Delivering on the promise of early detection with liquid biopsies

Liquid biopsy approaches are relatively well developed for cancer therapy monitoring and disease relapse, but they also have incredible potential in the cancer early detection and screening field. There are, however, several challenges to overcome before this potential can be met. Research in this area needs to be cohesive and, as a driver of research, Cancer Research UK is in an ideal position to enable this.

A Comparative Study of Serum Angiogenic Biomarkers in Cirrhosis and Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Its pathogenesis varies according to the underlying etiological factors, although in most cases it develops from liver cirrhosis. The disease progression is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. Aims: This study aims at contributing to our understanding of the role of angiogenic factors in the progression of liver disease. For this purpose, we evaluate the clinical significance of serum angiogenic markers (VEGF, Ang-1, Ang-2, the angiopoietin receptor Tie1/2, HGF, and PECAM-1) first in cirrhotic and HCC patients separately, and then comparing cirrhotic patients with and without HCC. Materials and Methods: We enrolled 62 patients, out of whom 33 were diagnosed with HCC and 29 with liver cirrhosis without signs of neoplasia. Patients underwent venous blood sampling before and after receiving treatments for the diagnosed disease. Serum markers were evaluated using ELISA assays for Tie1 and the Bio-Plex Multiplex system for the remaining ones. Biomarker levels were investigated as a function of clinical scores for disease staging (MELD and Fibrosis Index, FI). Results: In cirrhotic patients, Ang-1 and Ang-2 correlate with MELD (ρAng-1 = −0.73, p = 2E−5) and FI (ρAng-1 = −0.52, p = 7E−3, ρAng-2 = 0.53, p = 3E−3). A reduction of Ang-2 levels (p = 0.047) and of the Ang-2/Ang-1 ratio (p = 0.031) is observed in cirrhotic patients diagnosed with viral hepatitis after antiviral treatments. In HCC patients, Ang-1 negatively correlates with FI (ρ = −0.63, p = 1E−4), and PECAM-1 positively correlates with MELD (ρ = 0.44, p = 0.01). A significant Ang-1 reduction was observed in deceased patients during the study compared to ones who survived (p = 0.01). In HCC patients, VEGF levels were increased after tumor treatment (p = 0.037). Notably, HGF levels in cirrhotic patients with HCC are significantly raised (p = 0.017) compared to that in those without HCC. Conclusions: Our results suggest that serum angiogenic markers, with emphasis on Ang-1/2, can contribute to the development of quantitative tools for liver disease staging and therapy monitoring. The comparison between cirrhotic patients with and without HCC suggests that HGF levels are potentially useful for monitoring the insurgence of HCC after a cirrhosis diagnosis. High Ang-1 levels in HCC patients appear to have a protective role as well as prognostic significance.

The role of leptin in patients recovering from Anorexia Nervosa

Introduction: Anorexia nervosa (AN) is a mental disorder with the highest death rate. The characteristic feature of AN is endocrine dysregulations, including changes in adipose-tissue secreted hormones, especially adipokines. The most widely studied of them is leptin whose role in the pathophysiology and prognosis of AN is confirmed in more and more studies. The aim of the study was to summarize the role of endocrine disruptions with particular emphasis on leptin in the pathophysiology of AN. Material and methods: For the literature review, the electronic databases PubMed, Cochrane and Google Scholar search were used with the following keywords: eating disorders, adipokines, leptin, metreleptin, satiety, hunger, anorexia, obesity, for studies listed from database inception to October 2021. Results: Leptin, produced mainly by white adipose tissue, inhibits the hunger center in the hypothalamus by negative feedback with ghrelin secreted by the gastrointestinal tract. Leptin is involved in numerous biological functions, including body weight regulation, innate and adaptive immunity regulation, reproduction, and bone formation. Studies confirm decreased leptin levels in AN individuals. In recent years, extensive experience has been gained with leptin as a drug in clinical trials. The studies suggested that treatment can restore menstrual function and bone health and improve mood with unclear body weight effects. Conclusions: Focusing on leptin-related changes is a promising approach to improve AN management. Assessment of leptin levels in AN patients could be a useful tool for therapy monitoring. Treatment with leptin could reverse unfavourable changes induced by diet restriction, including mood symptoms, loss of bone mass and menstrual function. However, the results of these studies need confirmation on larger groups of patients.

On Demand Biosensors for Early Diagnosis of Cancer and Immune Checkpoints Blockade Therapy Monitoring from Liquid Biopsy

Recently, considerable interest has emerged in the development of biosensors to detect biomarkers and immune checkpoints to identify and measure cancer through liquid biopsies. The detection of cancer biomarkers from a small volume of blood is relatively fast compared to the gold standard of tissue biopsies. Traditional immuno-histochemistry (IHC) requires tissue samples obtained using invasive procedures and specific expertise as well as sophisticated instruments. Furthermore, the turnaround for IHC assays is usually several days. To overcome these challenges, on-demand biosensor-based assays were developed to provide more immediate prognostic information for clinicians. Novel rapid, highly precise, and sensitive approaches have been under investigation using physical and biochemical methods to sense biomarkers. Additionally, interest in understanding immune checkpoints has facilitated the rapid detection of cancer prognosis from liquid biopsies. Typically, these devices combine various classes of detectors with digital outputs for the measurement of soluble cancer or immune checkpoint (IC) markers from liquid biopsy samples. These sensor devices have two key advantages: (a) a small volume of blood drawn from the patient is sufficient for analysis, and (b) it could aid physicians in quickly selecting and deciding the appropriate therapy regime for the patients (e.g., immune checkpoint blockade (ICB) therapy). In this review, we will provide updates on potential cancer markers, various biosensors in cancer diagnosis, and the corresponding limits of detection, while focusing on biosensor development for IC marker detection.

Is miRNA Regulation the Key to Controlling Non-Melanoma Skin Cancer Evolution?

Non melanoma skin cancer (NMSC) is one of the most common types of skin cancer. It has a number of subtypes, which include basal cell carcinoma, cutaneous squamous cell carcinoma and Merkel cell carcinoma. MicroRNAs are short, non-coding RNA (ribonucleic acid) molecules, capable of regulating gene expression at a post transcriptional level. They play a pivotal role in a variety of physiologic cellular functions and pathologies, including malignant diseases. The development of miRNAs represents an important study field, which has been extensively exploited in melanoma for almost a decade with promising results, therefore we consider it a stepstone for further research projects also in non-melanoma skin cancers. The aim of our study was to explore the current literature in order to present the role of the different miRNAs in some of the most frequent types of NMSC pertaining to oncogenesis, evolution and therapy. The most relevant and accurate available data from the literature were evaluated. Our study concluded that there are almost 100 miRNAs which can be upregulated or downregulated and can play a role in oncogenesis. They can be easily identified in circulation, are stable and they can be important diagnosis/prognosis and therapy monitoring markers.

Cell-Free DNA Variant Sequencing Using Plasma and AR-V7 Testing of Circulating Tumor Cells in Prostate Cancer Patients

Prostate cancer (PCa) is the second most common malignant cancer and is a major cause of morbidity and mortality among men worldwide. There is still an urgent need for biomarkers applicable for diagnosis, prognosis, therapy prediction, or therapy monitoring in PCa. Liquid biopsies, including cell-free DNA (cfDNA) and circulating tumor cells (CTCs), are a valuable source for studying such biomarkers and are minimally invasive. In our study, we investigated the cfDNA of 34 progressive PCa patients, via targeted sequencing, for sequence variants and for the occurrence of CTCs, with a focus on androgen receptor splice variant 7 (AR-V7)-positive CTCs. The cfDNA content was associated with overall survival (OS; p = 0.014), disease-specific survival (DSS; p = 0.004), and time to treatment change (TTC; p = 0.001). Moreover, when considering all sequence variants grouped by their functional impact and allele frequency, a significant association with TTC (p = 0.017) was observed. When investigating only pathogenic or likely pathogenic gene variants, variants of the BRCA1 gene (p = 0.029) and the AR ligand-binding domain (p = 0.050) were associated with a shorter TTC. Likewise, the presence of CTCs was associated with a shorter TTC (p = 0.031). The presence of AR-V7-positive CTCs was associated with TTC (p < 0.001) in Kaplan–Meier analysis. Interestingly, all patients with AR-V7-positive CTCs also carried TP53 point mutations. Altogether, analysis of cfDNA and CTCs can provide complementary information that may support temporal and targeted treatment decisions and may elucidate the optimal choice within the variety of therapy options for advanced PCa patients.

A Neuromorphic Spiking Neural Network Detects Epileptic High Frequency Oscillations in the Scalp EEG

Background: Interictal High Frequency Oscillations (HFO) are measurable in scalp EEG. This has aroused interest in investigating their potential as biomarkers of epileptogenesis, seizure propensity, disease severity, and treatment response. The demand for therapy monitoring in epilepsy has kindled interest in compact wearable electronic devices for long- term EEG recording. Spiking neural networks (SNN) have been shown to be optimal architectures for being embedded in compact low-power signal processing hardware. Methods: We analyzed 20 scalp EEG recordings from 11 patients with pediatric focal lesional epilepsy. We designed a custom SNN to detect events of interest (EoI) in the 80-250 Hz ripple band and reject artifacts in the 500-900 Hz band. Results: We identified the optimal SNN parameters to automatically detect EoI and reject artifacts. The occurrence of HFO thus detected was associated with active epilepsy with 80% accuracy. The HFO rate mirrored the decrease in seizure frequency in 8 patients (p = 0.0047). Overall, the HFO rate correlated with seizure frequency (rho = 0.83, p < 0.0001, Spearman’s correlation).Conclusions: The fully automated SNN detected clinically relevant HFO in the scalp EEG. This is a further step towards non-invasive epilepsy monitoring with a low-power wearable device.

Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression

Multiple myeloma (MM) progression closely depends on the bidirectional crosstalk between tumor cells and the surrounding microenvironment, which leads to the creation of a tumor supportive niche. Extracellular vesicles (EVs) have emerged as key players in the pathological interplay between the malignant clone and near/distal bone marrow (BM) cells through their biologically active cargo. Here, we describe the role of EVs derived from MM and BM cells in reprogramming the tumor microenvironment and in fostering bone disease, angiogenesis, immunosuppression, drug resistance, and, ultimately, tumor progression. We also examine the emerging role of EVs as new therapeutic agents for the treatment of MM, and their potential use as clinical biomarkers for early diagnosis, disease classification, and therapy monitoring.

Novel Biomarkers of Gastric Adenocarcinoma: Current Research and Future Perspectives

Overall survival of gastric cancer remains low, as patients are often diagnosed with advanced stage disease. In this review, we give an overview of current research on biomarkers in gastric cancer and their implementation in treatment strategies. The HER2-targeting trastuzumab is the first molecular targeted agent approved for gastric cancer treatment. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are VEGF and Claudin 18.2. Expression of MET has been shown to be a negative prognostic factor in gastric cancer. Targeting the PD-1/PD-L1 pathway with immune checkpoint inhibitors has proven efficacy in advanced gastric cancer. Recent technology advances allow the detection of circulating tumor cells that may be used as diagnostic and prognostic indicators and for therapy monitoring in gastric cancer patients. Prognostic molecular subtypes of gastric cancer have been identified using genomic data. In addition, transcriptome profiling has allowed a comprehensive characterization of the immune and stromal microenvironment in gastric cancer and development of novel risk scores. These prognostic and predictive markers highlight the rapidly evolving field of research in gastric cancer, promising improved treatment stratification and identification of molecular targets for individualized treatment in gastric cancer.