This open access book reflects on matters of social and ethical concern raised in the daily practices of those working in and around precision oncology. Each chapter addresses the experiences, ...concerns and issues at stake for people who work in settings where precision oncology is practiced, enacted, imagined or discussed. It subsequently discusses and analyses bioethical dilemmas, scientific challenges and economic trade-offs, the need for new policies, further technological innovation, social work, as well as phenomenological research. This volume takes a broad actor-centred perspective as, whenever cancer is present, the range of actors with issues at stake appears almost unlimited. This perspective and approach opens up the possibility for further in-depth and diverse questions, posed by the actors themselves, such as: How are cancer researchers navigating biological uncertainties? How do clinicians and policy-makers address ethical dilemmas around prioritisation of care? What are the patients’ experiences with, and hopes for, precision oncology? How do policy-makers and entrepreneurs envisage precision oncology? These questions are of great interest to a broad audience, including cancer researchers, oncologists, policy-makers, medical ethicists and philosophers, social scientists, patients and health economists.
Biomarkers in Medicine is a comprehensive guide to understanding the current and future status of biomarkers. The book features 27 chapters focusing on disease biomarkers for diseases such as cancer, ...neurodegenerative diseases, cardiac diseases, metabolic conditions and much more. This book supplies readers with the unique insight of experts in multiple specialties in medicine and life sciences who have extensive experience in diagnostics and clinical laboratories. The book includes case studies and practical examples from different classes of biomarkers on different platforms, including new data for biomarkers in different therapeutic indications. In addition to presenting biomarker information, each chapter covers the relevant pathology and also emphasizes on preclinical and clinical manifestation of the disease process. Clinicians managing patients or clinical trials, clinical researchers, clinical laboratories, diagnostic companies, regulatory agencies, medical school graduate students, academic students, and the general public involved in healthcare delivery will all benefit from information presented in this book.
Many cancer patients are diagnosed at a stage in which the cancer is too far advanced to be cured, and most cancer treatments are effective in only a minority of patients undergoing therapy. Thus, ...there is tremendous opportunity to improve the outcome for people with cancer by enhancing detection and treatment approaches. Biomarkers will be instrumental in making that transition. Advances in biotechnology and genomics have given scientists new hope that biomarkers can be used to improve cancer screening and detection, to improve the drug development process, and to enhance the effectiveness and safety of cancer care by allowing physicians to tailor treatment for individual patients—an approach known as personalized medicine. However, progress overall has been slow, despite considerable effort and investment, and there are still many challenges and obstacles to overcome before this paradigm shift in oncology can become a reality.
Prepared by world leaders on this topic, Biomarkers in Cancer Screening and Early Detection offers a comprehensive, state-of-the-art perspective on the various research and clinical aspects of cancer ...biomarkers, from their discovery and development to their validation, clinical utility, and use in developing personalized cancer treatment. * Offers a comprehensive, state-of-the-art perspective on the various research and clinical aspects of cancer biomarkers * Provides immediately actionable information – and hopefully also inspiration – to move discovery and clinical application forward * Offers vital knowledge to help develop personalized cancer treatment for individual patients with specific cancers
Gastric cancer (GC) represents the fifth most frequently diagnosed cancer worldwide, with a poor prognosis in patients with advanced disease despite many improvements in systemic treatments in the ...last decade. In fact, GC has shown resistance to several treatment options, and thus, notable efforts have been focused on the research and identification of novel therapeutic targets in this setting. The tumor microenvironment (TME) has emerged as a potential therapeutic target in several malignancies including GC, due to its pivotal role in cancer progression and drug resistance. Therefore, several agents and therapeutic strategies targeting the TME are currently under assessment in both preclinical and clinical studies. The present study provides an overview of available evidence of the inflammatory TME in GC, highlighting different types of tumor-associated cells and implications for future therapeutic strategies.
Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). ...Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.
Genomics is majorly impacting therapeutics development in medicine. This book contains up-to-date information on the use of genomics in the design and analysis of therapeutic clinical trials with a ...focus on novel approaches that provide a reliable basis for identifying which patients are most likely to benefit from each treatment. It is oriented to both clinical investigators and statisticians. For clinical investigators, it includes background information on clinical trial design and statistical analysis. For statisticians and others who want to go deeper, it covers state-of-the-art adaptive designs and the development and validation of probabilistic classifiers. The author describes the development and validation of prognostic and predictive biomarkers and their integration into clinical trials that establish their clinical utility for informing treatment decisions for future patients.
To explore whether a cross-talk exists between PARP inhibition and PD-L1/PD-1 immune checkpoint axis, and determine whether blockade of PD-L1/PD-1 potentiates PARP inhibitor (PARPi) in tumor ...suppression.
Breast cancer cell lines, xenograft tumors, and syngeneic tumors treated with PARPi were assessed for PD-L1 expression by immunoblotting, IHC, and FACS analyses. The phospho-kinase antibody array screen was used to explore the underlying mechanism of PARPi-induced PD-L1 upregulation. The therapeutic efficacy of PARPi alone, PD-L1 blockade alone, or their combination was tested in a syngeneic tumor model. The tumor-infiltrating lymphocytes and tumor cells isolated from syngeneic tumors were analyzed by CyTOF and FACS to evaluate the activity of antitumor immunity in the tumor microenvironment.
PARPi upregulated PD-L1 expression in breast cancer cell lines and animal models. Mechanistically, PARPi inactivated GSK3β, which in turn enhanced PARPi-mediated PD-L1 upregulation. PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 resensitized PARPi-treated cancer cells to T-cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy
Our study demonstrates a cross-talk between PARPi and tumor-associated immunosuppression and provides evidence to support the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.
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We have come a long way in our understanding and treatment of neuroendocrine tumors since the term "karzinoide" was coined in 1907. Neuroendocrine tumors are a group of biologically and clinically ...heterogeneous neoplasms that most commonly originate in the lungs, GI tract, and pancreas. The selection of initial and subsequent therapies requires careful consideration of both tumor and treatment characteristics. With recent advances, we now have more tools for the diagnosis and treatment of our patients. This comprehensive review article summarizes recent advances in the field of neuroendocrine tumors and places them into context for best management practices.
TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted ...in TNF receptor-deficient (Tnfr-/-) mice are spontaneously rejected; however, the molecular mechanisms underlying this rejection are unclear. Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell-mediated antitumor responses. Peripheral accumulation of MDSCs was drastically impaired in Tnfr-/- mice. Signaling of TNFR-2, but not TNFR-1, promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein (c-FLIP) and inhibition of caspase-8 activity. Loss of TNFRs impaired the induction of MDSCs from bone marrow cells, but this could be reversed by treatment with caspase inhibitors. These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system.
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