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: Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV). Methods: A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe. Results: The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV. Conclusions: In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction–associated steatotic liver disease and alcohol-associated liver disease. Export

Background/Objectives: Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients. Methods: This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit. Results: In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6–13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0–4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients. Conclusions: In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC.

Purpose: Several targeted agents demonstrated efficacy in early clinical trials for gastrointestinal (GI) cancers, but in many cases, phase-III trials and/or approval by the European Medicines Agency (EMA) are lacking. The primary focus of this study was to assess the regulatory processes associated with use and reimbursement of off-label treatment in precision oncology and to evaluate the benefit of targeted therapy in a real-world population in Germany. Methods: Our cohort comprises 137 patients with GI cancers and is biased towards cancer entities with a high frequency of known targetable alterations, such as cholangiocarcinoma. Genetic testing was used to identify molecular targets, and therapy response was evaluated based on CT scans. Results: A molecular target for precision oncology was identified in 53 patients and 43 requests for cost coverage were submitted to health insurance companies. 60% of the requests received approval after initial application and another 7% after appeal. Half of the rejected requests were denied despite ESCAT IA level evidence. The median time between initiation of molecular testing and start of therapy was 75 days. 35 patients received matched targeted therapies (n = 28) or, in the case of MSI, immunotherapy (IO) (n = 7). We observed a trend in favor of molecular therapy when compared to the immediate prior treatment. Conclusion: Relevant treatment options were identified by molecular testing in a significant subset of patients. When targeted therapies that lack EMA approval are considered, treatment initiation may be delayed by the duration of the molecular analysis and the regulatory processes.

We here report on the management of a 54-year-old female patient who developed severe liver and multi-organ failure due to a severe veno-occlusive crisis in the context of sickle cell disease (SCD) and eventually underwent high urgency transplantation.After presentation to the emergency department with clinical signs of severe acute liver failure (ALF), a heterozygous sickle cell disease with recurrent symptomatic hemolytic crisis without any preexisting liver disease was diagnosed. The laboratory markers of liver function on admission are outlined in Table 1. In the past, a splenectomy and femoral head replacement after aseptic bone necrosis had been performed due to severe hemolytic crisis. A liver biopsy showed sinusoidal obstruction and congestion due to sickle cell aggregates (Figure 1) with no evidence of drug-toxic damage or advanced fibrosis. Sickle cell hepatopathy in sickle cell-associated intrahepatic cholestasis (SCIC) with ALF was diagnosed based on the histological picture, the clinical presentation, and the high sickle cell hemoglobin (HbS content (83%).Supportive drug therapy was initiated for ALF by means of continuous intravenous administration of ornithine aspartate, lactulose enemas, and continuous acetylcysteine infusion. In addition, the sickle cell crisis was treated with continuous glucose infusion and exchange transfusions, which lowered the HbS content to <20%. Due to the pre-existing immunization as result of the extensive pre-transfusions with detection of irregular erythrocyte antibodies, erythrocyte concentrates without anti Cw and anti E were administered.Despite these measures, the patient developed progressive liver failure (Table 1), which ultimately met the requirements for "high urgency" listing for liver transplantation, which was arranged after excluding contraindications 2 days after admission. In the course, the patient developed progressive multi-organ failure with severe encephalopathy, coagulopathy, lactic acidosis, and circulatory insufficiency. In terms of a bridge-to-transplant strategy, therapeutic plasma exchange and human albumin dialysis were initiated to treat the ALF and the hepatic encephalopathy, respectively, resulting in sufficient stabilization. A suitable donor organ was available 3 days after admission. The transplantation of the whole organ was performed in one stage without complications. The arterial anastomosis was performed as a branch patch of the recipient and donor gastroduodenal artery due to the existing anatomical conditions. Anastomization of the bile duct was performed as an end-to-end anastomosis. The cold ischemia time was 498 minutes.In the postoperative course, the HbS percentage rose to 41% necessitating further exchange transfusions. The patient suffered from prolonged postoperative delirium with inconspicuous neuro imaging results. In order to prevent further sickle cell crises and organ complications, a concept of a close HbS surveillance was initiated in close cooperation with the local treating hematologist to assure a sufficient lowering of HbS percentages below 20%, for which a kimal catheter was inserted prior to discharge. Prophylactic anticoagulation was administered during the inpatient stay, which was discontinued on discharge.No complications, particularly no further sickle cell crises, occurred over the further course under close hematological care with regular exchange transfusions, hydroxycarbamide treatment, and specialized follow-up at our liver transplant outpatient department. At the last presentation, 18 months after liver transplantation, the graft function was unrestricted with no evidence of advanced hepatic fibrosis (acoustic radiation force impulse imaging elastography 0.96 m/sec). The patient was on combined immunosuppression with tacrolimus (trough level aim 5-8 ng/ml) and mycophenolate (500 mg b.i.d.), had no history of acute rejection episodes, and will now be included in our surveillance biopsy guided personalized immunosuppression program.Vaso-occlusive crises with secondary organ failure including hepatobiliary damage can occur in the context of SCD (1). SCIC is a rare and severe form of sickle cell hepatopathy leading to local hypoxia with infarction and ballooning of the hepatocytes via sickle cell aggregates in the liver sinusoids. This can cause severe cholestasis and, in very few instances, result in acute liver failure (ALF) (2,3). The number of liver transplantations due to acute hepatic sickle cell crisis with irreversible organ failure is very low, so there is only limited experience. Levesque et al. summarized 21 published cases of liver transplantations in SCD patients and formulated recommendations for the pre- and postoperative management (1). The 5-year overall survival rate after transplantation was 65% in this cohort, comparable to that of recipients who undergo liver transplantation due to other diseases, while the rate of significant cerebral, micro- and macroangiopathic as well as septic complications was higher. The authors emphasized the need for close pre- and postoperative monitoring of hemoglobin S (HbS) levels for the early detection of imminent vascular occlusions. In addition, given the increased incidence of cerebral bleeding events and vascular occlusions in this patient population, it was recommended to clarify occuring neurological symptoms via neuro imaging with low threshold. Additionally, prophylactic anti-infective therapy was suggested in the light of increased sepsis rates. The patient cohort reported was very heterogeneous: only 7 patients underwent liver transplantation in the context of SCIC-associated liver failure, while the majority of patients was electively listed for transplantation and/or required transplantation due to another end-stage liver disease, so that the transplantation did not take place in an acute sickle cell crisis.In the few cases described in the literature, vascular complications such as thrombosis and...

Zusammenfassung: Ein 33-jähriger Patient mit unbehandelter Humane Immundefizienz Virus (HIV)-Infektion wurde aufgrund einer akuten Lungenembolie mit hämodynamischer Einschränkung zur weiteren Behandlung übernommen. Bei vorliegender B-Symptomatik (Fieber, Nachtschweiß und Gewichtsverlust) ergaben sich zunächst keine Hinweise auf ein Malignom und/oder eine opportunistische Infektion. Sonografisch zeigten sich initial wenig Aszites ohne Nachweis einer spontan bakteriellen Peritonitis (SBP) bei zugrunde liegender Fettleberhepatitis mit Hypoproteinämie und Rechtsherzdekompensation. Wir veranlassten die Einleitung einer antiretroviralen Therapie (ART). Es kam zu einem komplikativen Verlauf mit Entstehung einer fulminanten Peritonitis, die nicht auf eine breite antiinfektive Therapie ansprach. Im Weiteren zeigte sich eine respiratorische Verschlechterung mit progredienter Oxygenierungsstörung. Differenzialdiagnostisch wurde ein Immunrekonstitutionssyndrom (IRIS) vermutet und im Verlauf zunächst eine peritoneale und schließlich eine offene Lungentuberkulose (TB) diagnostiziert. Fazit Bei (hyper-)inflammatorischem Krankheitsbild unter neu begonnener ART sollte ein demaskierendes IRIS auf dem Boden einer bislang okkulten TB (TB-IRIS) frühzeitig differenzialdiagnostisch in Erwägung gezogen und gezielt therapiert werden. Vor Einleitung einer ART müssen opportunistische Infektionen, insbesondere eine TB bei klinischem Verdacht ggf. auch mittels Biopsie, ausgeschlossen werden.