NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts.

Transforming growth factor beta (TGF-β) signalling has become an attractive therapeutic target due to its pro-tumorigenic actions on epithelial cells and its immunosuppressive effects in the tumour microenvironment. In intrahepatic cholangiocarcinoma (iCCA), a highly aggressive malignancy of the biliary tract with poor prognosis, the latest clinical trials using TGF-β inhibitors have failed indicating that the specific actions carried out by TGF-β in iCCA are yet not well delineated. Here, we show that TGF-β signalling is highly active in iCCA and exerts a prominent suppressor effect on tumour cell lines and organoids established from iCCA metastases biopsies, that relies on a functional canonical SMAD2/3/4 signalling.

The Niemann-Pick C1 Protein of Patients with Hepatocellular Carcinoma Is Associated with Survival Time in Males and Tumor Size in Females.

The Niemann-Pick C1 (NPC1) protein regulates cellular cholesterol homeostasis, which is disrupted in hepatocellular carcinoma (HCC). Sex differences in cholesterol metabolism may also be related to NPC1 expression in HCC. A sex-specific analysis was, therefore, performed to investigate this further.

Building a Knowledge Base for Variant Annotation Using Therapy Recommendations in cBioPortal.

Molecular tumor boards present special challenges when it comes to information collection for case preparation. It is one of the most time-consuming tasks participating pathologists and oncologists face, limiting the number of cases that can be discussed in these specialized tumor boards and in turn can profit from a potential highly personalized therapy. Digital support is a necessity to enable medical professionals to efficiently make use of the vast amount of data available for each patient and their genomic and clinical profile.

Complex Roles of /SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy.

The non-receptor tyrosine phosphatase SHP2 has been at the center of cell signaling research for three decades. SHP2 is required to fully activate the RTK-RAS-ERK cascade, although the underlying mechanisms are not completely understood. , coding for SHP2, is the first identified proto-oncogene that encodes a tyrosine phosphatase, with dominantly activating mutations detected in leukemias and solid tumors.

Empowering personalized oncology: evolution of digital support and visualization tools for molecular tumor boards.

Background: Molecular tumor boards (MTBs) play a pivotal role in personalized oncology, leveraging complex data sets to tailor therapy for cancer patients. The integration of digital support and visualization tools is essential in this rapidly evolving field facing fast-growing data and changing clinical processes. This study addresses the gap in understanding the evolution of software and visualization needs within MTBs and evaluates the current state of digital support.

Comparing Survival of Perihilar Cholangiocarcinoma After R1 Resection Versus Palliative Chemotherapy for Unresected Localized Disease.

Background: Resection of perihilar cholangiocarcinoma (pCCA) is a complex procedure with a high risk of postoperative mortality and early disease recurrence. The objective of this study was to compare patient characteristics and overall survival (OS) between pCCA patients who underwent an R1 resection and patients with localized pCCA who received palliative systemic chemotherapy.

Methods: Patients with a diagnosis of pCCA between 1997-2021 were identified from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) registry.

The WERA cancer center matrix: Strategic management of patient access to precision oncology in a large and mostly rural area of Germany.

Purpose: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center.

Methods: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact.

Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis.

Background: Upregulation of the mitogen-activated protein kinase (MAPK) cascade is common in hepatocellular carcinoma (HCC). Neuroblastoma RAS viral oncogene homolog (NRAS) is mutated in a small percentage of HCC and is hitherto considered insufficient for hepatocarcinogenesis. We aimed to characterize the process of N-Ras-dependent carcinogenesis in the liver and to identify potential therapeutic vulnerabilities.

Identification of CD133 intercellsomes in intercellular communication to offset intracellular signal deficit.

CD133 (prominin 1) is widely viewed as a cancer stem cell marker in association with drug resistance and cancer recurrence. Herein, we report that with impaired RTK-Shp2-Ras-Erk signaling, heterogenous hepatocytes form clusters that manage to divide during mouse liver regeneration. These hepatocytes are characterized by upregulated CD133 while negative for other progenitor cell markers.

Critical evaluation of molecular tumour board outcomes following 2 years of clinical practice in a Comprehensive Cancer Centre.

Background: Recently, molecular tumour boards (MTBs) have been integrated into the clinical routine. Since their benefit remains debated, we assessed MTB outcomes in the Comprehensive Cancer Center Ostbayern (CCCO) from 2019 to 2021.

Methods And Results: In total, 251 patients were included.

Automated breast ultrasound (ABUS) for intraoperative margin control on surgical specimens in breast conserving surgery.

Purpose: As breast-conserving surgery (BCS) has become the standard for treatment of early breast cancer, the need for new technologies to improve intraoperative margin assessment has become clear. Close or positive margins during BCS lead to additional surgeries, treatment delay, additional stress for patients and increasing healthcare cost. Automated three-dimensional breast ultrasound (ABUS) systems are meant to overcome the shortcomings of hand-held ultrasound (HHUS).

Identification of Disparities in Personalized Cancer Care-A Joint Approach of the German WERA Consortium.

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers.

Characteristics and outcome of patients with small bowel adenocarcinoma (SBA).

Background: Small bowel adenocarcinoma (SBA) remains a rare malignancy accounting for less than 5% of all the gastrointestinal tract cancers. However, only limited data and expert guidelines are available for this entity. As a result, treatment concepts are predominantly derived from colorectal cancer.

Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities.

Cholangiocarcinoma (CCA) features a dismal prognosis with limited treatment options. Genomic studies have unveiled several promising targets in this disease, including fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH) mutations. To fully harness the potential of genomically informed therapies in CCA, it is necessary to thoroughly characterize the available model organisms, including cell lines.

Application of A U-Net for Map-like Segmentation and Classification of Discontinuous Fibrosis Distribution in Gd-EOB-DTPA-Enhanced Liver MRI.

We aimed to evaluate whether U-shaped convolutional neuronal networks can be used to segment liver parenchyma and indicate the degree of liver fibrosis/cirrhosis at the voxel level using contrast-enhanced magnetic resonance imaging. This retrospective study included 112 examinations with histologically determined liver fibrosis/cirrhosis grade (Ishak score) as the ground truth. The T1-weighted volume-interpolated breath-hold examination sequences of native, arterial, late arterial, portal venous, and hepatobiliary phases were semi-automatically segmented and co-registered.

Impact of Positive Lymph Nodes and Resection Margin Status on the Overall Survival of Patients with Resected Perihilar Cholangiocarcinoma: The ENSCCA Registry.

Background: Lymph node metastasis and positive resection margins have been reported to be major determinants of overall survival (OS) and poor recurrence-free survival (RFS) for patients who underwent resection for perihilar cholangiocarcinoma (pCCA). However, the prognostic value of positive lymph nodes independently from resection margin status on OS has not been evaluated. Methods: From the European Cholangiocarcinoma (ENSCCA) registry, patients who underwent resection for pCCA between 1994 and 2021 were included in this retrospective cohort study.

Antibodies against viral nucleo-, phospho-, and X protein contribute to serological diagnosis of fatal Borna disease virus 1 infections.

Borna disease virus 1 (BoDV-1) causes rare but often fatal encephalitis in humans. Late diagnosis prohibits an experimental therapeutic approach. Here, we report a recent case of fatal BoDV-1 infection diagnosed on day 12 after hospitalization by detection of BoDV-1 RNA in the cerebrospinal fluid.

Quantification of contrast agent uptake in the hepatobiliary phase helps to differentiate hepatocellular carcinoma grade.

This study aimed to assess the degree of differentiation of hepatocellular carcinoma (HCC) using Gd-EOB-DTPA-assisted magnetic resonance imaging (MRI) with T1 relaxometry. Thirty-three solitary HCC lesions were included in this retrospective study. This study's inclusion criteria were preoperative Gd-EOB-DTPA-assisted MRI of the liver and a histopathological evaluation after hepatic tumor resection.

RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues.

Aberrant activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/mitogen-activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain-containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild-type mice by hydrodynamic tail vein injection combined with sleeping beauty-mediated somatic integration.

Morphology Matters: A Critical Reappraisal of the Clinical Relevance of Morphologic Criteria From the 2019 WHO Classification in a Large Colorectal Cancer Cohort Comprising 1004 Cases.

The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly have an independent impact on patient prognosis. We reclassified a large single-center cohort of 1004 CRCs spanning 2 decades for adjusted WHO grade (low vs.

Identification and In-Depth Analysis of the Novel FGFR2-NDC80 Fusion in a Cholangiocarcinoma Patient: Implication for Therapy.

Fibroblast growth factor receptor 2 (FGFR2) fusions have emerged as a new therapeutic target for cholangiocarcinoma in clinical practice following the United States Food and Drug Administration (FDA) approval of Pemigatinib in May 2020. FGFR2 fusions can result in a ligand-independent constitutive activation of FGFR2 signaling with a downstream activation of multiple pathways, including the mitogen-activated protein (MAPK) cascade. Until today, only a limited number of fusion partners have been reported, of which the most prevalent is BicC Family RNA Binding Protein (BICC1), representing one-third of all detected FGFR2 fusions.

Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation.

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg.

Cellular Dissociation Grading Based on the Parameters Tumor Budding and Cell Nest Size in Pretherapeutic Biopsy Specimens Allows for Prognostic Patient Stratification in Esophageal Squamous Cell Carcinoma Independent From Clinical Staging.

Initial treatment planning in esophageal squamous cell carcinoma mainly relies on clinical staging. Recently, a highly prognostic grading system based on the cellular dissociation parameters Tumor Budding and Cell Nest Size has been proposed for resected esophageal squamous cell carcinoma. To probe for the transferability and relevance of this established novel grading system in the pretreatment setting, we evaluated Tumor Budding/Cell Nest Size in pretherapeutic biopsies of either primarily resected (cohort 1, n=80) or neoadjuvantly treated (cohort 2, n=75) esophageal squamous cell carcinoma.