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Abstract Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p

Introduction and Objectives: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. Materials and Methods: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. Results: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7). Conclusions: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials.

Abstract Background Clinically significant portal hypertension (CSPH) has been identified as an important prognostic factor in patients with hepatocellular carcinoma (HCC) undergoing curative treatment. This study aimed to assess PH estimates as prognostic factors in patients with HCC treated with immunotherapy. Methods All patients with HCC treated with an immunotherapeutic agent in first or subsequent lines at our tertiary care center between 2016 and 2021 were included (n = 50). CSPH was diagnosed using the established PH score for non-invasive PH estimation in pre-treatment CT data (cut-off ≥ 4). Influence of PH on overall survival (OS) and progression-free survival (PFS) was assessed in uni- and multivariable analyses. Results Based on the PH score, 26 patients (52.0%) were considered to have CSPH. After treatment initiation, patients with CSPH had a significantly impaired median OS (4.1 vs 33.3 months, p

Key Clinical Message Thrombotic microangiopathies are a side effect of anti‐VEGF therapies, which are often limited to the kidneys but can also occur systemically and be life‐threatening. Screening for increasing proteinuria is essential. Abstract We present the case of a 65‐year‐old male patient with a multifocal HCC, Barcelona clinic liver cancer (BCLC) classification B at the time of diagnosis. The HCC was treated with nine sessions of transarterial chemoembolization (TACE), and after a progress, the therapy was switched to a combination of atezolizumab and bevacizumab. Five months after therapy change, he presented with an acute kidney injury. The histopathology of the renal biopsy showed findings of a thrombotic microangiopathy (TMA), which we treated with 12 sessions of therapeutic plasma exchange in combination with steroids, resulting in a decreased TMA activity and later in a remission of the TMA. This case suggests the importance of monitoring the kidney function and proteinuria in patients under anti‐vascular endothelial growth factor (VEGF) therapy and shows a rare differential diagnosis for a worsening of kidney function in these patients. Furthermore, it shows that therapeutic plasma exchange might be a valuable therapeutic option for patients with TMA due to anti‐VEGF therapy.

Introduction and Objectives: Autoimmune liver diseases (AILDs) are rare and require precise evaluation, which is often challenging for medical providers. Chatbots are innovative solutions to assist healthcare professionals in clinical management. In our study, ten liver specialists systematically evaluated four chatbots to determine their utility as clinical decision support tools in the field of AILDs. Materials and Methods: We constructed a 56-question questionnaire focusing on AILD evaluation, diagnosis, and management of Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). Four chatbots -ChatGPT 3.5, Claude, Microsoft Copilot, and Google Bard- were presented with the questions in their free tiers in December 2023. Responses underwent critical evaluation by ten liver specialists using a standardized 1 to 10 Likert scale. The analysis included mean scores, the number of highest-rated replies, and the identification of common shortcomings in chatbots performance. Results: Among the assessed chatbots, specialists rated Claude highest with a mean score of 7.37 (SD = 1.91), followed by ChatGPT (7.17, SD = 1.89), Microsoft Copilot (6.63, SD = 2.10), and Google Bard (6.52, SD = 2.27). Claude also excelled with 27 best-rated replies, outperforming ChatGPT (20), while Microsoft Copilot and Google Bard lagged with only 6 and 9, respectively. Common deficiencies included listing details over specific advice, limited dosing options, inaccuracies for pregnant patients, insufficient recent data, over-reliance on CT and MRI imaging, and inadequate discussion regarding off-label use and fibrates in PBC treatment. Notably, internet access for Microsoft Copilot and Google Bard did not enhance precision compared to pre-trained models. Conclusions: Chatbots hold promise in AILD support, but our study underscores key areas for improvement. Refinement is needed in providing specific advice, accuracy, and focused up-to-date information. Addressing these shortcomings is essential for enhancing the utility of chatbots in AILD management, guiding future development, and ensuring their effectiveness as clinical decision-support tools.

Objectives To assess the sensitivity and specificity of the 2019 EULAR/American College of Rheumatology (ACR) classification criteria for systemic lupus erythematosus (SLE) in outpatients at an academic tertiary care centre and to compare them to the 1997 ACR and the 2012 Systemic Lupus International Collaborating Clinics criteria.Methods Prospective and retrospective observational cohort study.Results 3377 patients were included: 606 with SLE, 1015 with non-SLE autoimmune-mediated rheumatic diseases (ARD) and 1756 with non-ARD diseases (hepatocellular carcinoma, primary biliary cirrhosis, autoimmune hepatitis). The 2019 criteria were more sensitive than the 1997 criteria (87.0% vs 81.8%), but less specific (98.1% vs 99.5% in the entire cohort and 96.5% vs 98.8% in patients with non-SLE ARD), resulting in Youden Indexes for patients with SLE/non-SLE ARD of 0.835 and 0.806, respectively. The most sensitive items were history of antinuclear antibody (ANA) positivity and detection of anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies. These were also the least specific items. The most specific items were class III/IV lupus nephritis and the combination of low C3 and low C4 complement levels, followed by class II/V lupus nephritis, either low C3 or low C4 complement levels, delirium and psychosis, when these were not attributable to non-SLE causes.Conclusions In this cohort from an independent academic medical centre, the sensitivity and specificity of the 2019 lupus classification criteria were confirmed. Overall agreement of the 1997 and the 2019 criteria was very good.

Abstract Background Early tumor shrinkage (ETS) has been identified as a promising imaging biomarker for patients undergoing immunotherapy for several cancer entities. This study aimed to validate the potential of ETS as an imaging biomarker for patients undergoing immunotherapy for hepatocellular carcinoma (HCC). Methods We screened all patients with HCC that received immunotherapy as the first or subsequent line of treatment at our tertiary care center between 2016 and 2021. ETS was defined as the reduction in the sum of the sizes of target lesions, between the initial imaging and the first follow-up. The ETS was compared to the radiologic response, according to the modified response evaluation criteria in solid tumors (mRECIST). Furthermore, we evaluated the influence of ETS on overall survival (OS), progression-free survival (PFS), and the alpha-fetoprotein (AFP) response. Results The final analysis included 39 patients with available cross-sectional imaging acquired at the initiation of immunotherapy (baseline) and after 8–14 weeks. The median ETS was 5.4%. ETS was significantly correlated with the response according to mRECIST and with the AFP response. Patients with an ETS ≥10% had significantly longer survival times after the first follow-up, compared to patients with

Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor‐initiating cells (TICs) may play a key role in acquisition of resistance, but the exact relevance for HCC in this process remains to be defined. Primary and established hepatoma cell lines were exposed to long‐term sorafenib treatment to model acquisition of resistance. Treatment effects on TICs were estimated by sphere‐forming capacity in vitro, tumorigenicity in vivo, and flow cytometry. Adaptive molecular changes were assessed by whole transcriptome analyses. Compensatory mechanisms of resistance were identified and directly evaluated. Sustained antiproliferative effect following sorafenib treatment was observed in three of six HCC cell lines and was followed by rapid regrowth, thereby mimicking responses observed in patients. Resistant cells showed induction in sphere forming in vitro and tumor‐initiating capacity in vivo as well as increased number of side population and epithelial cell adhesion molecule‐positive cells. Conversely, sensitive cell lines showed consistent reduction of TIC properties. Gene sets associated with resistance and poor prognosis, including Hippo/yes‐associated protein (YAP), were identified. Western blot and immunohistochemistry confirmed increased levels of YAP. Combined treatment of sorafenib and specific YAP inhibitor consistently revealed synergistic antioncogenic effects in resistant cell lines. Conclusion: Resistance to antiangiogenic therapy might be driven by transient expansion of TICs and activation of compensatory pro‐oncogenic signaling pathways, including YAP. Specific targeting of TICs might be an effective therapeutic strategy to overcome resistance in HCC.

BackgroundIn patients with cirrhosis, portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, promoting an inflammatory state that can lead to the progression of liver disease and development of hepatocellular carcinoma (HCC). We aimed to investigate whether beta blockers (BBs), which can mediate portal hypertension, conferred survival benefits in patients treated with immune checkpoint inhibitors (ICIs).MethodsWe conducted a retrospective, observational study of 578 patients with unresectable HCC treated with ICI from 2017 to 2019 at 13 institutions across three continents. BB use was defined as exposure to BBs at any time during ICI therapy. The primary objective was to assess the association of BB exposure with overall survival (OS). Secondary objectives were to evaluate the association of BB use with progression-free survival (PFS) and objective response rate (ORR) according to RECIST 1.1 criteria.ResultsIn our study cohort, 203 (35%) patients used BBs at any point during ICI therapy. Of these, 51% were taking a nonselective BB. BB use was not significantly correlated with OS (hazard ratio [HR] 1.12, 95% CI 0.9-1.39, P = 0.298), PFS (HR 1.02, 95% CI 0.83-1.26, P = 0.844) or ORR (odds ratio [OR] 0.84, 95% CI 0.54-1.31, P = 0.451) in univariate or multivariate analyses. BB use was also not associated with incidence of adverse events (OR 1.38, 95% CI 0.96-1.97, P = 0.079). Specifically, nonselective BB use was not correlated with OS (HR 0.94, 95% CI 0.66-1.33, P = 0.721), PFS (HR 0.92, 0.66-1.29, P = 0.629), ORR (OR 1.20, 95% CI 0.58-2.49, P = 0.623), or rate of adverse events (OR 0.82, 95% CI 0.46-1.47, P = 0.510).ConclusionIn this real-world population of patients with unresectable HCC treated with immunotherapy, BB use was not associated with OS, PFS or ORR.

Abstract Background Assessment of muscle quantity by sonographic muscle indices could help identify patients at risk for fatal outcome during coronavirus disease‐2019 (COVID‐19). The aim of this study was to explore sonographic muscle indices as predictors of COVID‐19 outcome and to test the feasibility of sonographic muscle measurement in an isolation context. Methods Muscle indices, derived from the psoas muscle or thigh muscles, were quantified by sonography in a cohort of patients without COVID‐19 to obtain reference values for low muscle quantity. Gender‐specific median of different muscle indices were defined as threshold value for low muscle quantity. The prognostic relevance of low muscle quantity, was prospectively explored in two cohorts of hospitalized COVID‐19 patients. Optimal muscle index cutoff values predictive for 30 day mortality during COVID‐19 were determined by receiver operating characteristic‐area under the curve and Youden index calculation. Muscle quantity and known prognostic factors of COVID‐19 were analysed by multivariable log‐regression. Results Compared with other muscle indices, the psoas muscle area index (PMAI) showed the most favourable characteristics to predict outcome of COVID‐19 disease. Sonographic morphometry of patients without COVID‐19 (n = 136) revealed a gender‐specific median for PMAI (male: 291.1 mm2/m2, female 260.6 mm2/m2) as threshold value of low muscle quantity. Subsequently, COVID‐19 patients (Cohort I: n = 58; Cohort II: n = 55) were prospectively assessed by bedside sonography. The studied COVID‐19 patients developed a critical course of disease in 22.4% (Cohort I: n = 13/58) and 34.5% (Cohort II: n = 20/55). Mortality rate reached 12.1% (Cohort I: n = 7/58) and 20.0% (Cohort I: n = 11/55) within 30 days of follow up. COVID‐19 patients with a PMAI below the gender‐specific median showed a higher 30 day mortality in both COVID‐19 cohorts (log rank, P

Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a significant contributor to cancer-related mortality worldwide. Oxidative stress and lipid peroxidation play a key role in chronic liver diseases and have been shown to be pivotal for tumor initiation and progression. 4-hydroxy-nonenal (4-HNE), one of the major mediators of oxidative stress and a well-established biomarker for lipid peroxidation, can act as a signal transducer, inducing inflammation and exerting carcinogenic effects. However, the role of 4-HNE in primary liver cancer remains poorly explored. In this study, we investigated 4-HNE levels in 797 liver carcinomas, including 561 HCC and 236 iCCA, by immunohistochemistry. We then correlated 4-HNE levels with comprehensive clinical data and survival outcomes. In HCC, lower expression levels of 4-HNE were associated with vascular invasion, a high tumor grade, a macrotrabecular-massive HCC subtype, and poor overall survival. Concerning iCCA, large duct iCCA showed significantly higher 4-HNE levels when compared to small duct iCCA. Yet, in iCCA, 4-HNE levels did not correlate with known prognostic parameters or survival outcomes. To conclude, in HCC but not in iCCA, low amounts of 4-HNE predict unfavorable survival outcomes and are associated with aggressive tumor behavior. These findings provide insights into the role of 4-HNE in liver cancer progression and may enable novel therapeutic strategies.

Abstract Background The PAGE-B score (Platelet Age GEnder–HBV) selects chronic hepatitis B (cHB) patients showing no relevant 5-year risk for hepatocellular carcinoma (HCC). We, therefore, explored potential cost reduction following the introduction of a PAGE-B tailored ultrasound screening in a single center cohort of cHB patients receiving stable antiviral therapy. Methods cHB patients attending throughout the year 2018 were documented. Patients eligible for PAGE-B score were classified into high (≥18 points), intermediate (10–17 points) and low (≤9 points) HCC risk groups. Patients of the low HCC risk group could postpone HCC screening to reduce HCC screening expenses. Full costs for hepatic ultrasound were assessed. Results Throughout the year cHB patients (n = 607) attended our clinic, which included PAGE-B eligible patients (n = 227, 37.4%) of whom n = 94 (15.8%) were allocated to the low HCC risk group. Sonographic HCC screening during a median exam time of 12.4 min (IQR 9.2–17.2) resulted in total costs of 22.82 Euro/exam. Additional opportunistic expenses caused by patient’s lost earnings or productivity were 15.6–17.5 €/exam and 26.7 €/exam, respectively. Following a PAGE-B tailored HCC screening at our institution annual full costs for cHB patients could be reduced by 15.51%, which equals a cost reduction by 1.91% for our total sonography unit. In comparison, 1.35% up to 7.65% of HBV-infected patients of Caucasian descent could postpone HCC screening according to population-based estimates from Germany. Conclusions PAGE-B risk score adapted screening for HCC is an efficient and cost neutral tool to reduce costs for sonography in Caucasian patients with chronic hepatitis B receiving antiviral treatment.

Background and Aims: The multikinase inhibitor cabozantinib has been approved for hepatocellular carcinoma (HCC) previously treated with sorafenib. We report safety and efficacy data of an international, multicenter, real-life cohort of patients with advanced HCC treated with cabozantinib. Methods: Patients with HCC who were treated with cabozantinib were retrospectively identified across 11 centers in Austria, Switzerland, and Germany. Patients’ characteristics, adverse events, duration of treatment and overall survival (OS) data were analyzed until April 1, 2020. Results: Eighty-eight patients from 11 centers were included. The predominant underlying liver diseases were NAFLD/NASH in 26 (30%) and hepatitis C infection in 21 (24%) patients. Seventy-eight patients (89%) were classified as Barcelona clinic liver cancer (BCLC) stage C. Sixty patients (68%) were Child-Pugh A, whereas 22 (25%) were Child-Pugh B, respectively. Cabozantinib was used as systemic second- and third-line or later treatment in 41 (47%) and 46 (52%) patients, respectively. The following best responses under cabozantinib were documented: partial response in 6 (7%), stable disease in 28 (32%), and progressive disease in 28 (32%) patients, respectively. Fifty-two patients (59%) died during follow-up. The median OS from start of cabozantinib treatment was 7.0 months in the entire cohort and 9.7 months in Child-Pugh A patients, while Child-Pugh B patients had a median OS of 3.4 months, respectively. Thirty-seven (42%) patients fulfilled the CELESTIAL inclusion and exclusion criteria, showing a median OS of 11.1 months. Most common adverse events were fatigue (15.6%) and diarrhea (15.6%). Conclusion: Cabozantinib treatment was effective, safe, and feasible in patients with advanced HCC in patients with compensated cirrhosis. Patients in the real-life setting had more advanced liver disease – in which 25% of patients were Child-Pugh B. However, OS in patients with Child-Pugh A cirrhosis was similar to that reported in the phase 3 trial (CELESTIAL).

Background: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy, followed by intrahepatic cholangiocarcinoma (ICC). In addition, there is a mixed form for which only limited data are available. The aim of this study was to compare recurrence and survival of the mixed form within the cohorts of patients with HCC and ICC from a single center. Methods: Between January 2008 and December 2020, all patients who underwent surgical exploration for ICC, HCC, or mixed hepatocellular cholangiocarcinoma (mHC-CC) were included in this retrospective analysis. The data were analyzed, focusing on preoperative and operative details, histological outcome, and tumor recurrence, as well as overall and recurrence-free survival. Results: A total of 673 surgical explorations were performed, resulting in 202 resections for ICC, 344 for HCC (225 non-cirrhotic HCC, ncHCC; 119 cirrhotic HCC, cHCC), and 14 for mHC-CC. In addition, six patients underwent orthotopic liver transplant (OLT) in the belief of dealing with HCC. In 107 patients, tumors were irresectable (resection rate of 84%). Except for the cHCC group, major or even extended liver resections were required. Vascular or visceral extensions were performed regularly. Overall survival (OS) was highly variable, with a median OS of 17.6 months for ICC, 26 months for mHC-CC, 31.8 months for cHCC, and 37.2 months for ncHCC. Tumor recurrence was common, with a rate of 45% for mHC-CC, 48.9% for ncHCC, 60.4% for ICC, and 67.2% for cHCC. The median recurrence-free survival was 7.3 months for ICC, 14.4 months for cHCC, 16 months for mHC-CC, and 17 months for ncHCC. The patients who underwent OLT for mHC-CC showed a median OS of 57.5 and RFS of 56.5 months. Conclusions: mHC-CC has a comparable course and outcome to ICC. The cholangiocarcinoma component seems to be the dominant one and, therefore, may be responsible for the prognosis. ‘Accidental’ liver transplant for mHC-CC within the Milan criteria offers a good long-term outcome. This might be an option in countries with no or minor organ shortage.

Background & Aims: Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors. Methods: From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards. Results: Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels). Conclusions: Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy. Lay summary: Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.

Objective: Evaluation of the efficacy and safety of atezolizumab/bevacizumab in a real-world HCC cohort, including patients with impaired liver function and prior systemic therapy. Methods: Retrospective analysis of 147 HCC patients treated with atezolizumab/bevacizumab at six sites in Germany and Austria. Results: The overall response rate and disease control rate were 20.4% and 51.7%, respectively. Seventy-three patients (49.7%) met at least one major exclusion criterion of the IMbrave150 trial (IMbrave-OUT), whereas 74 patients (50.3%) were eligible (IMbrave-IN). Median overall survival (mOS) as well as median progression-free survival (mPFS) was significantly longer in IMbrave-IN versus IMbrave-OUT patients [mOS: 15.0 months (95% confidence interval (CI): 10.7–19.3] versus 6.0 months (95% CI: 3.2–8.9; p

Background: The aim was to evaluate the diagnostic potential of serum neurofilament light chain (sNfL) measurements in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: sNfL levels were determined by single molecule array assay in a retrospective cross-sectional cohort of 144 patients with systemic lupus erythematosus (SLE). After log-transformation of sNfL levels, mean sNfL levels were compared between NPSLE patients and SLE patients without neuropsychiatric disease using Student’s t test. Furthermore, the association of different neuropsychiatric manifestations with sNfL levels was assessed using a one-way analysis of variance (ANOVA) with post hoc analysis. Associations of sNfL with clinical and laboratory parameters were assessed by correlation and multiple linear regression analysis. Results: NPSLE patients ( n = 69) had significantly higher sNfL levels than SLE patients without neuropsychiatric disease manifestations ( n = 75; mean difference: 0.13, 95% CI: 0.04–0.22, p = 0.006). With regard to the category of NPSLE manifestation, mean sNfL levels were only increased in NPSLE patients with focal central nervous system (CNS) involvement ( n = 45; mean difference: 0.16, 95% CI: 0.02–0.30, p = 0.019), whereas mean sNfL levels of NPSLE patients with diffuse CNS and peripheral nervous system involvement did not differ from those of SLE patients without neuropsychiatric manifestations. Age and serum creatinine concentrations were identified as relevant contributors to sNfL levels. Conclusion: sNfL is a promising, easily accessible biomarker for neuropsychiatric involvement in SLE patients and might therefore complement the diagnostic workup of SLE patients with suspected involvement of the nervous system.

Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.

Portal vein infiltration (PVI) is a typical complication of HCC. Once diagnosed, it leads to classification as BCLC C with an enormous impact on patient management, as systemic therapies are henceforth recommended. Our aim was to investigate whether radiomics analysis using imaging at initial diagnosis can predict the occurrence of PVI in the course of disease. Between 2008 and 2018, we retrospectively identified 44 patients with HCC and an in-house, multiphase CT scan at initial diagnosis who presented without CT-detectable PVI but developed it in the course of disease. Accounting for size and number of lesions, growth type, arterial enhancement pattern, Child–Pugh stage, AFP levels, and subsequent therapy, we matched 44 patients with HCC who did not develop PVI to those developing PVI in the course of disease (follow-up ended December 2021). After segmentation of the tumor at initial diagnosis and texture analysis, we used LASSO regression to find radiomics features suitable for PVI detection in this matched set. Using an 80:20 split between training and holdout validation dataset, 17 radiomics features remained in the fitted model. Applying the model to the holdout validation dataset, sensitivity to detect occurrence of PVI was 0.78 and specificity was 0.78. Radiomics feature extraction had the ability to detect aggressive HCC morphology likely to result in future PVI. An additional radiomics evaluation at initial diagnosis might be a useful tool to identify patients with HCC at risk for PVI during follow-up benefiting from a closer surveillance.

Abstract: Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience. Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (

Cell–cell junctions are pivotal for embryogenesis and tissue homeostasis but also play a major role in tumorigenesis, tumor invasion, and metastasis. E-cadherin (CDH1) and N-cadherin (CDH2) are two adherens junction’s transmembrane glycoproteins with tissue-specific expression patterns in epithelial and neural/mesenchymal cells. Aberrant expression has been implicated in the process of epithelial–mesenchymal transition (EMT) in malignant tumors. We could hitherto demonstrate cis-E:N-cadherin heterodimer in endoderm-derived cells. Using immunoprecipitation in cultured cells of the line PLC as well as in human hepatocellular carcinoma (HCC)-lysates, we isolated E-N-cadherin heterodimers in a complex with the plaque proteins α- and β-catenin, plakoglobin, and vinculin. In confocal laser scanning microscopy, E-cadherin co-localized with N-cadherin at the basolateral membrane of normal hepatocytes, hepatocellular adenoma (HCA), and in most cases of HCC. In addition, we analyzed E- and N-cadherin expression via immunohistochemistry in a large cohort of 868 HCCs from 570 patients, 25 HCA, and respective non-neoplastic liver tissue, and correlated our results with multiple prognostic markers. While E- or N-cadherin were similarly expressed in tumor sites with vascular invasion or HCC metastases, HCC with vascular encapsulated tumor clusters (VETC) displayed slightly reduced E-cadherin, and slightly increased N-cadherin expression. Analyzing The Cancer Genome Atlas patient cohort, we found that reduced mRNA levels of CDH1, but not CDH2 were significantly associated with unfavorable prognosis; however, in multivariate analysis, CDH1 did not correlate with prognosis. In summary, E- and N-cadherin are specific markers for hepatocytes and derived HCA and HCC. E:N-cadherin heterodimers are constitutively expressed in the hepatocytic lineage and only slightly altered in malignant progression, thereby not complying with the concept of EMT.

Background: An association between immunotherapy and an increase in splenic volume (SV) has been described for various types of cancer. SV is also highly predictive of overall survival (OS) in patients with hepatocellular carcinoma (HCC). We evaluated SV and its changes with regard to their prognostic influence in patients with HCC undergoing immunotherapy. Methods: All patients with HCC who received immunotherapy in first or subsequent lines at our tertiary care center between 2016 and 2021 were screened for eligibility. SV was assessed at baseline and follow-up using an AI-based tool for spleen segmentation. Patients were dichotomized into high and low SV based on the median value. Results: Fifty patients were included in the analysis. The median SV prior to treatment was 532 mL. The median OS of patients with high and low SV was 5.1 months and 18.1 months, respectively (p = 0.01). An increase in SV between treatment initiation and the first follow-up was observed in 28/37 (75.7%) patients with follow-up imaging available. This increase in itself was not prognostic for median OS (7.0 vs. 8.5 months, p = 0.73). However, patients with high absolute SV at the first follow-up continued to have impaired survival (4.0 months vs. 30.7 months, p = 0.004). Conclusion: High SV prior to and during treatment was a significant prognostic factor for impaired outcome. Although a large proportion of patients showed an SV increase after the initiation of immunotherapy, this additional immuno-modulated SV change was negligible compared to long-standing changes in the splanchnic circulation in patients with HCC.

ObjectivesThe Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are immunonutritive scoring systems with proven predictive ability in various cancer entities, including hepatocellular carcinoma (HCC). We performed the first evaluation of the CONUT score for patients undergoing transarterial chemoembolization (TACE) and compared CONUT and PNI in the ability to predict median overall survival (OS).MethodsBetween 2010 and 2020, we retrospectively identified 237 treatment-naïve patients with HCC who underwent initial TACE at our institution. Both scores include the albumin level and total lymphocyte count. The CONUT additionally includes the cholesterol level. Both scores were compared in univariate and multivariate regression analyses taking into account established risk factors. In a second step, a subgroup analysis was performed on BCLC stage B patients, for whom TACE is the recommended first-line treatment.ResultsA high CONUT score and low PNI were associated with impaired median OS (8.7 vs. 22.3 months, p

Abstract Background To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. Methods Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. Results Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, −D, leptin and sEGFR in their sera. Conclusions Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, −D and leptin might show promising results in future studies. Clinical trials registration NCT01679405 August, 2012.

BackgroundPortal vein tumor thrombosis (PVTT) is a frequent complication of hepatocellular carcinoma (HCC), which leads to classification as advanced stage disease (regardless of the degree of PVTT) according to the Barcelona Clinic Liver Cancer Classification. For such patients, systemic therapy is the standard of care. However, in clinical reality, many patients with PVTT undergo different treatments, such as resection, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), or best supportive care (BSC). Here we examined whether patients benefited from such alternative therapies, according to the extent of PVTT.MethodsThis analysis included therapy-naïve patients with HCC and PVTT treated between January 2005 and December 2016. PVTT was classified according to the Liver Cancer study group of Japan as follows: Vp1 = segmental PV invasion; Vp2 = right anterior or posterior PV; Vp3 = right or left PV; Vp4 = main trunk. Overall survival (OS) was analyzed for each treatment subgroup considering the extent of PVTT. We performed Cox regression analysis with adjustment for possible confounders. To further attenuate selection bias, we applied propensity score weighting using the inverse probability of treatment weights.ResultsA total of 278 treatment-naïve patients with HCC and PVTT were included for analysis. The median observed OS in months for each treatment modality (resection, TACE/SIRT, sorafenib, BSC, respectively) was 32.4, 8.1, N/A, and 1.7 for Vp1; 10.7, 6.9, 5.5, and 1.2 for Vp2; 6.6, 7.5, 2.9, and 0.6 for Vp3; and 8.0, 3.6, 5.3, and 0.7 for Vp4. Thus, the median OS in the resection group in case of segmental PVTT (Vp1) was significantly longer compared to any other treatment group (all p values ConclusionsTreatment strategy for HCC with PVTT should not be limited to systemic therapy in general. The extent of PVTT should be considered when deciding on treatment alternatives. In patients with segmental PVTT (Vp1), resection should be evaluated.

Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.

Background Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.

BACKGROUND:External validation of prognostic risk models is essential before they are implemented in clinical practice. This study evaluated the recently developed MEGNA score for survival prediction after resection of intrahepatic cholangiocarcinoma (ICC), with a focus on the direct comparison of its prognostic value to that of the current International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) Cancer staging system. MATERIAL AND METHODS:Between 1997 and 2018, 417 consecutive patients with ICC were referred to our tertiary care centre and were retrospectively identified out of a dedicated clinical database. Of this group, 203 patients underwent surgical resection and met the inclusion criteria. Multivariate analysis was performed to assess the predictors of the recently proposed MEGNA score regarding overall survival (OS). Concordance indices (C-indices) and integrated Brier scores (IBS) were calculated to assess the ability of both the MEGNA score and the current (8th) edition of the UICC/AJCC Cancer staging system to predict individual patient outcome. RESULTS:Stratification according to the MEGNA score resulted in a median OS of 34.5 months, 26.1 months, 21.5 months, and 16.6 months for MEGNA scores 0, 1, 2, and ≥3, respectively (log rank p < 0.001). However, of the five factors that contribute to the MEGNA score, age > 60 years was not a predictor for poor OS in our cohort. The C-index for the MEGNA score was 0.58, the IBS was 0.193. The 8th edition of the UICC/AJCC system performed slightly better, with a C-index of 0.61 and an IBS of 0.186. CONCLUSION:The ability of the MEGNA score to predict individual patient outcome was only moderate in this external validation. Its prognostic value did not reach that of the more widely known and used UICC/AJCC system. However, neither scoring system performed well enough to support clear-cut clinical decisions.

Abstract Background In hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed. Methods IGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS). Results Liver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC (p

Abstract Background Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. Methods A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell’s C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. Results The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell’s C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P

The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the prognostic ability of the CALLY index for patients with HCC undergoing transarterial chemoembolization (TACE). We retrospectively identified 280 treatment-naïve patients with HCC that underwent an initial TACE at our institution, between 2010 and 2020. We compared the CALLY index to established risk factors in univariate and multivariate regression analyses for associations with median overall survival (OS). A low CALLY score was associated with low median OS (low vs. high CALLY: 9.0 vs. 24.0 months, p < 0.001). In the multivariate analysis, the CALLY index remained an independent prognostic predictor (p = 0.008). Furthermore, all factors of the CALLY index reached significance in univariate and in-depth multivariate analyses. However, the concordance index (C-index) of the CALLY index (0.60) was similar to the C-indices of established immunonutritive and inflammation scoring systems (range: 0.54 to 0.63). In conclusion, the CALLY index showed promise as a stratification tool for patients with HCC undergoing TACE. Notably, the CALLY index was not superior to other immunonutritive and inflammation scoring systems in predicting the median OS. Thus, future studies should re-evaluate the mathematical calculation of the index, particularly the contributions of individual parameters.

A combination of albumin-bilirubin (ALBI) grading and the Prognostic Nutritional Index (PNI) was identified recently as a highly predictive tool for patients with hepatocellular carcinoma (HCC) undergoing tumor ablation. The present study evaluated this combination in patients undergoing transarterial chemoembolization (TACE). Between 2010 and 2020, 280 treatment-naïve patients were retrospectively identified. The influence of ALBI grade, PNI and the novel ALBI-PNI on the median overall survival (OS) was assessed. In the next step, the prognostic ability of the combined approach was compared to established scoring systems. Both ALBI grade 2−3 and a low PNI were highly predictive for median OS (ALBI grade 1–3: 39.0 vs. 16.3 vs. 5.4 months, p < 0.001; high vs. low PNI: 21.4 vs. 7.5, p < 0.001). The combination of both resulted in a median OS of 39.0, 20.1, 10.3, and 5.4 months (p < 0.001). With a Concordance Index (C-Index) of 0.69, ALBI-PNI outperformed each individual score (ALBI 0.65, PNI 0.64) and was also better than BCLC, HAP, mHAP-II, and the Six-and-Twelve score (C-Indices 0.66, 0.60, 0.59, and 0.55). Thus, the easy-to-calculate ALBI-PNI may be a promising stratification tool for patients with HCC undergoing TACE, reflecting both immunonutritive status and liver function.

Background: Intrahepatic cholangiocarcinoma (iCCA) accounts for about 10% of primary liver cancer. Surgery is the only potentially curative treatment. We report on our current series of 229 consecutive hepatic resections for iCCA, which is one of the largest Western single-center series published so far. Methods: Between January 2008 to December 2020, a total of 286 patients underwent 307 surgical explorations for intended liver resection of iCCA at our department. Data were analyzed with regard to (1) preoperative treatment of tumor, (2) operative details, (3) perioperative morbidity and mortality, (4) histopathology, (5) outcome measured by tumor recurrence, treatment of recurrence and survival and (6) prognostic factors for overall and disease-free survival. Results: the resectability rate was 74.6% (229/307). In total, 202 primary liver resections, 21 repeated, 5 re-repeated, and 1 re-re-repeated liver resections were performed. In primary liver resections there were 77% (155/202) major hepatectomies. In 39/202 (20%) of patients additional hepatic wedge resections and in 87/202 (43%) patients additional 119 other surgical procedures were performed next to hepatectomy. Surgical radicality in first liver resections was 166 R0-, 33 R1- and 1 R2-resection. Following the first liver resection, the calculated 1-, 3- and 5-year-survival is 80%, 39%, and 22% with a median survival of 25.8 months. Until the completion of data acquisition, tumors recurred in 123/202 (60.9%) patients after a median of 7.5 months (range 1–87.2 months) after resection. A multivariate cox regression revealed tumor size (p < 0.001), T stage (p < 0.001) and N stage (p = 0.003) as independent predictors for overall survival. N stage (p = 0.040), preoperative therapy (p = 0.005), T stage (p = 0.004), tumor size (p = 0.002) and M stage (p = 0.001) were independent predictors for recurrence-free survival. Conclusions: For complete surgical removal, often extended liver resection in combination with complex vascular or biliary reconstruction is required. However, despite aggressive surgery, tumor recurrence is frequent and long-term oncological results are poor. This indicated that surgery alone is unlikely to make great strides in improving prognosis of patients with iCCA, instead clearly suggesting that liver resection should be incorporated in multimodal treatment concepts.

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months in the pCTX + TACE group versus 13.1 months in the pCTX group (p = 0.008). Controlling for albumin, bilirubin, ECOG (Eastern Cooperative Oncology Group) performance status, and UICC (Union for International Cancer Control) stage, the addition of TACE still conferred an OS benefit of 12.95 months (p = 0.014). A propensity score matching analysis yielded an OS benefit of 14 months from the time of unresectability for the pCTX + TACE group (p = 0.020). The addition of TACE to pCTX may provide an OS benefit for patients with unresectable iCCA. Thus, patients with liver-dominant iCCA undergoing standard-of-care pCTX should be considered for additional treatment with TACE.

Several scoring systems have been devised to objectively predict survival for patients with intrahepatic cholangiocellular carcinoma (ICC) and support treatment stratification, but they have failed external validation. The aim of the present study was to improve prognostication using an artificial intelligence-based approach. We retrospectively identified 417 patients with ICC who were referred to our tertiary care center between 1997 and 2018. Of these, 293 met the inclusion criteria. Established risk factors served as input nodes for an artificial neural network (ANN). We compared the performance of the trained model to the most widely used conventional scoring system, the Fudan score. Predicting 1-year survival, the ANN reached an area under the ROC curve (AUC) of 0.89 for the training set and 0.80 for the validation set. The AUC of the Fudan score was significantly lower in the validation set (0.77, p < 0.001). In the training set, the Fudan score yielded a lower AUC (0.74) without reaching significance (p = 0.24). Thus, ANNs incorporating a multitude of known risk factors can outperform conventional risk scores, which typically consist of a limited number of parameters. In the future, such artificial intelligence-based approaches have the potential to improve treatment stratification when models trained on large multicenter data are openly available.

(1) Background: Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy. Besides tumor, nodal, and metastatic status, the UICC TNM classification describes further parameters such as lymphangio- (L0/L1), vascular (V0/V1/V2), and perineural invasion (Pn0/Pn1). The aim of this study was to analyze the influence of these parameters on recurrence and survival. (2) Methods: All surgical explorations for patients with ICC between January 2008 and June 2018 were collected and further analyzed in our institutional database. Statistical analyses focused on perineural, lymphangio-, and vascular invasion examined histologically and their influence on tumor recurrence and survival. (3) Results: Of 210 patients who underwent surgical exploration, 150 underwent curative-intended resection. Perineural invasion was present in 41, lymphangioinvasion in 21, and vascular invasion in 37 patients (V1 n = 34, V2 n = 3). Presence of P1, V+ and L1 was significantly associated with positivity of each other of these factors (p < 0.001, each). None of the three parameters showed direct influence on tumor recurrence in general, but perineural invasion influenced extrahepatic recurrence significantly (p = 0.019). Whereas lymphangio and vascular invasion was neither associated with overall nor recurrence-free survival, perineural invasion was significantly associated with a poor 1-, 3- and 5-year overall survival (OS) of 80%, 35%, and 23% for Pn0 versus 75%, 23%, and 0% for Pn1 (p = 0.027). Concerning recurrence-free survival (RFS), Pn0 showed a 1-, 3- and 5-year RFS of 42%, 18%, and 16% versus 28%, 11%, and 0% for Pn1, but no significance was reached (p = 0.091). (4) Conclusions: Whereas lymphangio- and vascular invasion showed no significant influence in several analyses, the presence of perineural invasion was associated with a significantly higher risk of extrahepatic tumor recurrence and worse overall survival.

Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. Materials and Methods: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. Results: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. Conclusion: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.

Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.