Sophie Schlosser-Hupf

Background/Objectives: Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide, and treatment efficacy is often limited by tumor heterogeneity and therapy resistance. Preclinical models, particularly three-dimensional (3D) cell cultures, are increasingly used to better mimic the tumor microenvironment and improve the predictive value of drug testing. This study aimed to compare the effectiveness of different pharmacological treatments for HCC in two-dimensional (2D) monolayer and 3D spheroid HepG2 culture models and to investigate the underlying cell death mechanisms. The multikinase inhibitors sorafenib and regorafenib, the epigenetic histone deacetylase (HDAC) inhibitor panobinostat, and the metabolic phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503 were evaluated as single agents and in combination. Results: All tested compounds induced cell death and reduced cellular ATP levels in both 2D and 3D systems. Combination treatments of sorafenib or regorafenib with either panobinostat or NCT-503 generally showed no significant deviation from additivity in cytotoxicity and cellular energy levels, although significant sub-additive deviations were observed for some panobinostat combinations in the ATP analyses. Mechanistically, panobinostat induced apoptotic cell death, as indicated by caspase-3 and PARP cleavage, increased caspase-3/7 activity, and inhibition by the pan-caspase inhibitor zVAD-FMK, whereas NCT-503-mediated cell death occurred largely independently of canonical caspase-mediated apoptosis in 2D cultures. Although similar effects were observed in 3D spheroids, cell death responses were attenuated compared with 2D cultures, whereas reductions in cellular ATP levels remained comparable, indicating a differentiated relationship between ATP depletion and cell death in 2D and 3D cultures. Conclusions: In summary, combining tyrosine kinase inhibition with epigenetic or metabolic targeting agents increased cell death and impaired cellular energy homeostasis more effectively than single-agent treatment in HepG2 cells, with no significant deviation from additivity detected in most combination analyses. Notably, 3D-cultured HepG2 cells showed attenuated cell death responses despite comparable reductions in cellular ATP levels, highlighting differences in drug responses between 2D and 3D culture models. These findings support the use of 3D culture models as a complementary approach to conventional 2D systems for evaluating drug responses, particularly as they reveal an attenuated cell death response compared with 2D cultures.

Background/Objectives: Acute-on-chronic liver failure (ACLF) is a life-threatening complication of cirrhosis, characterized by organ failures and high short-term mortality. Alcohol-related cirrhosis is one of the most frequent underlying etiologies of ACLF in Europe. Infections, particularly those leading to sepsis are recognized triggers; however, their relative contribution, clinical features, and prognostic impact in critically ill patients with alcohol-related cirrhosis remain incompletely defined. This study aimed to systematically identify and characterize precipitating events of ACLF in this population and to compare outcomes between sepsis- and non-sepsis-related cases. Methods: We conducted a retrospective cohort study including 188 ICU patients with alcohol-related cirrhosis who were treated for ACLF at a tertiary university medical center. ACLF was defined and graded according to the European Association for the Study of the Liver—Chronic Liver Failure Consortium (EASL-CLIF) criteria, and sepsis was diagnosed according to Sepsis-3 definitions. Clinical data, precipitating events, microbiological evidence, organ support requirements, and in-hospital outcomes were systematically analyzed. Results: Sepsis was the most frequent precipitating event, identified in 118 patients (62.8%), while 70 patients (37.2%) developed ACLF due to non-septic triggers such as gastrointestinal bleeding. Patients with sepsis-associated ACLF presented with more advanced disease (ACLF grade 2–3 in 80.5% vs. 57.1%, p = 0.004), higher Chronic Liver Failure Consortium—Acute-on-Chronic Liver Failure Score (CLIF-C ACLF) scores (median 55 vs. 50, p = 0.04), longer ICU stays (median 11 vs. 4.5 days, p < 0.001), and markedly higher in-hospital mortality (60.2% vs. 20.0%, p < 0.001) compared to patients without sepsis. Pneumonia (48.3%), urinary infections (17.8%) and spontaneous bacterial peritonitis (16.1%) were the leading infectious foci triggering sepsis. Microbiological evidence was obtained in 82.2% of sepsis cases, with frequent polymicrobial infections and opportunistic pathogens including Enterococcus faecium and Candida albicans. Conclusions: In critically ill patients with alcohol-related cirrhosis, infections leading to sepsis are the predominant precipitating event of ACLF and the strongest determinant of short-term prognosis. Compared with non-sepsis triggers, sepsis-associated ACLF is characterized by more severe disease, greater need for organ support, longer ICU stays, and substantially higher mortality. These findings highlight the urgent need for early recognition, rapid diagnostic strategies, and optimized infection management to improve outcomes in this high-risk population.

Background: Acute-on-chronic liver failure (ACLF) is a severe, rapidly progressing syndrome in patients with liver cirrhosis, often triggered by bacterial infections. Piperacillin/Tazobactam is a key antibiotic in this setting, and therapeutic drug monitoring (TDM) helps optimize its dosing. This study evaluates the impact of an interprofessional TDM strategy for Piperacillin/Tazobactam in ACLF patients in the ICU. Methods: This retrospective ICU study evaluated an interprofessional TDM approach for optimizing Piperacillin/Tazobactam dosing in critically ill ACLF patients. The team, consisting of physicians, clinical pharmacists, and staff nurses, engaged in shared decision making, collaboratively interpreting TDM results and adjusting the dosing accordingly. This study included 26 patients with ACLF who underwent initial TDM and 7 who received follow-up TDM. Piperacillin/Tazobactam dosing was modified based on TDM recommendations, with serum concentrations measured weekly. Adherence to and the implementation of interprofessional dosing recommendations were systematically analyzed to assess the impact of this approach. Results: The initial TDM showed that 30.8% of patients had Piperacillin/Tazobactam levels within the target range, while 53.8% were above and 15.4% below. The interprofessional team recommended dose reductions in seven patients, increases in three, and no change in eleven, with five requiring antibiotic modifications. At the first follow-up TDM, 20.0% reached target levels, while 80.0% remained above, with no subtherapeutic cases. The team recommended one further dose reduction and maintained dosing in four patients. All recommendations were fully implemented, demonstrating strong adherence to the collaborative protocol. Conclusions: The interprofessional TDM strategy optimized Piperacillin/Tazobactam dosing in ACLF patients with full adherence to the recommendations. This collaborative approach improves outcomes and supports global efforts to curb antibiotic resistance.

Objectives The admission of patients with liver cirrhosis to the intensive care unit (ICU) due to infections is a frequent occurrence, often leading to complications such as hepatic encephalopathy, renal failure and circulatory collapse, significantly elevating mortality risks. Accurate and timely diagnosis and intervention are critical for improving therapeutic outcomes. In this context, medical scoring systems in ICUs are essential for precise diagnosis, severity assessment and appropriate therapeutic strategies. There are no specific models for the prediction of mortality in ICU patients with liver cirrhosis-associated infections. This study aims to develop an improved prognostic scoring system for predicting in-hospital mortality among liver cirrhosis patients with infections in the ICU. This scoring system is designed to enhance the predictive accuracy of in-hospital mortality complementing existing sepsis and liver-specific prognostic models. Methods A retrospective analysis was conducted in 620 patients with liver cirrhosis, treated for infections in the ICU of a German university hospital during 2017–19. Advanced statistical techniques were employed to develop and validate the LIVERAID (LIVER And Infectious Diseases)-ICU score, a novel scoring system specifically tailored for liver cirrhosis patients in the ICU with infections. The development of the multivariable logistic regression model involved selecting variables with the highest prognostic efficacy, and its predictive performance was assessed using calibration plots and the concordance statistic (c-index) to evaluate both calibration and discrimination. Results The LIVERAID-ICU score integrates Child-Pugh class, serum urea levels and respiratory metrics. It is designed for bedside calculation using basic clinical and laboratory data, with no need for additional tools. In the validation cohort, the LIVERAID-ICU score exhibited enhanced sensitivity and specificity (AUC=0.83) in forecasting in-hospital mortality of patients with liver cirrhosis-associated infections when compared with established scores like Sequential Organ Failure Assessment (SOFA) (p=0.045), Model for End-Stage Liver Disease (MELD) (p=0.097), Child (pConclusion The newly developed LIVERAID-ICU score represents a robust, streamlined and easy tool for predicting in-hospital mortality in liver cirrhosis patients with infections, surpassing the predictive capabilities of established liver or sepsis scores like SOFA, MELD, Child and CLIF-C ACLF. The reliance of the LIVERAID-ICU score on fundamental clinical and laboratory data facilitates its global application in ICUs, enabling immediate application at the bedside for patients with liver cirrhosis during episodes of suspected or confirmed infections.

(1) Background: Acute-on-chronic liver failure (ACLF) is a severe, rapidly progressing disease in patients with liver cirrhosis. Meropenem is crucial for treating severe infections. Therapeutic drug monitoring (TDM) offers an effective means to control drug dosages, especially vital for bactericidal antibiotics like meropenem. We aimed to assess the outcomes of implementing TDM for meropenem using an innovative interprofessional approach in ACLF patients on a medical intensive care unit (ICU). (2) Methods: The retrospective study was conducted on a medical ICU. The outcomes of an interprofessional approach comprising physicians, hospital pharmacists, and staff nurses to TDM for meropenem in critically ill patients with ACLF were examined in 25 patients. Meropenem was administered continuously via an infusion pump after the application of an initial loading dose. TDM was performed weekly using high-performance liquid chromatography (HPLC). Meropenem serum levels, implementation of the recommendations of the interprofessional team, and meropenem consumption were analyzed. (3) Results: Initial TDM for meropenem showed a mean meropenem serum concentration of 20.9 ± 9.6 mg/L in the 25 analyzed patients. Of note, in the initial TDM, only 16.0% of the patients had meropenem serum concentrations within the respective target range, while 84.0% exceeded this range. Follow-up TDM showed serum concentrations of 15.2 ± 5.7 mg/L (9.0–24.6) in Week 2 and 11.9 ± 2.3 mg/L (10.2–13.5) in Week 3. In Week 2, 41.7% of the patients had meropenem serum concentrations that were within the respective target range, while 58.3% of the patients were above this range. In Week 3, 50% of the analyzed serum concentrations of meropenem were within the targeted range, and 50% were above the range. In total, 100% of the advice given by the interprofessional team regarding meropenem dosing or a change in antibiotic therapy was implemented. During the intervention period, the meropenem application density was 37.9 recommended daily doses (RDD)/100 patient days (PD), compared to 42.1 RDD/100 PD in the control period, representing a 10.0% decrease. (4) Conclusions: Our interprofessional approach to TDM significantly reduced meropenem dosing, with all the team’s recommendations being implemented. This method not only improved patient safety but also considerably decreased the application density of meropenem.

Background and Objectives: Alveolar echinococcosis (AE) is a highly variable disease able to present as structurally diverse cysts in different organs based on the host’s immunological state as well as the time between diagnosis and the primary infection. Bacterial superinfections, especially with anaerobic pathogens from the Clostridiaceae genus, can further alter the radiological findings due to pneumobilia, newly formed abscess formations, and inflammatory changes. Materials and Methods: We present a case of a 71-year-old Caucasian male admitted to our intensive care unit with septic shock, pneumobilia, and a complex cyst of the liver with calcification, as shown by an initial CT. Because of the septic shock, the patient was started on broad-band antibiotics. Clostridiaceae infection was considered an important differential diagnosis due to the presence of pneumobilia observed in the initial CT, without a history of previous endoscopy. Furthermore, serology for echinococcus was positive, and blood cultures showed growth of C. perfringens. Therefore, the patient was additionally treated with albendazole. After recovery, further staging was conducted, showing complete remission of the cyst and a left-over lesion classified as Alveolar Echinococcosis Ulm Classification (AEUC) V. In summary, the patient had a pre-existing, controlled AE infection that became superinfected with C. perfringens, likely attributable to the anaerobic necrotic tissue, leading to septicemia. Results: The anaerobic tissue within the AE cyst provided an ideal medium for C. perfringens to replicate, leading to cyst infection, which subsequently caused septic shock and pneumobilia. The initial findings from CT and MRI were confounded by the superinfection, demonstrating the diagnostic challenges of AE, especially when presenting with complications. Conclusions: Diagnosing AE remains a demanding task, even with the excellent tools available through serology, coupled with CT, FDG-PET-CT, and MRI. Notably, older superinfected cysts can pose difficulties when integrated into the appropriate diagnostic context. Prompt diagnosis is critical for the accurate treatment of echinococcosis and its complications, such as bacterial superinfections. From a clinical perspective, septicemia from Clostridiaceae and infections with C. perfringens—pathogens capable of inducing pneumobilia—should be regarded as significant differential diagnoses for pneumobilia in the absence of a recent history of endoscopy.