Search

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.)

Background: The determinants of the response to checkpoint immunotherapy in hepatocellular carcinoma (HCC) remain poorly understood. The organisation of the immune response in the tumour microenvironment (TME) is expected to govern immunotherapy outcomes but spatial immunotypes remain poorly defined., Objective: We hypothesised that the deconvolution of spatial immune network architectures could identify clinically relevant immunotypes in HCC., Design: We conducted highly multiplexed imaging mass cytometry on HCC tissues from 101 patients. We performed in-depth spatial single-cell analysis in a discovery and validation cohort to deconvolute the determinants of the heterogeneity of HCC immune architecture and develop a spatial immune classification that was tested for the prediction of immune checkpoint inhibitor (ICI) therapy., Results: Bioinformatic analysis identified 23 major immune, stroma, parenchymal and tumour cell types in the HCC TME. Unsupervised neighbourhood detection based on the spatial interaction of immune cells identified three immune architectures with differing involvement of immune cells and immune checkpoints dominated by either CD8 T-cells, myeloid immune cells or B- and CD4 T-cells. We used these to define three major spatial HCC immunotypes that reflect a higher level of intratumour immune cell organisation: depleted, compartmentalised and enriched. Progression-free survival under ICI therapy differed significantly between the spatial immune types with improved survival of enriched patients. In patients with intratumour heterogeneity, the presence of one enriched area governed long-term survival., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Desmoplastic small round blue cell tumor (DSRCT) is a highly aggressive fatal sarcoma without evidence-based therapeutic guidelines. We present here seven patients with DSRCT including immunohistochemistry combined with fluorescence in situ hybridization (FISH), next generation sequencing (NGS, n  = 6) as well as OncoScan array ( n  = 3) analyses and show consecutive therapeutic approaches. All seven DSRCT patients presented with an extended abdominal mass; median age at diagnosis was 24.8 years. NGS analyses revealed five class 4 or 5 sequence variants. Remarkably, OncoScan and targeted analyses by FISH identified genomic gains of CCND1 in two cases. Cyclin D1 expression was present in all seven tumors as shown by immunohistochemical staining. Multimodal therapeutic concepts included systemic therapies, resection, and radiation. Six patients were treated as first-line therapy with conventional chemotherapy. All except one patient had a dismal therapy response. Subsequent therapy lines consisted of chemotherapeutic combinations followed by targeted therapies. Due to Cyclin D1 expression, the CDK4/6 inhibitor palbociclib was applied to four patients. The median therapy duration until disease progression in these patients was 4.5 months (range, 1.5-5 months). So, CCND1 genomic gain and Cyclin D1 expression are common features pointing to cell-cycle deregulation as a possible therapeutic target., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Verena I. Gaidzik et al.)

Background: Malnutrition is common in patients with cirrhosis, eventually leading to sarcopenia and loss of bone mass., Aims: The aims of this study was the assessment of body composition (BC) and bone mineral density (BMD) in patients with decompensated cirrhosis and the prognostic impact on survival after transjugular intrahepatic portosystemic shunt (TIPS) implantation., Methods: BMD and BC of 107 patients with cirrhosis undergoing TIPS implantation were prospectively analyzed by dual-energy X-ray absorptiometry. The prevalence and predisposing risk factors for reduced BMD and sarcopenia were assessed. Impact on 12-month survival after TIPS implantation was evaluated., Results: Sarcopenia was diagnosed in 48.6 % of the patients with a predominance of male patients (58.7% vs. 25.0 %, p = 0.001). 67.2 % had reduced BMD. Low BMI was independently associated with sarcopenia (OR 0.751 (95 % CI: 0.662;0.852), p < 0.001) and reduced BMD (OR 0.851 (0.773;0.937), p = 0.001). Patients with reduced BMD, but not sarcopenia, had impaired 12-month survival after TIPS-implantation (61.2% vs. 82.9 %, p = 0.030). Subgroup analysis showed that this was especially valid for female patients., Conclusions: Sarcopenia and reduced BMD are frequently observed in patients with decompensated cirrhosis. Reduced BMD negatively affects post-TIPS survival. Since malnutrition is a leading cause, assessment of nutritional status and specific treatment should be included in clinical practice., Competing Interests: Conflicts of Interest DB: lecture fees from W. L. Gore & Associates GmbH; Travel Grant: Gilead Science; MS: lecture fees from Falk Foundation e.V., W. L. Gore & Associates, Bentley InnoMed GmbH; MR, JS, KL, MMS, AD, LS, RT: No conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question., Aims: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO., Methods: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial., Study Outcomes: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted., Sample Size: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm., Discussion: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology., Trial Registration: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alteplase/placebo is provided by Boehringer Ingelheim at no costs. Boehringer Ingelheim was given opportunity to review the manuscript for medical/scientific accuracy and intellectual property considerations. The authors did not receive any payment related to trial/manuscript development.

Purpose To explore the potential benefits of deep learning-based artifact reduction in sparse-view cranial CT scans and its impact on automated hemorrhage detection. Materials and Methods In this retrospective study, a U-Net was trained for artifact reduction on simulated sparse-view cranial CT scans in 3000 patients, obtained from a public dataset and reconstructed with varying sparse-view levels. Additionally, EfficientNet-B2 was trained on full-view CT data from 17 545 patients for automated hemorrhage detection. Detection performance was evaluated using the area under the receiver operating characteristic curve (AUC), with differences assessed using the DeLong test, along with confusion matrices. A total variation (TV) postprocessing approach, commonly applied to sparse-view CT, served as the basis for comparison. A Bonferroni-corrected significance level of .001/6 = .00017 was used to accommodate for multiple hypotheses testing. Results Images with U-Net postprocessing were better than unprocessed and TV-processed images with respect to image quality and automated hemorrhage detection. With U-Net postprocessing, the number of views could be reduced from 4096 (AUC: 0.97 [95% CI: 0.97, 0.98]) to 512 (0.97 [95% CI: 0.97, 0.98], P < .00017) and to 256 views (0.97 [95% CI: 0.96, 0.97], P < .00017) with a minimal decrease in hemorrhage detection performance. This was accompanied by mean structural similarity index measure increases of 0.0210 (95% CI: 0.0210, 0.0211) and 0.0560 (95% CI: 0.0559, 0.0560) relative to unprocessed images. Conclusion U-Net-based artifact reduction substantially enhanced automated hemorrhage detection in sparse-view cranial CT scans. Keywords: CT, Head/Neck, Hemorrhage, Diagnosis, Supervised Learning Supplemental material is available for this article. © RSNA, 2024.

The standard of care to treat small- and medium-sized macular holes (<400 µm diameter) consists of a conventional transconjunctival sutureless pars plana vitrectomy followed by ILM peeling and endotamponade, mainly with gas or in some cases with silicone oil, resulting in closure rates of over 90% and good functional results. Large (>400 µm diameter), chronic and persistent macular holes remain a surgical challenge since closure rates and functional results decrease with larger macular hole diameters. Various modifications of the conventional surgical technique were introduced to improve anatomic and functional success in refractory cases not suitable for conventional macular hole surgery. These techniques comprise the positioning of tissue at the top of the hole to improve closure as performed by an inner limiting membrane flap and free flap preparation or the transplantation of autologous retinal tissue, lens capsule or amniotic membrane. For the treatment of very large and persistent macular holes, the induction of a localized retinal detachment at the posterior pole by subretinal injection of balanced salt solution and a subsequent attenuation of the rim of the hole during fluid-air exchange has been suggested as a promising surgical technique. In particular, accurate patient education about the expected surgical outcome in this specific group of patients appears important., Competing Interests: Declaration of Competing Interest The authors declare that no conflicts of interest exist: The authors received no financial support for the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In recent years, the pathophysiological concept of decompensated liver cirrhosis has undergone significant changes. Until a few years ago, the focus of pathophysiological considerations was on the hyperdynamic circulation resulting from portal hypertension. In recent years, emerging data suggests that increased bacterial translocation leading to systemic inflammation plays an important role in patients with decompensated liver cirrhosis. This inflammation affects a variety of extrahepatic organs. Nowadays, liver cirrhosis is considered not only a condition confined to the liver but rather an inflammatory-triggered multisystem disease. The existing inflammation serves as the common pathophysiological explanation for the diverse impact of liver cirrhosis on several extrahepatic organs. It plays a significant role in the development of conditions such as hepatorenal syndrome, cirrhotic cardiomyopathy, hepatopulmonary syndrome, hepatic encephalopathy, and even in the emergence of cirrhosis-associated relative adrenal insufficiency. These new pathophysiological insights hold clinical significance as they influence the prophylaxis and treatment of patients with decompensated liver cirrhosis., Competing Interests: DB: Vortragstätigkeit: Falk Foundation, W. L. Gore & Associates; Reisesponsering: Gilead Science; Forschungsförderung: Dr. Rolf M. Schwiete-Stiftung MS: Vortragstätigkeit für Falk Foundation e.V., W. L. Gore & Associates, Bentley InnoMed GmbH, (Thieme. All rights reserved.)

Chordomas are very rare malignant neoplasms of the bone occurring almost exclusively along the spine. As the tumours are thought to arise from notochordal remnants, the vast majority of chordomas express the TBXT gene, resulting in detectable nuclear amounts of its gene product brachyury. This T-Box transcription factor is commonly recognised as being essential in chordoma cells, and limiting TBXT expression is thought to be the key factor in controlling this tumour. Although the tumour is rare, distinct molecular differences and vulnerabilities have been described with regard to its location and the progression status of the disease, rendering it mandatory for novel cell lines to reflect all relevant chordoma subtypes. Here, we describe a novel chordoma cell line arising from the pleural effusion of a disseminated, poorly differentiated chordoma. This cell line, U-CH22, represents a highly aggressive terminal chordoma and, therefore, fills a relevant gap within the panel of available cell culture models for this orphan disease. CDK7 and CDK9 inhibition was lately identified as being effective in reducing viability in four chordoma cell lines, most likely due to a reduction in brachyury levels. In this study, we determined the capability of the CDK7 inhibitor THZ1 and the CDK1/2/5/9 inhibitor dinaciclib to reduce TBXT expression at mRNA and protein levels in a broad range of nine cell lines that are models of primary, recurrent, and metastasised chordoma of the clivus and the sacrum.

Background: The proliferation of digital disease-detection systems has led to an increase in earlier warning signals, which subsequently have resulted in swifter responses to emerging threats. Such highly sensitive systems can also produce weak signals needing additional information for action. The delays in the response to a genuine health threat are often due to the time it takes to verify a health event. It was the delay in outbreak verification that was the main impetus for creating EpiCore., Objective: This paper describes the potential of crowdsourcing information through EpiCore, a network of voluntary human, animal, and environmental health professionals supporting the verification of early warning signals of potential outbreaks and informing risk assessments by monitoring ongoing threats., Methods: This paper uses summary statistics to assess whether EpiCore is meeting its goal to accelerate the time to verification of identified potential health events for epidemic and pandemic intelligence purposes from around the world. Data from the EpiCore platform from January 2018 to December 2022 were analyzed to capture request for information response rates and verification rates. Illustrated use cases are provided to describe how EpiCore members provide information to facilitate the verification of early warning signals of potential outbreaks and for the monitoring and risk assessment of ongoing threats through EpiCore and its utilities., Results: Since its launch in 2016, EpiCore network membership grew to over 3300 individuals during the first 2 years, consisting of professionals in human, animal, and environmental health, spanning 161 countries. The overall EpiCore response rate to requests for information increased by year between 2018 and 2022 from 65.4% to 68.8% with an initial response typically received within 24 hours (in 2022, 94% of responded requests received a first contribution within 24 h). Five illustrated use cases highlight the various uses of EpiCore., Conclusions: As the global demand for data to facilitate disease prevention and control continues to grow, it will be crucial for traditional and nontraditional methods of disease surveillance to work together to ensure health threats are captured earlier. EpiCore is an innovative approach that can support health authorities in decision-making when used complementarily with official early detection and verification systems. EpiCore can shorten the time to verification by confirming early detection signals, informing risk-assessment activities, and monitoring ongoing events., (©Nomita Divi, Jaś Mantero, Marlo Libel, Onicio Leal Neto, Marinanicole Schultheiss, Kara Sewalk, John Brownstein, Mark Smolinski. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 15.03.2024.)

Hepatic vein outflow obstruction causes congestion of the liver, leading to necrosis, fibrosis, and portal hypertension (PH). A transjugular intrahepatic portosystemic shunt (TIPS) reduces congestion and PH by providing artificial outflow. The aim of the study was to investigate fibrosis progression in patients with Budd-Chiari syndrome (BCS) and TIPS using transient elastography (TE). From 2010 to 2022, 25 patients received 80 TEs using FibroScan ® , Echosens, Paris, France (3.2 ± 2.1 per patient). TIPS function was assessed via Doppler ultrasound or radiological intervention. At the time of TE examination, 21 patients had patent shunts. Four patients had occluded shunts but normal pressure gradients during the intervention. The first TE measurement performed 9.8 ± 6.8 years after the BCS diagnosis showed stiffness values of 24.6 ± 11.5 kPa. A second or last measurement performed 7.0 ± 2.9 years after the first measurement showed similar stiffness values of 24.1 ± 15.7 kPa ( p = 0.943). Except for three patients, the liver stiffness was always >12 kPa, indicating advanced fibrosis. Stiffness values obtained <5 years ( n = 8, 23.8 ± 9.2 kPa) or >5 years after the BCS diagnosis (24.9 ± 12.7 kPa) did not differ ( p = 0.907). In addition, stiffness was not related to the interval between BCS and TIPS implantation ( p = 0.999). One patient received liver transplantation, and two patients died from non-hepatic causes. Most patients developed mild to moderate cirrhosis, possibly during the early phase of the disease. Timing of TIPS did not influence fibrosis progression. This and the release of portal hypertension may argue in favor of a generous TIPS implantation practice in patients with BCS.