Tumor vessel normalization via PFKFB3 inhibition alleviates hypoxia and increases tumor necrosis in rectal cancer upon radiotherapy.

Treatment of patients with locally advanced rectal cancer (RC) is based on neoadjuvant chemoradiotherapy followed by surgery. In order to reduce the development of therapy resistance, it is necessary to further improve previous treatment approaches. Recent in vivo experimental studies suggested that the reduction of tumor hypoxia by tumor vessel normalization (TVN), through the inhibition of the glycolytic activator PFKFB3 could significantly improve tumor response to therapy. We have evaluated in vitro and in vivo the effects of the PFKFB3 inhibitor 2E-3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) on cell survival, clonogenicity, migration, invasion and metabolism using colorectal cancer cells, patient-derived tumor organoids (PDO) and xenografts (PDX). 3PO treatment of colorectal cancer cells increased radiation-induced cell death and reduced cancer cell invasion. Moreover, Gene Set Enrichment Analysis shows that 3PO is able to alter the metabolic status of PDOs towards oxidative phosphorylation. Additionally, in vivo neoadjuvant treatment with 3PO induced TVN, alleviated tumor hypoxia and increased tumor necrosis. Our results support PFKFB3 inhibition as a possible future neoadjuvant addition for rectal cancer patients.

Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients' Outcome.

Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), the impact of radiotherapy on the TME and specifically the tumor immune microenvironment (TIME) is increasingly recognized. Both promoting as well as suppressing effects on anti-tumor immunity have been reported in response to rectal cancer (chemo-)radiotherapy and various targets for combination therapies are under investigation. A literature review was conducted searching the PubMed database for evidence regarding the pleiotropic effects of (chemo-)radiotherapy on the rectal cancer TIME, including alterations in cytokine levels, immune cell populations and activity as well as changes in immune checkpoint proteins. Radiotherapy can induce immune-stimulating and -suppressive alterations, potentially mediating radioresistance. The response is influenced by treatment modalities, including the dosage administered and the highly individual intrinsic pre-treatment immune status. Directly addressing the main immune cells of the TME, this review aims to highlight therapeutical implications since efficient rectal cancer treatment relies on personalized strategies combining conventional therapies with immune-modulating approaches, such as immune checkpoint inhibitors.

Joint image and motion reconstruction for PET using a B-spline motion model.

We present a novel joint image and motion reconstruction method for PET. The method is based on gated data and reconstructs an image together with a motion function. The motion function can be used to transform the reconstructed image to any of the input gates. All available events (from all gates) are used in the reconstruction. The presented method uses a B-spline motion model, together with a novel motion regularization procedure that does not need a regularization parameter (which is usually extremely difficult to adjust). Several image and motion grid levels are used in order to reduce the reconstruction time. In a simulation study, the presented method is compared to a recently proposed joint reconstruction method. While the presented method provides comparable reconstruction quality, it is much easier to use since no regularization parameter has to be chosen. Furthermore, since the B-spline discretization of the motion function depends on fewer parameters than a displacement field, the presented method is considerably faster and consumes less memory than its counterpart. The method is also applied to clinical data, for which a novel purely data-driven gating approach is presented.

Joint reconstruction of image and motion in gated positron emission tomography.

We present a novel intrinsic method for joint reconstruction of both image and motion in positron emission tomography (PET). Intrinsic motion compensation methods exclusively work on the measured data, without any external motion measurements. Most of these methods separate image from motion estimation: They use deformable image registration/optical flow techniques in order to estimate the motion from individually reconstructed gates. Then, the image is estimated based on this motion information. With these methods, a main problem lies in the motion estimation step, which is based on the noisy gated frames. The more noise is present, the more inaccurate the image registration becomes. As we show both visually and quantitatively, joint reconstruction using a simple deformation field motion model can compete with state-of-the-art image registration methods which use robust multilevel B-spline motion models.

A new and general method for blind shift-variant deconvolution of biomedical images.

We present a new method for blind deconvolution of multiple noisy images blurred by a shift-variant point-spread-function (PSF). We focus on a setting in which several images of the same object are available, and a transformation between these images is known. This setting occurs frequently in biomedical imaging, for example in microscopy or in medical ultrasound imaging. By using the information from multiple observations, we are able to improve the quality of images blurred by a shift-variant filter, without prior knowledge of this filter. Also, in contrast to other work on blind and shift-variant deconvolution, in our approach no parametrization of the PSF is required. We evaluate the proposed method quantitatively on synthetically degraded data as well as qualitatively on 3D ultrasound images of liver. The algorithm yields good restoration results and proves to be robust even in presence of high noise levels in the images.

Quality-based registration and reconstruction of optical tomography volumes.

Ultramicroscopy, a novel optical tomographic imaging modality related to fluorescence microscopy, allows to acquire cross-sectional slices of small specially prepared biological samples with astounding quality and resolution. However, scattering of the fluorescence light causes the quality to decrease proportional to the depth of the currently imaged plane. Scattering and beam thickness of the excitation laser light cause additional image degradation. We perform a physical simulation of the light scattering in order to define a quantitative function of image quality with respect to depth. This allows us to establish 3D-volumes of quality information in addition to the image data. Volumes are acquired at different orientations of the sample, hence providing complementary regions of high quality. We propose an algorithm for rigid 3D-3D registration of these volumes incorporating voxel quality information, based on maximizing an adapted linear correlation term. The quality ratio of the images is then used, along with the registration result, to create improved volumes of the imaged object. The methods are applied on acquisitions of a mouse brain and mouse embryo to create outstanding three-dimensional reconstructions.