Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma.

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Battle of the biopsies: Role of tissue and liquid biopsy in hepatocellular carcinoma.

The diagnosis and management of hepatocellular carcinoma (HCC) have improved significantly in recent years. With the introduction of immunotherapy-based combination therapy, there has been a notable expansion in treatment options for patients with unresectable HCC. Simultaneously, innovative molecular tests for early detection and management of HCC are emerging. This progress prompts a key question: as liquid biopsy techniques rise in prominence, will they replace traditional tissue biopsies, or will both techniques remain relevant? Given the ongoing challenges of early HCC detection, including issues with ultrasound sensitivity, accessibility, and patient adherence to surveillance, the evolution of diagnostic techniques is more relevant than ever. Furthermore, the accurate stratification of HCC is limited by the absence of reliable biomarkers which can predict response to therapies. While the advantages of molecular diagnostics are evident, their potential has not yet been fully harnessed, largely because tissue biopsies are not routinely performed for HCC. Liquid biopsies, analysing components such as circulating tumour cells, DNA, and extracellular vesicles, provide a promising alternative, though they are still associated with challenges related to sensitivity, cost, and accessibility. The early results from multi-analyte liquid biopsy panels are promising and suggest they could play a transformative role in HCC detection and management; however, comprehensive clinical validation is still ongoing. In this review, we explore the challenges and potential of both tissue and liquid biopsy, highlighting that these diagnostic methods, while distinct in their approaches, are set to jointly reshape the future of HCC management.

Pilot Study by Liquid Biopsy in Gastrointestinal Stromal Tumors: Analysis of PDGFRA D842V Mutation and Hypermethylation of SEPT9 Presence by Digital Droplet PCR.

Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential for early diagnosis via liquid biopsy, focusing on the PDGFRA D842V mutation and SEPT9 hypermethylated gene. We utilized ddPCR to analyze the predominant PDGFRA mutation (D842V) in surgical tissue samples from 15 GIST patients, correlating with pathologists' diagnoses. We expanded our analysis to plasma samples to compare DNA alterations between tumor tissue and plasma, also investigating SEPT9 gene hypermethylation. We successfully detected the PDGFRA D842V mutation in GIST tissues by ddPCR. Despite various protocols to enhance mutation detection in early-stage disease, it remained challenging, likely due to the low concentration of DNA in plasma samples. Additionally, the results of Area Under the Curve (AUC) for the hypermethylated SEPT9 gene, analyzing concentration, ratio, and abundance were 0.74 (95% Confidence Interval (CI): 0.52 to 0.97), 0.77 (95% CI: 0.56 to 0.98), and 0.79 (95% CI: 0.59 to 0.99), respectively. As a rare disease, the early detection of GIST through such biomarkers is particularly crucial, offering significant potential to improve patient outcomes.

Cell-Molecular Interactions of Nano- and Microparticles in Dental Implantology.

The role of metallic nano- and microparticles in the development of inflammation has not yet been investigated. Soft tissue biopsy specimens of the bone bed taken during surgical revisions, as well as supernatants obtained from the surface of the orthopedic structures and dental implants (control), were examined. Investigations were performed using X-ray microtomography, X-ray fluorescence analysis, and scanning electron microscopy. Histological studies of the bone bed tissues were performed. Nanoscale and microscale metallic particles were identified as participants in the inflammatory process in tissues. Supernatants containing nanoscale particles were obtained from the surfaces of 20 units of new dental implants. Early and late apoptosis and necrosis of immunocompetent cells after co-culture and induction by lipopolysaccharide and human venous blood serum were studied in an experiment with staging on the THP-1 (human monocytic) cell line using visualizing cytometry. As a result, it was found that nano- and microparticles emitted from the surface of the oxide layer of medical devices impregnated soft tissue biopsy specimens. By using different methods to analyze the cell-molecule interactions of nano- and microparticles both from a clinical perspective and an experimental research perspective, the possibility of forming a chronic immunopathological endogenous inflammatory process with an autoimmune component in the tissues was revealed.

Role of noncoding RNAs in pancreatic ductal adenocarcinoma associated cachexia.

Cachexia is an acute syndrome that is very commonly observed in patients with cancer. Cachexia is the number one cause of death in patients with metastatic disease and is also the major factor for physical toxicity and financial burden. More importantly, the majority of patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) cancer undergo cachexia. Pancreatic cancer causes deaths of ∼50,000 Americans and about 400,000 people worldwide every year. The high mortality rates in metastatic PDAC are due to systemic pathologies and cachexia, which quickens death in these patients. About 90% of all patients with PDAC undergo wasting of muscle causing mobility loss and leading to a number of additional pathological conditions. PDAC-associated cancer cachexia emanates from complex signaling cues involving both mechanical and biological signals. Tumor invasion is associated with the loss of pancreatic function-induced digestive disorders and malabsorption, which causes subsequent weight loss and eventually promotes cachexia. Besides, systemic inflammation of patients with PDAC could release chemical cues (e.g., cytokine-mediated Atrogin-1/MAFbx expression) that participate in muscle wasting. Our understanding of genes, proteins, and cytokines involved in promoting cancer cachexia has evolved considerably. However, the role of epigenetic factors, particularly the role of noncoding RNAs (ncRNAs) in regulating PDAC-associated cachexia is less studied. In this review article, the most updated knowledge on the various ncRNAs including microRNAs (miRs), long noncoding RNA (lncRNAs), piwi interacting RNAs (PiwiRNAs), small nucleolar RNA (snoRNAs), and circular RNAs (circRNA) and their roles in cancer cachexia are described.

Plasma Cell-Free DNA Genotyping: From an Emerging Concept to a Standard-of-Care Tool in Metastatic Non-Small Cell Lung Cancer.

Plasma cell-free DNA (cfDNA) genotyping is an alternative to tissue genotyping, particularly when tissue specimens are insufficient or unavailable, and provides critical information that can be used to guide treatment decisions in managing patients with non-small cell lung cancer (NSCLC). In this article, we review the evolution of plasma cfDNA genotyping from an emerging concept, through development of analytical methods, to its clinical applications as a standard-of-care tool in NSCLC. The number of driver or resistance mutations recommended for testing in NSCLC continues to increase. Because of the expanding list of therapeutically relevant variants, comprehensive testing to investigate larger regions of multiple genes in a single run is often preferable and saves on time and cost, compared with performing serial single-gene assays. Recent advances in nucleic acid next-generation sequencing have led to a rapid expansion in cfDNA genotyping technologies. Analytic assays that have received regulatory approval are now routinely used as diagnostic companions in the setting of metastatic NSCLC. As the demand for plasma-based technologies increases, more regulatory approvals of cfDNA genotyping assays are expected in the future. Plasma cfDNA genotyping is currently aiding oncologists in the delivery of personalized care by facilitating matching of patients with targeted therapy and monitoring emergence of resistance to therapy in NSCLC. Further advances currently underway to increase assay sensitivity and specificity will potentially expand the use of plasma cfDNA genotyping in early cancer detection, monitoring response to therapy, detection of minimal residual disease, and measurement of tumor mutational burden in NSCLC. IMPLICATIONS FOR PRACTICE: Plasma cell-free DNA (cfDNA) genotyping offers an alternative to tissue genotyping, particularly when tissue specimens are insufficient or unavailable. Advances in cfDNA genotyping technologies have led to analytic assays that are now routinely used to aid oncologists in the delivery of personalized care by facilitating matching of patients with targeted therapy and monitoring emergence of resistance to therapy. Further advances underway to increase assay sensitivity and specificity will potentially expand the use of plasma cfDNA genotyping in early cancer detection, monitoring response to therapy, detection of minimal residual disease, and evaluation of tumor mutational burden in non-small cell lung cancer.

[Bone and soft tissue tumours in children : Proposal for a rational diagnostic approach]. / Knochen- und Weichteiltumoren im Kindesalter : Vorschlag für ein rational-diagnostisches Vorgehen.

CLINICAL/METHODOLOGICAL ISSUE: Bone and soft tissue tumours are often incidental findings in children. Because they are usually benign tumours, nonspecialised radiologists generally have little experience in the diagnosis and differentiation from malignant tumours. Various imaging techniques are used in the diagnosis of skeletal tumours. STANDARD RADIOLOGICAL METHODS: Imaging techniques used to evaluate bone and soft tissue tumours include sonography, computed tomography (CT) and magnetic resonance imaging (MRI). METHODOLOGICAL INNOVATIONS: An algorithm to determine malignancy of bone and soft tissue tumours in children is proposed. PERFORMANCE: By using the presented algorithms, further diagnostic procedures such as biopsies can be avoided in the majority of children with bone and soft tissue tumours. Aggressive bone lesions and unclear soft tissue tumours are guided to biopsy to confirm diagnosis. ACHIEVEMENTS: The algorithms presented are based on the proposals of European professional societies and have been adapted by the authors for use in children and adolescents. PRACTICAL RECOMMENDATIONS: In the clarification of soft tissue tumours, sonography is the first diagnostic tool; depending on the sonographic findings, MRI is the technique for further clarification. Biopsy confirmation of the diagnosis in unclear cases or in cases of probable malignancy should be carried out in a paediatric oncology centre.

Squamous cell carcinoma arising from an ischial pressure ulcer initially suspected to be necrotizing soft tissue infection: A case report.

BACKGROUND: Pressure ulcers are the most common complications in bedridden patients or those with spinal cord injuries. Marjolin's ulcer refers to a malignant transformation arising from burn scars or chronic nonhealing wounds-such as pressure ulcers-over many years. Squamous cell carcinoma is the major histopathologic type of Marjolin's ulcer, and the gold standard for diagnosis is tissue biopsy. Medical professionals may have difficulty distinguishing pressure ulcers from Marjolin's ulcer, especially when the latter presents with invasive infections. Thus, malignant transformations arising from pressure ulcers are frequently overlooked. Herein, we describe a case of squamous cell carcinoma arising from pressure ulcers on the left ischium, which was initially identified as a necrotizing soft tissue infection. CASE REPORT: A 59-year-old paraplegic patient presented with stage 3 left ischial pressure ulcer, which involves full-thickness skin loss and extends into deep subcutaneous tissue, and arrived at our hospital with suspected sepsis. Upon physical examination, the patient presented with fever and shivering. Initial examination and imaging findings revealed the presence of necrotizing soft tissue infections. Three weeks later, rapid increase in granulation in the deep part of the ulcer was observed. Samples from multiples ulcer sites were collected for tissue biopsy. Finally, histological examination revealed well-differentiated squamous cell carcinoma. The patient received radiation therapy and chemotherapy and died 11 months after the diagnosis. CONCLUSION: Malignant transformations arising from pressure ulcers may closely resemble pressure ulcer infections. In these cases, tissue biopsies should be performed during primary care for the infection to exclude malignant transformations.

Whole-Body Characterization of Estrogen Receptor Status in Metastatic Breast Cancer with 16α-18F-Fluoro-17ß-Estradiol Positron Emission Tomography: Meta-Analysis and Recommendations for Integration into Clinical Applications.

Estrogen receptor (ER) status by immunohistochemistry (IHC) of cancer tissue is currently used to direct endocrine therapy in breast cancer. Positron emission tomography (PET) with 16α-18F-fluoro-17ß-estradiol (18 F-FES) noninvasively characterizes ER ligand-binding function of breast cancer lesions. Concordance of imaging and tissue assays should be established for 18 F-FES PET to be an alternative or complement to tissue biopsy for metastatic lesions. We conducted a meta-analysis of published results comparing 18 F-FES PET and tissue assays of ER status in patients with breast cancer. PubMed and EMBASE were searched for English-language manuscripts with at least 10 patients and low overall risk of bias. Thresholds for imaging and tissue classification could differ between studies but had to be clearly stated. We used hierarchical summary receiver-operating characteristic curve models for the meta-analysis. The primary analysis included 113 nonbreast lesions from 4 studies; an expanded analysis included 327 total lesions from 11 studies. Treating IHC results as the reference standard, sensitivity was 0.78 (95% confidence region 0.65-0.88) and specificity 0.98 (0.65-1.00) for the primary analysis of nonbreast lesions. In the expanded analysis including non-IHC tissue assays and all lesion sites, sensitivity was 0.81 (0.73-0.87) and specificity 0.86 (0.68-0.94). These results suggest that 18 F-FES PET is useful for characterization of ER status of metastatic breast cancer lesions. We also review current best practices for conducting 18 F-FES PET scans. This imaging assay has potential to improve clinically relevant outcomes for patients with (historically) ER-positive metastatic breast cancer, including those with brain metastases and/or lobular histology. IMPLICATIONS FOR PRACTICE: 16α-18F-fluoro-17ß-estradiol positron emission tomography (18 F-FES PET) imaging assesses estrogen receptor status in breast cancer in vivo. This work reviews the sensitivity and specificity of 18 F-FES PET in a meta-analysis with reference tissue assays and discusses best practices for use of the tracer as an imaging biomarker. 18 F-FES PET could enhance breast cancer diagnosis and staging as well as aid in therapy selection for patients with metastatic disease. Tissue sampling limitations, intrapatient heterogeneity, and temporal changes in molecular markers make it likely that 18 F-FES PET will complement existing assays when clinically available in the near future.

Evaluation of the guaiac fecal occult blood test for detection of gastrointestinal bleeding in the rhesus macaque (Macaca mulatta).

BACKGROUND: Gastrointestinal (GI) hemorrhage accompanies several common diseases of rhesus macaques (Macaca mulatta). Guaiac fecal occult blood testing (gFOBT) is a non-invasive means to detect such bleeding in several species; however, there are currently no data indicating reliability of this test to detect GI hemorrhage in macaques. METHODS: We evaluated sensitivity and specificity of gFOBT to detect simulated and biopsy-associated bleeding in the stomach, duodenum, and colon of 15 rhesus macaques. Fecal samples were analyzed via gFOBT for 72 hours. RESULTS: Guaiac fecal occult blood testing was more sensitive to detect lower vs upper GI bleeding; sensitivity was volume-dependent in the upper GI tract. Single-test specificity was 95.2%. Repeated fecal collections increased gFOBT sensitivity without affecting specificity. CONCLUSIONS: Guaiac fecal occult blood testing is a useful screening test for both upper and lower GI bleeding in rhesus macaques. For highest sensitivity, gFOBT should be performed on three fecal samples collected 24 hours apart.