major changes to their treatment.