BackgroundCancer cachexia is a multifactorial wasting syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force‐generating capacity. We address these issues in a novel transgenic mouse model Kras, Trp53, and Pdx‐1‐Cre (KPC) of pancreatic ductal adenocarcinoma using multi‐parametric magnetic resonance measures.MethodsKPC mice (n = 10) were divided equally into two groups (n = 5 per group) depending on the size of the tumour, that is, tumour size <250 and >250 mm3. Using multi‐parametric magnetic resonance measures, we demonstrated the changes in the gastrocnemius muscle at the microstructural level. In addition, we evaluated skeletal muscle contractile function in KPC mice using an in vivo approach.ResultsIncrease in tumour size resulted in decrease in gastrocnemius maximum cross‐sectional area, decrease in T2 relaxation time, increase in magnetization transfer ratio, decrease in mean diffusivity, and decrease in radial diffusivity of water across the muscle fibres. Finally, we detected significant decrease in absolute and specific force production of gastrocnemius muscle with increase in tumour size.ConclusionsOur findings indicate that increase in tumour size may cause alterations in structural and functional parameters of skeletal muscles and that MR parameters may be used as sensitive biomarkers to non‐invasively detect structural changes in cachectic muscles.
Although it has been demonstrated that High Intensity Focused Ultrasound (HIFU) can induce vascular cauterization, acoustic hemostasis technology has not been successful in making the transition from proof-of-concept to clinical settings. One reason for this lack of acceptance is the limited understanding of the fundamental mechanisms involved in ultrasound-vessel and ultrasound-blood interactions. The aim of this research was to investigate the hematological and biochemical mechanisms which are influenced by HIFU induced coagulation. HIFU was used to induce coagulation in an in vitro hematological flow system and in animal models. The flow circuit and in vivo arteries were instrumented with flow probes and thermocouples in the treatment region. Physiological parameters were recorded throughout the in vivo experiments. Blood samples were drawn for analysis prior to, during, and immediately following each HIFU treatment. Clotting time, complete blood count, and biochemical analysis were performed immediately and citrated samples were immediately centrifuged and frozen for future analysis. Results indicate that HIFU can change local and systemic levels of thombin/anti-thrombin complex (TAT) and tissue plasminogen activator (tPA), as well as induce changes in activated clotting time (ACT). These results indicate that HIFU can induce coagulation via the coagulation cascades (TAT) and that normal hematological response to thrombus formation is unaffected.
High-power, short-exposure time, High Intensity Focused Ultrasound (HIFU) treatment protocols are under development that offer the potential to increase procedure throughput and optimize individual therapies. Histological examination and optical image analysis of tissues following dynamic HIFU exposure in ex vivo bovine liver have revealed that cells undergo a fundamentally different form of cell death. The rapid temperature rise due to the HIFU exposure leaves the cells structurally intact but no longer viable, similar to the cell "fixation" induced by snap-freezing. These results suggest that careful choice of both staining technique and metric for determining cell death are important in quantifying type and morphology of cell ablation, and more broadly, safety and efficacy of treatment. This finding is similar to those obtained and under discussion in the laser and RF ablation communities. Specifically, the NADH staining technique is superior to H&E for assessing cell viability, and an alternative measure of cell death may be preferable to the binary thermal dose threshold currently the standard for HIFU treatment. [Work supported by NIH.]
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