Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.

Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF. The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH₂ production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array. Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function analysis uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF. Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease.

Acute decompensation (AD) of cirrhosis is a heterogeneous clinical entity associated with moderate mortality. In some patients, this condition develops quickly into the more deadly acute-on-chronic liver failure (ACLF), in which other organs such as the kidneys or brain fail. The aim of this study was to characterize the blood lipidome in a large series of patients with cirrhosis and identify specific signatures associated with AD and ACLF development. Serum untargeted lipidomics was performed in 561 patients with AD (518 without and 43 with ACLF) (discovery cohort) and in 265 patients with AD (128 without and 137 with ACLF) in whom serum samples were available to perform repeated measurements during the 28-day follow-up (validation cohort). Analyses were also performed in 78 patients with AD included in a therapeutic albumin trial (43 patients with compensated cirrhosis and 29 healthy individuals). The circulating lipid landscape associated with cirrhosis was characterized by a generalized suppression, which was more manifest during AD and in non-surviving patients. By computing discriminating accuracy and the variable importance projection score for each of the 223 annotated lipids, we identified a sphingomyelin fingerprint specific for AD of cirrhosis and a distinct cholesteryl ester and lysophosphatidylcholine fingerprint for ACLF. Liver dysfunction and infections were the principal net contributors to these fingerprints, which were dynamic and interchangeable between patients with AD whose condition worsened to ACLF and those who improved. Notably, blood lysophosphatidylcholine levels increased in these patients after albumin therapy. Our findings provide insights into the lipid landscape associated with decompensation of cirrhosis and ACLF progression and identify unique non-invasive diagnostic biomarkers of advanced cirrhosis. Analysis of lipids in blood from patients with advanced cirrhosis reveals a general suppression of their levels in the circulation of these patients. A specific group of lipids known as sphingomyelins are useful to distinguish between patients with compensated and decompensated cirrhosis. Another group of lipids designated cholesteryl esters further distinguishes patients with decompensated cirrhosis who are at risk of developing organ failures.

Medical image segmentation is challenging due to the need for expert annotations and the variability of these manually created labels. Previous methods tackling label variability focus on 2D segmentation and single modalities, but reliable 3D multi-modal approaches are necessary for clinical applications such as in oncology. In this paper, we propose a framework for generating reliable and unbiased labels with minimal radiologist input for supervised 3D segmentation, reducing radiologists’ efforts and variability in manual labeling. Our framework generates AI-assisted labels through a two-step process involving 3D multi-modal unsupervised segmentation based on feature clustering and semi-supervised refinement. These labels are then compared against traditional expert-generated labels in a downstream task consisting of 3D multi-modal bone tumor segmentation. Two 3D-Unet models are trained, one with manually created expert labels and the other with AI-assisted labels. Following this, a blind evaluation is performed on the segmentations of these two models to assess the reliability of training labels. The framework effectively generated accurate segmentation labels with minimal expert input, achieving state-of-the-art performance. The model trained with AI-assisted labels outperformed the baseline model in 61.67% of blind evaluations, indicating the enhancement of segmentation quality and demonstrating the potential of AI-assisted labeling to reduce radiologists’ workload and improve label reliability for 3D multi-modal bone tumor segmentation. The code is available at https://github.com/acurtovilalta/3D_LabelGeneration .

Background: Atypical cartilaginous tumors (ACT), formerly classified as Grade 1 chondrosarcomas (CS1) of the extremities, are hyaline cartilage-producing neoplasms. The WHO classification (4th edition, 2013) redefined ACT as locally aggressive rather than malignant tumors, prompting a shift toward less aggressive surgical management. This study reports data of a single, tertiary musculoskeletal tumor center and compares the long-term oncological outcomes of wide resections and intralesional curettage for primary ACT. Methods: This retrospective study included 61 patients with ACT treated at a tertiary tumor center between 2003 and 2023. Patients were divided into two cohorts: Cohort 1 was treated before 2013 with wide or radical resection, while cohort 2 was treated with an intralesional approach. Data on recurrence, revision rates, survival, and predictors of outcomes were analyzed using Kaplan–Meier survival analysis and log-rank testing. Results: Wide resections were performed in 24 patients, requiring prosthetic reconstruction in 76% of cases. Intralesional curettage was performed in 37 patients. Local recurrence occurred in 8% in wide resections versus 16% of curettage cases (p = 0.198), with no significant difference in time to recurrence between cohorts. Unplanned revision rates were higher in the wide resection group (42%) compared to curettage (35%), driven primarily by prosthesis-related complications. Overall survival was high in both groups (88% in wide resections vs. 94% in curettage; p = 0.705). Resection margins, and metastases were identified as significant predictors of both recurrence and tumor-related death. Conclusions: Intralesional curettage provides comparable oncological outcomes to wide resections with reduced morbidity, supporting its use as the preferred treatment for ACT in appropriately selected patients.