Mild hyperthermia with magnetic resonance- guided high intensity focused ultrasound combined with salvage chemoradiation for recurrent rectal cancer.

INTRODUCTION: Pelvic recurrences from rectal cancer present a challenging clinical scenario. Hyperthermia represents an innovative treatment option in combination with concurrent chemoradiation to enhance therapeutic effect. We provide the initial results of a prospective single center feasibility study (NCT02528175) for patients undergoing rectal cancer retreatment using concurrent chemoradiation and mild hyperthermia with MR-guided high intensity focused ultrasound (MR-HIFU). METHODS: All patients were deemed ineligible for salvage surgery and were evaluated in a multidisciplinary fashion with a surgical oncologist, radiation oncologist and medical oncologist. Radiation was delivered to a dose of 30.6 Gy in 1.8 Gy per fraction with concurrent capecitabine. MR-HIFU was delivered on days 1, 8 and 15 of concurrent chemoradiation. Our primary objective was feasibility and toxicity. RESULTS: Six patients (total 11 screened) were treated with concurrent chemoradiation and mild hyperthermia with MR-HIFU. Tumor size varied between 3.1-16.6 cm. Patients spent an average of 228 min in the MRI suite and sonication with the external transducer lasted an average of 35 min. There were no complications on the day of the MR-HIFU procedure and all acute toxicities (no grade >/=3 toxicities) resolved after completion of treatment. There were no late grade >/=3 toxicities. CONCLUSION: Mild hyperthermia with MR-HIFU, in combination with concurrent chemoradiation for appropriately selected patients, is safe for localized pelvic recurrences from rectal cancer. The potential for MR-HIFU to be applied in the recurrent setting in rectal cancer treatment requires further technical development and prospective evaluation.

Understanding progressive tissue loss and wound burden in combat casualties: lessons learnt for future operational capability.

Understanding tissue loss following injury is important due to its prevalence among the war-wounded and the impact it has on subsequent treatment and rehabilitation. Progressive tissue loss is a type of tissue loss that has complicated extremity injury in recent conflicts. It has resulted in more proximal residual limb lengths and has influenced rehabilitation. Quantifying wound burden in combat casualties remains a challenge due to poor quality of data sets that lack the capacity for detailed analysis. The aims of this article are to outline the current hurdles in attempting to quantify wound burden in combat casualties and to propose simple interventions to improve data capture for future analysis.

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.

Thin and superthin free flaps: An innovative approach to pediatric extremity reconstruction.

INTRODUCTION: Published standards for the management of open extremity fractures have improved limb salvage, fracture union, and deep infection rates, but the aesthetic and functional importance of our flap choices has been overlooked. Thin and superthin free flaps exhibit advantages over traditional free flaps in some situations but have seldom been reported in children. The aim of this paper is to present our experience of thin and superthin free flaps in pediatric extremity reconstruction. METHODS: Children (≤13 years) who underwent soft tissue reconstruction using a thin and superthin free flap following major extremity trauma are presented. RESULTS: Five patients (5 flaps) met the inclusion criteria. The median age was 9 (range 6-13). There were 3 Gustilo IIIB open fractures and 2 multiplanar degloving injuries. The median mangled extremity severity score (MESS) was 4 (range 2-6). The median time from injury to definitive soft tissue closure was 72 h (range 28-120 h). Four anterolateral thigh (ALT) flaps were raised as thin flaps, and 1 superficial circumflex iliac artery perforator (SCIP) was raised as a superthin flap. There was one re-exploration owing to venous congestion, and a second venous anastomosis was performed to enhance flap drainage. The same ALT flap exhibited necrosis at one margin, which was debrided and grafted before discharge. There were no other flap complications. No flap-related secondary surgeries were required. CONCLUSION: Thin and superthin free flaps are viable options in pediatric extremity reconstruction. They exhibit excellent aesthetic and functional contouring when a slender fasciocutaneous flap is needed, especially when body habitus renders traditional options unfavorable.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Single-Center Evaluation of Treatment Success Using Two Different Protocols for MRI-Guided Transurethral Ultrasound Ablation of Localized Prostate Cancer.

OBJECTIVES: To assess differences in 24-month oncologic and functional outcomes in men with low to intermediate-risk prostate cancer treated with MRI-guided transurethral ultrasound ablation (TULSA) using intentionally conservative versus intensified treatment parameters. PATIENTS AND METHODS: Patients from a single center involved in two multicenter trials were included in this analysis. This included 14 of 30 patients with Gleason 3 + 3 from a Phase I study using intentionally conservative treatment parameters, and 15 of 115 patients with Gleason ≤ 3 + 4 from a pivotal study using intensified parameters. Follow-up data compared across these cohorts included 12-month biopsy and MRI for all patients, and 24-month PSA, micturition and quality of life (IIEF, IPSS, IPSS-QOL). The prognostic value of baseline parameters and PSA kinetics on 12-month histological recurrence was evaluated by logistic regression. RESULTS: 12-month biopsy revealed clinically significant residual disease in 4 (29%) and 2 (14%) patients from the Phase I and pivotal studies, respectively. PSA nadir was 0.7 ng/ml for Phase I and 0.5 ng/ml for pivotal study patients. Patient age at diagnosis, use of MRI fusion/systematic prostate biopsy, number of obtained cores at initial biopsy, PSA course, and PSA nadir were identified as prognostic factors for treatment success. All but one patient from each cohort maintained erection firmness sufficient for penetration. No cases of pad use were reported at 24 months. There were no Grade 4 or higher adverse events, and no late toxicity related to the procedure. CONCLUSION: Two-year follow-up demonstrated the efficacy of TULSA for the treatment of localized prostate cancer, and the durability of PSA and functional outcomes. Intensifying treatment parameters in the pivotal trial had no impact on safety or functional outcomes through 24 months, while reducing the recurrence rate for clinically significant disease. Careful patient selection by MRI fusion/systematic prostate biopsy and adequate follow-up through routine 12-month biopsy are recommended.

Magnetic resonance imaging-guided transurethral ultrasound ablation in patients with localised prostate cancer: 3-year outcomes of a prospective Phase I study.

OBJECTIVES: To report the 3-year follow-up of a Phase I study of magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) in 30 men with localised prostate cancer. Favourable 12-month safety and ablation precision were previously described. PATIENTS AND METHODS: As a mandated safety criterion, TULSA was delivered as near whole-gland ablation, applying 3-mm margins sparing 10% of peripheral prostate tissue in 30 men. After 12-month biopsy and MRI, biannual follow-up included prostate-specific antigen (PSA), adverse events (AEs), and functional quality-of-life assessment, with repeat systematic biopsy at 3 years. RESULTS: A 3-year follow-up was completed by 22 patients. Between 1 and 3 years, there were no new serious or severe AEs. Urinary and bowel function remained stable. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median (interquartile range) nadir of 0.33 (0.1-0.4) ng/mL, stable to 0.8 (0.4-1.6) ng/mL at 3 years. Serial biopsies identified clinically significant disease in 10/29 men (34%) and any cancer in 17/29 (59%). By 3 years, seven men had recurrence (four histological, three biochemical) and had undergone salvage therapy without complications (including six prostatectomies). At 3 years, three of 22 men refused biopsy, and two of the 22 (9%) had clinically significant disease (one new, one persistent). Predictors of salvage therapy requirement included less extensive ablation coverage and higher PSA nadir. CONCLUSION: With 3-year Phase I follow-up, TULSA demonstrates safe and precise ablation for men with localised prostate cancer, providing predictable PSA and biopsy outcomes, without affecting functional abilities or precluding salvage therapy.

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 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.

Plastic surgery training in the UK: Results from a national survey of trainee experiences.

BACKGROUND: Plastic surgery training in the UK continues to evolve towards an outcome-based rather than time-served curriculum. UK plastic surgery trainees are appointed nationally, and are assessed according to national standards, but training is delivered regionally. This study sought opinion from current UK plastic surgery trainees in order to highlight strengths and shortcomings of the higher surgical training programme. METHOD: A cross-sectional study was designed and administered by the UK Plastic Surgery Trainees Association (PLASTA). A questionnaire was distributed to all UK plastic surgery trainees holding a National Training Number, using the REDCap web-based application. RESULTS: Of the 320 UK plastic surgery trainees, 131 (41%) participated in this survey, with responses from all 12 UK training regions. The most common subspecialty career aspirations for trainees were hand surgery, cleft lip and palate, lower limb and oncoplastic breast reconstruction. The survey highlighted regional variation in teaching programmes, the ability to achieve indicative operative logbook numbers, and training in aesthetic surgery. Of the trainees, 82% expressed a desire to undertake a fellowship within their training, but most did not know whether their deanery would support this. Fifteen per cent of the respondents were currently training flexibly and the majority of these had experienced negative behaviours towards their less than full time working status. Of the respondents, 44% reported stress, 25% reported a lack of autonomy and 17% reported feeling burnt out at work at least once a week. A total of 85% perceived that they did not have access to a mentoring service. CONCLUSIONS: Plastic surgery remains a popular and highly competitive surgical speciality in the UK, and many trainees reported high levels of satisfaction during their training. Aspects of training that could be improved have been highlighted and recommendations made accordingly.

MR Imaging-Guided Transurethral Ultrasound Ablation of Localized Prostate Cancer: Preliminary Experience from a Single Center in a Prospective, Multi-Center, Single-Arm Clinical Trial.

This report details a single-center experience of using magnetic resonance imaging-guided transurethral ultrasound ablation (TULSA) for whole-gland prostate treatment. Nine men with organ-confined low-to-intermediate-risk prostate cancer underwent the TULSA procedure. The primary endpoint of reduction of more than 75% was achieved in 8 of 9 patients, and all patients demonstrated a histologic benefit at 12-month biopsy. No major urinary or gastrointestinal side effects were observed, and there were no postprocedural changes in erectile firmness. These findings suggest that TULSA is potentially safe and efficacious for patients with low-to-intermediate-risk disease.

Breath-hold MR-HIFU hyperthermia: phantom and in vivo feasibility.

Background: The use of magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) to deliver mild hyperthermia requires stable temperature mapping for long durations. This study evaluates the effects of respiratory motion on MR thermometry precision in pediatric subjects and determines the in vivo feasibility of circumventing breathing-related motion artifacts by delivering MR thermometry-controlled HIFU mild hyperthermia during repeated forced breath holds.Materials and methods: Clinical and preclinical studies were conducted. Clinical studies were conducted without breath-holds. In phantoms, breathing motion was simulated by moving an aluminum block towards the phantom along a sinusoidal trajectory using an MR-compatible motion platform. In vivo experiments were performed in ventilated pigs. MR thermometry accuracy and stability were evaluated.Results: Clinical data confirmed acceptable MR thermometry accuracy (0.12-0.44 °C) in extremity tumors, but not in the tumors in the chest/spine and pelvis. In phantom studies, MR thermometry accuracy and stability improved to 0.37 ± 0.08 and 0.55 ± 0.18 °C during simulated breath-holds. In vivo MR thermometry accuracy and stability in porcine back muscle improved to 0.64 ± 0.22 and 0.71 ± 0.25 °C during breath-holds. MR-HIFU hyperthermia delivered during intermittent forced breath holds over 10 min duration heated an 18-mm diameter target region above 41 °C for 10.0 ± 1.0 min, without significant overheating. For a 10-min mild hyperthermia treatment, an optimal treatment effect (TIR > 9 min) could be achieved when combining 36-60 s periods of forced apnea with 60-155.5 s free-breathing.Conclusion: MR-HIFU delivery during forced breath holds enables stable control of mild hyperthermia in targets adjacent to moving anatomical structures.

Pediatric Cervicofacial Actinomycosis: Lessons From a Craniofacial Unit.

Actinomycosis is a rare disease that remains difficult to diagnose and manage. Prompted by 2 recent cases the authors sought evidence-based conclusions about best practice. A systematic review was conducted using standard PRISMA methodology. The study was registered prospectively (PROSPERO: CRD42018115064). Thirty-three children from 23 series are described. The mean age was 8 years (range 3-17). Fifty-five percent were female. Twenty cases involved bone (usually mandible); 13 cases involved cervicofacial soft tissue. Poor dental hygiene and oral trauma were implicated. The median diagnostic delay was 12 weeks (range 1-156 weeks). The median duration of definitive antibiotic therapy was 17 weeks (range 1-130 weeks). Although diagnostic delay did not correlate with number of surgeries, bony involvement was associated with more procedures (P = 0.008, unpaired t test). All (6) cases with residual infection had bony involvement (P = 0.06, Fisher exact test). Neither diagnostic delay nor number of surgeries significantly influenced infection-free outcome which, instead, relies on aggressive surgical debridement and prolonged antibiotic therapy. Mandibular involvement exhibits a higher surgical burden and chronicity in around a third of cases. As dental caries are implicated in mandibular disease, preventative strategies must focus on improving pediatric oral hygiene.

The Ideal Nipple Reconstruction Shield.

Reconstruction of the nipple-areola complex is the culmination of a long road for patients who have suffered breast cancer. The postoperative dressing of the reconstructive nipple must protect it from mechanical forces, trauma, and infection. A broad array of dressings has been used for the reconstructed nipple. The authors propose the use of a readily available adhesive eye protector as a simple and cost-effective dressing for the reconstructed nipple-areola complex.

Beyond the L-Strut: Redefining the Biomechanics of Rhinoplasty Using Topographic Optimization Modeling.

Rhinoplasty utilizes cartilage harvested from the nasal septum as autologous graft material. Traditional dogma espouses preservation of the "L-strut" of dorsal and caudal septum, which is less resistant to axial loading than virgin septum. Considering the 90° angle between dorsal and caudal limbs, the traditional L-strut also suffers from localized increases in internal stresses leading to premature septal "cracking," structural-scale deformation, or both. Deformation and failure of the L-strut leads to nasal deviation, saddle deformity, loss of tip support, or restriction of the nasal valve. The balance between cartilage yield and structural integrity is a topographical optimization problem. Guided by finite element (FE) modelling, recent efforts have yielded important modifications including the chamfering of right-angled corners to reduce stress concentrations and the preservation of a minimum width along the inferior portion of the caudal strut. However, all existing FE studies offer simplified assumptions to make the construct easier to model. This review article highlights advances in our understanding of septal engineering and identifies areas that require more work to further refine the balance between the competing interests of graft acquisition and the maintenance of nasal structural integrity.

Multiparametric MRI Characterization of Funaki Types of Uterine Fibroids Considered for MR-Guided High-Intensity Focused Ultrasound (MR-HIFU) Therapy.

RATIONALE AND OBJECTIVES: To compare quantitative multiparametric magnetic resonance imaging (mpMRI) data of symptomatic uterine fibroids being considered for MR-guided high-intensity focused ultrasound ablation with fibroid characterization based on the Funaki Classification scheme. MATERIALS AND METHODS: This was a prospective, Institutional Review Board -approved, Health Insurance Portability, and Accountability Act-compliant study. Informed consent was obtained. From December 2013 to April 2015, 48 women with symptomatic fibroids underwent screening with mpMRI protocol including sagittal/axial T2-weighted fast spin-echo, sagittal diffusion-weighted, and sagittal dynamic contrast-enhanced 3D T1-weighted gradient echo imaging on a 3T magnet. All fibroids were assigned Funaki type 1, 2, or 3 based on T2-weighted imaging. Differences in size, perfusion, and diffusion/intravoxel incoherent motion parameters among the three Funaki types were determined using linear mixed model. A logistic regression analysis was performed to select the best model in predicting type 3 fibroids. RESULTS: A total of 100 fibroids were assessed (20 type 1, 66 type 2, and 14 type 3). Apparent diffusion coefficient and D of type 3 fibroids were significantly higher than those of type 1 (P < 0.0001, P < 0.0001) and 2 fibroids (P = 0.004, P < 0.0001) respectively. Transfer constant of type 3 fibroids was significantly higher than type 1 (P = 0.0357), but not than type 2 (P = 0.0752). A cutoff value of D = 1 × 10-3 mm2/s offers an accuracy, sensitivity, and specificity of 76%, 71%, and 77%, respectively, for the diagnosis of Funaki 3 fibroids. CONCLUSION: mpMRI-derived quantitative parameters may enable a more objective selection of patients prior to MR-guided high-intensity focused ultrasound therapy.