Magnetic Resonance Imaging-Guided Transurethral Ultrasound Ablation of Prostate Cancer

Purpose: Magnetic resonance imaging-guided transurethral ultrasound ablation uses directional thermal ultrasound under magnetic resonance imaging thermometry feedback control for prostatic ablation. We report 12-month outcomes from a prospective multicenter trial (TACT). Materials and methods: A total of 115 men with favorable to intermediate risk prostate cancer across 13 centers were treated with whole gland ablation sparing the urethra and apical sphincter. The co-primary 12-month endpoints were safety and efficacy. Results: In all, 72 (63%) had grade group 2 and 77 (67%) had NCCN® intermediate risk disease. Median treatment delivery time was 51 minutes with 98% (IQR 95-99) thermal coverage of target volume and spatial ablation precision of ±1.4 mm on magnetic resonance imaging thermometry. Grade 3 adverse events occurred in 9 (8%) men. The primary endpoint (U.S. Food and Drug Administration mandated) of prostate specific antigen reduction ≥75% was achieved in 110 of 115 (96%) with median prostate specific antigen reduction of 95% and nadir of 0.34 ng/ml. Median prostate volume decreased from 37 to 3 cc. Among 68 men with pretreatment grade group 2 disease, 52 (79%) were free of grade group 2 disease on 12-month biopsy. Of 111 men with 12-month biopsy data, 72 (65%) had no evidence of cancer. Erections (International Index of Erectile Function question 2 score 2 or greater) were maintained/regained in 69 of 92 (75%). Multivariate predictors of persistent grade group 2 at 12 months included intraprostatic calcifications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume and a PI-RADS™ 3 or greater lesion at 12-month magnetic resonance imaging (p <0.05). Conclusions: The TACT study of magnetic resonance imaging-guided transurethral ultrasound whole gland ablation in men with localized prostate cancer demonstrated effective tissue ablation and prostate specific antigen reduction with low rates of toxicity and residual disease

The effect of primary blast shock wave on skeletal muscle

Explosives continue to be one of the main mechanisms of injury of military personnel and civilians in conflict zones. The range of explosive devices (e.g., mines, artillery shells, improvised explosive devices (IEDs) and grenades) and the variety of environments in which they detonate (e.g., buried in the ground, on the surface, in the air or in confined spaces) means that the mechanical insult to the body and the subsequent injuries are highly variable. One unexplained phenomenon that can follow a blast injury is progressive tissue loss (PTL) in which apparently healthy soft tissue decays in the days and weeks afterwards. The overarching goal of this thesis is to study the effects of primary blast shock wave on the cellular microenvironment of skeletal muscle, in order to understand the role that a blast wave has on the onset of PTL. RNA analysis was carried out on legacy tissue samples from two in vivo experiments involving the exposure of skeletal muscle to a shock wave. The analysis showed that there were several common pathways between the models, and no single mechanism of cell death predominated. Instead, apoptosis, necrosis and necroptosis were upregulated to similar degrees. Therefore indicating that there is a cellular response in skeletal muscle when exposed to a blast wave. Following a review of the literature a 3D model of skeletal muscle was developed by seeding a hydrogel with muscle cells, which demonstrated alignment and myotube fusion after 13 days. Sequencing of the hydrogel RNA revealed expression of key myotube differentiation markers, including Myosin heavy chain isoforms, Paired box proteins 7 and Myogenin. The 3D model was attached to deformable posts and the deflection of the post used to determine the tension generated by the muscle model. Hydrogen peroxide was used as a positive control for injury and the response was characterised using metabolic and RNA sequencing data. The response of the 3D hydrogels to a blast wave was investigated by placing them in an explosively-driven frustum shock tube. The tube was calibrated for a range of explosive charges and measurements showed that 30 g of PE7 explosive produced a blast wave at the target location with a peak overpressure of 697 kPa and a positive phase duration of 2.39ms-1. The blast wave was equivalent to 3.23 kg-TNT at 2 m (assuming a hemispherical blast) and using a blast lethality model was predicted to be more than 50% lethal. A charge of 5 g produced a blast wave that was predicted to be non-lethal. Skeletal muscle hydrogels showed different responses to explosive loading: the 30 g charge resulted in a significant drop in cellular metabolic activity at 2 hours which failed to return to baseline by day 7. The 5 g charge resulted in an increase in metabolic activity over baseline by day 7 indicating that the cells has recovered. There was no detectable change in the tension generated by the hydrogels for either blast condition. In conclusion, this thesis has demonstrated that there is cellular injury from primary blast shock waves, reflected in alterations in metabolic activity and creatinine kinase release, and that this cellular response can be seen in analysis of in vivo tissue samples and captured with a 3D in vitro tissue scaffold model using an experimental blast tube. This suggest that primary blast wave could be responsible for initiating the signalling pathway that results in PTL

Hyperthermia Mediated Drug Delivery using Thermosensitive Liposomes and MRI-Controlled Focused Ultrasound

The clinical efficacy of chemotherapy in solid tumours is limited by systemic toxicity and the inability to deliver a cytotoxic concentration of anticancer drugs to all tumour cells. Temperature sensitive drug carriers provide a mechanism for triggering the rapid release of chemotherapeutic agents in a targeted region. Thermally mediated drug release also leverages the ability of hyperthermia to increase tumour blood flow, vessel permeability, and drug cytotoxicity. Drug release from thermosensitive liposome drug carriers in the tumour vasculature serves as a continuous intravascular infusion of free drug originating at the tumour site. However, localized drug release requires precise heating to improve drug delivery and efficacy in tumours while minimizing drug exposure in normal tissue. Focused ultrasound can noninvasively heat millimeter-sized regions deep within the body, and can be combined with MR thermometry for precise temperature control. This thesis describes the development of strategies to achieve localized hyperthermia using MRI-controlled focused ultrasound, for the purpose of image-guided heat-triggered drug release from thermosensitive drug carriers. First, a preclinical MRI-controlled focused ultrasound system was developed as a platform for studies of controlled hyperthermia and drug delivery in rabbits. The feasibility of using ultrasound hyperthermia to achieve localized doxorubicin release from thermosensitive liposomes was demonstrated in normal rabbit muscle. Second, strategies were described for using MR thermometry to control ultrasound heating at a muscle-bone interface based on MR temperature measurements in adjacent soft tissue, demonstrating localized drug delivery in adjacent muscle and bone marrow. Third, fluorescence microscopy was employed to demonstrate that increased overall drug accumulation in rabbit VX2 tumours corresponds to high levels of bioavailable drug reaching their active site in the nuclei of tumour cells. The results of this thesis demonstrate that image-guided drug delivery using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia can be used to noninvasively achieve precisely localized drug deposition in soft tissue, at bone interfaces, and in solid tumours. Clinical application of this work could provide a noninvasive means of enhancing chemotherapy in a variety of solid tumours.Ph

The pulsatile head mass, ‘uncommon things are sometimes common’. A case series

Introduction: Superficial temporal artery aneurysms account for less than 1% of all reported aneurysms. It is often the result of mild blunt trauma to the side of the head and patients present several weeks later with a pulsatile head mass. Presentation of case: We report two cases referred to surgery in a 3 month period, from the same GP, of patients which this condition. The first case is a 21 year old carpenter who sustained blunt trauma during a rugby match to the side of the head. He presented several weeks later with headache and an otherwise painless pulsatile mass. The second case refers to a 20 year old male who received blunt trauma to the side of head from an assault. He was referred to his GP due family observing a painless pulsatile mass to the scalp. Discussion: These cases highlight the relatively little force required to cause this pathological process. Management of this condition is by surgical excision. Simple examination techniques to obliterate the pulse locally can reveal the diagnosis. Subsequent literature search allowed discussion of the management of this rare but important differential diagnosis of a pulsatile head mass. Conclusion: Although rare, STA represents a complication of low energy trauma that requires elective surgical management

Is Post-Burn Scarring a Research Priority?

National and international research budgets are insufficient to approve all requests for funding, even if a methodology is of high quality and the outputs are likely to have an impact on improving patient outcomes [...

The effect of injected dose on localized tumor accumulation and cardiac uptake of doxorubicin in a Vx2 rabbit tumor model using MR-HIFU mild hyperthermia and thermosensitive liposomes

Purpose When doxorubicin (DOX) is administered via lyso-thermosensitive liposomes (LTLD), mild hyperthermia enhances localized delivery to heated vs. unheated tumors. The optimal LTLD dose and the impact of different doses on systemic drug distribution are unknown. Materials and methods: In this study, we evaluated local and systemic DOX delivery with three LTLD doses (0.1, 0.5, and 2.5 mg/kg) in a Vx2 rabbit tumor model. Temporally and spatially accurate controlled hyperthermia was achieved using a clinical MR-HIFU system for the intended heating duration (40 min). Results: DOX concentration in tissues delivered from LTLD combined with MR-HIFU mild hyperthermia are dose-dependent, including heated/unheated tumor, heart, and other healthy organs. Higher DOX accumulation and tumor-to-heart drug concentration ratio, defined as the ratio of DOX delivered into the tumor vs the heart, were observed in heated tumors compared to unheated tumors in all three tested doses. The DOX uptake efficiency for each mg/kg of LTLD injected IV of heated tumor was significantly higher than that of unheated tumor and heart within the tested dose range (0.1-2.5 mg/kg). The DOX uptake for the heart linearly scaled up as a function of dose while that for the heated tumor showed some evidence of saturation at the high dose of 2.5 mg/kg. Conclusions: These results provide guidance on clinical protocol design of hyperthermia-triggered drug delivery

Protocol for a Global Burns Research Priority Setting Partnership to agree the most important unanswered questions in international burns care

INTRODUCTION: Burns affect 11 million people globally and can result in long-term disability with substantial associated healthcare costs. There is limited research funding to support trials to provide evidence for clinical decision-making. Research prioritisation ensures that research focuses on the topics most important to stakeholders, addressing issues of research waste and evidence gaps. The aim of this project is to agree the global top 10 research priorities important to international patients, carers and clinicians from all income status countries. METHODS AND ANALYSIS: The Global Burns Research Priority Setting Partnership will use James Lind Alliance methods to establish the top 10 research priorities in global burns care. An initial international online multilingual survey will collect candidate research priorities from stakeholders. To increase equity in participation, the survey will also be available via the social media app WhatsApp. Additionally, interviews will be conducted. Data will be analysed to identify and collate research questions and to verify that the priorities are true clinical uncertainties. This list will then be ranked by stakeholders in order of importance via a second online survey. Finally, a consensus meeting will identify the top 10 research priorities. ETHICS AND DISSEMINATION: The University of Bristol Medical School Faculty Ethical Committee has approved this project. Research into burn care should be prioritised to ensure that funding is focused where most needed. This should be undertaken internationally, to ensure inclusion of the views of professionals and patients from lower income countries, where the incidence of thermal burns is highest. The involvement of the James Lind Alliance will ensure that the methodology is robust and that the patient voice is heard. The final top 10 priorities will be disseminated to funders, governments and researchers internationally to inform future global burns research