Regional citrate anticoagulation (RCA) is recommended by guidelines over systemic heparinization for continuous renal replacement therapy (CRRT). However, its use in patients with impaired citrate metabolism poses specific challenges and standardized guidance for managing RCA-related metabolic complications remains lacking. A modified Delphi study was conducted according to a predefined protocol and reported in adherence with the CREDES (Conducting and REporting of DElphi Studies) checklist. The international expert panel comprised 29 clinicians and researchers from Europe, United States and Canada, with recognized expertise in RCA for CRRT in critically ill patients. Three iterative survey rounds were conducted to obtain agreement with proposed statements. Twenty-three experts completed all Delphi rounds, achieving consensus on twenty-two statements. RCA was considered feasible in patients with liver dysfunction, severe shock, or hyperlactatemia, with close monitoring and citrate dosing adjustment. Citrate accumulation can be prevented and managed using a stepwise approach, focused on reducing citrate delivery and discontinuing RCA in cases of overt accumulation. Metabolic alkalosis and electrolyte disturbances were identified as relevant but manageable complications, underscoring the need for individualizing CRRT settings. These consensus statements support the use of RCA during CRRT in critically ill patients with impaired citrate metabolism and provide practical guidance for monitoring and management of metabolic complications. However they reflect expert opinion, especially for questions with limited data and low-level evidence.
Isolated bilateral fractures of the lesser tuberosity of the humerus represent an exceptionally rare subset of proximal humerus fractures. A 66‑year‑old active woman with chronic steroid‑induced osteoporosis presented with bilateral shoulder pain after a ground‑level fall down a step. Clinical examination demonstrated marked bilateral loss of internal rotation strength with positive belly‑press and bear‑hug tests, whereas external rotation was preserved. Standard radiographs, CT, and MRI confirmed displaced bilateral lesser tuberosity avulsion fractures in porotic bone, with the subscapularis tendon attached to the fragments and an otherwise intact rotator cuff. Given the degree of displacement, functional impairment, and high functional demands, a single‑stage bilateral open surgical procedure was performed in the beach‑chair position through a deltopectoral approach, consisting of long head biceps tenotomy with tenodesis using a 5‑mm titanium anchor (ArthroVims®; VIMS, Villeneuve-lès-Bouloc, France) and suture‑based fixation of the lesser tuberosity fragments using nonabsorbable Smartloop® and SmartTape™ sutures (FX Solutions, Viriat, France), tailored to the small, porotic fragments. Postoperative management consisted of sling immobilization for six weeks, immediate pendulum exercises, passive external rotation limited to 0° from week 3, and active mobilization from week 6, resulting in excellent shoulder function at only three months' follow‑up. This case illustrates the feasibility of simultaneous bilateral surgery in an osteoporotic patient, with fixation adapted to poor bone quality (suture fixation rather than screw fixation) and systematic management of the long head of the biceps in the setting of pulley involvement. Only three cases of isolated bilateral lesser tuberosity fractures have been reported to date, underscoring the rarity of this injury pattern, the value of advanced imaging, and the role of operative treatment in displaced fractures.
Background Chronic Achilles tendon rupture remains a challenging condition, particularly in cases involving large tendon defects that preclude end-to-end repair. Among reconstructive options, techniques using local tissues avoid the donor-site morbidity associated with tendon transfers. This study describes a modified gastrosoleus fascial turndown flap based on the Rush technique, reinforced with the plantaris tendon, and reports preliminary clinical outcomes. Methodology A total of 13 patients presenting with chronic Achilles tendon rupture (≥4 weeks) with a defect ≥6 cm were included. All underwent reconstruction using a tubularized gastrosoleus fascial flap based on the Rush principle, combined with plantaris tendon augmentation in a framing configuration. Outcomes were assessed using the Achilles Tendon Total Rupture Score (ATRS), the American Orthopaedic Foot & Ankle Society (AOFAS) score, and the ability to perform heel raises. Body mass index (BMI) was analyzed descriptively as an exploratory variable, given the limited sample size precluding formal statistical analysis. Results At a mean follow-up of 16.1 ± 2.7 months, the mean ATRS was 81.0 ± 3.9, and the mean AOFAS score was 83.9 ± 2.3. Patients performed a mean of 14.5 ± 1.3 single-leg heel raises. No reruptures or complications were observed. The mean BMI was 25.2 ± 3.4 kg/m², with a slight decrease in ATRS observed in overweight patients. Conclusions The modified Rush technique with plantaris tendon augmentation appears to be a reproducible biological option for the management of chronic Achilles tendon ruptures with large defects. In this preliminary series, satisfactory functional outcomes were observed, supporting the feasibility of a fully biological reconstruction strategy using local tissues without tendon sacrifice. This approach may represent a potential alternative to tendon transfers for defects ≥6 cm.
Background. Advanced non-small cell lung cancer (NSCLC) lacking actionable molecular alterations remains a major clinical challenge, with immunotherapy and chemoimmunotherapy representing the main treatment options. Although natural killer (NK) cells are key effectors of innate antitumor immunity, their role within the NSCLC tumor microenvironment (TME) remains incompletely understood. Methods. NK-92 cells and NSCLC A549 and H1299 lines were cultured in 2D, 3D, in co-cultures, and exposed to radiotherapy (5-7.5 Gy) or chemotherapy (gemcitabine, pemetrexed, cisplatin). Functional effects were evaluated by MTS, Annexin-V, β-galactosidase assays, synergism analyses, and confocal imaging. Gene expression was assessed using quantitative real-time PCR (qRT-PCR) and digital droplet PCR (ddPCR). Spatial transcriptomics via Nanostring Digital Spatial Profiling (DSP) was performed on tissue microarrays (TMAs) prepared from NSCLC patients tissues collected at IHU RespirERA (Nice, France), then bulk RNA sequencing was conducted. Results. We investigated whether conventional anticancer treatments and purinergic signaling could modulate NK cell-mediated antitumor activity. Chemotherapy, but not radiotherapy, significantly altered the expression of NK cell-activating ligands on NSCLC cells. Accordingly, co-culture experiments showed that pre-treatment with gemcitabine or pemetrexed enhanced NK cell-mediated tumor cell killing. These agents also increased tumor immunogenicity by upregulating NK-activating ligands and inducing a senescence-associated secretory phenotype. Digital spatial profiling of patient-derived NSCLC tissues revealed higher P2RX7 expression in tumors lacking actionable alterations, which was associated with NK cell-related transcriptional signatures. In vitro, P2RX7 expression decreased following co-culture of NK-92 cells with chemotherapy-pretreated NSCLC cells. Moreover, pharmacological inhibition of P2X7 receptor with AZ10606120 promoted NK-92 cell infiltration into NSCLC spheroids. Combination experiments further demonstrated that AZ10606120 synergized with pemetrexed or cisplatin to enhance NK cell-mediated cytotoxicity. Conclusions. Overall, our findings provide strong rationale for combinatorial strategies integrating chemotherapy with NK-targeted immunomodulation. These results further identify purinergic signaling as a promising therapeutic axis to expand treatment options for this patient population.
Introduction Le ponésimod a montré un profil de sécurité favorable comparé au tériflunomide à deux ans. L’étude d’extension en ouvert OPTIMUM ELT (extension à long terme) a permis d’évaluer l’exposition prolongée au ponésimod. Objectifs Analyser les résultats de sécurité après une exposition au ponésimod 20mg allant jusqu’à 7,9 ans dans l’étude d’extension OPTIMUM-ELT. Méthodes Après l’étude principale et une période de wash-out de 14 à 44jours, les patients ont reçu ponésimod 20mg (P/P ou T/P). Les événements indésirables (EI), les événements indésirables graves (EIG), les infections opportunistes, les lymphopénies de grade 4 et les arrêts de traitement ont été évalués sur toute la durée d’exposition et dans l’extension seule. Les données analysées incluent 565 patients du groupe P/P. Résultats Parmi les patients P/P, 96,1 % ont présenté au moins un EI dont 16,6 % d’EIG. Les EI les plus fréquents incluaient rhinopharyngite (26,5 %), élévation des ALAT (25,7 %), COVID-19 (20,5 %), céphalées (19,1 %) et lymphopénie (12,2 %). Pendant la période, 14,9 % des patients ont interrompu le traitement. Trois infections opportunistes (0,3 %) ont été détectées, dont une seule jugée liée au traitement, sans aucun cas de leucoencéphalopathie multifocale progressive (LEMP). 3.2 % des patients ont présenté une lymphopénie de grade 4 pendant la période d’extension. Discussion L’incidence globale des EI, EIG et infections opportunistes demeure stable, sans augmentation liée à l’exposition prolongée. L’absence de LEMP et la faible fréquence des arrêts de traitement confirment la tolérance du ponésimod. Le profil observé est cohérent avec celui de l’étude principale, sans signal inattendu. Conclusion Après près de huit ans d’exposition, le ponésimod démontre un profil de sécurité favorable, soutenant son utilisation à long terme.
