Improved levels of checkpoint molecule PD-L1 on peripheral blood monocyte subsets in obstructive sleep apnea syndrome patients upon hypoglossal nerve stimulation.

Oxidative stress in patients suffering from obstructive sleep apnea syndrome (OSAS) is associated with a low-grade systemic inflammation, immune disturbance, and increased invasion of monocytes into the endothelium. Besides continuous positive airway pressure (PAP), hypoglossal nerve stimulation (HNS) has become a promising treatment option for patients with OSAS. We aimed to analyse the influence of HNS therapy on the cellular characteristics relevant for adhesion and immune regulation of circulating CD14/CD16 monocyte subsets. Whole blood flow cytometric measurements were performed to analyse the expression levels of different adhesion molecules and checkpoint molecule PD-L1 (programmed death-ligand 1) in connection with pro-inflammatory plasma cytokine IL-8 and the clinical values of BMI (body mass index), AHI (apnea-hypopnea index), ODI (oxygen desaturation index), and ESS (Epworth sleepiness scale) upon HNS treatment. Hypoglossal nerve stimulation treatment significantly improved the expression of adhesion molecule CD162 (P-selectin receptor) on non-classical monocytes and significantly downregulated the expression of PD-L1 on all three monocyte subsets. We conclude that the holistic improvement of different parameters such as the oxygenation of the peripheral blood, a reduced systemic inflammation, and the individual sleeping situation upon HNS respiratory support, leads to an improved immunologic situation.

[Quality Indicators Show Higher Fulfilment in Centers Certified by the German Cancer Society]. / Qualitätsindikatoren zeigen bessere Erfüllungsquoten in DKGzertifizierten Zentren.

AIM: In 2003, a certification program was introduced by the German Cancer Society in Germany to ensure high standards of oncological care. The present study investigated whether there were differences in the concordance to guideline-based recommendations between centers certified by the German Cancer Society and medical facilities without such certification. In this context, quality indicators derived from clinical guidelines were evaluated. METHODS: The database of the cancer registry of Rhineland-Palatinate, Germany was used to calculate fulfilment of target values for 14 quality indicators. Analysis of quality indicators followed specifications given in treatment S3-guidelines for breast, colorectal and lung cancer. Analyses were done by R and SAS. RESULTS: All 14 quality indicators showed that concordance with guideline-based recommendations was higher in certified centers compared to uncertified medical facilities; 13 of these differences were statistically significant. CONCLUSION: Higher quality of oncological treatment in certified centers has widely been discussed in the WiZen study. The results of our study support this assumption with respect to concordance with quality indicators.

[Liver transplantation in viral and autoimmune liver diseases]. / Lebertransplantation bei viralen und autoimmunen Lebererkrankungen.

BACKGROUND: Despite substantial progress in the management of viral and autoimmune liver diseases, these entities remain relevant indications for liver transplantation. AIMS: To provide an overview of the current knowledge regarding the management of viral and autoimmune liver diseases before and after liver transplantation. MATERIALS AND METHODS: Selective literature search, including current guidelines and abstracts of key scientific meetings. RESULTS AND DISCUSSION: Viral and autoimmune liver disease can be effectively treated in most cases, which has resulted in an overall decline in liver transplantations for this indication group. However, hepatitis D infection and primary sclerosing cholangitis remain difficult-to-treat liver diseases in some patients and may progress to end-stage liver disease despite best possible management. Viral or autoimmune hepatitis can lead to fulminant liver failure requiring emergency liver transplantation. In patients who are transplanted due to viral or autoimmune liver disease, specific measures to prevent recurrence of these diseases after transplantation are mandatory. In view of effective treatment modalities for chronic hepatitis B and C, even liver grafts from donors infected with these viruses can be considered for liver transplantation under certain circumstances.

Systemic Treatment of Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Multicenter Trial.

INTRODUCTION: The tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib represent the first-line systemic therapy of choice for patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Under sorafenib and lenvatinib, HCC patients have shown increasingly improved overall survival in clinical studies over the years. In contrast, data on overall survival for patients with HCC recurrence after LT under TKIs are scarce and limited to small retrospective series. In this retrospective, multicenter study, we investigated the efficacy of TKI therapy and the influence of immunosuppression in patients with HCC recurrence after LT. METHODS: Retrospective data were collected from four transplant centers from Germany and Austria. We included patients with HCC recurrence after LT between 2007 and 2020 who were treated with a TKI. RESULTS: In total, we analyzed data from 46 patients with HCC recurrence after LT. The most common underlying liver disease was hepatitis C, accounting for 52.2%. The median time to relapse was 11.8 months (range 0-117.7 months). The liver graft was affected in 21 patients (45.7%), and 36 patients (78.3%) had extrahepatic metastases at initial diagnosis of recurrence, with the lung being the most commonly affected (n = 25, 54.3%). Of the total, 54.3% (n = 25) of the patients were initially treated locally; 39 (85.8%) and 7 (15.2%) patients received sorafenib and lenvatinib, respectively, as first-line systemic therapy. Median overall survival of the whole cohort was 10.9 months (95% confidence interval (95% CI) 6.9-14.9 months) and median progression free survival was 5.7 months (95% CI 2.0-9.4 months) from treatment initiation. CONCLUSION: Since history of liver transplantation is considered a contraindication for immunotherapy, prognosis of patients with HCC recurrence after LT remains poor.

Distinguishing the impact of distinct obstructive sleep apnea syndrome (OSAS) and obesity related factors on human monocyte subsets.

Obstructive sleep apnea syndrome (OSAS) and obesity go hand in hand in the majority of patients and both are associated with a systemic inflammation, immune disturbance and comorbidities such as cardiovascular disease. However, the unambiguous impact of OSAS and obesity on the individual inflammatory microenvironment and the immunological consequences of human monocytes has not been distinguished yet. Therefore, aim of this study was to investigate the impact of OSAS and obesity related factors on the inflammatory microenvironment by performing flow cytometric whole blood measurements of CD14/CD16 monocyte subsets in normal weight OSAS patients, patients with obesity but without OSAS, and patients with OSAS and obesity, compared to healthy donors. Moreover, explicitly OSAS and obesity related plasma levels of inflammatory mediators adiponectin, leptin, lipocalin and metalloproteinase-9 were determined and the influence of different OSAS and obesity related factors on cytokine secretion and expression of different adhesion molecules by THP-1 monocytes was analysed. Our data revealed a significant redistribution of circulating classical and intermediate monocytes in all three patient cohorts, but differential effects in terms of monocytic adhesion molecules CD11a, CD11b, CD11c, CX3CR1, CD29, CD49d, and plasma cytokine levels. These data were reflected by differential effects of OSAS and obesity related factors leptin, TNFα and hypoxia on THP-1 cytokine secretion patterns and expression of adhesion molecules CD11b and CD49d. In summary, our data revealed differential effects of OSAS and obesity, which underlines the need for a customized therapeutic regimen with respect to the individual weighting of these overlapping diseases.

Assessment and incorporation of in vitro correlates to pharmacokinetic outcomes in antibody developability workflows.

In vitro assessments for the prediction of pharmacokinetic (PK) behavior of biotherapeutics can help identify corresponding liabilities significantly earlier in the discovery timeline. This can minimize the need for extensive early in vivo PK characterization, thereby reducing animal usage and optimizing resources. In this study, we recommend bolstering classical developability workflows with in vitro measures correlated with PK. In agreement with current literature, in vitro measures assessing nonspecific interactions, self-interaction, and FcRn interaction are demonstrated to have the highest correlations to clearance in hFcRn Tg32 mice. Crucially, the dataset used in this study has broad sequence diversity and a range of physicochemical properties, adding robustness to our recommendations. Finally, we demonstrate a computational approach that combines multiple in vitro measurements with a multivariate regression model to improve the correlation to PK compared to any individual assessment. Our work demonstrates that a judicious choice of high throughput in vitro measurements and computational predictions enables the prioritization of candidate molecules with desired PK properties.

Imaging-Derived Biomarkers Integrated with Clinical and Laboratory Values Predict Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Purpose: To investigate the prognostic value of computed tomography (CT) derived imaging biomarkers in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and develop a predictive nomogram model. Patients and Methods: This retrospective study included 178 patients with histopathologically confirmed HCC who underwent liver transplantation between 2007 and 2021 at the two academic liver centers. We evaluated dedicated imaging features from baseline multiphase contrast-enhanced CT supplemented by several clinical findings and laboratory parameters. Time-to-recurrence was estimated by Kaplan-Meier analysis. Univariable Cox proportional hazard regression and multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to assess independent prognostic factors for recurrence. A nomogram model was then built based on the independent factors selected through LASSO regression, to predict the probabilities of HCC recurrence at one, three, and five years. Results: The rate of HCC recurrence after LT was 17.4% (31 of 178). The LASSO analysis revealed six independent predictors associated with an elevated risk of tumor recurrence. These predictors included the presence of peritumoral enhancement, the presence of over three tumor lesions, the largest tumor diameter greater than 3 cm, serum alpha-fetoprotein (AFP) levels exceeding 400 ng/mL, and the presence of a tumor capsule. Conversely, a history of bridging therapies was found to be correlated with a reduced risk of HCC recurrence. In addition, Kaplan-Meier curves showed patients with irregular margin, satellite nodules, or small lesions displayed shorter time-to-recurrence. Our nomogram demonstrated good performance, yielding a C-index of 0.835 and AUC values of 0.86, 0.88, and 0.85 for the predictions of 1-year, 3-year, and 5-year TTR, respectively. Conclusion: Imaging parameters derived from baseline contrast-enhanced CT showing malignant behavior and aggressive growth patterns, along with serum AFP and history of bridging therapies, show potential as biomarkers for predicting HCC recurrence after transplantation.

Cirrhosis-Based Acute-on-Chronic Liver Failure Is Marked by Inflammation and Impaired Liver Regeneration Despite Stat3 Activation.

Background and Aims: Acute-on-chronic liver failure (ACLF) is associated with excessive systemic inflammation, cell death, and organ failures. Yet, little is known about the hepatic histopathology of ACLF. Here, we assessed the histopathology and regenerative capacity of the liver in ACLF with or without cirrhosis. Methods: Liver specimens of patients with compensated cirrhosis (N = 37), acute decompensation (N = 40), and ACLF with (N = 18) or without (N = 10) cirrhosis were assessed for morphological features and the pro-regenerative Stat3 pathway. Results: ACLF was associated with high levels of lobular inflammation, tissue necrosis, and apoptosis. In patients with cirrhosis, the percentage of pStat3-positive hepatocytes was increasing with disease severity (3.5%/10.4%/21% for compensated cirrhosis/acute decompensation/cirrhosis-ACLF; P < .001), but lower in noncirrhotic ACLF vs cirrhosis-ACLF (21% vs 13%; P = .02). A distinct pattern of the expression of the proliferation marker Ki-67, a downstream effector marker of pStat3, was observed. Ki-67-positive hepatocytes were more frequent in patients with cirrhosis-ACLF compared to compensated cirrhosis or acute decompensation (4.9% vs 1.3% vs 1.8%; P < .05), but much lower in cirrhosis-ACLF vs noncirrhotic ACLF (4.9% vs 13.5%; P = .01). The ratio of Ki-67-positive to pStat3-positive hepatocytes was lowest in cirrhosis-ACLF and predicted 3-month transplant-free survival accurately (area under the curve = 0.95, P < .00001). Conclusion: Our study identifies hepatic inflammation and Stat3 activation as hallmarks of ACLF. In cirrhosis-ACLF, Stat3 activation does not appear to translate in effective liver regeneration, which is distinct from noncirrhotic ACLF.