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Immunomodulatory Intraperitoneal Chemotherapy with DACHPt-Loaded Biomaterial Nanoparticles in Colorectal Carcinomatosis
No full textInternational audiencePressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a promising therapeutic option for the treatment of colorectal cancer-derived peritoneal carcinomatosis (CRC-PC) because of the possibility to spread high concentration of drugs throughout the entire peritoneal cavity while limiting the systemic side effects. However, PIPAC effectiveness is hampered by rapid drug clearance from the peritoneal cavity and poor drug specificity towards tumor nodules. This study employed diaminocyclohexane platinum-loaded hyaluronic acid–polyarginine nanoparticles (DACHPt NPs) for pressurized locoregional treatment of CRC-PC, aiming to compare the anticancer and immunomodulatory activities of free oxaliplatin and its active moiety, DACHPt, when delivered via nanoparticles. DACHPt NPs, produced via microfluidics presented a hydrodynamic volume of approximately 150 nm and marked DACHPt encapsulation efficiency (≈ 60 %). In vitro DACHPt NPs displayed a higher cytotoxic activity on murine colorectal carcinoma cell line (CT26) than oxaliplatin solution (IC50: 4.79 µm vs 19.77 µm). Notably, DACHPt NPs demonstrated superior anticancer efficacy than oxaliplatin on a CT26-derived PC mouse model treated with PIPAC (mean survival: 29.5 days vs 22.5 days, respectively). This effect is associated to immunomodulatory properties of DACHPt NPs that induced a significant reduction of the granulocyte population within spleen, peritoneal fluid and tumor nodules and increased CD8 + T lymphocytes percentage in tumor nodules (CD8 + cells: 5.5 %) when compared to the saline group (CD8 + cells: 1.5 %). These findings suggest that DACHPt NPs not only possess superior anticancer effect than oxaliplatin solution, but also contribute to re-shape the immunosuppressive microenvironment toward a more antitumoral immune setting
KILDA: identifying KIV-2 repeats from kmers
No full textInternational audienceHigh concentration of lipoprotein(a) [Lp(a)], a lipoprotein with proatherogenic properties, is an important risk f actor f or cardio v ascular disease. T his concentration is mostly genetically determined by a complex interplay between the number of kringle IV type 2 repeats and Lp(a)-affecting variants. Besides Lp(a) plasma concentration, there is an unmet need to identify individuals most at risk based on their LPA genotype. We de v eloped KILDA (KIv2 Length Determined from a kmer Analysis), a Nextflow pipeline, to identify the number of kringle IV type 2 repeats and Lp(a)-affecting variants directly from kmers generated from FAS TQ files. T he pipeline w as tested on the 10 0 0 Genomes Project ( n = 2459) and results were equivalent to DRAGEN-LPA ( R 2 = 0.92). In silico datasets proved the robustness of KILDA's predictions under different scenarios of sequencing co v erage and quality. In brief , KILD A is a robust, open-source, and free-to-use pipeline that can identify the number of kringle IV type 2 repeats and Lp(a)-associated variants even when inputting low-coverage libraries
1487P Extended follow-up at 42 months of atezolizumab–bevacizumab in advanced HCC: Insights from the CHIEF prospective study
No full textInternational audienceBackgroundThe IMbrave150 trial positioned Atezolizumab–Bevacizumab (AtezoBev) as first-line treatment for advanced HCC. We report the first long-term real-world data from the French CHIEF cohort.MethodsCHIEF is a prospective multicenter cohort including patients treated with first-line AtezoBev across 32 French centers. OS and PFS were estimated using Kaplan–Meier methods. Subgroup comparisons used log-rank tests; univariate Cox models identified prognostic factors. Tumor response was assessed by best radiological evaluation.ResultsAmong 880 patients (median age 69, 88% male), liver disease was at least alcohol-related in 58%, metabolic in 16%, viral in 15%. At baseline, 78% were Child–Pugh A, 22% B; 55% had esophageal varices (EV) (26% large). BCLC stages were A (5%), B (28%), and C (67%). Multifocal disease, macrovascular invasion, and extrahepatic spread were present in 35%, 47%, and 32%, respectively. ALBI grades were 1 (33%), 2 (61%), and 3 (6%), and 30% had AFP ≥400 ng/mL. After 31.8 months median follow-up, overallConclusionsThe unprecedented 42 months OS rates further underscore the sustained long-term OS benefit of AtezoBeva in advanced HCC
84P Efficacy and safety of selective internal radiation therapy (SIRT) combined with chemotherapy and immunotherapy in locally advanced intrahepatic cholangiocarcinoma
No full textInternational audienceBackgroundIntrahepatic cholangiocarcinoma (iCCA) accounts for 15% of primary liver cancers, with less than 30% diagnosed at a resectable stage. Despite improvements in systemic therapies, the prognosis remains poor. This study aimed to evaluate the efficacy and safety of combining SIRT, chemotherapy and immunotherapy in this setting.MethodsA monocentric retrospective cohort of patients with locally advanced iCCA treated with SIRT combined with chemotherapy (GEMCIS or GEMOX) with or without durvalumab, between 2017 and 2024. SIRT was performed after a median of 1 cycle of systemic therapy, using resin microspheres (SIR-Spheres) with personalized dosimetry. The median tumor-absorbed dose was 110Gy (IQR : 93-149). Response was evaluated using the mRECIST criteria. Adverse events were graded using CTCAE v5.0.ResultsForty patients were included (16 GEMCIS-durvalumab, 14 GEMCIS and 10 GEMOX), with a median age of 66.3 years. All patients were PS 0/1, and 28% had advanced fibrosis (F3/F4). At baseline, 50% had ≥2 iCCA lesions; the median sum of target lesions diameters was 91mm (IQR : 75-111). The objective response rate was 53%, consisting of 15% complete responses and 38% partial responses. The best response was stable disease in 25% of patients, and 22% experienced early progression. Grade ≥3 toxicitiesConclusionsThe combination of SIRT with standard chemotherapy ± durvalumab achieved high response rates and promising survival in locally advanced iCCA. Radiological downstaging allowing secondary resection occurred in 10% of patients. This is the first report of this triplet combination in this setting and further investigation is warranted
Concordance of symptoms perceived by patients receiving haemodialysis and those reported by nurses and nephrologists: a cross-sectional, multicentre, observational study using the REIN registry
No full textInternational audienceABSTRACT Background Patients receiving haemodialysis (HD) experience symptoms that impact quality of life. This study assessed the concordance of symptoms and symptom severity of HD patients and their perception by nurses and nephrologists. Methods A cross-sectional, observational study using the 30-item Dialysis Symptom Index (DSI) questionnaire was conducted in six dialysis centres in France from 1 March 2022 to 30 June 2023. Patients were interviewed during dialysis sessions. Nurses and nephrologists were asked to complete the DSI questionnaire thereafter, to report patient symptoms they considered present. Responses were compared using sensitivity and the Cohen's κ estimate for an interrater agreement involving presence (yes/no) and intensity (5-point Likert scale). Results A total of 256 patients, 123 nurses and 27 nephrologists participated. Patients reported four symptoms as most severe (score >3): restless legs or difficulty keeping still, feeling tired or lack of energy, bone or joint pain and trouble falling asleep. Comparisons showed a sensitivity ≥50% for 1/30 symptoms by nurses and 3/30 by nephrologists. Concordance for the presence of symptoms between nurses–patients and nephrologists–patients was low (κ >0.21–<0.40). Patient–nurse agreement was very low for 14 symptoms (46.6%), low for 15 (50.0%) and moderate for 1 (3.4%). Patient–nephrologist agreement was very low for 21 symptoms (70.0%) and low for 9 (30.0%). Nurse–nephrologist disagreement occurred for three symptoms (10.0%), very low agreement for 25 symptoms (83.3%) and low for 2 symptoms (6.7%). Conclusions Nurses and nephrologists underestimate the presence and severity of symptoms perceived by patients. Future systematic assessment of symptoms by patient-reported outcome measures should be considered
ROSCA: Robust and Scalable Security Alert Correlation and Prioritisation using the MITRE ATT&CK Framework
No full textInternational audienceIn large organisations and complex infrastructures, the overwhelming volume of security alerts often results in analyst fatigue, delayed responses, and missed attacks. Security Operations Centers (SOCs) typically rely on black-box commercial solutions, offering limited transparency into their alert classification mechanisms and lacking the flexibility for in-house adaptation or re-implementation. To address these limitations and improve situational awareness, this paper proposes ROSCA, an efficient alert prioritisation method grounded in the MITRE ATT&CK kill chain model. The proposed approach automatically aggregates and correlates alerts based on their shared attributes, enabling the construction of contextualised cases. Each case is assigned a score reflecting its threat level, before being presented to analysts within a prioritised queue. Our method handles multi-stage attack patterns and supports rapid processing through a robust, noise-tolerant scoring mechanism designed for interpretability and operational integration. We validate the effectiveness of ROSCA on real-world alert data and compare it against the MATE framework, demonstrating superior prioritisation accuracy and more reliable identification of critical alerts
Single-cell genomics of the mouse olfactory cortex reveals contrasts with neocortex and ancestral signatures of cell type evolution
No full textInternational audienceUnderstanding the molecular logic of cortical cell-type diversity can illuminate cortical circuit function and evolution. Here, we performed single-nucleus transcriptome and chromatin accessibility analyses to compare neurons across three- to six-layered cortical areas of adult mice and across tetrapod species. We found that, in contrast to the six-layered neocortex, glutamatergic neurons of the three-layered mouse olfactory (piriform) cortex displayed continuous rather than discrete variation in transcriptomic profiles. Subsets of piriform and neocortical glutamatergic cells with conserved transcriptomic profiles were distinguished by distinct, area-specific epigenetic states. Furthermore, we identified a prominent population of immature neurons in piriform cortex and observed that, in contrast to the neocortex, piriform cortex exhibited divergence between glutamatergic cells in laboratory versus wild-derived mice. Finally, we showed that piriform neurons displayed greater transcriptomic similarity to cortical neurons of turtles, lizards and salamanders than to those of the neocortex. In summary, despite over 200 million years of coevolution alongside the neocortex, olfactory cortex neurons retain molecular signatures of ancestral cortical identity
Prognostic Impact of Early Appropriate Antimicrobial Therapy in Critically Ill Patients With Nosocomial Pneumonia Due to Gram-Negative Pathogens: A Multicenter Cohort Study
No full textInternational audienceOBJECTIVES: To evaluate whether early appropriate antimicrobial therapy (EAAT) is associated with improved outcomes in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP), or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria (GNB). DESIGN: Retrospective cohort study based on prospectively collected data. SETTING: Thirty-two French ICUs (OutcomeRéa network). PATIENTS: All patients with a first HAP, vHAP, or VAP due to GNB during their ICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The relationship between EAAT and day 28 all-cause mortality (primary endpoint) was explored through Cox proportional-hazard models, with subgroup analyses according to pneumonia types, causative GNB, features of EAAT, and the occurrence of septic shock at pneumonia diagnosis. The course of Sequential Organ Failure Assessment (SOFA) score values, the clinical cure rate at day 14, and the time to mechanical ventilation (MV) weaning and ICU discharge after pneumonia diagnosis were investigated as secondary endpoints. Among the 804 included patients, 495 (61.6%) received EAAT (single-drug, 25.4%; combination, 36.2%). Day 28 mortality was 32.6%. EAAT was not independently associated with this outcome (adjusted hazard ratio, 0.87; 95% CI, 0.67–1.12). This result was confirmed in subgroup analyses as in a second model considering all episodes of pneumonia occurring during the ICU stay. EAAT was not associated with a faster decrease in SOFA score values ( p = 0.11), a higher day 14 clinical cure rate (overall, 43.7%), or a shorter MV duration (cause-specific hazard ratio [HR] for extubation, 0.84; 95% CI, 0.69–1.01) or ICU stay (cause-specific HR for discharge alive, 0.85; 95% CI, 0.72–1.00). CONCLUSIONS: In this study, EAAT was not associated with a reduced day 28 mortality, a faster resolution of organ failure, a higher day 14 clinical cure rate, or a shorter time to MV weaning or ICU discharge in critically ill patients with HAP, vHAP, or VAP due to GNB. However, a prognostic benefit from EAAT cannot be ruled out due to lack of statistical power
Machine learning to detect recent recreational drug use in intensive cardiac care units
No full textInternational audienceBackground: Although recreational drug use is a strong risk factor for acute cardiovascular events, systematic testing is currently not performed in patients admitted to intensive cardiac care units, with a risk of underdetection. To address this issue, machine learning methods could assist in the detection of recreational drug use.Aims: To investigate the accuracy of a machine learning model using clinical, biological and echocardiographic data for detecting recreational drug use in patients admitted to intensive cardiac care units.Methods: From 07 to 22 April 2021, systematic screening for all traditional recreational drugs (cannabis, opioids, cocaine, amphetamines, 3,4-methylenedioxymethamphetamine) was performed by urinary testing in all consecutive patients admitted to intensive cardiac care units in 39 French centres. The primary outcome was recreational drug detection by urinary testing. The framework involved automated variable selection by eXtreme Gradient Boosting (XGBoost) and model building with multiple algorithms, using 31 centres as the derivation cohort and eight other centres as the validation cohort.Results: Among the 1499 patients undergoing urinary testing for drugs (mean age 63±15 years; 70% male), 161 (11%) tested positive (cannabis: 9.1%; opioids: 2.1%; cocaine: 1.7%; amphetamines: 0.7%; 3,4-methylenedioxymethamphetamine: 0.6%). Of these, only 57% had reported drug use. Using nine variables, the best machine learning model (random forest) showed good performance in the derivation cohort (area under the receiver operating characteristic curve=0.82) and in the validation cohort (area under the receiver operating characteristic curve=0.76).Conclusions: In a large intensive cardiac care unit cohort, a comprehensive machine learning model exhibited good performance in detecting recreational drug use, and provided valuable insights into the relationships between clinical variables and drug use through explainable machine learning techniques
Recurrence of CKD-associated pruritus after discontinuation of difelikefalin
No full textInternational audienceNo abstract availabl