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The article discusses a study on how bacterial colony with multidrugresistant bacteria is associated with high mortality rate in patients with cirrhosis. It mentions several MDR bacteria including Enterococcus faecium, methicillin resistant staphylococcus aureus and Pseudomonas aeruginosa. It suggests prevention of spreading of MDR bacteria in the digestive tract or the skin. It mentions that asymptomatic colonisation with MDR bacteria causes mortality in cirrhosis.

Aim: Interleukin (IL)‐10 and IL‐12 contribute to immune responses against hepatitis B virus (HBV) infection. Polymorphisms in the IL‐10 and IL‐12A genes might affect the clinical outcome of HBV infection. We evaluated the association of IL‐10 rs1800896 and rs3024490, and IL‐12A rs568408 and rs2243115 with the progression of HBV infection and development of severe liver disease stages in a white European population. Method: A total of 636 white European patients with chronic HBV infection, 239 individuals with spontaneous HBV surface antigen seroclearance, and 254 healthy controls were enrolled. The chronic HBV infection group included patients with hepatitis B envelope antigen (HBeAg) negative chronic hepatitis B (n = 255), with HBeAg positive chronic hepatitis B (n = 99) and with HBeAg negative HBV infection (n = 228). A total of 104 chronically infected patients were diagnosed with liver cirrhosis. Serum levels of cytokines were measured in patients with HBV infection (n = 195) and in healthy controls (n = 160). Results: In adjusted multivariate analysis, the IL‐10 rs1800896 AG/GG genotypes were significantly associated with an increased probability of HBV surface antigen seroclearance (OR = 1.75, 95% CI 1.04–2.94, p = 0.034), with an increased likelihood of HBeAg negative chronic infection (OR = 1.93, 95% CI 1.05–3.54, p = 0.034) and with increased serum cytokines levels in female patients. In contrast, the IL‐12A rs568408 AG/AA genotypes were independently associated with an increased risk to develop liver cirrhosis, with an OR of 1.90 (95% CI 1.07–3.39, p = 0.029) in male patients. Conclusion: The current study shows a sex‐related association of the IL‐10 single‐nucleotide polymorphism rs1800896 and IL‐12A single‐nucleotide polymorphism rs568408 with different stages of HBV infection and with HBV‐related liver cirrhosis in white European patients. [ABSTRACT FROM AUTHOR]

Background Secondary sclerosing cholangitis (SSC) is a rare disease with poor prognosis. Cases of SSC have been reported following coronavirus disease 2019 (COVID-SSC). The aim of this study was to compare COVID-SSC to SSC in critically ill patients (SSC-CIP) and to assess factors influencing transplant-free survival. Methods In this retrospective, multicenter study involving 127 patients with SSC from 9 tertiary care centers in Germany, COVID-SSC was compared to SSC-CIP and logistic regression analyses were performed investigating factors impacting transplant-free survival. Results Twenty-four patients had COVID-SSC, 77 patients SSC-CIP, and 26 patients other forms of SSC. COVID-SSC developed after a median of 91 days following COVID-19 diagnosis. All patients had received extensive intensive care treatment (median days of mechanical ventilation, 48). Patients with COVID-SSC and SSC-CIP were comparable in most of the clinical parameters and transplant-free survival was not different from other forms of SSC (P =.443, log-rank test). In the overall cohort, the use of ursodeoxycholic acid (UDCA) (odds ratio [OR], 0.36 [95% confidence interval {CI},.16–.80], P =.013; log-rank P <.001) and high serum albumin levels (OR, 0.40 [95% CI,.17–.96], P =.040) were independently associated with an increased transplant-free survival, while the presence of liver cirrhosis (OR, 2.52 [95% CI, 1.01–6.25], P =.047) was associated with worse outcome. Multidrug-resistant organism (MDRO) colonization or infection did not impact patients' survival. Conclusions COVID-SSC and CIP-SSC share the same clinical phenotype, course of the disease, and risk factors for its development. UDCA may be a promising therapeutic option in SSC, though future prospective trials are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the progression of chronic liver diseases (CLD) was investigated. WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-β1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. WISP1 expression is induced by TGF-β1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD. • WISP1 expression in liver tissue and the serum of cirrhosis patients is higher than in healthy individuals or HCC patients. • TGF-β1 induces WISP1 expression in hepatocytes. • Expression levels of TGF-β1 and WISP1 correlate in HCC patients. • High WISP1 expression in HCC liver tissue is associated with increased survival. • WISP1 balances proliferation, apoptosis and cell cycle control. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular cancer is the most common type of primary liver cancer. It is the third leading cause of cancer-related deaths worldwide and its incidence is increasing: >1 million new cases per year expected by 2025. Despite advances in treatment in recent years, diagnosis is associated with poor overall survival. Treatment of hepatocellular cancer depends on the patient's general health and fitness, how well the liver is working, the number and size of tumors in the liver, and whether or not the tumor has spread to other neighboring or distant parts of the body. The combination of atezolizumab plus bevacizumab, two intravenously administered antibodies, is the preferred first-line treatment for patients with advanced hepatocellular cancer that has spread from the liver to other neighboring or distant parts of the body. This study investigated how long patients whose hepatocellular cancer continues to grow (progress) despite one or more prior tumor therapies live when they receive atezolizumab plus bevacizumab. These patients, treated with atezolizumab plus bevacizumab at various hospitals in Germany and Austria, lived about 16 months, which is about 5–8 months longer than patients receiving approved drugs. The safety profile was consistent with previous reports. Atezolizumab plus bevacizumab is the standard of care for first-line systemic therapy for advanced hepatocellular carcinoma (aHCC). Data on the efficacy and safety of atezolizumab plus bevacizumab in patients with aHCC who have received prior systemic therapy are not available. Methods: Patients with aHCC who received atezolizumab plus bevacizumab after at least one systemic treatment between December 2018 and March 2022 were retrospectively identified in 13 centers in Germany and Austria. Patient characteristics, tumor response rates, progression-free survival (PFS), overall survival (OS), and adverse events (AE) were analyzed. Results: A total of 50 patients were identified; 41 (82%) were male. The median age at initiation of treatment with atezolizumab plus bevacizumab was 65 years, 41 (82%) patients had cirrhosis, 30 (73%) Child A, 9 (22%) B, and 2 (5%) C. A total of 34 patients (68%) received atezolizumab plus bevacizumab in the second-line setting and 16 (32%) in later lines. The best radiologic tumor responses were complete remission (2%), partial remission (30%), stable disease (36%), and progressive disease (18%), resulting in an objective response rate of 32% and a disease control rate of 68%. Median OS was 16.0 months (95% confidence interval 5.6–26.4 months), and median PFS was 7.1 months (95% confidence interval 4.4–9.8 months). AE grades 3–4 were observed in seven (14%) and resulted in death in three patients (6%). There were five (10%) bleeding events with a grade ≥ 3, including one (2%) with a fatal outcome. Conclusions: Atezolizumab plus bevacizumab is effective in patients with aHCC who did not have access to this option as first-line therapy. The safety profile was consistent with previous reports. [ABSTRACT FROM AUTHOR]

Objectives: Stenosis of the biliary anastomosis predisposes liver graft recipients to bacterial cholangitis. Antibiotic therapy (AT) is performed according to individual clinical judgment, but duration of AT remains unclear. Methods: All liver graft recipients with acute cholangitis according to the Tokyo criteria grade 1 and 2 after endoscopic retrograde cholangiography (ERC) were included. Outcome of patients treated with short AT (<7 days) was compared to long AT (>6 days). Recurrent cholangitis (RC) within 28 days was the primary end point. Results: In total, 30 patients were included with a median of 313 (range 34–9849) days after liver transplantation until first proven cholangitis. Among 62 cases in total, 51/62 (82%) were graded as Tokyo‐1 and 11/62 (18%) as Tokyo‐2. Overall median duration of AT was 6 days (1–14) with 36 cases (58%) receiving short AT and 26 (42%) receiving long AT. RC was observed in 10 (16%) cases, without significant difference in occurrence of RC in short versus long AT cases. CRP and bilirubin were significantly higher in patients with long AT, while low serum albumin and low platelets were associated with risk of RC. Conclusion: A shorter antibiotic course than 7 days shows good results in selected, ERC‐treated patients for post‐transplantation biliary strictures. [ABSTRACT FROM AUTHOR]

Introduction: MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients. Materials and methods: All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients. Results: 59 (6%) colonized and 895 (94%) noncolonized HCC patients were included. Enterobacterales with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant Enterococcus faecium with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis. Conclusion: MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents. [ABSTRACT FROM AUTHOR]

Introduction: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. Patients and methods: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). Results: 45.5% female, median age 60 years (range, 27–84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90–98), 3-year OS = 84.3 (CI: 78–90) and 5-year OS = 77.5 (CI: 70–85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. Conclusions: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma is one of the most common cancers in the world with increasing incidence. In advanced stages, according to the Barcelona Clinic Liver Cancer (BCLC) staging defined by number, size, vessel infiltration status, and patient's performance status, the therapy of choice is systemic therapy. For several years, the tyrosine kinase inhibitor sorafenib was the only therapeutic option. Atezolizumab and bevacizumab are administered as a combination therapy promoting PD-L1 inhibition and anti-VEGF activity, which yields synergistic effects against cancer. The IMBRAVE150 trial investigated the use of this combination therapy versus that of sorafenib and showed an increase in overall patient survival to nearly 20 months. In this work, we investigated the real-world efficacy and safety of this combination in different centers. The combination of atezolizumab and bevacizumab (A + B) is the new standard of care for the systemic first-line treatment of hepatocellular carcinoma (HCC). However, up to now there are only few data on the safety and efficacy of A + B in real life. We included patients with advanced HCC treated with A + B as first-line therapy at four cancer centers in Germany and Austria between December 2018 and August 2021. Demographics, overall survival (OS), and adverse events were assessed until 15 September 2021. We included 66 patients. Most patients had compensated cirrhosis (n = 34; 52%), while Child–Pugh class B cirrhosis was observed in 23 patients (35%), and class C cirrhosis in 5 patients (8%). The best responses included a complete response (CR) in 7 patients (11%), a partial response (PR) in 12 patients (18%), stable disease (SD) in 22 patients (33%), and progressive disease in 11 patients (17%). The median progression-free (PFS) survival was 6.5 months, while the median overall survival (OS) was not reached in this cohort (6-month OS: 69%, 12-month OS: 60%, 18-month OS: 58%). Patients with viral hepatitis seemed to have a better prognosis than patients with HCC of non-viral etiology. The real-world PFS and OS were comparable to those of the pivotal IMBRAVE trial, despite including patients with worse liver function in this study. We conclude that A + B is also highly effective in a real-life setting, with manageable toxicity, especially in patients with compensated liver disease. In patients with compromised liver function (Child B and C), the treatment showed low efficacy and, therefore, it should be well considered before administration to these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal carcinoma (CRC) is one of the most prevalent malignomas worldwide and a leading cause of cancer associated mobidity and mortality. While screening and therapeutic developments have improved long-term survival and cure rates, a considerable fraction of patients suffers disease progression and death. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are amongst the cornerstones of therapy in advanced-stage CRC. However, while prospective clinical trials have confirmed the benefit of including those agents into the regimes for advanced CRC, disease progression or therapy-related toxicities might require physicians to switch from anti-EGFR-based therapies to alternative treatments. With limiting options in later treatment lines however, re-exposure to anti-EGFR-based therapy regimes is a valuable option and evidence for this approach is limited. This real-world study from a large oncology center in germany includes data from more than 500 patients to underscore the benefit of anti-EGFR re-exposure in patients with advanced CRC. Background and Aims: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. Methods: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). Results: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). Conclusions: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation. [ABSTRACT FROM AUTHOR]

Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CR P and AF P in I mmuno T herap Y) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p < 0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers. [Display omitted] • Baseline serum AFP ≥100 ng/ml and CRP ≥1 mg/dl were independently associated with worse OS in ICB-treated patients with HCC. • A score based on these two variables predicts disease control rate and overall survival in ICB-treated patients with HCC. • The score was validated in an independent cohort of ICB-treated patients with HCC. • In sorafenib-treated patients with HCC, the score was prognostic for overall survival but not predictive for disease control rate. [ABSTRACT FROM AUTHOR]

Background & Aims: Symptoms of patients with gastric cancer (GC) are often unspecific and differences in symptoms between patients with cardia and non-cardia GC have been poorly investigated. We aimed to characterize symptoms of patients with cardia and non-cardia GC. Methods: Patients with cardia (Siewert type II and III) and non-cardia GC were recruited in the German multicenter cohort of the Gastric Cancer Research (staR) study between 2013 and 2017. Alarm, dyspeptic and reflux symptoms at the time of presentation were documented using a self-administered questionnaire. Results: A completed self-administered questionnaire was available for 568/759 recruited patients (132 cardia GC, 436 non-cardia GC, male 61%, mean age 64 years). Dyspeptic symptoms were more common in patients with non-cardia GC (69.0 vs. 54.5%, p=0.0024). Cardia GC patients reported more frequently alarm symptoms (69.7 vs. 44.7%, p<0.0001), and were more likely to have Union for International Cancer Control (UICC) stage III-IV (54.1vs. 38.9%, p=0.0034). Especially, dysphagia and weight loss were more common in patients with cardia GC (49.2 vs. 6.4 %, p<0.0001 and 37.1 vs. 25.7%, p=0.02, respectively). No differences between the two groups were observed with respect to reflux symptoms. Patients with alarm symptoms were more likely to have UICC stage III-IV at presentation (69.4 vs. 42.9%, p<0.0001). Conclusions: In clinical practice the symptom pattern at presentation may serve as a hint for tumor localization. Despite the fact that they are common in the general population, dyspeptic symptoms offer a chance for earlier GC detection. Thus, in patients with dyspeptic symptoms who fail empiric approaches, endoscopy should not be delayed. [ABSTRACT FROM AUTHOR]

Objectives: Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail. Methods: Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list. Results: In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0–1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died. Conclusions: Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CCA, bile duct cancer) is a rare malignant disease with a poor prognosis. For several years interdisciplinary tumor boards (TuB) with the participation of experts from various disciplines have been organized to optimize medical treatment for patients suffering from oncological diseases. Objective: This study addressed the question whether the introduction of TuB leads to a better life expectancy and quality of life for patients with CCA. Material and methods: In this retrospective study 161 patients treated for CCA were investigated. The patient collective was divided in two groups (TuB+ vs. TuB−) and a propensity score matching was carried out. Results: The patient group TuB+ included 109 patients (67.7%) and the control group (TuB−) included 52 patients (32.3%). Using propensity score matching 84 patients in the TuB+ and 50 in the TuB group were identified and matched. The survival rates of the matched patients demonstrated an advantage for patients in the TuB+ group (1-year survival rate 61.9%, 5‑year survival rate 23.6%, 10-year survival rate 18.0%) over patients in the TuB−group (1-year survival rate 32.0%, 5‑year survival rate 8.0%, 10-year survival rate 0%) with p < 0.001. The results of the univariate (hazard ratio, HR 0.513, 95% confidence interval, CI 0.350–0.751, p = 0.001) and the multivariate Cox proportional hazard models (HR 0.459, 95% CI 0.303–0.694, p < 0.001) showed a significant benefit in survival for patients in the TuB+ group. Conclusion: This article shows that the introduction of a TuB meeting can provide a measurable benefit for patients with CCA. Hence it is recommended that all cases of patients with CCA should be discussed in a TuB. [ABSTRACT FROM AUTHOR]

Objective: Vancomycin-resistant enterococci (VRE) are of major concern in infection control. Although broad infection control actions to check VRE have been implemented, VRE remain part of daily infection preven- tion in clinical settings. Cleaning procedures in the inanimate ward environment might play a key role in controlling VRE. In order to optimize infection control management at University Hospital Frankfurt, Germany (UHF), this study evaluates the impact of H2O2-containing cleaning wipes compared to Glucoprotamin containing wipes on VRE prevalence in intensive care wards. Methods: Retrospective analyses were conducted of the VRE prevalence on environmental materials obtained from three intensive care units (ICU) at UHF for 17 months prior to (T1) and during the 25 months after (T2) the implementation of H2O2-containing cleaning wipes from January 2016 to June 2019. The bactericidal power of the two disinfectants against VRE was compared using the 4-field test according to EN 16615 (2015). Results: At T1 and T2, n=666 and n=710 environmental samples, re- spectively, were obtained. At T1, 24.2% (n=161/666; 95% confidence interval: 21.0–27.6) and at T2, 6.9% (n=49/710; 5.1–9.0) samples were positive for VRE. In vitro disinfectant testing did not reveal any superiority of H2O2 over glucoprotamin. No effect on the VRE prevalence in patients' rectal screening materials was observed. Conclusion: Though Glucoprotamin and H2O2 were in vitro equally effective against VRE, the prevalence of VRE in ICU environment at UHF de- creased after implementation of H2O2-containig wipes. This might be due to multiple factors, of which we consider the impact of the Hawthorne effect to be the strongest. Success of infection control strategies might depend on the compliance of the persons critically in- volved. Transparent information on infection control strategies is sug- gested to increase compliance and should therefore be considered both in daily infection control and outbreak management. [ABSTRACT FROM AUTHOR]

Introduction: Nivolumab is the first checkpoint-inhibitor approved for the treatment of advanced HCC patients. Real-life experience data of nivolumab treatment in HCC patients, especially those with advanced liver disease, is scarce.Materials and methods: All patients with confirmed advanced HCC and nivolumab treatment from three large German centers were retrospectively analyzed. Clinical parameters and outcome were assessed.Results: A total of 34 patients were included. At the time of treatment initiation 5 patients (14.7%) were classified as stage BCLC B and 29 (85.3%) BCLC C, respectively. 25 (73.5) patients had received prior sorafenib treatment. All patients presented with cirrhosis, namely Child-Pugh stages A (56%) or B (41%), respectively. At time of patient's assessment, 20 out of 34 (58.8%) patients had died. Grade 3 toxicities occurred in two patients (5.9%). Best overall responses were partial response in four patients (11.8%) and stable disease in eight patients (23.5%). The median overall survival of the whole cohort was 7.5 weeks (range 0-46). Child-Pugh B stage disease at treatment start was significantly associated with poor outcome.Discussion: Nivolumab treatment seems safe and clinical efficacious. Patients with advanced liver disease require further prospective evaluation due to probable limited efficacy of nivolumab. [ABSTRACT FROM AUTHOR]

The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Both molecules prevent in vitro the binding of FUBP1 to its single-stranded target DNA FUSE , and they induce deregulation of FUBP1 target genes in HCC cells. Our results suggest the interference with the FUBP1/ FUSE interaction as a further molecular mechanism that, in addition to the inactivation of TOP1, may contribute to the therapeutic potential of CPT/SN-38. Targeting of FUBP1 in HCC therapy with SN-38/irinotecan could be a particularly interesting option because of the high FUBP1 levels in HCC cells and their dependency on FUBP1 expression. [ABSTRACT FROM AUTHOR]

Background & Aims Infections with multidrug-resistant gram-negative bacteria are significantly impairing the prognosis of patients with liver disease. In particular, carbapenem resistance further narrows therapeutic options. This study investigates the impact of carbapenem-resistant gram-negative bacteria on the outcome of patients with liver disease and cirrhosis. Methods Between January 2011 and July 2015, 132 patients treated at the tertiary liver transplant centre at University Hospital Frankfurt, Germany, were tested positive for carbapenem-resistant gram-negative bacteria and retrospectively analysed in this study. Risk factors for fatal outcome were evaluated using multivariate regression analysis. Competing-risk analysis was performed on patients tested positive for Enterobacteriaceae or non-fermenting species, for example, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia. Subgroup analysis of cirrhotic patients was performed on a matched cohort of cirrhotic patients, comparable model for end-stage liver disease and tested negative for carbapenem-resistant gram-negative bacteria. Results 97 (73.5%) and 35 (26.5%) patients were infected or colonised with carbapenem-resistant gram-negative bacteria respectively. Within the observation period, 61/132 (46.2%) patients died, with sepsis being the leading cause (38/61, 62.3%). Decompensated liver disease, sepsis and admission to intensive care unit were independent risk factors for fatal outcome. Lethal sepsis in patients positive for non-fermenting bacteria was significantly more frequent than in those positive for Enterobacteriaceae, independently from liver function. Subgroup analysis of cirrhotic patients showed that sepsis (54.9% vs 13%) and lethal sepsis were significantly more frequent after detection of carbapenem-resistant gram-negative bacteria, independently from localisation of pathogen detection. Conclusions Patients with advanced liver disease are prone to fatal infections caused by carbapenem-resistant gram-negative bacteria. [ABSTRACT FROM AUTHOR]

Aim Immunotherapy in cancer is a recent and very promising approach, namely the inhibition of the PD/programmed death-ligand 1 (PD-L1) axis. Here we aimed to investigate the prognostic value of a soluble form of PD-L1 in hepatocellular carcinoma (HCC) patients. Methods HCC patients were prospectively recruited and soluble programmed death-ligand 1 (sPD-L1) levels were determined. sPD-L1 levels were compared to stages of cirrhosis and HCC. The association of the sPD-L1 levels and overall survival (OS) was assessed. Results Two hundred fifteen patients with HCC were prospectively included. The median serum sPD-L1 concentration in patients with HCC was 0.5 ng/ml (range 0.03–6.04). Soluble PD-L1 levels positively correlated with the stage of cirrhosis and with stages of HCC. Furthermore, sPD-L1 correlated positively with a marker of macrophage activation (sCD163) and inflammation (C-reactive protein). The cut-off for high-level sPD-L1 (>0.8 ng/ml) was defined by sPD-L1 levels determined in a healthy control cohort. Patients with high serum sPD-L1 concentrations had an increased mortality risk (hazard ratio 3.340, 95 % confidence interval 1.609–6.934, P < 0.001), while very low PD-L1 levels seem to come along with better prognosis. High sPD-L1 levels were associated with mortality independently from cirrhosis stage, alpha-fetoprotein and sCD163 levels in a multivariate Cox regression model. Conclusions We conclude that a high sPD-L1 level is a possible prognostic indicator for a poor outcome in HCC patients. The predictive value of sPD-L1 levels for a successful anti-PD1/PD-L1 therapy should be investigated in the future. [ABSTRACT FROM AUTHOR]

Mutations in the Park2 gene, encoding the RING-HECT hybrid E3 ubiquitin ligase parkin, are responsible for a common familial form of Parkinson disease. By mono- and polyubiquitinating target proteins, parkin regulates various cellular processes, including degradation of proteins within the 26 S proteasome, a large multimeric degradation machine. In our attempt to further elucidate the function of parkin, we have identified the proteasomal ubiquitin receptor Rpn13/ADRM1 as a parkin-interacting protein. We show that the N-terminal ubiquitin-like (Ubl) domain of parkin binds directly to the pleckstrin-like receptor for ubiquitin (Pru) domain within Rpn13. Using mutational analysis and NMR, we find that Prubinding involves the hydrophobic patch surrounding Ile-44 in the parkin Ubl, a region that is highly conserved between ubiquitin and Ubl domains. However, compared with ubiquitin, the parkin Ubl exhibits greater than 10-fold higher affinity for the Pru domain. Moreover, knockdown of Rpn13 in cells increases parkin levels and abrogates parkin recruitment to the 26 S proteasome, establishing Rpn13 as the major proteasomal receptor for parkin. In contrast, silencing Rpn13 did not impair parkin recruitment to mitochondria or parkin- mediated mitophagy upon carbonyl cyanide m-chlorophenyl hydrazone-induced mitochondrial depolarization. However, it did delay the clearance of mitochondrial proteins (TIM23, TIM44, and TOM20) and enhance parkin autoubiquitination. Taken together, These findings implicate Rpn13 in linking park in to the 26 S proteasome and regulating the clearance of mitochondrial proteins during mitophagy. [ABSTRACT FROM AUTHOR]

Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1-weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd-Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced MRI, which currently provides the most sensitive detection of HCC in patients. Immunohistochemical analyses revealed that the Gd-Rho-HSA-NPs were localized to macrophages, which were – similar to HCC in patients – fewer in number in HCC as compared to the liver tissue, which is in agreement with the negative contrasting of HCC in Gd-Rho-HSA-NP-enhanced MRI. Poloxamine-coated NPs showed lower accumulation in the tumor macrophages and caused a longer lasting enhancement of the MRI signal. These data indicate that Gd-Rho-HSA-NPs enable sensitive detection of HCC by T1-weighted MRI in mice with endogenous HCC through their uptake by macrophages. Poloxamine coating of the NPs delayed the tumor localization of the NPs. [ABSTRACT FROM AUTHOR]

Abstract: Background: The identification of new biomarkers to predict the aggressiveness of hepatocellular carcinoma (HCC) and supplement the current set of prognosis and treatment algorithms is an important clinical need. Extracellular microRNAs (miRNAs) circulating in the blood are a new class of highly promising disease markers. Aim: Here we investigated the prognostic potential of miR-1 and miR-122 in sera from patients with HCC. Methods: RNA was extracted from 195 sera of HCC patients and 54 patients with liver cirrhosis, obtained at the time of study enrolment. miR-1 and miR-122 levels were correlated with overall survival (OS), Cancer of the Liver Italian Program (CLIP) score, Barcelona Clinic Liver Cancer stage, clinical chemistry parameters and tumor specific treatment. Results: Patients with higher miR-1 and miR-122 serum levels showed longer OS than individuals with lower miR-1 and miR-122 serum concentrations (hazard ratio [HR] 0.440, 95% confidence interval [CI] 0.233–0.831, P =0.011 for miR-1 and HR 0.493, 95% CI 0.254–0.956, P =0.036 for miR-122, respectively). Serum miR-1 and miR-122 concentrations did not differ significantly between patients with HCC and liver cirrhosis. An age-, sex-, tumor stage and treatment-adjusted multivariate Cox regression analysis revealed that miR-1 serum levels (HR 0.451, 95% CI 0.228–0.856, P =0.015) were independently associated with OS, whereas serum miR-122 was not. miR-1 serum levels showed no relevant correlation with clinical chemistry liver parameters, whereas serum miR-122 correlated with clinical chemistry parameters of hepatic necroinflammation, liver function and synthetic capacity. Conclusion: Our data indicate that serum miR-1 is a new independent parameter of OS in HCC patients and may therefore improve the predictive value of classical HCC staging scores. [Copyright &y& Elsevier]

Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and microenvironmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67--positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCCmodel as revealed by magnetic resonance imaging.Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novelmechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment. [ABSTRACT FROM AUTHOR]

Selective autophagy can be mediated via receptor molecules that link specific cargoes to the autophagosomal membranes decorated by ubiquitin-like microtubule-associated protein light chain 3 (LC3) modifiers. Although several autophagy receptors have been identified, little is known about mechanisms controlling their functions in vivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promoted selective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencing of optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterial proliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selective autophagy. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

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., Competing Interests: Conflicts of interest A.L. reports receiving consulting fees from Advanz Pharma, AlfaSigma, Takeda, and Albireo Pharma, and speaker fees from Gilead, Abbvie, MSD, Intercept Pharma, AlfaSigma, GSK, and Incyte. BS received grant support from AstraZeneca and Eisai; speaker honoraria from Eisai; and travel support from AbbVie, AstraZeneca, Ipsen, and Gilead. MP received travel support from Bayer, BMS, Ipsen, Lilly, MSD, and Roche; he is a consultant for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; and he received travel support from Bayer, BMS, Ipsen, and Roche. HW received consulting and speaker fees from Roche, AstraZeneca, Eisai, and Ipsen., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. All rights reserved.)

Background: A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination., Methods: ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer-generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed., Findings: Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 10·4 months (80% CI 9·2-12·0) in the group that received standard treatment and 10·5 months (10·2-11·1) in the group that received alternating treatment (HR 0·90, 80% CI 0·72-1·13; p=0·56). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease)., Interpretation: Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment., Funding: Celgene/Bristol Myers Squibb., Competing Interests: Declaration of interests KD reports honoraria from AstraZeneca and support for travel, accommodation, and expenses from Servier, GSK, Bristol Myers Squibb, and AstraZeneca. SB reports honoraria for scientific presentations from Celgene, Servier, and MSD, fees for consultancy or advisory roles from Celgene, Servier, Incyte, Janssen-Cilag, AstraZeneca, MSD, and Bristol Myers Squibb, and support for travel, accommodation, and expenses from Lilly. MR reports honoraria for speakers' bureaus from Roche, Falk, and Servier and approved patents (EP18783030.2-1109, combination treatment of pancreatic cancer targeting PI3K signalling; EP20206259.2, analysis of tissue samples using quantitative phase-contrast microscopy). TJE reports research funding from Baxalta/Shire, support for travel, accommodation, and expenses from Ipsen, fees for consultancy or advisory roles from Eisai, MSD, Bayer, Roche, Sanofi, Bristol Myers Squibb, Incyte, AstraZeneca, Merck Serono, Pierre Fabre, Servier, Lilly, Ipsen, and Daiichi Sankyo Europe. OW reports honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Merck, MSD, Novartis, Roche, and Zentiva, consultancy fees from Amgen, Bayer, Bristol Myers Squibb, Celgene, Eisai, Incyte, Ipsen, Merck, MSD, Novartis, Roche, and Servier, and support for travel, accommodation, and expenses from Abbvie, Bayer, Bristol Myers Squibb, Gilead, Ipsen, Medac, Merck, Pierre Fabre, and Roche. DPM reports research funding to his institution from Amgen and Servier, honoraria from Merck Serono, Amgen, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, MSD, Pierre Fabre, Onkowissen, Sanofi, Lilly, Institut für klinische Krebsforschung, AstraZeneca/MedImmune, Incyte, and Takeda, and fees for consultancy or advisory roles from Merck Serono, Amgen, MSD, Roche, Servier, Incyte, Bristol Myers Squibb, Pierre Fabre, Lilly, Cor2Ed, IQvia, and Onkowissen. PM reports grants from Lilly, royalties and licenses from Elsevier, consultancy fees from Lilly and Ipsen, honoraria for speakers' bureaus from Falk, Amgen, and Roche, and support for travel, accommodation, and expenses from Galapagos. DP reports consultancy fees and honoraria paid to his institution from Boehringer Ingelheim, Deciphera, and PharmaMar, support for travel, accommodation, and expenses paid to his institution from PharmaMar, fees for consultancy or advisory roles paid to his institution from Boehringer Ingelheim, Deciphera, PharmaMar, and Thermosome, and research funding paid to his institution from Bristol Myers Squibb, PharmaMar, Roche, EUSA Pharma, and Boehringer Ingelheim. AR-S reports honoraria from Amgen, Roche, Merck Serono, Bristol Myers Squibb, MSD, MCI Group, and AstraZeneca, support for travel, accommodation, and expenses from Roche, Amgen, Pierre Fabre, and MSD, fees for consultancy or advisory roles from Abbvie, Amgen, Boehringer Ingelheim, Roche, Merck Serono, Bristol Myers Squibb, MSD, AstraZeneca, Pierre Fabre, Daiichi Sankyo, Janssen-Cilag, and Servier, and research funding paid to her institution from Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, AstraZeneca, Lilly, Servier, AIO-Studien, Rafael Pharmaceuticals, Erytech Pharma, and BioNTech. HP reports honoraria from Bristol Myers Squibb and AstraZeneca, support for travel, accommodation, and expenses from Abbvie, iOMEDICO, and Merck, fees for consultancy or advisory roles from Roche, Bristol Myers Squibb, Pfizer, Bayer, Novartis, Takeda, Janssen-Cilag, Gilead, Amgen, Abbvie, GSK, BeiGene, Oncopeptides, Incyte, Seagen, and Kedrion, and leadership and fiduciary roles for PiTri Studien. VH reports research funding paid to his institution from Merck, Amgen, and Roche, fees for consultancy and advisory roles from Merck, Amgen, Roche, MSD, Bristol Myers Squibb, MSD Oncology, Novartis, Pierre Fabre, TERUMO, GSK, Servier/Pfizer, AstraZeneca, Oncosil, and Nordic Bioscience, honoraria from Roche, Amgen, Sanofi, Merck, Servier, Pfizer, Pierre Fabre, AstraZeneca, MSD, and Seagen, and support for travel, accommodation, and expenses from Merck. FK reports research funding from Celgene and consultancy fees from Bayer and Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport., Methods: To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of α-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer., Findings: Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer., Interpretation: We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer., Funding: Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute., Competing Interests: Declaration of interests OW: Personal fees from Amgen, Bayer, BMS, Celgene, Daiicgi Sankyo, Eisai, Incyte, Ipsen, Merck, MSD, Novartis, Pierre Fabre, Roche, Servier; honoraria for lectures and/or presentations from Amgen, AstraZeneca, Bayer, BMS, Eisai, Ipsen, MSD, Novartis, Roche, Zentiva; support for attending meetings and/or travel: Abbvie, AstraZeneca, Bayer, BMS, Gilead, Ipsen, Medac, Merck, Pierre Fabre, Roche. SZ: Consultancy and/or speaker’s bureau: Abbvie, BioMarin, Boehringer Ingelheim, Gilead, GSK, Ipsen, Madrigal, Merck/MSD, NovoNordisk, SoBi. JUM: Grants or contracts from any entity, AstraZeneca, consulting fees: AstraZeneca, Roche, Ipsen, Eisai; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca, Roche, Ipsen, Eisai. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Die Übersicht über die Interessenskonflikte der Autorinnen und Autoren ist im Leitlinienreport veröffentlicht.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: Die Autorinnen/Autoren geben an, dass die Interessenkonflikte im Leitlinienreport dargelegt sind.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Competing Interests: Die Übersicht über die Interessenskonflikte der Autorinnen und Autoren ist im Leitlinienreport veröffentlicht.

Interleukin-1 beta (IL-1β) promotes liver disease progression and hepatocarcinogenesis in chronic hepatitis B (CHB). Single nucleotide polymorphisms (SNPs) within the promotor region of the IL-1β gene can affect the progression towards liver cirrhosis and hepatocellular carcinoma (HCC). Aims: We aimed to investigate the association of three common IL-1β SNPs with hepatitis B virus (HBV)-related HCC in Caucasian patients. Method: A Caucasian cohort of 99 patients with HBe antigen (Ag)-positive CHB, 255 patients with HBeAg-negative CHB and 278 inactive carriers (IC) were enrolled. 105 patients were diagnosed with liver cirrhosis, and 64 with HCC and cirrhosis. Genotyping of the IL-1β rs1143623, rs1143627 and rs16944 was performed. Results: The rs1143627 TT and rs16944 CC genotypes were more frequent in patients with HCC compared to patients without liver tumours (48% vs. 33%, p = 0.018 and 47% vs. 31%, p = 0.001, respectively). In multivariate analysis, the rs16944 CC genotype was independently associated with HCC (OR = 6.44 [95% CI 1.50-27.59] p = 0.012). The haplotype, including rs1143623 TT and rs16944 CC, was a risk factor for HCC development (OR = 1.55 [95% CI 1.04-2.32] p = 0.031). Conclusions: We identified an association of common IL-1β SNPs with HBV-related HCC in a Caucasian population. The effect was independent of the phases of chronic HBV infection, which are currently regarded as important HCC risk factors.

Anal cancer is a rare disease with increasing incidence. In patients with locally recurrent or metastatic disease which cannot be treated with chemoradiotherapy or salvage surgery systemic first-line chemotherapy with carboplatin and paclitaxel is standard of care. For patients who progress after first-line therapy and are still eligible for second-line therapy Programmed cell death protein 1 (PD-1) antibodies are potential therapeutic options. However, prediction of response to immunotherapy is still challenging including anal cancer. We report here to our knowledge the first anal cancer case with microsatellite instability (MSI) due to MLH1 mutation and a deep and ongoing response to Nivolumab treatment. Namely, thorough analysis of the primary tumor as well as metastatic sites by next generation sequencing (NGS) revealed that MSI was formally only found in the metastatic sites but not in the primary tumor. Concomitantly, tumor mutational burden (TMB) was higher in the metastatic site than in the primary tumor. Therefore, we conclude that all anal cancer patients should be tested for MSI and whenever possible molecular analysis should be performed rather from metastatic sites than from the primary tumor., Competing Interests: CONFLICTS OF INTEREST Ursula Pession, Jan Jeroch, Falko Schulze, Katrin Eichler, and Daniel Martin have nothing to declare. Melanie Demes received consulting/lecture fees from Amgen, AstraZeneca, Bayer, Biocartis, Diaceutics, Roche, Sophia Genetics. Peter Wild received consulting/lecture fees from AstraZeneca, Janssen, Roche, Astellas, Bayer, Bristol-Myers Squibb, Janssen, Novartis, Thermo Fisher Scientific, MSD, Qiagen, Molecular Health, Sophia Genetics. Oliver Waidmann received consulting/lecture fees from Amgen, AstraZeneca, Bayer, BMS, Celgene, Eisai, Falk, Incyte, Ipsen, Merck, MSD, Novartis, Roche, Servier, and Shire., (Copyright: © 2022 Demes et al.)

Purpose: This study compares the safety and efficacy of the ePTFE-covered self-expansible nitinol stent (VIATORR® Controlled Expansion, Gore, Flagstaff, USA) with the ePTFE-covered, balloon-expandable, metallic stent (BeGraft peripheral, Bentley, Hechingen, Germany) for the creation of the transjugular intrahepatic portosystemic shunt (TIPS)., Material and Methods: From September 2016 to December 2020, 72 consecutive patients receiving TIPS for acute variceal bleeding (rescue and early TIPS, n = 15) or for prophylaxis of variceal rebleeding (n = 57) were enrolled. The main contraindications were patients with vascular liver disease (portal vein thrombosis and Budd-Chiari syndrome). Forty patients (55.6%) received a Viatorr CX stent and 32 patients (44.4%) a BeGraft peripheral stent. Safety endpoints were technical and clinical adverse events and early deaths within 30 days after TIPS implantation. Efficacy endpoints were rebleeding rates, recurrence of large varices requiring endoscopic band ligation, or TIPS revision., Results: Groups receiving the Viatorr CX or BeGraft peripheral stent were comparable in all respects except the TIPS indication for acute variceal bleeding (5% vs. 25%, p = 0.015). All patients had a successful intervention, and the physical variables of stent implantation (intervention and fluoroscopy time, reduction of the portosystemic pressure gradient) as well as adjunctive embolization of varices were similar in both groups. Severe clinical complications (Viatorr CX: 5% vs. BeGraft peripheral: 3.1%, p = 0.692), post-TIPS hepatic encephalopathy (12.5% vs. 18.8%, p = 0.743) and death (5% vs. 0%, p = 0.793) were not different between Viatorr CX and BeGraft peripheral groups. With respect to efficacy, freedom from rebleeding and from variceal band ligation during follow-up (100% vs. 100%, p = 1.0), as well as the need for shunt revision (10.5% vs. 18.8%, p = 0.327), was comparable., Conclusion: Compared to the present gold standard, the Viatorr CX stent, the balloon-expandable BeGraft peripheral stent, showed similar results with respect to safety and efficacy., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

The prognostic role of platelet count in hepatocellular carcinoma (HCC) remains unclear, and in fact both thrombocytopenia and thrombocytosis are reported as predictors of unfavourable outcomes. This study aimed to clarify the prognostic value of preoperative platelet count in potentially resectable HCC. We retrospectively reviewed 128 patients who underwent hepatic resection for HCC at a tertiary academic centre (2007−2019). Patient data were modelled by regression analysis, and platelet count was treated as a continuous variable. 89 patients had BCLC 0/A tumours and 39 had BCLC B tumours. Platelet count was higher in patients with larger tumours and lower in patients with higher MELD scores, advanced fibrosis, and portal hypertension (p < 0.001 for all listed variables). After adjusting for BCLC stage and tumour diameter, low platelet count associated with reduced overall survival (hazard ratio 1.25 per 50/nL decrease in platelet count, 95% confidence interval (CI) 1.02−1.53, p = 0.034) and increased perioperative mortality (odds ratio 1.96 per 50/nL decrease in platelet count, 95% CI 1.19−3.53, p = 0.014). Overall, low platelet count correlates with increased liver disease severity, inferior survival, and excess perioperative mortality in resectable HCC. These insights might be applied in clinical practice to better select patients for resection.

Background: Multiple systemic therapy options have been recently approved for the treatment of hepatocellular carcinoma (HCC). In particular, immuno-oncology combination therapies can now achieve impressive response rates and significantly prolonged survival with good tolerability. These immuno-oncology (IO)-based combinations are currently not only evaluated for the therapy of advanced HCC, but increasingly also in earlier stages in terms of peri-interventional therapy concepts and also for down-sizing to local therapies. In the context of liver transplantation (LTx), a particularly critical benefit/risk assessment must be made before the use of immunotherapeutics in the context of multimodal concepts, since the risk of a potentially lethal rejection can be significantly increased by immunotherapy., Methods: This review is based on a selective literature search performed between December 2020 and April 2021 in the PubMed and Cochrane Library databases. Guidelines, expert opinions, and recommendations from professional societies were given special consideration., Results: Nearly one in five LTx in Germany are performed due to HCCs. In this context, LTx is a curative therapy option not only for the underlying liver disease but also for the malignant tumor. Individual case reports indicate that IO therapy prior to LTx may increase the risk of rejection or liver failure after subsequent liver transplantation. Since 2015, immunotherapeutics have also been widely used for tumor therapy in patients after LTx. In small case series, rejection rates of 36%, associated with rejection-related mortality of 20% of treated patients, have been described. A similar incidence of rejection has also been described following the use of immunotherapeutics in patients after other organ transplantations., Conclusion: In the context of organ transplantation, IO therapy carries the risk of graft rejection, which can lead to graft loss and also patient death. However, from today's point of view, IO-based therapy can be considered in the context of organ transplantation with a careful benefit/risk assessment., Competing Interests: Arndt Vogel: Beratertätigkeit/Vorträge: Amgen, Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Incyte, Ipsen, PierreFabre, MSD, Sirtex, BTG, Servier, Terumo. Martina Sterneck: keine. Florian W. R. Vondran: keine. Oliver Waidmann: Beratertätigkeit: Amgen, Bayer, BMS, Celgene, Eisai, Incyte, Ipsen, Merck Serono, MSD, Novartis, Roche, Servier, Shire. Vortragstätigkeit: AstraZeneca, Bayer, BMS, Celgene, Eisai, Ipsen, Novartis, Roche, Shire. Erstattung von Reisekosten: Abbvie, Bayer, BMS, Gilead, Ipsen, Medac, Merck. Klinische Studien: Basilea, Incyte, Else Kröner-Fresenius-Stiftung, Medac, Merck Serono, MSD. Ingo Klein: keine. Udo Lindig: keine. Silvio Nadalin: keine. Utz Settmacher: keine. Frank Tacke: Beratungs- und Vortragstätigkeit: Roche, BMS, Ipsen, MSD, Chiesi, Novartis. Hans-Jürgen Schlitt: keine. Henning Wege: Berater- und Vortragshonorare von Bayer, Roche, MSD und Eisai. Studien für Roche, MSD und Eisai, (Thieme. All rights reserved.)

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., Competing Interests: Honoraria for speaker, consultancy, and advisory role to A.V.: Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Ipsen, PierreFabre, and MSD. Honoraria for speaker, consultancy, and advisory role to A.S.: Roche, BMS, and Servier. Honoraria for speaker, consultancy, and advisory role to M.A.G.C.: Roche, Bayer, EISAI, MSD, and Servier. Honoraria for speaker, consultancy, and advisory role to C.M.L.: Roche, Novartis, EISAI, MSD, CSL Behring, AbbVie, and Gilead. Honoraria for speaker to C.L.: EISAI. Honoraria for speaker role to P.J.: Ipsen. Honoraria for speaker and advisory role to U.E.: AstraZeneca, Bayer, EISAI, Ipsen, Lilly, Novartis, Roche, and SIRTEX. Honoraria for speaker and advisory role to A.W.: Bayer, BMS, Eisai and Sanofi, Leo Pharma, Eisai, Ipsen, and Roche, travel support from Merck and Servier, A.W. is an Editorial Board Member of Liver Cancer. A.J. received speaker fees from AbbVie, MSD, Eisai, and Roche; travel grant from Servier, BMS, Amgen, and Lilly, sponsoring from Lilly, Cellgene, and Amgen, and personal fees from Servier, Amgen, Eisai, and Bayer. Honoraria for speaker and advisory board to A.K.: Roche Pharma AG; Eisai GmbH; Abbvie Deutschland, Janssen-Cilag; Boston Scientific Corp.; Micro-Tech Europe. Honoraria for speaker and advisory role to R.G.: Ad-Boards Bayer, Eisai/MSD, Ipsen, and Roche. Travel support and honoraria for speaker to F.F.: Abbvie, Ipsen, and Fresenius. Honoraria for speaker, consultancy, and advisory role to O.W.: Amgen, Bayer, BMS, Celgene, Eisai, Incyte, Ipsen, Merck Serono, MSD, Novatis, Roche, Servier, Shire, AstraZeneca, Abbvie, Gilead, and Medac. Honoraria for speaker, consultancy, and advisory role to M.V.: Roche, BMS, EISAI, Bayer, Lilly, AstraZeneca, Merck Serono, Sirtex, MSD, Ipsen, Nordic Pharma, and Amgen. Honoraria for speaker, consultancy, and advisory role to J.B.: Roche, BMS, EISAI, MSD, Novartis, and Ipsen. Honoraria for speaker, consultancy, and advisory role to A.D.: Roche, Bayer, Lilly, Novartis, EISAI, AstraZeneca, Merck, Ipsen, PierreFabre, Service, and Merck., (Copyright © 2022 by S. Karger AG, Basel.)

Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes. Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts. Results: Carbapenem-resistant (CR) Klebsiella pneumoniae ( n =9) and CR Pseudomonas aeruginosa ( n =7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN. Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schultze, Ferstl, Villinger, Hogardt, Bechstein, Göttig, Wichelhaus, Zeuzem, Trebicka, Waidmann, Welker and Kempf.)

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1-5 and 8-12 of a 28-day cycle, REG on days 2-22. Two dose levels were used: FTD/TPI 25 mg/m 2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m 2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m 2 b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51-5.29), median OS 11.1 months (95% CI: 2.3-18.2). Conclusion: The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Few data exist on health-related quality of life (QoL) in patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy (Awad L ZE, Mesbah M Boston, MA. Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Kluwer Academic Publishers 2002). The QOLIXANE study is a prospective, noninterventional, multicenter substudy of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer (PARAGON) registry, which evaluated QoL in patients with mPC receiving first-line gemcitabine and nab-paclitaxel chemotherapy in real-life setting. QoL was prospectively measured via EORTC QLQ-C30 questionnaires at baseline and every month thereafter. Therapy and efficacy parameters were prospectively collected. Main objectives were the rate of patients without deterioration of Global Health Status/QoL (GHS/QoL) at 3 and 6 months. Six hundred patients were enrolled in 95 German study sites. Median progression-free survival was 5.9 months (95% confidence interval [CI], 5.2-6.3). Median overall survival (OS) was 8.9 months (95% CI, 7.9-10.2), while median time to deterioration of GHS/QoL was 4.7 months (95% CI, 4.0-5.6). With a baseline GHS/QoL score of 46 (SD, 22.8), baseline QoL of the patients was severely impaired, in most cases due to loss in role functioning and fatigue. In the Kaplan-Meier analysis, 61% and 41% of patients had maintained GHS/QoL after 3 and 6 months, respectively. However, in the QoL response analysis, 35% and 19% of patients had maintained (improved or stable) GHS/QoL after 3 and 6 months, respectively, while 14% and 9% had deteriorated GHS/QoL with the remaining patients being nonevaluable. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a hazard ratio of 0.86 (P < .0001). Patients with mPC have poor QoL at baseline that deteriorates within a median of 4.7 months. Treatment with gemcitabine and nab-paclitaxel is associated with maintained QoL in relevant proportions of patients. However, overall, results remain poor, reflecting the aggressive nature of the disease., (© 2020 Union for International Cancer Control.)

Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.

Background: Cholangiocarcinoma (CCA, bile duct cancer) is a rare malignant disease with a poor prognosis. For several years interdisciplinary tumor boards (TuB) with the participation of experts from various disciplines have been organized to optimize medical treatment for patients suffering from oncological diseases., Objective: This study addressed the question whether the introduction of TuB leads to a better life expectancy and quality of life for patients with CCA., Material and Methods: In this retrospective study 161 patients treated for CCA were investigated. The patient collective was divided in two groups (TuB+ vs. TuB-) and a propensity score matching was carried out., Results: The patient group TuB+ included 109 patients (67.7%) and the control group (TuB-) included 52 patients (32.3%). Using propensity score matching 84 patients in the TuB+ and 50 in the TuB group were identified and matched. The survival rates of the matched patients demonstrated an advantage for patients in the TuB+ group (1-year survival rate 61.9%, 5‑year survival rate 23.6%, 10-year survival rate 18.0%) over patients in the TuB-group (1-year survival rate 32.0%, 5‑year survival rate 8.0%, 10-year survival rate 0%) with p < 0.001. The results of the univariate (hazard ratio, HR 0.513, 95% confidence interval, CI 0.350-0.751, p = 0.001) and the multivariate Cox proportional hazard models (HR 0.459, 95% CI 0.303-0.694, p < 0.001) showed a significant benefit in survival for patients in the TuB+ group., Conclusion: This article shows that the introduction of a TuB meeting can provide a measurable benefit for patients with CCA. Hence it is recommended that all cases of patients with CCA should be discussed in a TuB.

Recently published genomic data revealed substantial differences of gallbladder and extrahepatic as well as intrahepatic cholangiocarcinoma. However, these data have no influence on the choice of systemic therapy to date. This review shall provide a concise overview of epidemiology and pathogenesis of gallbladder carcinoma as well as the differences in the mutational profile in comparison to cholangiocarcinoma. Furthermore, the present evidence-based options in systemic therapy are discussed and a future perspective on potentially upcoming therapies is provided., Competing Interests: Oliver Waidmann hat Honorare für Beratung oder Vorträge, bzw. Reisekostenerstattungen oder Unterstützung für wissenschaftliche Projekte von folgenden Firmen erhalten: Abbvie, Amgen, Basilea, Bayer, BMS, Celgene, Eisai, Gilead, Incyte, Incyte, Ipsen, Lilly, Medac, Merck kGA, Merck Serono, MSD, Novartis, Roche, Servier und Shire.Jörg Trojan hat Honorare für Beratung oder Vorträge, bzw. Reisekostenerstattungen oder Unterstützung für wissenschaftliche Projekte von folgenden Firmen erhalten: Amgen, Bayer Healthcare, Bioprojet, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, PCI Biotech, Roche und Servier., (© Georg Thieme Verlag KG Stuttgart · New York.)