2,633 research outputs found
Epigenetic regulation of somatostatin receptors in neuroendocrine tumors:A Novel Therapeutic Approach?
The overexpression of somatostatin type-2 receptors (SSTR2) on neuroendocrine tumor (NET) cells forms a pivotal biomarker for theranostic approaches. Radiolabeled somatostatin analogues (SSAs), most frequently [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE for nuclear imaging and therapy, respectively, have shown to be of great importance for NET disease management. [177Lu]Lu-DOTATATE treatment, known as peptide receptor radionuclide therapy (PRRT), is EMA and FDA approved for unresectable or metastatic, progressive, well-differentiated SSTR2-positive gastroenteropancreatic NET patients. However, complete responses after therapy are rare and progressive disease is often observed. Approaches to further improve PRRT efficacy are thus of great need. The aim of the studies described in this thesis is to upregulate SSTR2 on NET cells by modulating the epigenetic machinery, in order to increase radiolabeled SSA uptake and ultimately improve treatment response. Furthermore, we aimed to gain more insights into the interaction between epigenetic marks and the regulation of SSTR2 expression. Our studies were performed preclinically using different NET cell lines. In addition to in vitro studies with these cell lines, mice with tumors derived from these cell lines and NET patient tissue samples were used. Furthermore, the effect of epigenetic drugs on the uptake of [68Ga]Ga-DOTATATE was investigated in NET patients
Epigenetic regulation of somatostatin receptors in neuroendocrine tumors:A Novel Therapeutic Approach?
The overexpression of somatostatin type-2 receptors (SSTR2) on neuroendocrine tumor (NET) cells forms a pivotal biomarker for theranostic approaches. Radiolabeled somatostatin analogues (SSAs), most frequently [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE for nuclear imaging and therapy, respectively, have shown to be of great importance for NET disease management. [177Lu]Lu-DOTATATE treatment, known as peptide receptor radionuclide therapy (PRRT), is EMA and FDA approved for unresectable or metastatic, progressive, well-differentiated SSTR2-positive gastroenteropancreatic NET patients. However, complete responses after therapy are rare and progressive disease is often observed. Approaches to further improve PRRT efficacy are thus of great need. The aim of the studies described in this thesis is to upregulate SSTR2 on NET cells by modulating the epigenetic machinery, in order to increase radiolabeled SSA uptake and ultimately improve treatment response. Furthermore, we aimed to gain more insights into the interaction between epigenetic marks and the regulation of SSTR2 expression. Our studies were performed preclinically using different NET cell lines. In addition to in vitro studies with these cell lines, mice with tumors derived from these cell lines and NET patient tissue samples were used. Furthermore, the effect of epigenetic drugs on the uptake of [68Ga]Ga-DOTATATE was investigated in NET patients
Raman Spectroscopy Techniques for the Detection and Management of Breast Cancer
Breast cancer has recently become the most common cancer worldwide, and with increased incidence, there is increased pressure on health services to diagnose and treat many more patients. Mortality and survival rates for this particular disease are better than other cancer types, and part of this is due to the facilitation of early diagnosis provided by screening programmes, including the National Health Service breast screening programme in the UK. Despite the benefits of the programme, some patients undergo negative experiences in the form of false negative mammograms, overdiagnosis and subsequent overtreatment, and even a small number of cancers are induced by the use of ionising radiation. In addition to this, false positive mammograms cause a large number of unnecessary biopsies, which means significant costs, both financially and in terms of clinicians' time, and discourages patients from attending further screening. Improvement in areas of the treatment pathway is also needed. Surgery is usually the first line of treatment for early breast cancer, with breast conserving surgery being the preferred option compared to mastectomy. This type of operation achieves the same outcome as mastectomy - removal of the tumour - while allowing the patient to retain the majority of their normal breast tissue for improved aesthetic and psychological results. Yet, re-excision operations are often required when clear margins are not achieved, i.e. not all of the tumour is removed. This again has implications on cost and time, and increases the risk to the patient through additional surgery.
Currently lacking in both the screening and surgical contexts is the ability to discern specific chemicals present in the breast tissue being assessed/removed. Specifically relevant to mammography is the presence of calcifications, the chemistry of which holds information indicative of pathology that cannot be accessed through x-rays. In addition, the chemical composition of breast tumour tissue has been shown to be different to normal tissue in a variety of ways, with one particular difference being a significant increase in water content. Raman spectroscopy is a rapid, non-ionising, non-destructive technique based on light scattering. It has been proven to discern between chemical types of calcification and subtleties within their spectra that indicate the malignancy status of the surrounding tissue, and differentiate between cancerous and normal breast tissue based on the relative water contents.
Furthermore, this thesis presents work aimed at exploring deep Raman techniques to probe breast calcifications at depth within tissue, and using a high wavenumber Raman probe to discriminate tumour from normal tissue predominantly via changes in tissue water content. The ability of transmission Raman spectroscopy to detect different masses and distributions of calcified powder inclusions within tissue phantoms was tested, as well as elucidating a signal profile of a similar inclusion through a tissue phantom of clinically relevant thickness. The technique was then applied to the measurement of clinically active samples of bulk breast tissue from informed and consented patients to try to measure calcifications. Ex vivo specimens were also measured with a high wavenumber Raman probe, which found significant differences between tumour and normal tissue, largely due to water content, resulting in a classification model that achieved 77.1% sensitivity and 90.8% specificity. While calcifications were harder to detect in the ex vivo specimens, promising results were still achieved, potentially indicating a much more widespread influence of calcification in breast tissue, and to obtain useful signal from bulk human tissue is encouraging in itself. Consequently, this work demonstrates the potential value of both deep Raman techniques and high wavenumber Raman for future breast screening and tumour margin assessment methods
Social network analysis of cell networks improves deep learning for prediction of molecular pathways and key mutations in colorectal cancer
Colorectal cancer (CRC) is a primary global health concern, and identifying the molecular pathways, genetic subtypes, and mutations associated with CRC is crucial for precision medicine. However, traditional measurement techniques such as gene sequencing are costly and time-consuming, while most deep learning methods proposed for this task lack interpretability. This study offers a new approach to enhance the state-of-the-art deep learning methods for molecular pathways and key mutation prediction by incorporating cell network information. We build cell graphs with nuclei as nodes and nuclei connections as edges of the network and leverage Social Network Analysis (SNA) measures to extract abstract, perceivable, and interpretable features that explicitly describe the cell network characteristics in an image. Our approach does not rely on precise nuclei segmentation or feature extraction, is computationally efficient, and is easily scalable. In this study, we utilize the TCGA-CRC-DX dataset, comprising 499 patients and 502 diagnostic slides from primary colorectal tumours, sourced from 36 distinct medical centres in the United States. By incorporating the SNA features alongside deep features in two multiple instance learning frameworks, we demonstrate improved performance for chromosomal instability (CIN), hypermutated tumour (HM), TP53 gene, BRAF gene, and Microsatellite instability (MSI) status prediction tasks (2.4%–4% and 7–8.8% improvement in AUROC and AUPRC on average). Additionally, our method achieves outstanding performance on MSI prediction in an external PAIP dataset (99% AUROC and 98% AUPRC), demonstrating its generalizability. Our findings highlight the discrimination power of SNA features and how they can be beneficial to deep learning models’ performance and provide insights into the correlation of cell network profiles with molecular pathways and key mutations
Progress in diagnosing and treating thyroid squamous cell carcinoma under the 5th edition of WHO classification
Squamous cell carcinoma of the thyroid (SCCT) is a rare thyroid gland malignancy, with only a few hundred cases reported in the literature, mostly as case reports or small sample studies. In the previous WHO classification, squamous cell carcinoma of the thyroid was defined as a carcinoma composed entirely of squamous cells without differentiated carcinoma components. It was once included in the WHO tumor classification separately. However, the 2022 WHO classification of squamous cell carcinoma of the thyroid was reclassified as a morphologic subtype of anaplastic thyroid carcinoma (ATC). The squamous cell carcinoma pattern is similar to the other histologic types of ATC, but the phenotype associated has a poorer prognosis. The typical clinical manifestation of this condition is a cervical mass, accompanied by indications and symptoms of compression on adjacent structures such as the esophagus and trachea in advanced stages. Secondary squamous cell carcinoma of the thyroid may occur due to the spread of squamous carcinoma of the larynx or esophagus or distant metastases from other sites. Diagnosis of squamous cell carcinoma of the thyroid includes neck Ultrasound (US), Computed Tomography (CT) or Magnetic Resonance Imaging (MRI), puncture tissue biopsy, and full endoscopy to identify metastatic lesions from the nasopharynx, oropharynx, hypopharynx, larynx, esophagus, or bronchi and to help with the initial staging of the tumor. Current treatment modalities include surgery, radiotherapy, chemotherapy, or a combination. Because of the poor prognosis of patients with this disease, the short survival period, usually less than one year, and the difficulty of preoperative diagnosis, this article reviews the epidemiological features, origin, clinical features, pathological features, and differential diagnosis to improve the diagnosis and treatment of this disease by clinicians
Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea
ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK
Biological function and clinical implication of coagulation proteins during malignant transformation of pancreatic cells
The premalignant pancreatic cellular genotype can remain stable for years before rapid malignant transformation, often associated with inflammation. Tissue factor (TF) is an inflammatory modulator regulated by factor VIIa (fVIIa) for its levels and activity. The presence of TF in PDAC and its role in cell proliferation, angiogenesis, and metastasis suggests that TF may be a marker of the inflammatory microenvironment driving precursor lesions of pancreatic cancer. This study examined the in vitro influence of TF on pancreatic epithelial cells and its clinical value in detecting malignant transformation within pancreatic cyst fluid (PCyF). PCyF from 27 patients with pancreatic cystic lesions was analysed in a blinded fashion. TF and fVIIa levels were measured (ELISA), and the fVIIa:TF ratios were calculated. A cut-off value for TF concentration was determined and compared to the conventional assessment parameters (radiological features, CEA and amylase). Patients were categorised into four groups based on cytopathology and two groups based on indication for resection (‘resective’). Significant histological stage-dependent increases in TF levels were observed. Mean TF concentration was significantly higher (p=0.006) in the resective (high-grade dysplasia & malignant; 1.17 ng/ml, 95% CI 0.68, 1.67) vs non-resective group (benign & low-grade dysplasia; 0.27 ng/ml, 95% CI 0.1, 0.44), with a strong positive correlation (r= 0.746, p <0.001, TF cut-off 0.75 ng/ml, AUC 0.877, p=0.002). The fVIIa:TF ratio did not add further value. Incubation of pancreatic cells with recombinant TF resulted in increased expression of a marker of epithelial to mesenchymal transition (Vimentin). This influence was moderated by supplementation with fVIIa in benign (hTERT-HPNE) but not overtly malignant pancreatic cells (AsPC-1). Cyst-associated TF levels appear to correlate with cytological progression to the malignant phenotype and may allow better discrimination (specificity 94%) of the ‘resective’ lesion, reduce healthcare costs and offer a more nuanced tool for monitoring indeterminate cystic lesions
Development and validation of novel and quantitative MRI methods for cancer evaluation
Quantitative imaging biomarkers (QIB) offer the opportunity to further the evaluation of cancer at presentation as well as predict response to anti-cancer therapies before and early during treatment with the ultimate goal of truly personalised medical care and the mitigation of futile, often detrimental, therapy. Few QIBs are successfully translated into clinical practice and there is increasing recognition that rigorous methodologies and standardisation of research pipelines and techniques are required to move a theoretically useful biomarker into the clinic.
To this end, I have aimed to give an overview of what I believe to be some of key elements within the research field beginning with the concept of imaging biomarkers, introducing concepts in development and validation, before providing a summary of the current and future utility of a range of quantitative MR imaging biomarkers techniques within the oncological imaging field.
The original, prospective, research moves from the technical and analytical validation of a novel QIB use (T1 mapping in cancer), first in vivo qualification of this biomarker in cancer patient response assessment and prediction (sarcoma and breast cancer as well as prostate cancer separately), and then moving on to application of more established QIBs in cancer evaluation (R2*/BOLD imaging in head and neck cancer) as well as how existing MR data can be post-processed to improved cancer evaluation (further metrics derived from diffusion weighted imaging in head and neck cancer and textural analysis of existing clinical MR images utility in prostate cancer detection)
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