2,105 research outputs found
Master of Science
thesisMeningiomas are the most common primary brain tumors, accounting for 36.6% of all tumors with âŒ20,000 cases annually in the U.S. Although 65-80% of cases are benign (World Health Organization [WHO] Grade I), recurrence over a long period can be seen, especially for subtotal resections and higher-grade tumors (II and III). Radiotherapy is a common primary or adjuvant therapy, but its mechanisms of action in the setting of distinct subtypes of meningioma remain unknown. Hypoxia-inducible factor 1 (HIF1) plays a key role in cellular response to oxygen tension, modulates multiple downstream genes, controls tissue vascularization, and may serve as a resistance-promoting mechanism in tumors. The aim of this study was to evaluate the clinical impact of the HIF1-signaling pathway in meningioma characterization as well as the impact of radiotherapy on meningiomas in the setting of HIF1 knockout. Clinical samples from patients with meningiomas, primary derived cell lines (GAR, JEN, SAM, MCT, BSH, IOMM-LEE), and HIF1 generated knockouts (GAR-1589) were utilized. Multiple immunohistochemical markers and a fractal-based microvascularity quantification showed that Grade I meningiomas â„3 cm showed greater staining for MIB and von Willebrand Factor as well as an average 19-month shorter survival. In addition, a MIB index â„3 showed high specificity (82.5%) but not sensitivity (36%) for predicting progression-free survival. Cell proliferation and apoptosis in response to radiation doses depended on cell density, HIF1A mutational status, and oxygen tension. Higher plated densities of cells showed resistance to radiation for various primary meningioma cell lines. GAR cells demonstrated greater response to high-dose radiation than GAR-1589 cells in 2D and 3D cultures, while neither cell line responded to fractionated radiotherapy. Hypoxic environments reduced the efficacy of radiation, in fact showing increased cell proliferation with low doses of radiation. GAR-1589 cell, however, showed greater increases in cell apoptosis during radiotherapy in normoxic environments than GAR cells. Multimodal imaging using tumor bioluminescence, positron emission tomography tracers, and MRI showed potential for evaluating various characteristics of primary brain tumors noninvasively using an orthotopic rodent model. These results offer some correlation clinically and experimentally regarding the importance of HIF1 and tumor resistance
Hypoxic Cell Waves around Necrotic Cores in Glioblastoma: A Biomathematical Model and its Therapeutic Implications
Glioblastoma is a rapidly evolving high-grade astrocytoma that is
distinguished pathologically from lower grade gliomas by the presence of
necrosis and microvascular hiperplasia. Necrotic areas are typically surrounded
by hypercellular regions known as "pseudopalisades" originated by local tumor
vessel occlusions that induce collective cellular migration events. This leads
to the formation of waves of tumor cells actively migrating away from central
hypoxia. We present a mathematical model that incorporates the interplay among
two tumor cell phenotypes, a necrotic core and the oxygen distribution. Our
simulations reveal the formation of a traveling wave of tumor cells that
reproduces the observed histologic patterns of pseudopalisades. Additional
simulations of the model equations show that preventing the collapse of tumor
microvessels leads to slower glioma invasion, a fact that might be exploited
for therapeutic purposes.Comment: 29 pages, 9 figure
A simple mathematical model of cyclic hypoxia and hypofractionated radiotherapy
There is now substantial evidence that the population of cells that
experience fluctuating oxygen levels ("cyclic" hypoxia) are more radioresistant
than chronically hypoxic ones and hence, this population likely determines
radiotherapy (RT) response, in particular for hypofractionated RT, where
reoxygenation may not be as prominent. A considerable effort has been devoted
to examining the impact of hypoxia on hypofractionated RT; however, much less
attention has been paid to cyclic hypoxia specifically and the role its
kinetics may play in determining the efficacy of these treatments. Here, a
simple model of cyclic hypoxia and fractionation effects was worked out to
quantify this. Cancer clonogen survival was estimated using the linear
quadratic model, modified to account for oxygen enhancement effects. An
analytic approximation for oxygen transport away from a random network of
capillaries with fluctuating oxygen levels was used to model inter-fraction
tissue oxygen kinetics. Using relevant literature parameter values,
inter-fraction fluctuations in oxygenation were found to result in an added 1-2
logs of clonogen survival fraction in going from five fractions to one for the
same nominal biologically effective dose (i.e., excluding the effects of oxygen
levels on radiosensitivity). Although significant, the loss of cell-killing
with increasing hypofractionation is not nearly as large as previous estimates
based on the assumption of complete reoxygenation between fractions. Most
ultra-hypofractionated regimens currently in place offer sufficiently high
doses to counter this loss of cell killing, although care should be taken in
implementing single-fraction regimens
DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6
Background:
There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases.
Methods:
Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan.
Results:
In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (ve), tumour enhancing fraction (EF), and microvascular uniformity (assessed with the fractal measure box dimension, d0) (R2=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan.
Conclusion:
Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers
Targeting Tumor Perfusion and Oxygenation Modulates Hypoxia and Cancer Sensitivity to Radiotherapy and Systemic Therapies
Hypoxia, a partial pressure of oxygen (pO2) below physiological needs, is a limiting factor affecting the efficiency of radiotherapy. Indeed, the reaction of reactive oxygen species
(ROS, produced by water radiolysis) with DNA is readily reversible unless oxygen stabilizes
the DNA lesion. While normal tissue oxygenation is around 40 mm Hg, both rodent and
human tumors possess regions of tissue oxygenation below 10 mm Hg, at which tumor cells
become increasingly resistant to radiation damage (radiobiological hypoxia) (Gray, 1953).
Because of this so-called âoxygen enhancement effectâ, the radiation dose required to
achieve the same biologic effect is about three times higher in the absence of oxygen than in
the presence of normal levels of oxygen (Gray et al., 1953; Horsman & van der Kogel, 2009).
Hypoxic tumor cells, which are therefore more resistant to radiotherapy than well
oxygenated ones, remain clonogenic and contribute to the therapeutic outcome of
fractionated radiotherapy (Rojas et al., 1992)
Malignant Gliomas: A Case Study
Malignant gliomas, of grade III and grade IV malignancy, are incurable neoplasms that arise from cells with several well-characterized genetic profile abnormalities that cause uncontrollable growth and infiltration in the brain. Presenting symptoms of both generalized and focal neurological abnormalities are induced by increased intracranial pressure and focal neuronal dysfunction, respectively. On average, patients experience 3 months or less of clinical history before receiving diagnosis based on multifactorial comparison of clinical and pathological presentation of the tumor. Following diagnosis, maximal safe resection and adjuvant radiotherapy and concurrent chemotherapy typically ensues with subsequent management chemotherapy regimens. Despite aggressive treatment approaches, progression or recurrence is highly typical based on 5-yr survival rates of 5.1% and 27.9% of grade IV glioblastoma multiforme (GBM) and grade III anaplastic astrocytoma (AA), respectively, the two most common malignant gliomas. Severely progressive clinical and functional deterioration in the terminal stage of care may warrant cessation of curative care replaced with maximal palliative care. Brain tumor patients experience the burden of terminal illness as other cancer patients do, but with added neurological-specific impairments that reduce quality of life. Possible causes of death include herniation, tumor progression, and systemic illness, but can be potentially multifactorial. The following manuscript characterizes the pathological mechanisms of oncogenesis and growth, followed by a comprehensive review of the clinical care for brain tumor patients from symptom onset to cause of death. To aid in the clinical applicability of these concepts, a case study of a single patient âWLâ, who received a diagnosis of grade III anaplastic astrocytoma following 3 months of visual deterioration, will prompt the clinical review by illustration of disease course and treatment
Enhanced perfusion following exposure to radiotherapy: a theoretical investigation
Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumourâs response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies
From tumour perfusion to drug delivery and clinical translation of in silico cancer models
In silico cancer models have demonstrated great potential as a tool to improve drug design, optimise the delivery of drugs to target sites in the host tissue and, hence, improve therapeutic efficacy and patient outcome. However, there are significant barriers to the successful translation of in silico technology from bench to bedside. More precisely, the specification of unknown model parameters, the necessity for models to adequately reflect in vivo conditions, and the limited amount of pertinent validation data to evaluate models' accuracy and assess their reliability, pose major obstacles in the path towards their clinical translation. This review aims to capture the state-of-the-art in in silico cancer modelling of vascularised solid tumour growth, and identify the important advances and barriers to success of these models in clinical oncology. Particular emphasis has been put on continuum-based models of cancer since they - amongst the class of mechanistic spatio-temporal modelling approaches - are well-established in simulating transport phenomena and the biomechanics of tissues, and have demonstrated potential for clinical translation. Three important avenues in in silico modelling are considered in this contribution: first, since systemic therapy is a major cancer treatment approach, we start with an overview of the tumour perfusion and angiogenesis in silico models. Next, we present the state-of-the-art in silico work encompassing the delivery of chemotherapeutic agents to cancer nanomedicines through the bloodstream, and then review continuum-based modelling approaches that demonstrate great promise for successful clinical translation. We conclude with a discussion of what we view to be the key challenges and opportunities for in silico modelling in personalised and precision medicine
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