146 research outputs found
Quantification of tumour heterogenity in MRI
Cancer is the leading cause of death that touches us all, either directly or indirectly.
It is estimated that the number of newly diagnosed cases in the Netherlands will increase
to 123,000 by the year 2020. General Dutch statistics are similar to those in
the UK, i.e. over the last ten years, the age-standardised incidence rate1 has stabilised
at around 355 females and 415 males per 100,000. Figure 1 shows the cancer incidence
per gender. In the UK, the rise in lifetime risk of cancer is more than one in three and depends on many factors, including age, lifestyle and genetic makeup
Advanced perfusion quantification methods for dynamic PET and MRI data modelling
The functionality of tissues is guaranteed by the capillaries, which supply the microvascular
network providing a considerable surface area for exchanges between blood and tissues.
Microcirculation is affected by any pathological condition and any change in the blood supply
can be used as a biomarker for the diagnosis of lesions and the optimization of the treatment.
Nowadays, a number of techniques for the study of perfusion in vivo and in vitro are
available. Among the several imaging modalities developed for the study of microcirculation,
the analysis of the tissue kinetics of intravenously injected contrast agents or tracers is the
most widely used technique. Tissue kinetics can be studied using different modalities: the
positive enhancement of the signal in the computed tomography and in the ultrasound
dynamic contrast enhancement imaging; T1-weighted MRI or the negative enhancement of
T2* weighted MRI signal for the dynamic susceptibility contrast imaging or, finally, the
uptake of radiolabelled tracers in dynamic PET imaging. Here we will focus on the perfusion
quantification of dynamic PET and MRI data. The kinetics of the contrast agent (or the tracer)
can be analysed visually, to define qualitative criteria but, traditionally, quantitative
physiological parameters are extracted with the implementation of mathematical models.
Serial measurements of the concentration of the tracer (or of the contrast agent) in the tissue
of interest, together with the knowledge of an arterial input function, are necessary for the
calculation of blood flow or perfusion rates from the wash-in and/or wash-out kinetic rate
constants. The results depend on the acquisition conditions (type of imaging device, imaging
mode, frequency and total duration of the acquisition), the type of contrast agent or tracer
used, the data pre-processing (motion correction, attenuation correction, correction of the
signal into concentration) and the data analysis method.
As for the MRI, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a
non-invasive imaging technique that can be used to measure properties of tissue
microvasculature. It is sensitive to differences in blood volume and vascular permeability that
can be associated with tumour angiogenesis. DCE-MRI has been investigated for a range of
clinical oncologic applications (breast, prostate, cervix, liver, lung, and rectum) including
cancer detection, diagnosis, staging, and assessment of treatment response. Tumour
microvascular measurements by DCE-MRI have been found to correlate with prognostic
factors (such as tumour grade, microvessel density, and vascular endothelial growth factor
expression) and with recurrence and survival outcomes. Furthermore, DCE-MRI changes
measured during treatment have been shown to correlate with outcome, suggesting a role as
a predictive marker. The accuracy of DCE-MRI relies on the ability to model the
pharmacokinetics of an injected contrast agent using the signal intensity changes on
sequential magnetic resonance images. DCE-MRI data are usually quantified with the
application of the pharmacokinetic two-compartment Tofts model (also known as the
standard model), which represents the system with the plasma and tissue (extravascular
extracellular space) compartments and with the contrast reagent exchange rates between
them. This model assumes a negligible contribution from the vascular space and considers
the system in, what-is-known as, the fast exchange limit, assuming infinitely fast
transcytolemmal water exchange kinetics. In general, the number, as well as any assumption
about the compartments, depends on the properties of the contrast agent used (mainly
gadolinium) together with the tissue physiology or pathology studied. For this reason, the
choice of the model is crucial in the analysis of DCE-MRI data. The value of PET in clinical oncology has been demonstrated with studies in a variety of
cancers including colorectal carcinomas, lung tumours, head and neck tumours, primary and
metastatic brain tumours, breast carcinoma, lymphoma, melanoma, bone cancers, and other
soft-tissue cancers. PET studies of tumours can be performed for several reasons including
the quantification of tumour perfusion, the evaluation of tumour metabolism, the tracing of
radiolabelled cytostatic agents. In particular, the kinetic analysis of PET imaging has showed,
in the past few years, an increasing value in tumour diagnosis, as well as in tumour therapy,
through providing additional indicative parameters. Many authors have showed the benefit
of kinetic analysis of anticancer drugs after labelling with radionuclide in measuring the
specific therapeutic effect bringing to light the feasibility of applying the kinetic analysis to
the dynamic acquisition. Quantification methods can involve visual analysis together with
compartmental modelling and can be applied to a wide range of different tracers. The
increased glycolysis in the most malignancies makes 18F-FDG-PET the most common
diagnostic method used in tumour imaging. But, PET metabolic alteration in the target tissue
can depend by many other factors. For example, most types of cancer are characterized by
increased choline transport and by the overexpression of choline kinase in highly proliferating
cells in response to enhanced demand of phosphatidylcholine (prostate, breast, lung, ovarian
and colon cancers). This effect can be diagnosed with choline-based tracers as the 18Ffluoromethylcholine
(18F-FCH), or the even more stable 18F-D4-Choline. Cellular
proliferation is also imaged with 18F-fluorothymidine (FLT), which is trapped within the
cytosol after being mono phosphorylated by thymidine kinase-1 (TK1), a principal enzyme
in the salvage pathway of DNA synthesis. 18F-FLT has been found to be useful for noninvasive
assessment of the proliferation rate of several types of cancer and showed high
reproducibility and accuracy in breast and lung cancer tumours.
The aim of this thesis is the perfusion quantification of dynamic PET and MRI data of patients
with lung, brain, liver, prostate and breast lesions with the application of advanced models.
This study covers a wide range of imaging methods and applications, presenting a novel
combination of MRI-based perfusion measures with PET kinetic modelling parameters in
oncology. It assesses the applicability and stability of perfusion quantification methods,
which are not currently used in the routine clinical practice.
The main achievements of this work include: 1) the assessment of the stability of perfusion
quantification of D4-Choline and 18F-FLT dynamic PET data in lung and liver lesions,
respectively (first applications in the literature); 2) the development of a model selection in
the analysis of DCE-MRI data of primary brain tumours (first application of the extended
shutter speed model); 3) the multiparametric analysis of PET and MRI derived perfusion
measurements of primary brain tumour and breast cancer together with the integration of
immuohistochemical markers in the prediction of breast cancer subtype (analysis of data
acquired on the hybrid PET/MRI scanner).
The thesis is structured as follows:
- Chapter 1 is an introductive chapter on cancer biology. Basic concepts, including the causes
of cancer, cancer hallmarks, available cancer treatments, are described in this first chapter.
Furthermore, there are basic concepts of brain, breast, prostate and lung cancers (which are
the lesions that have been analysed in this work). - Chapter 2 is about Positron Emission Tomography. After a brief introduction on the basics
of PET imaging, together with data acquisition and reconstruction methods, the chapter
focuses on PET in the clinical settings. In particular, it shows the quantification techniques
of static and dynamic PET data and my results of the application of graphical methods,
spectral analysis and compartmental models on dynamic 18F-FDG, 18F-FLT and 18F-D4-
Choline PET data of patients with breast, lung cancer and hepatocellular carcinoma.
- Chapter 3 is about Magnetic Resonance Imaging. After a brief introduction on the basics of
MRI, the chapter focuses on the quantification of perfusion weighted MRI data. In particular,
it shows the pharmacokinetic models for the quantification of dynamic contrast enhanced
MRI data and my results of the application of the Tofts, the extended Tofts, the shutter speed
and the extended shutter speed models on a dataset of patients with brain glioma.
- Chapter 4 introduces the multiparametric imaging techniques, in particular the combined
PET/CT and the hybrid PET/MRI systems. The last part of the chapter shows the applications
of perfusion quantification techniques on a multiparametric study of breast tumour patients,
who simultaneously underwent DCE-MRI and 18F-FDG PET on a hybrid PET/MRI scanner.
Then the results of a predictive study on the same dataset of breast tumour patients integrated
with immunohistochemical markers. Furthermore, the results of a multiparametric study on
DCE-MRI and 18F-FCM brain data acquired both on a PET/CT scanner and on an MR
scanner, separately. Finally, it will show the application of kinetic analysis in a radiomic
study of patients with prostate cancer
Sarcoma treatment in the era of molecular medicine
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.Peer reviewe
Sarcoma treatment in the era of molecular medicine
open42siThe authors thank the European EuSARC initiative, which addresses the clinical challenges posed by sarcomas and aims at accelerating the translation of new molecular findings into clinical practice through the organization of annual conferences that foster interdisciplinary and international collaboration in the field of sarcomas (www.eusarc.com).Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.openGrunewald T.G.P.; Alonso M.; Avnet S.; Banito A.; Burdach S.; Cidre-Aranaz F.; Di Pompo G.; Distel M.; Dorado-Garcia H.; Garcia-Castro J.; Gonzalez-Gonzalez L.; Grigoriadis A.E.; Kasan M.; Koelsche C.; Krumbholz M.; Lecanda F.; Lemma S.; Longo D.L.; Madrigal-Esquivel C.; Morales-Molina A.; Musa J.; Ohmura S.; Ory B.; Pereira-Silva M.; Perut F.; Rodriguez R.; Seeling C.; Al Shaaili N.; Shaabani S.; Shiavone K.; Sinha S.; Tomazou E.M.; Trautmann M.; Vela M.; Versleijen-Jonkers Y.M.H.; Visgauss J.; Zalacain M.; Schober S.J.; Lissat A.; English W.R.; Baldini N.; Heymann D.Grunewald T.G.P.; Alonso M.; Avnet S.; Banito A.; Burdach S.; Cidre-Aranaz F.; Di Pompo G.; Distel M.; Dorado-Garcia H.; Garcia-Castro J.; Gonzalez-Gonzalez L.; Grigoriadis A.E.; Kasan M.; Koelsche C.; Krumbholz M.; Lecanda F.; Lemma S.; Longo D.L.; Madrigal-Esquivel C.; Morales-Molina A.; Musa J.; Ohmura S.; Ory B.; Pereira-Silva M.; Perut F.; Rodriguez R.; Seeling C.; Al Shaaili N.; Shaabani S.; Shiavone K.; Sinha S.; Tomazou E.M.; Trautmann M.; Vela M.; Versleijen-Jonkers Y.M.H.; Visgauss J.; Zalacain M.; Schober S.J.; Lissat A.; English W.R.; Baldini N.; Heymann D
Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics
Humans are exposed to a complex mix of man-made electric and magnetic fields (MFs) at many different frequencies, at home and at work. Epidemiological studies indicate that there is a positive relationship between residential/domestic and occupational exposure to extremely low frequency electromagnetic fields and some types of cancer, although some other studies indicate no relationship. In this review, after an introduction on the MF definition and a description of natural/anthropogenic sources, the epidemiology of residential/domestic and occupational exposure to MFs and cancer is reviewed, with reference to leukemia, brain, and breast cancer. The in vivo and in vitro effects of MFs on cancer are reviewed considering both human and animal cells, with particular reference to the involvement of reactive oxygen species (ROS). MF application on cancer diagnostic and therapy (theranostic) are also reviewed by describing the use of different magnetic resonance imaging (MRI) applications for the detection of several cancers. Finally, the use of magnetic nanoparticles is described in terms of treatment of cancer by nanomedical applications for the precise delivery of anticancer drugs, nanosurgery by magnetomechanic methods, and selective killing of cancer cells by magnetic hyperthermia. The supplementary tables provide quantitative data and methodologies in epidemiological and cell biology studies. Although scientists do not generally agree that there is a cause-effect relationship between exposure to MF and cancer, MFs might not be the direct cause of cancer but may contribute to produce ROS and generate oxidative stress, which could trigger or enhance the expression of oncogenes
Study of serial markers of biological response in rectal cancer patients receiving preoperative chemoradiotherapy with or without biological agents
The key to understanding the heterogeneous behaviour of similar stage locally advance rectal cancer lies in the understanding of tumour biology. The aim of this project was to investigate the biological behaviour of rectal cancers and its alterations in response to neoadjuvant chemoradiotherapy, by studying the intrinsic radiosensitivity, pathophysiology and angiogenesis of rectal cancers. It was intended to provide information that may help risk-stratify patients for individualised treatments including optimal timing of surgery after chemoradiotherapy. Consecutive patients with locally advanced, non-metastatic rectal cancer, who were considered suitable for long-course neoadjuvant chemoradiotherapy, were prospectively recruited. Radiosensitivity was studied by investigating the timing of DNA repair analysis with single cell gel electrophoresis (comet assay). The tumour pathophysiology and angiogenesis was investigated in vivo by novel functional imaging techniques (multiparametric magnetic resonance imaging and dynamic contrast enhanced computed tomography). It is demonstrated that rectal cancer tissue consists of cells with heterogeneous radiosensitivities and functional microvascularity. Until six weeks after NCRT, the DNA repair remains inhibited with progressive devascularisation and increasing hypoxic blood volume resulting in loss of tumour cells. Thereafter, variable fractions of cancer cell may continue to perish or survive with corresponding changes in vascularity. Therefore, the period between the sixth and eleventh weeks after neoadjuvant therapy is a critical time when surviving cells from rectal cancers may develop aggressive traits with long-term consequences. Hence, biological assessment of locally advance rectal cancers after six weeks post-NCRT may help risk-stratify patients for individualised therapy
The Development of Hyaluronan-Based Contract Agents for the Intraoperative Detection of Pancreatic Tumors
Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. Tumor-specific intraoperative fluorescence imaging could improve staging and surgical resection, thereby improving prognosis. In the first study, hyaluronic acid derived NPs with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG accumulated significantly in an orthotopic pancreatic ductal adenocarcinoma model with safety profile both in vitro and in vivo. To maximize tumor signal, while minimizing signal in healthy pancreas and RES capture of macromolecules, in the next study, we describe the rational development of a series of hyaluronic acid (HA) conjugates that vary in molecular weight and are conjugated to near-infrared fluorescent (NIRF) dyes that have differences in hydrophilicity, serum protein binding affinity, and clearance mechanism. We systematically investigated the roles of each of these properties on tumor accumulation, relative biodistribution, and the impact of intraoperative imaging of orthotopic, syngeneic pancreatic cancer. Overall, each HA-NIRF conjugate displayed intra-pancreatic tumor enhancement compared to uninvolved pancreas at 24 and 96 h. Regardless of HA molecular weight, Cy7.5 conjugation directed biodistribution to the liver, spleen, and bowels. Conjugation of IRDye-800 to 5 and 20 kDa HA resulted in low liver and spleen signal, while preserving tumor contrast enhancement up to 14-fold compared to healthy pancreas. When IRDye800 was conjugated to 100 kDa HA, the conjugate preferentially distributed to RES organs. When assessing the imaging efficacy of HA-based conjugates in hepatic metastases, those that accumulated to the liver utmost (HA100k-Cy7.5, HA100k-IRDye800, NanoICG) turned to aid the identification of hepatic malignancy with hypo-contrast. These studies demonstrate that by tuning HA molecular weight and the physicochemical properties of the conjugated moiety, in this case a NIRF probe, peritoneal biodistribution can be substantially altered to achieve optimized delivery to tumors with robust contrast enhancement for intraoperative imaging to abdominal tumors. Aside from assisting the accurate delineation of primary tumor, HA-NIRF conjugates demonstrated potential for identification of occult metastases in the intraoperative setting, as a versatile tool for accurate staging
Literature-based discovery of known and potential new mechanisms for relating the status of cholesterol to the progression of breast cancer
Breast cancer has been studied for a long period of time and from a variety of perspectives in order to understand its pathogeny. The pathogeny of breast cancer can be classified into two groups: hereditary and spontaneous. Although cancer in general is considered a genetic disease, spontaneous factors are responsible for most of the pathogeny of breast cancer. In other words, breast cancer is more likely to be caused and deteriorated by the dysfunction of a physical molecule than be caused by germline mutation directly. Interestingly, cholesterol, as one of those molecules, has been discovered to correlate with breast cancer risk. However, the mechanisms of how cholesterol helps breast cancer progression are not thoroughly understood. As a result, this study aims to study known and discover potential new mechanisms regarding to the correlation of cholesterol and breast cancer progression using literature review and literature-based discovery. The known mechanisms are further classified into four groups: cholesterol membrane content, transport of cholesterol, cholesterol metabolites, and other. The potential mechanisms, which are intended to provide potential new treatments, have been identified and checked for feasibility by an expert
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