Bernsen MR, van Straten M, Kotek G
… +5 more, Warnert EAH, Haeck JC, Ruggiero A, Wielopolski PA, Krestin GP
Recent Results Cancer Res
· 2020 · PMID 32594384
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Imaging in Oncology is rapidly moving from the detection and size measurement of a lesion to the quantitative assessment of metabolic processes and cellular and molecular interactions. Increasing insights into cancer as...Imaging in Oncology is rapidly moving from the detection and size measurement of a lesion to the quantitative assessment of metabolic processes and cellular and molecular interactions. Increasing insights into cancer as a complex disease with involvement of the tumor stroma in tumor pathobiological processes have made it clear that for successful control of cancer, treatment strategies should not only be directed at the cancer cells but should also take aspects of the tumor microenvironment into account. This requires an understanding of the complex molecular and cellular interactions in cancer tissue. Recent developments in imaging technology have increased the possibility to image various pathobiological processes in cancer development and response to treatment. For computed tomography (CT) and magnetic resonance imaging (MRI) various improvements in hardware, software, and imaging probes have lifted these modalities from classical anatomical imaging techniques to techniques suitable to image and quantify various physiological processes and molecular and cellular interactions. Next to a more general overview of possible imaging targets in oncology, this chapter provides an overview of the various developments in CT and MRI technology and some specific applications.
Recent Results Cancer Res
· 2020 · PMID 32594383
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Since their discovery by Wilhelm Conrad Röntgen in 1895, X-rays have become the most widely available, typically fastest, and usually most cost-effective medical imaging modality today. From the early radiographic approa...Since their discovery by Wilhelm Conrad Röntgen in 1895, X-rays have become the most widely available, typically fastest, and usually most cost-effective medical imaging modality today. From the early radiographic approaches using X-ray films as detectors, the portfolio of medical X-ray imaging devices developed into a large range of dedicated instrumentation for various applications. While X-ray imaging has come a long way, there are some physical properties of X-rays, which have not yet been fully exploited, and which may offer quite some room for further enhancements of current X-ray imaging equipment. Firstly, X-ray imaging today is mainly black and white, despite the fact that X-ray generators actually create a full spectrum of X-ray energies, and that the interactions of X-rays that occur within the human body are not the same for all energies and every material. Exploiting these spectral dependencies allows to not only obtain a black and white CT image, but also to obtain more molecularly specific information, which is relevant particularly in oncological precision radiology. The second aspect of X-rays, and so far in radiology mainly neglected and unused, is the physical fact that X-rays can also be interpreted in the wave picture, and not only as presently been done in the particle picture. If interpreted as waves, X-rays-just like visible light-experience a phase shift in matter, and this-if exploited correctly-can produce a new class of X-ray images, which then depict the wave interactions of X-rays with matter, rather than only the attenuating properties, as done until now.
Marass F, Castro-Giner F, Szczerba BM
… +4 more, Jahn K, Kuipers J, Aceto N, Beerenwinkel N
Recent Results Cancer Res
· 2020 · PMID 31605238
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Next-generation sequencing of DNA and RNA obtained from liquid biopsies of cancer patients may reveal important insights into disease progression and metastasis formation, and it holds the promise to enable new methods f...Next-generation sequencing of DNA and RNA obtained from liquid biopsies of cancer patients may reveal important insights into disease progression and metastasis formation, and it holds the promise to enable new methods for noninvasive screening and clinical decision support. However, implementing liquid biopsy sequencing protocols is challenged by capturing circulating tumor cells or cell-free tumor DNA from blood samples, by amplifying genomic DNA and RNA in a reliable and unbiased manner, and by extracting biologically meaningful signals from the noisy sequencing data. In this chapter, we discuss computational methods for the analysis of DNA and RNA sequencing data obtained from liquid biopsies, addressing these challenges.
Recent Results Cancer Res
· 2020 · PMID 31605237
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Extracellular micro- and nanoscale membrane vesicles produced by different cells progressively attract the attention of the scientific community. They function as mediators of intercellular communication and transport ge...Extracellular micro- and nanoscale membrane vesicles produced by different cells progressively attract the attention of the scientific community. They function as mediators of intercellular communication and transport genetic material and signaling molecules between the cells. In the context of keeping homeostasis, the extracellular vesicles contribute to the regulation of various systemic and local processes. Vesicles released by the tumor and activated stromal cells exhibit multiple functions including support of tumor growth, preparation of the pre-metastatic niches, and immune suppression. Considerable progress has been made regarding the criteria of classification of the vesicles according to their origin, content, and function: Exosomes, microvesicles, also referred to as microparticles or ectosomes, and large oncosomes were defined as actively released vesicles. Additionally, apoptotic bodies represented by a highly heterogeneous population of particles produced during apoptosis, the programmed cell death, should be considered. Because the majority of isolation techniques do not allow the separation of different types of vesicles, a joined term "extracellular vesicles" (EVs) was recommended by the ISEV community for the definition of vesicles isolated from either the cell culture supernatants or the body fluids. Because EV content reflects the content of the cell of origin, multiple studies on EVs from body fluids in the context of cancer diagnosis, prediction, and prognosis were performed, actively supporting their high potential as a biomarker source. Here, we review the leading achievements in EV analysis from body fluids, defined as EV-based liquid biopsy, and provide an overview of the main EV constituents: EV surface proteins, intravesicular soluble proteins, EV RNA including mRNA and miRNA, and EV DNA as potential biomarkers. Furthermore, we discuss recent developments in technology for quantitative EV analysis in the clinical setting and future perspectives toward miniaturized high-precision liquid biopsy approaches.
Recent Results Cancer Res
· 2020 · PMID 31605236
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Lung cancer is the number one cause of cancer-related mortality worldwide. To improve disease outcome, it is crucial to implement biomarkers into the clinics which assist physicians in their decisions regarding diagnosis...Lung cancer is the number one cause of cancer-related mortality worldwide. To improve disease outcome, it is crucial to implement biomarkers into the clinics which assist physicians in their decisions regarding diagnosis, prognosis, as well as prediction of treatment response. Liquid biopsy offers an opportunity to obtain such biomarkers in a minimal invasive manner by retrieving tumor-derived material from body fluids of the patient. The abundance of circulating microRNAs is known to be altered in disease and has therefore been studied extensively as a cancer biomarker. Circulating microRNAs present a variety of favorable characteristics for application as liquid biopsy-based biomarkers, including their high stability, relatively high abundance, and presence is nearly all body fluids. Although the application of circulating microRNAs for the management of lung cancer has not entered the clinics yet, several studies showed their utility for diagnosis, prognosis, and efficacy prediction of various treatment strategies, including surgery, radio-/chemotherapy, as well as targeted therapy. To compensate for their limited tumor specificity, several microRNAs are frequently combined into microRNA panels. Moreover, the possibility to combine single microRNAs or microRNA panels with tumor imaging or other cancer-specific biomarkers has the potential to increase specificity and sensitivity and could lead to the clinical application of novel multi-marker combinations.
Recent Results Cancer Res
· 2020 · PMID 31605235
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Deregulation of microRNA expression has been shown to play an important role in human malignancies. The identification of circulating-free miRNAs in biofluids a decade ago led to great enthusiasm and motivation to develo...Deregulation of microRNA expression has been shown to play an important role in human malignancies. The identification of circulating-free miRNAs in biofluids a decade ago led to great enthusiasm and motivation to develop non-invasive tests based on the expression of these small non-coding RNAs. Herein, we review the progress within the field of research for identifying circulating miRNA cancer biomarkers and discuss the advantages and challenges associated with this. We also discuss the methodological and analytical variables, which may influence the final miRNA quantification and the importance of standardizing pre-analytical, analytical, and post-analytical processes in order to enable a successful translation of the results from basic research into the clinics.
Recent Results Cancer Res
· 2020 · PMID 31605234
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An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor cells constantly adapt to external pressures-i.e.,...An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor cells constantly adapt to external pressures-i.e., systemic treatment-with the selection and expansion of resistant subclones and the emergence of heterogeneous overlapping genomic alterations of resistance. The current standard for molecular characterization in cancer is the performance of a tissue tumor biopsy at the time of diagnosis and, when possible, a re-biopsy at the time of progression. However, tissue biopsy is not always feasible or practical and may underestimate tumor heterogeneity and clonal dynamics. Circulating DNA fragments carrying tumor-specific sequence alterations (circulating tumor DNA, ctDNA) are released from cancer cells into the bloodstream, representing a variable and generally small fraction of the total circulating cell-free DNA. Tumor genotyping in ctDNA (liquid biopsy) offers potential advantages versus the standard tumor tissue biopsy, including non-invasiveness and representation of molecular heterogeneity. Technical advances in sequencing platforms have led to dramatic improvements in variant detection sensitivity and specificity that allow for the detection and quantification of low levels of ctDNA. This provides valuable information on both actionable mutations and captures real-time variations in tumor dynamics. Liquid biopsy clinical applications include molecular diagnosis, determination of tumor load as a surrogate marker of early response, monitoring of mutations of resistance to targeted therapy and detection of minimal residual disease after cancer surgery. The aim of this chapter is to provide an overview of the biological rational and technical background of ctDNA analysis, as well as on the main clinical applications of liquid biopsy in dynamic treatment stratification in solid tumors. Special emphasis will be made on the current and potential benefits of the implementation of ctDNA in clinical practice, mainly in melanoma, lung, and colorectal cancer.
Recent Results Cancer Res
· 2020 · PMID 31605233
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Colorectal cancer is one of the leading cause of death by cancer worldwide in both men and women. Liquid biopsy belongs nowadays to the landscape of cancer management biological tools. In this chapter, we will describe a...Colorectal cancer is one of the leading cause of death by cancer worldwide in both men and women. Liquid biopsy belongs nowadays to the landscape of cancer management biological tools. In this chapter, we will describe and discuss the actual, potential and future applications of cfDNA analysis in plasma of patients with colorectal cancer in early or metastatic stage. During the last decade, the development of molecular biology assays like digital PCR or next-generation sequencing made the analysis of cfDNA in plasma possible with an excellent sensitivity and applications like early detection, diagnosis, prognosis, response to treatment, monitoring of an emerging resistance, mapping of the disease molecular landscape or evaluation of the residual disease are now feasible. cfDNA detection has several promising applications in the management of patients with colorectal cancer, but prospective randomised clinical trials are still lacking to make liquid biopsy ready for prime-time.
Recent Results Cancer Res
· 2020 · PMID 31605232
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In only few years, circulating tumor DNA (ctDNA) in breast cancer has moved from purely fundamental research to nearby daily use for treatment selection and drug-resistance assessment. Indeed, technical advances and wide...In only few years, circulating tumor DNA (ctDNA) in breast cancer has moved from purely fundamental research to nearby daily use for treatment selection and drug-resistance assessment. Indeed, technical advances and widespread use of next-generation sequencing or digital PCR allowed for detection of very low amount of tumor DNA in bloodstream. The use of ctDNA as liquid biopsy able either to monitor tumor burden under treatment or to overcome tumor heterogeneity and identify potential targetable drivers. Time has come to define how ctDNA can be implemented for early or metastatic breast cancer management. Data from retrospective analyses of prospective trials have recently highlighted the potential advantages but also the limitations of ctDNA, in particular for patients under endocrine therapy.
Recent Results Cancer Res
· 2020 · PMID 31605231
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Most malignancies are characterized by remarkable molecular heterogeneity. The understanding of genetic and epigenetic processes underlying tumor heterogeneity has become increasingly important for the clinical managemen...Most malignancies are characterized by remarkable molecular heterogeneity. The understanding of genetic and epigenetic processes underlying tumor heterogeneity has become increasingly important for the clinical management of cancer patients. This includes the identification of patients who likely benefit from conventional or targeted therapies, classification of patients into risk groups based on their mutational landscape, and the detection of molecular mechanisms that drive treatment resistance and cancer progression. Detection of tumor heterogeneity by tumor tissue genotyping is hampered by the fact that tissue sampling is often insufficient for comprehensive genetic assessment and is associated with a higher risk of surgical complications. Detection and profiling of circulating tumor DNA (ctDNA) have emerged as a promising alternative to direct tumor genotyping. It potentially enables noninvasive and quantitative characterization of the full genetic landscape and identification of clonal evolution during treatment and towards disease progression in cancer patients. In the present chapter, we explore the role of noninvasive genotyping and ctDNA profiling for accurate and robust characterization of various types of tumor heterogeneity and its relevance for management of patients with hematologic and solid cancers.
Recent Results Cancer Res
· 2020 · PMID 31605230
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ctDNA provided by liquid biopsy offers a promising alternative to tumor biopsy as it gives a non-invasive and «real-time» access to the cancer genome and reflects tumor intra and extra heterogeneity. ctDNA has shown grow...ctDNA provided by liquid biopsy offers a promising alternative to tumor biopsy as it gives a non-invasive and «real-time» access to the cancer genome and reflects tumor intra and extra heterogeneity. ctDNA has shown growing clinical interest for cancer diagnosis, prognosis, theragnostics, therapeutic monitoring, and clonal evolution tracking. A major technical limit for ctDNA analysis from body fluids is the extremely low proportion of ctDNA compared to non-malignant cell-free DNA, underscoring the need for highly sensitive and specific detection techniques. The control of pre-analytical procedures appears essential for optimal ctDNA analysis and need to be standardized for clinical research applications. This chapter provides insights into major current technologies for ctDNA detection. Overall, PCR-based techniques are able to detect limited molecular alterations and have a high sensitivity suitable for monitoring purposes while NGS-based approaches are broad range molecular screening assays more specifically indicated for treatment selection. We briefly reviewed new technical innovations that are now available for ctDNA detection.
Recent Results Cancer Res
· 2020 · PMID 31605229
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The clinical implications of being able to accurately detect tumor-derived DNA in the circulation, termed circulating tumor DNA (ctDNA), could be enormous. Already, a plethora of clinical applications is under validation...The clinical implications of being able to accurately detect tumor-derived DNA in the circulation, termed circulating tumor DNA (ctDNA), could be enormous. Already, a plethora of clinical applications is under validation that include detection of minimal residual disease and predicting recurrence, monitoring response and resistance to treatment, identifying targets for therapies, and early detection. ctDNA is only a fraction of the total cell-free DNA (cfDNA) which confounds its detection and sometimes conceals its properties. To use ctDNA as a cancer biomarker with confidence, we need to understand its nature. Its characteristics, including size, half-life, and amount, are critical for the development of tests for its detection and discrimination from the rest of the cfDNA. Technological advances have enabled the detection and quantification of individual fragments of cfDNA, which is pivotal for clinical applications. Understanding the causes, the source of and the mechanisms of release of ctDNA are important for the interpretation of test results. Despite the many advances in understanding the nature and biology of ctDNA, we do not yet have a clear appreciation of the processes that govern its presence and levels in the circulation. ctDNA is not detectable in the blood of every cancer patient, and there is not a directly proportional relationship to tumor type, size, or stage. It is not clear if the lack of correlation with these specific clinical parameters is strictly due to technical or biological challenges. Better understanding of the pathophysiology of ctDNA is therefore important for the improvement of clinical applications and interpretation of their results.
Recent Results Cancer Res
· 2020 · PMID 31605228
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The development of metastatic disease accounts for the vast majority of cancer-related deaths in solid tumor malignancies. Distant metastases primarily develop as a result of tumor cell dissemination through the circulat...The development of metastatic disease accounts for the vast majority of cancer-related deaths in solid tumor malignancies. Distant metastases primarily develop as a result of tumor cell dissemination through the circulatory system.
Recent Results Cancer Res
· 2020 · PMID 31605227
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With active screening for early detection and advancements in treatment, there has been a significant decrease in mortality from breast cancer. However, a significant proportion of patients with non-metastatic breast can...With active screening for early detection and advancements in treatment, there has been a significant decrease in mortality from breast cancer. However, a significant proportion of patients with non-metastatic breast cancer at time of diagnosis will relapse. Therefore, it is suggested that the dissemination of bloodstream tumor cells (circulating tumor cells, CTCs) undetectable by currently available diagnostic tools occurs during the early stages of breast cancer progression, and may be the potential source of micrometastases responsible for treatment failures. Here, we review the clinical significance of CTCs, as detected by the FDA-approved CellSearch System, in both metastatic and non-metastatic breast cancer patients. Studies so far suggest that CTCs are prognostic of poorer outcomes in breast cancer patients; however, there is currently insufficient data to support use of CTC data to guide treatment. Therefore, there are ongoing studies to evaluate the utility of assessing CTC phenotypes to develop personalized breast cancer treatment, which will be reviewed in this chapter.
Recent Results Cancer Res
· 2020 · PMID 31605226
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Circulating tumour cells (CTCs) constitute a potential tumour surrogate that could serve as "liquid biopsy" with the advantage to be a minimally invasive approach compared to traditional tissue biopsies. As CTCs are thou...Circulating tumour cells (CTCs) constitute a potential tumour surrogate that could serve as "liquid biopsy" with the advantage to be a minimally invasive approach compared to traditional tissue biopsies. As CTCs are thought to be the source of metastatic lesions, their analysis represents a potential means of tracking cancer cells from the primary tumour en route to distant sites, thus providing valuable insights into the metastatic process. However, several problems, such as their rarity in the peripheral blood, the technical limitations of single-cell downstream analysis and their phenotypic variability, make CTC detection and molecular characterisation very challenging. Nevertheless, in the last decade, there has been an exponential increase of interest in the development of powerful cellular and molecular methodologies applied to CTCs. In this chapter, we focus on the recent advances of functional studies and molecular profiling of CTCs. We will also highlight the clinical relevance of CTC detection and enumeration, and discuss their potential as tumour biomarkers with special focus on lung cancer.
Recent Results Cancer Res
· 2020 · PMID 31605225
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Full text
Circulating tumor cells (CTCs) represent novel biomarkers, since they are obtainable through a simple and noninvasive blood draw or liquid biopsy. Here, we review the high-definition single-cell analysis (HD-SCA) workflo...Circulating tumor cells (CTCs) represent novel biomarkers, since they are obtainable through a simple and noninvasive blood draw or liquid biopsy. Here, we review the high-definition single-cell analysis (HD-SCA) workflow, which brings together modern methods of immunofluorescence with more sophisticated image processing to rapidly and accurately detect rare tumor cells among the milieu of platelets, erythrocytes, and leukocytes in the peripheral blood. In particular, we discuss progress in methods to measure CTC morphology and subcellular protein expression, and we highlight some initial applications that lead to fundamental new insights about the hematogenous phase of cancer, as well as its performance in early-stage diagnosis and treatment monitoring. We end with an outlook on how to further probe CTCs and the unique advantages of the HD-SCA workflow for improving the precision of cancer care.
Kalinich M, Kwan TT, Toner M
… +2 more, Haber DA, Maheswaran S
Recent Results Cancer Res
· 2020 · PMID 31605224
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Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream,...Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.
Kolinsky MP, Stoecklein N, Lambros M
… +5 more, Gil V, Rodrigues DN, Carreira S, Zafeiriou Z, de Bono JS
Recent Results Cancer Res
· 2020 · PMID 31605223
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The classification of human cancers has traditionally relied on the tissue of origin, the histologic appearance and anatomical extent of disease, otherwise referred to as grade and stage. However, this system fails to ex...The classification of human cancers has traditionally relied on the tissue of origin, the histologic appearance and anatomical extent of disease, otherwise referred to as grade and stage. However, this system fails to explain the highly variable clinical behaviour seen for any one cancer. Molecular characterization through techniques such as next-generation sequencing (NGS) has led to an appreciation of the extreme genetic heterogeneity that underlies most human cancers. Because of the difficulties associated with fresh tissue biopsy, interest has increased in using circulating tumour material, such as circulating tumour cells (CTCs), as a non-invasive way to access tumour tissue. CTC enumeration has been demonstrated to have prognostic value in metastatic breast, colon and prostate cancers. Recent studies have also shown that CTCs are suitable material for molecular characterization, using techniques such as reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and NGS. Furthermore, genetic analysis of CTCs may be more suitable to study tumour heterogeneity and clonal evolution than fresh tissue biopsy. Whether blood-based biopsy techniques will be accepted as a replacement to fresh tissue biopsies remains to be seen, but there is reason for optimism. While significant barriers to this acceptance exist, blood-based biopsy techniques appear to be reliable and representative alternatives to fresh tissue biopsy.
Boya M, Chu CH, Liu R
… +2 more, Ozkaya-Ahmadov T, Sarioglu AF
Recent Results Cancer Res
· 2020 · PMID 31605222
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Circulating tumor cells (CTCs) are responsible for the metastatic spread of cancer and therefore are extremely valuable not only for basic research on cancer metastasis but also as potential biomarkers in diagnosing and...Circulating tumor cells (CTCs) are responsible for the metastatic spread of cancer and therefore are extremely valuable not only for basic research on cancer metastasis but also as potential biomarkers in diagnosing and managing cancer in the clinic. While relatively non-invasive access to the blood tissue presents an opportunity, CTCs are mixed with approximately billion-times more-populated blood cells in circulation. Therefore, the accuracy of technologies for reliable enrichment of the rare CTC population from blood samples is critical to the success of downstream analyses. The focus of this chapter is to provide the reader an overview of significant advances made in the development of diverse CTC enrichment technologies by presenting the strengths of individual techniques in addition to specific challenges remaining to be addressed.
Todenhöfer T, Pantel K, Stenzl A
… +1 more, Werner S
Recent Results Cancer Res
· 2020 · PMID 31605221
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The traditional model of metastatic progression postulates that the ability to form distant metastases is driven by random mutations in cells of the primary tumor.The traditional model of metastatic progression postulates that the ability to form distant metastases is driven by random mutations in cells of the primary tumor.