Heterogeneous enhancement pattern in DCE-MRI reveals the morphology of normal lymph nodes: an experimental study

Purpose: To investigate the heterogeneous enhancement pattern in normal lymph nodes of healthy mice by different albumin-binding contrast agents. Methods: The enhancement of normal lymph nodes was assessed in mice by dynamic contrast-enhanced MRI (DCE-MRI) after the administration of two contrast agents characterized by different albumin-binding properties: gadopentetate dimeglumine (Gd-DTPA) and gadobenate dimeglumine (Gd-BOPTA). To take into account potential heterogeneities of the contrast uptake in the lymph nodes, k-means cluster analysis was performed on DCE-MRI data. Cluster spatial distribution was visually assessed. Statistical comparison among clusters and contrast agents was performed on semiquantitative parameters (AUC, wash-in rate, and wash-out rate) and on the relative size of the segmented clusters. Results: Cluster analysis of DCE-MRI data revealed at least two main clusters, localized in the outer portion and in the inner portion of each lymph node. With both contrast agents, AUC (p < 0.01) and wash-in (p < 0.05) rates were greater in the inner cluster, which also showed a steeper wash-out rate than the outer cluster (Gd-BOPTA, p < 0.01; Gd-DTPA, p=0.056). The size of the outer cluster was greater than that of the inner cluster by Gd-DTPA (p < 0.05) and Gd-BOPTA (p < 0.01). The enhancement pattern of Gd-DTPA was not significantly different from the enhancement pattern of Gd-BOPTA. Conclusion: DCE-MRI in normal lymph nodes shows a characteristic heterogeneous pattern, discriminating the periphery and the central portion of the lymph nodes. Such a pattern deserves to be investigated as a diagnostic marker for lymph node staging

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)

Measurement of the vascular input function in mice for DCE-MRI

DCE-MRI is an important technique in the study of small animal cancer models because its sensitivity to vascular changes opens the possibility of quantitative assessment of early therapeutic response. However, extraction of physiologically descriptive parameters from DCE-MRI data relies upon measurement of the vascular input function (VIF), which represents the contrast agent concentration time course in the blood plasma. This is difficult in small animal models due to artifacts associated with partial volume, inflow enhancement, and the limited temporal resolution achievable with MR imaging. In this work, the development of a suite of techniques for high temporal resolution, artifact resistant measurement of the VIF in mice is described. One obstacle in VIF measurement is inflow enhancement, which decreases the sensitivity of the MR signal to the presence of contrast agent. Because the traditional techniques used to suppress inflow enhancement degrade the achievable spatiotemporal resolution of the pulse sequence, improvements can be achieved by reducing the time required for the suppression. Thus, a novel RF pulse which provides spatial presaturation contemporaneously with the RF excitation was implemented and evaluated. This maximizes the achievable temporal resolution by removing the additional RF and gradient pulses typically required for suppression of inflow enhancement. A second challenge is achieving the temporal resolution required for accurate characterization of the VIF, which exceeds what can be achieved with conventional imaging techniques while maintaining adequate spatial resolution and tumor coverage. Thus, an anatomically constrained reconstruction strategy was developed that allows for sampling of the VIF at extremely high acceleration factors, permitting capture of the initial pass of the contrast agent in mice. Simulation, phantom, and in vivo validation of all components were performed. Finally, the two components were used to perform VIF measurement in the murine heart. An in vivo study of the VIF reproducibility was performed, and an improvement in the measured injection-to-injection variation was observed. This will lead to improvements in the reliability of quantitative DCE-MRI measurements and increase their sensitivity

A Novel Ultrasound Elastography Technique for Evaluating Tumor Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer

Breast cancer is the second most diagnosed cancer in women, estimated to affect 1 in 8 women during their lifetime. About 10% to 20% of new breast cancer cases are diagnosed with locally advanced breast cancer (LABC). LABC tumors are usually larger than 5 cm and/or attached to the skin or chest wall. It has been reported that when such cases are treated with surgery alone, metastasis and mortality rates are high, especially where skin involvement or attachment to the chest wall is extensive. As such, efficient treatment for this kind of breast cancer includes neoadjuvant chemotherapy (NAC) to shrink the tumor and detach it from the chest wall followed by surgery. Several studies have shown that there is a strong correlation between response to NAC and improved treatment outcomes, including survival rate. Unfortunately, 30% to 40% of patients do not respond to chemotherapy, hence losing critical treatment time and resources. Predicting a patient’s response at the early stages of treatment can help physicians make informed decisions about whether to continue the treatment or use an alternative treatment if a poor response is predicted. Such early and accurate response prediction can shorten the wasted time and reduce resources dedicated to patients while they endure significant side effects. Therefore, it is important to identify this group of non-responder patients as early as possible so that they can be prescribed alternative treatments. Current methods for evaluating LABC response to NAC are based on changes in tumor dimensions using physical examinations or standard anatomical imaging. Such changes may take several months to be detectable. Studies have shown that there is a correlation between LABC response to NAC and tumor softening. In other words, in contrast to responder patients where tumor stiffness generally decreases in response to NAC, in non-responder patients the stiffness of the tumor increases or does not change significantly. As such, a reliable and widely available breast elastography technique can have a major impact on the effective treatment of LABC patients. In this study, we first develop a tissue-mechanics-based method for improving the accuracy of ultrasound elastography. This method consists of 3 steps that are applied to the displacement fields generated from conventional motion-tracking methods. These three steps include: smoothing the displacement fields using Laplacian filtering, enforcing tissue incompressibility equation to refine the displacement fields, and finally enforcing tissue compatibility equation to refine the strain fields. The method was promising through validation using in silico, phantom, and in vivo studies. A huge improvement of this method compared to other motion-tracking methods is its ability in generating lateral displacement with high accuracy. This becomes especially important when the displacement and strain fields are used as inputs to an inverse-problem framework for calculating the stiffness characteristics of tissue, for example, Young’s modulus. We then use this enhanced ultrasound elastography technique to assess the response of LABC patients to NAC based on monitoring the stiffness of their tumors throughout the chemotherapy course. Our results show that this method is effective in predicting patients’ responses accurately as early as 1 week after NAC initiation

Investigation of hypoxia in syngeneic rat prostate tumors after irradiation with photons or carbon ions by multimodal imaging and histology

Tumor hypoxia has been widely recognized as a significant factor that increases treatment resistance and promotes malignant progression. High linear energy transfer (LET) radiotherapy (RT), e.g. with carbon ions (12C-ions), is expected to overcome this resistance factors as its lethality is less dependent on tumor oxygenation as compared to conventional low LET photon irradiation. However, the exact interplay between irradiation response, vascular changes, perfusion, and hypoxia is still not well understood, especially with respect to high LET RT. In the present thesis, the hypoxic status of syngeneic Dunning R3327 rat prostate tumor model sublines was characterized prior to and after irradiation with either low LET photons or high LET 12C-ions by multimodal imaging and histology. The initial oxygenation status of three subcutaneously transplanted Dunning tumor sublines (H, HI and AT1) was determined by photoacoustic imaging (PAI) which included the development and validation of a new PAI analysis protocol. The new protocol enabled the distinction of the three sublines based on their oxygenation profiles and their response towards external changes in oxygen supply. Subsequently, the effects of curative and sub-curative single dose irradiations with either photons or 12C-ions on the two hypoxic tumor sublines (HI and AT1) were investigated by pharmacokinetic modeling of longitudinal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data. For this, a novel method for estimating the contrast agent’s arrival time was developed in cooperation with the group for Image Analysis and Learning of the Interdisciplinary Center for Scientific Computing of Heidelberg University. It enables a delay correction of the contrast agent arrival time which improves fit accuracy and the reliability of the pharmacokinetic modeling results. The moderately differentiated HI-tumor showed increased vascular permeability 7 days after irradiation without any modality or dose dependency, while the anaplastic and chronic hypoxic AT1-tumor revealed an earlier and stronger treatment response after 12C-ion irradiation as compared to the more delayed response after photon irradiation. Again, no dose dependency was detected. Finally, a longitudinal histology study after irradiation of the AT1-tumor with curative doses of either photons or 12C-ions revealed that hypoxia developed slightly faster after 12C-ion than after photon irradiation. Furthermore, this study validated the relative biological effectiveness (RBE) for 12C-ions, which was determined previously for the endpoint local tumor control, on a microscopic level within the first 10 days. Additionally, reasonable time points for a future multimodal imaging study with PAI, sequential positron emission tomography (PET) and DCE-MRI measurements as well as histology were determined. In conclusion, this thesis proved PAI and the novel analysis protocol to be a feasible method for the characterization of the three Dunning tumor sublines with respect to their oxygenation. The different sensitivities of the HI- and AT1-tumors towards the two irradiation modalities indicate that the irradiation-induced vascular response depends on the structural-functional status of the tumor vasculature. The dose-independent response of both tumor sublines towards the two irradiation modalities suggests that the initial vascular response only plays a minor role with respect to local tumor control at high single doses

PET-MR Imaging of Hypoxia and Vascularity in Breast Cancer

Breast cancer is the most common cancer in the UK and in women globally. Imaging methods like mammography, ultrasound (US) and magnetic resonance imaging (MRI) play an important role in the diagnosis and management of breast cancer; they are generally utilised to provide anatomical or structural description of tumours in the clinical setting. It is widely accepted that the tumour microenvironment influences the phenotype, progression and treatment of breast cancer. This gave the impetus to move beyond tumour visualization in images to radiomics in order to provide additional disease characterisation and early biomarkers of tumour response. Due to their ability to assess physiological processes in vivo, positron emission tomography (PET) and MRI can provide non-invasive characterisation of the tumour microenvironment, including perfusion, vascular permeability, cellularity and hypoxia, which is associated with poor clinical outcome and metastasis. Clinical imaging studies in breast tumours have hitherto assessed tumour physiological parameters separately, with only few directly comparing data from these modalities. To this end, hybrid PET-MRI represents an attractive option as it can allow examination of functional processes and features of tumours simultaneously, while also conferring methodological advantages to the way imaging information is combined. The main aim of this thesis is to provide a better understanding of breast cancer pathophysiology using simultaneous PET and multi-parametric MRI. In particular, this work aims to explore relationships between imaging biomarkers of tumour vascularity measured by dynamic contrast-enhanced (DCE) MRI, cellularity using diffusion-weighted imaging (DWI) and hypoxic status using 18F-fluoromisonidazole (18F-FMISO) PET. Correlations between functional PET-MRI parameters and immunohistochemical (IHC) biomarkers of hypoxia and vascularity as well as MRI morphological tumour descriptors are also presented. The thesis concludes with an investigation of the utility of MRI markers of perfusion and surrogate markers of hypoxia to quantitatively monitor and predict pathological response in patients undergoing neoadjuvant chemotherapy (NACT) and provides projections for future work

Addressing the false positive MRI phenotype in prostate cancer diagnosis and management

Multiparametric magnetic resonance imaging (mpMRI) is set to dominate the diagnosis and active surveillance of prostate cancer. However, false positive MRIs confound clinical decision-making and prompt unwarranted biopsies that carry morbidity risks. This is a significant issue: NICE currently recommends pre-biopsy MRI in men with suspected prostate cancer and, as 80,000 patients undergo biopsy every year in England and Wales, between 12,600 to 17,300 are expected to be biopsy-negative. Furthermore, MRI in active surveillance (AS) is strongly recommended by NICE for risk stratification at baseline and for the detection of oncological progression. However, MRI-based AS is new and it is still unknown when observed dynamic MRI changes reflect true transition to clinically significant disease. Recognising this on imaging is important for optimising clinical decisions and reducing the overall number of biopsies during AS. In this thesis it will be shown that MRI lesions seen in biopsy-naïve individuals with clinically significant cancer are larger, more conspicuous and more diffusion-restricted compared to phenotypes seen in men without significant disease. Furthermore, in men with indeterminate MRI phenotypes, PSA density and index lesion ADC predict the presence of significant cancer through a logistic regression model (mean cross-validated AUC: 0.77 [95% CI: 0.67–0.87]) and could help men avoid unnecessary biopsies. It is also shown that false positive MRI phenotypes in such men arise in prostatic regions with increased overall cellularity and expanded epithelium, while assuming either focal or diffuse patterns. In addition, it is demonstrated that MRI-based AS can be safely used to monitor men with insignificant disease, as approximately 84.7% (95% CI: 82.0–87.6) and 71.8% (95% CI: 68.2–75.6) of patients remain on AS at 3 and 5 years (with those with MRI-visible disease at baseline exiting earlier). Finally, it will be shown that progressing MRI lesions during imaging-based AS have two distinct histological phenotypes: one characterised by increased overall cellularity and expansion of epithelial areas (typically seen with transition to higher grade cancer) and another by moderate, standalone stromal hyperplasia seen in cases of pathological stability, not ideally requiring biopsy. This finding could lead to the development of radiological metrics that distinguish the two progression types and spare men from unnecessary biopsies in AS contexts