Hyperoxic BOLD-MRI-Based Characterization of Breast Cancer Molecular Subtypes Is Independent of the Supplied Amount of Oxygen: A Preclinical Study.

Hyperoxic BOLD-MRI targeting tumor hypoxia may provide imaging biomarkers that represent breast cancer molecular subtypes without the use of injected contrast agents. However, the diagnostic performance of hyperoxic BOLD-MRI using different levels of oxygen remains unclear. We hypothesized that molecular subtype characterization with hyperoxic BOLD-MRI is feasible independently of the amount of oxygen. Twenty-three nude mice that were inoculated into the flank with luminal A (n = 9), Her2+ (n = 5), and triple-negative (n = 9) human breast cancer cells were imaged using a 9.4 T Bruker BioSpin system. During BOLD-MRI, anesthesia was supplemented with four different levels of oxygen (normoxic: 21%; hyperoxic: 41%, 71%, 100%). The change in the spin-spin relaxation rate in relation to the normoxic state, ΔR2*, dependent on the amount of erythrocyte-bound oxygen, was calculated using in-house MATLAB code. ΔR2* was significantly different between luminal A and Her2+ as well as between luminal A and triple-negative breast cancer, reflective of the less aggressive luminal A breast cancer's ability to better deliver oxygen-rich hemoglobin to its tissue. Differences in ΔR2* between subtypes were independent of the amount of oxygen, with robust distinction already achieved with 41% oxygen. In conclusion, hyperoxic BOLD-MRI may be used as a biomarker for luminal A breast cancer identification without the use of exogenous contrast agents.

Cross-Modality Imaging of Murine Tumor Vasculature-a Feasibility Study.

Tumor vasculature and angiogenesis play a crucial role in tumor progression. Their visualization is therefore of utmost importance to the community. In this proof-of-principle study, we have established a novel cross-modality imaging (CMI) pipeline to characterize exactly the same murine tumors across scales and penetration depths, using orthotopic models of melanoma cancer. This allowed the acquisition of a comprehensive set of vascular parameters for a single tumor. The workflow visualizes capillaries at different length scales, puts them into the context of the overall tumor vessel network and allows quantification and comparison of vessel densities and morphologies by different modalities. The workflow adds information about hypoxia and blood flow rates. The CMI approach includes well-established technologies such as magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), and ultrasound (US), and modalities that are recent entrants into preclinical discovery such as optical coherence tomography (OCT) and high-resolution episcopic microscopy (HREM). This novel CMI platform establishes the feasibility of combining these technologies using an extensive image processing pipeline. Despite the challenges pertaining to the integration of microscopic and macroscopic data across spatial resolutions, we also established an open-source pipeline for the semi-automated co-registration of the diverse multiscale datasets, which enables truly correlative vascular imaging. Although focused on tumor vasculature, our CMI platform can be used to tackle a multitude of research questions in cancer biology.

Expanding LogP: Present possibilities.

INTRODUCTION: Due to the high candidate exclusion rate during a drug development process, an early prediction of the pharmacokinetic behavior would be needed. Accordingly, high performance bioaffinity chromatography (HPBAC) approaches are growing in popularity, however, there is a lack of knowledge and no consensus about the relation between HPBAC measurements, in vivo distribution and blood brain barrier (BBB) penetration behavior. With respect to radiotracers, there is almost no reference data available for plasma protein binding (PPB), permeability (Pm) and the membrane coefficient (KIAM). Thus, this study was aimed at exploring the relevance of measuring PPB, Pm and KIAM for the prediction of BBB penetration. METHODS: Measurements of %PPB, Pm and KIAM were performed using HPBAC. In total, 113 compounds were tested, 43 with brain uptake, 30 not showing brain uptake and 40 with known interactions with efflux transporters. Additionally, ClogP and HPLC logPowpH7.4 data were collected. RESULTS: %PPB, KIAM, Pm and ClogP values were in the same range for each of the three groups. A significant difference was observed for the HPLC logPowpH7.4 between CNS penetrating drug group (CNSpos) and the non-penetrating drug group (CNSneg), as well as for the CNSneg towards the drug group interacting with efflux transporters (DRUGefflux). However, as the other experimental data, also the HPLC logPowpH7.4 showed a broad overlapping of the single values between the groupings. CONCLUSION: Experimental reference values (logP, Pm, KIAM & PPB) of commonly used PET tracers and drugs showing different BBB penetration behavior are provided. The influence of the logP on brain uptake depends strongly on the selected method. However, using a single parameter (experimental or calculated) to predict BBB penetration or for the classification of drug groups is inexpedient.

Navigated TKA After Osteotomy Versus Primary Navigated TKA: A Matched-Pair Analysis.

This article presents clinical and radiological outcome analysis of navigated total knee arthroplasty (TKA) following osteotomy compared with primary navigated TKA implantation. The study group (29 legs) received navigated TKA (Columbus with deep-dish, cruciate-retaining inlay, Aesculap AG, Tuttlingen, Germany) following distal femoral (6 legs) or high tibial (23 legs) osteotomy, and the control group (29 legs) received a primary navigated TKA. All patients were examined clinically and radiologically in a retrospective matched-pair analysis. Both groups showed comparable clinical scores (Oxford Knee Score, Tegner and Lysholm scores, and Knee Society Score). Radiological evaluations offered no relevant differences. The study group showed a significant mediolateral ligamentous instability (3 legs ≤5°, 1 leg 6°-9°, 25 legs ≥10° mediolateral deviation) compared with the control group (14 legs ≤5°, 9 legs 6°-9°, 6 legs >10°; P<.001). Significantly higher mediolateral ligamentous instability was seen in otherwise comparable clinical and radiological results in patients with navigated TKA implantation following osteotomy, compared with primary TKA. [Orthopedics; 2016. 39(3):S77-S82.].

Whole-body vibration versus eccentric training or a wait-and-see approach for chronic Achilles tendinopathy: a randomized clinical trial.

STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To test the hypothesis that whole-body vibration training results in greater improvements in symptoms and pain, structural changes, and muscle flexibility and strength of the triceps surae muscle-tendon unit than those achieved with eccentric training or with a wait-and-see approach. BACKGROUND: The potential use of vibration training for the treatment of Achilles tendinopathy has not been explored. METHODS: Fifty-eight patients (mean age, 46.0 years) with Achilles tendinopathy were randomly assigned to a 12-week intervention using whole-body vibration training, eccentric training, or a wait-and-see approach. Pain, tendon structure and path, and muscle flexibility and strength were assessed at baseline and follow-up, and compared using mixed-factor analyses of variance. RESULTS: Pain improvements at the midsection of the tendon were greater in the vibration- and eccentric-training groups than in the wait-and-see group (mean difference from the vibration-training group, -18.0; 95% confidence interval [CI]: -35.0, -1.1; mean difference from the eccentric-training group, -27.0; 95% CI: -50.9, -3.1). Improvements in pain at the musculotendinous junction were greater in the eccentric-training group than in the other groups (mean difference from the vibration-training group, -31.4; 95% CI: -60.7, -2.0; mean difference from the wait-and-see group, -50.2; 95% CI: -82.3, -18.1). Improvements in most participants were achieved in the vibration-training group, followed by the eccentric-training group. CONCLUSION: Vibration training may be an alternative or a complementary treatment in patients who do not respond well to eccentric training, especially in those with insertional pain. LEVEL OF EVIDENCE: Therapy, level 2b-.