The importance of preclinical models for cholangiocarcinoma drug discovery.

Introduction: Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches.

Areas Covered: The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens.

B-CLL with negative F-FDG PET/CT and intensive solitary lesion on PSMA PET/CT mimicking prostate cancer bone metastases.

Positron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-radioligands is currently suggested by several clinical guidelines for the assessment of prostate cancer (PCa) in various clinical settings. However, PSMA will also be overexpressed in different cancers, which should be considered on the PSMA PET/CT reading in patients with concomitant neoplastic diseases. We report a case of 82-year-old male presented with prostate and history of oesophageal cancer and B-cell chronic lymphocytic leukemia (B-CLL).

Prognostic and functional role of the nuclear export receptor 1 (XPO1) in gastrointestinal cancers: a potential novel target?

In the last decades the survival of metastatic gastrointestinal (GI) cancer patients could have been significantly extended due to the introduction of targeted- and immunotherapy. However, only the minority of patients will experience long-lasting survival. Hence, novel therapeutics are clearly necessary for GI cancer patients.

The Cdk inhibitor dinaciclib as a promising anti-tumorigenic agent in biliary tract cancer.

Biliary tract cancer (BTC) is a rare malignancy with rising incidence. The therapeutic options are limited and the overall survival remains poor. Cyclin-dependent kinases, drivers of cell cycle and transcription have numerous biological functions and are known to be dysregulated in numerous tumor entities.

ADP-heptose attenuates -induced dendritic cell activation.

Sophisticated immune evasion strategies enable to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between and host immunity, spatial profiling was used to monitor immune cells in infected gastric tissue.

HtrA-Dependent E-Cadherin Shedding Impairs the Epithelial Barrier Function in Primary Gastric Epithelial Cells and Gastric Organoids.

Impaired E-cadherin (Cdh1) functions are closely associated with cellular dedifferentiation, infiltrative tumor growth and metastasis, particularly in gastric cancer. The class-I carcinogen () colonizes gastric epithelial cells and induces Cdh1 shedding, which is primarily mediated by the secreted bacterial protease high temperature requirement A (HtrA). In this study, we used human primary epithelial cell lines derived from gastroids and mucosoids from different healthy donors to investigate HtrA-mediated Cdh1 cleavage and the subsequent impact on bacterial pathogenesis in a non-neoplastic context.

NLRP3 promotes allergic responses to birch pollen extract in a model of intranasal sensitization.

Introduction & Objective: Allergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest.

The Interplay between Perioperative Oxidative Stress and Hepatic Dysfunction after Human Liver Resection: A Prospective Observational Pilot Study.

Post-hepatectomy liver failure (PHLF) remains the major contributor to death after liver resection. Oxidative stress is associated with postoperative complications, but its impact on liver function is unclear. This first in-human, prospective, single-center, observational pilot study evaluated perioperative oxidative stress and PHLF according to the ISGLS (International Study Group for Liver Surgery).

New insights into possible HDAC inhibitor resistance in DLBCL - Comment on 'defining cellular responses to HDAC-selective inhibitors reveals that efficient targeting of HDAC3 is required to elicit cytotoxicity and overcome naïve resistance to pan-HDACi in diffuse large B cell lymphoma' by Havas et al.

• This editorial provides a brief overview of the role of HDACs in diffuse large B-cell lymphoma (DLBCL). • Possible mechanisms of HDAC inhibitor resistance in DLBCL are discussed in detail. • It highlights the need for developing HDAC isoform-specific inhibitors.

The efficacy of ferroptosis-inducing compounds IKE and RSL3 correlates with the expression of ferroptotic pathway regulators CD71 and SLC7A11 in biliary tract cancer cells.

Introduction: Biliary tract cancer (BTC) is a lethal disease with a bad overall survivability, partly arising from inadequate therapeutic alternatives, detection at a belated stage, and a resistance to common therapeutic approaches. Ferroptosis is a form of programmed cell death that depends on reactive oxygen species (ROS) and iron, causing excessive peroxidation of polyunsaturated fatty acids (PUFAs). Therefore, the objective of this investigation is, whether ferroptosis can be induced in BTC in vitro and whether this induction is dependent on specific molecular markers.

Image-based consensus molecular subtyping in rectal cancer biopsies and response to neoadjuvant chemoradiotherapy.

The development of deep learning (DL) models to predict the consensus molecular subtypes (CMS) from histopathology images (imCMS) is a promising and cost-effective strategy to support patient stratification. Here, we investigate whether imCMS calls generated from whole slide histopathology images (WSIs) of rectal cancer (RC) pre-treatment biopsies are associated with pathological complete response (pCR) to neoadjuvant long course chemoradiotherapy (LCRT) with single agent fluoropyrimidine. DL models were trained to classify WSIs of colorectal cancers stained with hematoxylin and eosin into one of the four CMS classes using a multi-centric dataset of resection and biopsy specimens (n = 1057 WSIs) with paired transcriptional data.

Oncogenic MTOR Signaling Axis Compensates BTK Inhibition in a Chronic Lymphocytic Leukemia Patient with Richter Transformation: A Case Report and Review of the Literature.

Introduction: Targeting the B-cell receptor pathway via ibrutinib, a specific inhibitor of Bruton's tyrosine kinase, has shown marked clinical efficacy in treatment of patients with chronic lymphocytic leukemia (CLL), thus becoming a preferred first line option independent of risk factors. However, acquired resistance to ibrutinib poses a major clinical problem and requires the development of novel treatment combinations to increase efficacy and counteract resistance development and clinical relapse rates.

Case Presentation: In this study, we performed exome and transcriptome analyses of an ibrutinib resistant CLL patient in order to investigate genes and expression patterns associated with ibrutinib resistance.

Enhancing anti-CD274 (PD-L1) targeting through combinatorial immunotherapy with bispecific antibodies and fusion proteins: from preclinical to phase II clinical trials.

Introduction: Immune checkpoint inhibitors have achieved great success in the treatment of many different types of cancer. Programmed cell death protein ligand 1 (PD-L1, CD274) is a major immunosuppressive immune checkpoint and a target for several already approved monoclonal antibodies. Despite this, novel strategies are under development, as the overall response remains low.

Gene expression inhibitors for the treatment of liver fibrosis: drugs under preclinical and early clinical investigation.

Introduction: Liver fibrosis represents an unmet medical condition with growing incidence and only limited therapeutic options. Interfering with dysregulated gene expression was considered a specific treatment approach, and we are here reviewing the current options to modulate transcription and translation with small molecule inhibitors of involved enzymes, transcription factors or by using non-coding RNA molecules (RNA interference) or DNA antisense oligonucleotides. Despite promising results in preclinical models, only limited data are available from studies in humans.

Management of metastatic colorectal cancer in patients ≥70 years - a single center experience.

Background: Age-standardized mortality rates for metastatic colorectal cancer (mCRC) are highest among elderly patients. In current clinical guidelines, treatment recommendations for this patient population are based on a limited number of clinical trials.

Patients And Methods: In this monocentric, retrospective analysis we characterized patients aged ≥70 years undergoing systemic therapy for mCRC and overall survival (OS) was investigated.

Ouabain at nanomolar concentrations is cytotoxic for biliary tract cancer cells.

Biliary tract cancer is a deadly disease with limited therapeutic options. Ouabain is a well-known inhibitor of the pumping function of Na+/K+-ATPase, though there is evidence that low concentrations of ouabain lead to a reduction of cell viability of cancer cells independent of its inhibition of the pumping function of the Na+/K+-ATPase. Regarding the impact of ouabain on biliary tract cancer, no data is currently available.

The SAlzburg PEritoneal SUrface CAlculator (SAPESUCA): The First Web-Based Application for Peritoneal Surface Area Quantification.

(1) Background: Peritoneal metastasized colorectal cancer is associated with a worse prognosis. The combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) showed promising results in selected patients, but standardization is lacking so far. We present the first tool enabling standardized peritoneal surface area (PSA) quantification in patients undergoing CRS and HIPEC: The SAlzburg PEritoneal SUrface CAlculator (SAPESUCA).

Evaluation of Tazemetostat as a Therapeutically Relevant Substance in Biliary Tract Cancer.

Biliary tract cancer (BTC) is a gastrointestinal malignancy associated with a poor survival rate. Current therapies encompass palliative and chemotherapeutic treatment as well as radiation therapy, which results in a median survival of only one year due to standard therapeutic ineffectiveness or resistance. Tazemetostat is an FDA-approved inhibitor of enhancer of Zeste homolog 2 (EZH2), a methyltransferase involved in BTC tumorigenesis via trimethylation of histone 3 at lysine 27 (H3K27me3), an epigenetic mark associated with silencing of tumor suppressor genes.

HDACs as an emerging target in endocrine tumors: a comprehensive review.

Introduction: The pathogenic role of deregulated histone (de-)acetylation by histone deacetyles (HDACs) has been demonstrated in several human cancers. While some HDAC inhibitors (HDACi) have been approved for individual entities, for endocrine tumors such translation into clinical practice has not yet been achieved.

Areas Covered: Relevant results identified by structured searches in PubMed as well as in reference lists are summarized in a narrative review to discuss the current knowledge of HDAC involvement and their therapeutic relevance in endocrine tumors.