Novel multiparametric MRI detects improved future liver remnant quality post-dual vein embolization.

BACKGROUND: Optimisation of the future liver remnant (FLR) is crucial to outcomes of extended liver resections. This study aimed to assess the quality of the FLR before and after dual vein embolization (DVE) by quantitative multiparametric MRI. METHODS: Of 100 patients with liver metastases recruited in a clinical trial (Precision1:NCT04597710), ten consecutive patients with insufficient FLR underwent quantitative multiparametric MRI pre- and post-DVE (right portal and hepatic vein). FLR volume, liver fibro-inflammation (corrected T1) scores and fat percentage (proton density fat fraction, PDFF) were determined. Patient metrics were compared by Wilcoxon signed-rank test and statistical analysis done using R software. RESULTS: All patients underwent uncomplicated DVE with improvement in liver remnant health, median 37 days after DVE: cT1 scores reduced from median (interquartile range) 790 ms (753-833 ms) to 741 ms (708-760 ms) p = 0.014 [healthy range <795 ms], as did PDFF from 11% (4-21%), to 3% (2-12%) p = 0.017 [healthy range <5.6%]. There was a significant increase in median (interquartile range) FLR volume from 33% (30-37%)% to 49% (44-52%), p = 0.002. CONCLUSION: This non-invasive and reproducible MRI technique showed improvement in volume and quality of the FLR after DVE. This is a significant advance in our understanding of how to prevent liver failure in patients undergoing major liver surgery.

Optimization of tumor-treating field therapy for triple-negative breast cancer cells in vitro via frequency modulation.

PURPOSE: Currently, tumor-treating field (TTField) therapy utilizes a single "optimal" frequency of electric fields to achieve maximal cell death in a targeted population of cells. However, because of differences in cell size, shape, and ploidy during mitosis, optimal electric field characteristics for universal maximal cell death may not exist. This study investigated the anti-mitotic effects of modulating electric field frequency as opposed to utilizing uniform electric fields. METHODS: We developed and validated a custom device that delivers a wide variety of electric field and treatment parameters including frequency modulation. We investigated the efficacy of frequency modulating tumor-treating fields on triple-negative breast cancer cells compared to human breast epithelial cells. RESULTS: We show that frequency-modulated (FM) TTFields are as selective at treating triple-negative breast cancer (TNBC) as uniform TTFields while having a greater efficacy for combating TNBC cell growth. TTField treatment at a mean frequency of 150 kHz with a frequency range of ± 10 kHz induced apoptosis in a greater number of TNBC cells after 24 h as compared to unmodulated treatment which led to further decreased cell viability after 48 h. Furthermore, all TNBC cells died after 72 h of FM treatment while cells that received unmodulated treatment were able to recover to cell number equivalent to the control. CONCLUSION: TTFields were highly efficacious against TNBC growth, FM TTFields showed minimal effects on epithelial cells similar to unmodulated treatment.

Efficacy and selectivity of tumor-treating field therapy for triple-negative breast cancer cells via in-house delivery device.

PURPOSE: Triple-negative breast cancer continues to be one of the leading causes of death in women, making up 7% of all cancer deaths. Tumor-treating electric fields are low-energy, low-frequency oscillating electric fields that induce an anti-proliferative effect on mitotic cells in glioblastoma multiforme, non-small cell lung cancer, and ovarian cancer. Little is known about effects of tumor-treating fields on triple-negative breast cancer and known research for tumor-treating fields only utilizes low (< 3 V/cm) electric field intensities. METHODS: We have developed an in-house field delivery device capable of high levels of customization to explore a much wider variety of electric field and treatment parameters. Furthermore, we investigated the selectivity of tumor-treating field treatment between triple-negative breast cancer and human breast epithelial cells. RESULTS: Tumor-treating fields show greatest efficacy against triple-negative breast cancer cell lines between 1 and 3 V/cm electric field intensities while having little effect on epithelial cells. CONCLUSION: These results provide a clear therapeutic window for tumor-treating field delivery to triple-negative breast cancer.

Precision medicine for liver tumours with quantitative MRI and whole genome sequencing (Precision1 trial): study protocol for observational cohort study.

INTRODUCTION: Radiogenomic analysis of patients being considered for liver resection is seldom performed in the clinic despite recent evidence indicating that quantitative MRI could improve posthepatectomy outcomes. Meanwhile, the increasingly accessible results from whole genome sequencing reporting on clinically actionable genetic biomarkers are yet to be fully integrated into the clinical care pathway. METHODS AND ANALYSIS: A prospective observational cohort study of up to 200 participants is planned, recruiting adults with primary or secondary liver cancer being considered for liver resection at Hampshire Hospitals NHS Foundation Trust. The data will be evaluated to address the primary endpoint to calculate the proportion of participants in which the results from whole genome sequencing would have resulted in a change in clinical management. Participants will be offered an additional non-invasive quantitative MRI scan prior to the operation and the impact of the imaging results on treatment decision-making will be evaluated. ETHICS AND DISSEMINATION: This study was reviewed by the NHS Health Research Authority and given favourable opinion by the Brighton and Sussex Research Ethics Committee (REC reference: 20/PR/0222). Research findings will be discussed with a patient and public involvement and engagement group, presented at relevant scientific conferences and published in open access journals. TRIAL REGISTRATION NUMBER: NCT04597710.

Image-Guided Magnetic Thermoseed Navigation and Tumor Ablation Using a Magnetic Resonance Imaging System.

Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image-guided remote-control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage-guided Ablation (MINIMA), a novel, minimally invasive, MRI-guided ablation technique, which has the potential to avoid traditional toxicities, is presented. It comprises a thermoseed navigated to a target site using magnetic propulsion gradients generated by an MRI scanner, before inducing localized cell death using an MR-compatible thermoablative device. The authors demonstrate precise thermoseed imaging and navigation through brain tissue using an MRI system (0.3 mm), and they perform thermoablation in vitro and in vivo within subcutaneous tumors, with the focal ablation volume finely controlled by heating duration. MINIMA is a novel theranostic platform, combining imaging, navigation, and heating to deliver diagnosis and therapy in a single device.

Quantitative magnetic resonance imaging predicts individual future liver performance after liver resection for cancer.

The risk of poor post-operative outcome and the benefits of surgical resection as a curative therapy require careful assessment by the clinical care team for patients with primary and secondary liver cancer. Advances in surgical techniques have improved patient outcomes but identifying which individual patients are at greatest risk of poor post-operative liver performance remains a challenge. Here we report results from a multicentre observational clinical trial (ClinicalTrials.gov NCT03213314) which aimed to inform personalised pre-operative risk assessment in liver cancer surgery by evaluating liver health using quantitative multiparametric magnetic resonance imaging (MRI). We combined estimation of future liver remnant (FLR) volume with corrected T1 (cT1) of the liver parenchyma as a representation of liver health in 143 patients prior to treatment. Patients with an elevated preoperative liver cT1, indicative of fibroinflammation, had a longer post-operative hospital stay compared to those with a cT1 within the normal range (6.5 vs 5 days; p = 0.0053). A composite score combining FLR and cT1 predicted poor liver performance in the 5 days immediately following surgery (AUROC = 0.78). Furthermore, this composite score correlated with the regenerative performance of the liver in the 3 months following resection. This study highlights the utility of quantitative MRI for identifying patients at increased risk of poor post-operative liver performance and a longer stay in hospital. This approach has the potential to inform the assessment of individualised patient risk as part of the clinical decision-making process for liver cancer surgery.

Multi-modal imaging probe for assessing the efficiency of stem cell delivery to orthotopic breast tumours.

Stem cells have been utilised as anti-cancer agents due to their ability to home to and integrate within tumours. Methods to augment stem cell homing to tumours are being investigated with the goal of enhancing treatment efficacy. However, it is currently not possible to evaluate both cell localisation and cell viability after engraftment, hindering optimisation of therapy. In this study, luciferase-expressing human adipocyte-derived stem cells (ADSCs) were incubated with Indium-111 radiolabelled iron oxide nanoparticles to produce cells with tri-modal imaging capabilities. ADSCs were administered intravenously (IV) or intracardially (IC) to mice bearing orthotopic breast tumours. Cell fate was monitored using bioluminescence imaging (BLI) as a measure of cell viability, magnetic resonance imaging (MRI) for cell localisation and single photon emission computer tomography (SPECT) for cell quantification. Serial monitoring with multi-modal imaging showed the presence of viable ADSCs within tumours as early as 1-hour post IC injection and the percentage of ADSCs within tumours to be 2-fold higher after IC than IV. Finally, histological analysis was used to validate engraftment of ADSC within tumour tissue. These findings demonstrate that multi-modal imaging can be used to evaluate the efficiency of stem cell delivery to tumours and that IC cell administration is more effective for tumour targeting.

Noninvasive quantification of oxygen saturation in the portal and hepatic veins in healthy mice and those with colorectal liver metastases using QSM MRI.

PURPOSE: This preclinical study investigated the use of QSM MRI to noninvasively measure venous oxygen saturation (SvO2) in the hepatic and portal veins. METHODS: QSM data were acquired from a cohort of healthy mice (n = 10) on a 9.4 Tesla MRI scanner under normoxic and hyperoxic conditions. Susceptibility was measured in the portal and hepatic veins and used to calculate SvO2 in each vessel under each condition. Blood was extracted from the inferior vena cava of 3 of the mice under each condition, and SvO2 was measured with a blood gas analyzer for comparison. QSM data were also acquired from a cohort of mice bearing liver tumors under normoxic conditions. Susceptibility was measured, and SvO2 calculated in the portal and hepatic veins and compared to the healthy mice. Statistical significance was assessed using a Wilcoxon matched-pairs signed rank test (normoxic vs. hyperoxic) or a Mann-Whitney test (healthy vs. tumor bearing). RESULTS: SvO2 calculated from QSM measurements in healthy mice under hyperoxia showed significant increases of 15% in the portal vein (P < 0.05) and 21% in the hepatic vein (P < 0.01) versus normoxia. These values agreed with inferior vena cava measurements from the blood gas analyzer (26% increase). SvO2 in the hepatic vein was significantly lower in the colorectal liver metastases cohort (30% ± 11%) than the healthy mice (53% ± 17%) (P < 0.05); differences in the portal vein were not significant. CONCLUSION: QSM is a feasible tool for noninvasively measuring SvO2 in the liver and can detect differences due to increased oxygen consumption in livers bearing colorectal metastases.

Bringing the heavy: carbon ion therapy in the radiobiological and clinical context.

Radiotherapy for the treatment of cancer is undergoing an evolution, shifting to the use of heavier ion species. For a plethora of malignancies, current radiotherapy using photons or protons yields marginal benefits in local control and survival. One hypothesis is that these malignancies have acquired, or are inherently radioresistant to low LET radiation. In the last decade, carbon ion radiotherapy facilities have slowly been constructed in Europe and Asia, demonstrating favorable results for many of the malignancies that do poorly with conventional radiotherapy. However, from a radiobiological perspective, much of how this modality works in overcoming radioresistance, and extending local control and survival are not yet fully understood. In this review, we will explain from a radiobiological perspective how carbon ion radiotherapy can overcome the classical and recently postulated contributors of radioresistance (α/ß ratio, hypoxia, cell proliferation, the tumor microenvironment and metabolism, and cancer stem cells). Furthermore, we will make recommendations on the important factors to consider, such as anatomical location, in the future design and implementation of clinical trials. With the existing data available we believe that the expansion of carbon ion facilities into the United States is warranted.

Structural and functional effects of metastases in rat brain determined by multimodal MRI.

Metastasis to the brain results in significant impairment of brain function and poor patient survival. Currently, magnetic resonance imaging (MRI) is under-utilised in monitoring brain metastases and their effects on brain function. Here, we sought to establish a model of focal brain metastasis in the rat that enables serial multimodal structural and functional MRI studies, and to assess the sensitivity of these approaches to metastatic growth. Female Berlin-Druckrey-IX rats were injected intracerebrally with metastatic ENU1564 cells in the ventroposterior medial nucleus (VPM) of the thalamus, a relay node of the whisker-to-barrel cortex pathway. Animals underwent multimodal structural and vascular MRI, as well as functional MRI of the cortical blood oxygenation level dependent (BOLD) responses to whisker pad stimulation. T2 , diffusion, magnetisation transfer and perfusion weighted MRI enabled differentiation between a central area of more advanced metastatic growth and penumbral regions of co-optive perivascular micrometastatic growth, with magnetisation transfer MRI being the most sensitive to micrometastatic growth. Areas of cortical BOLD activation in response to whisker pad stimulation were significantly reduced in the hemisphere containing metastases in the VPM. The reduction in BOLD response correlated with metastatic burden in the thalamus, and was sensitive to the presence of smaller metastases than currently detectable clinically. Our findings suggest that multimodal MRI provides greater sensitivity to tumour heterogeneity and micrometastatic growth than single modality contrast-enhanced MRI. Understanding the relationships between these MRI parameters and the underlying pathology may greatly enhance the utility of MRI in diagnosis, staging and monitoring of brain metastasis.

Selective permeabilization of the blood-brain barrier at sites of metastasis.

BACKGROUND: Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases. METHODS: BALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadolinium- diethylenetriaminepentaacetic acid, horseradish peroxidase, or radiolabeled trastuzumab ((111)In-BnDTPA-Tz) was injected intravenously. BBB permeability was assessed in vivo using gadolinium-enhanced T1-weighted magnetic resonance imaging and confirmed histochemically. Brain uptake of (111)In-BnDTPA-Tz was determined using in vivo single photon emission computed tomography/computed tomography. Endothelial expression of TNF receptors was determined immunohistochemically in both mouse and human brain tissue containing metastases. Group differences were analyzed with one-way analysis of variance followed by post hoc tests, Wilcoxon signed rank test, and Kruskal-Wallis with Dunn's multiple comparison test. All statistical tests were two-sided. RESULTS: Localized expression of TNF receptor 1 (TNFR1) was evident on the vascular endothelium associated with brain metastases. Administration of TNF or LT permeabilized the BBB to exogenous tracers selectively at sites of brain metastasis, with peak effect at 6 hours. Metastasis-specific uptake ratio of (111)In-BnDTPA-Tz was also demonstrated after systemic TNF administration vs control (0.147±0.066 vs 0.001±0.001). Human brain metastases displayed a similar TNF receptor profile compared with the mouse model, with predominantly vascular TNFR1 expression. CONCLUSIONS: These findings describe a new approach to selectively permeabilize the BBB at sites of brain metastases to aid in detection of micrometastases and facilitate tumor-specific access of chemotherapeutic agents. We hypothesize that this permeabilization works primarily though TNFR1 activation and has the potential for clinical translation.

Enhanced dosimetry procedures and assessment for EBT2 radiochromic film.

PURPOSE: Quantitatively determine an optimum image analysis procedure to mitigate inhomogeneities within the EBT2 film and from scanning for accurate absolute dose measurement deposited by an external radiation therapy beam. Multichannel dosimetry procedures were conceived, described, and quantitatively tested against single and dual channel dosimetry. METHODS: A solid water(TM) block was placed on CT imaging and treatment tables in a configuration that avoids bulky compressive devices. CT markers helped register the CT to the treatment plan and the radiation dose distribution from the radiochromic film. The CT images were digitally rotated and resampled to match the spatial resolution of the scanned dosimetric distribution and treatment plan. The ECLIPSE treatment plan planes were digitally translated through digital triangulation of the treatment isocenter to the CT markers in the CT image. A 6 MV photon beam, conforming to the treatment plan, irradiated the EBT2 film sandwiched between solid water(TM) slabs. The exposed radiochromic film images were rotated and translated to the CT images using coincident markers in the CT image that are associated with "tattoos" marked on the radiochromic film. The exposed radiochromic film gray-levels from a flatbed scanner in reflection mode were converted to dose using calibration films. The test dose distribution was scanned and averaged six times to reduce temporal noise. This study generated dose distributions using the red channel alone, green channel alone, ratio of the red to blue channel, ratio of the green to blue channel, a hybrid approach combining the green to blue ratio for higher doses (>80 cGy) with the red to blue ratio (<80 cGy), multichannel averaging and optimized autonomous multichannel correction. Single channel, multichannel, and channel ratio methods for processing the exposed radiochromic film were compared to the treatment plan via gamma analysis. The ellipsoidal decision surface was defined by its axes of 3% of the maximum dose and 3 mm in the horizontal and vertical directions. RESULTS: The multichannel dosimetry procedures provided excellent agreement with calculation of the dose distribution as determined by the gamma analysis. The green channel mostly performed as well or better than the red channel. The green to blue channel ratio for doses when combined with red to blue ratio ("Hybrid") achieved a high level performance. In addition, new registration procedures were developed and tested for aiding the comparison of calculated and experimentally determined dose distributions. CONCLUSIONS: This study described, developed, and tested new processing methods for reducing inaccuracies in absolute dose determination due to inhomogeneities within the film and from scanning. This study found better performance using optimized multichannel following averaging of all color channels. Combining the channel ratios in a hybrid approach also achieved high performance. Averaging the test films reduced temporal noise that severely degraded the blue channel. This methodology avoided using cumbersome, registered correction matrices. Novel registration and digital rotation of CT images enabled quantitative testing and helped improve contact between the radiochromic film and phantom.

Fiducial markers in prostate for kV imaging: quantification of visibility and optimization of imaging conditions.

The purpose of this work is to investigate possible smaller, less-dense fiducial markers implantable into the prostate for target localization and patient repositioning verification in an on-board kV-kV imaging system on a proton gantry. The experiments used a pelvic phantom and a variety of commercially available fiducial markers: CIVCO carbon marker of ϕ; 1 × 3 mm, gold seed markers of ϕ; 0.8 × 3 mm and ϕ; 1.2 × 3 mm, and IBA Visicoil helical gold linear markers in diameters of 0.35, 0.50, 0.75 and 1.15 mm. Two orthogonal on-board kV imagers were arranged for digital radiographic imaging of the phantom through the lateral and anterior-posterior directions. The contrast-to-noise ratio (CNR) for a given marker was calculated and used as a quantitative measure of its visibility. The patient entrance skin exposure (ESE) was measured and parameterized for kVp, mAs and source-to-surface distance. The ratio of CNR to ESE was first introduced to characterize the efficiency for imaging a marker using a given x-ray technique in order to optimize the marker's visibility and simultaneously minimize the x-ray imaging dose. If CNR > 2, which corresponds to a significance p < 0.05, is required for acceptable visibility, the carbon marker and the smallest Visicoil marker are not suitable for imaging through dense bone but the others are capable of being employed in the clinic. It is predicted that other markers in development should have a greater thickness than equivalent of 0.14 mm thick gold in order to produce the acceptable visibility in the lateral kV imaging. The linear Visicoil marker of ϕ; 0.50 × 5 mm is most suitable for kV imaging in the prostate for proton therapy as it induces the least proton dose perturbation amongst the acceptable markers. An optimal range of 120-130 kVp and 40-80 mAs is determined using the maximal CNR/ESE and CNR > 2 for laterally imaging this marker in the prostate.