Association of follow-up imaging frequency with temporal incidence and patterns of distant failure following (chemo) radiotherapy for HPV related oropharyngeal cancer.

OBJECTIVES: Emerging data supports radical intent therapy for oligometastatic (OM) relapsed human papilloma virus (HPV+) related oropharyngeal cancer (OPC). We assess the association of follow-up imaging frequency amongst HPV + OPC, with temporal and spatial patterns of distant relapse, to inform rationalisation of routine post-treatment imaging. MATERIALS AND METHODS: A retrospective single centre cohort study was carried out of consecutive HPV + OPC patients treated with radical intent (chemo)radiotherapy ((CT)RT) between 2011 and 2019. OM state was defined as ≤ 5 metastasis, none larger than 3 cm (OMs) or, if interval from last negative surveillance imaging > 6-months, then ≤ 10 metastasis, none larger than 5 cm, (OMp). Patients not meeting OMs / OMp criteria were deemed to have incurable diffuse metastatic disease (DMdiffuse). RESULTS: 793 HPV-OPC patients were identified with median follow-up 3.15years (range 0.2-8.9). 52 (6.6 %) patients had radiologically identified DM at first failure and were considered for analysis. The median time to recurrence was 15.1 months (range: 2.6-63 months). 87 % of distant metastasis (DM) occurred in the first two years after treatment. Twenty-seven (52 %) patients had OM (OMs or OMp) at time of failure, with 31 % having OMs. The median time from completion of treatment to diagnosis of DMdiffuse vs OM was 22.2 months (range: 2.6-63.1 months) vs 11.6 months (range: 3.5-32.5 months). The probability of being diagnosed with OM vs DMdiffuse increased with reducing interval from last negative surveillance scan to imaging identifying DM (≤6 months 88.9 %, 7-12 months 71.4 %, 13-24 months 35 %, > 24 months 22.2 %). CONCLUSION: We demonstrate that a reduced interval between last negative imaging and subsequent radiological diagnosis of DM is associated with increased likelihood of identification of OM disease. Consideration of increased frequency of surveillance imaging during the first two years of follow up is supported, particularly for patients at high risk of distant failure.

First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. CONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy.

Exploring Hypoxia in Prostate Cancer With T2-weighted Magnetic Resonance Imaging Radiomics and Pimonidazole Scoring.

BACKGROUND/AIM: Radiomics involves high throughput extraction of mineable precise quantitative imaging features that serve as non-invasive prognostic or predictive biomarkers. High levels of hypoxia are associated with a poorer prognosis in prostate cancer and limit radiation therapy efficacy. Most patients with prostate cancer undergo magnetic resonance imaging (MRI) as a part of their diagnostics, and T2 imaging is the most utilised imaging method. The aim of this study was to determine whether hypoxia in prostate tumors could be identified using a radiomics model extracted from T2-weighted MR images. MATERIALS AND METHODS: Eighty eight intermediate or high-risk prostate cancer patients were evaluated. Prior to radical prostatectomy, all patients received pimonidazole (PIMO). PIMO hypoxic scores were assigned in whole-mount sections from prostatectomy specimens by an experienced pathologist who was blinded to MRI. The region of interest used for radiomics analysis included the prostatic index tumor. Radiomics extraction yielded 165 features using a special evaluation version of RadiomiX [RadiomiX Research Toolbox version 20180831 (OncoRadiomics SA, Liège, Belgium)] for non-clinical use. Multivariable logistic regression with Elastic Net regularization was utilised using 10 times repeated 10-fold cross-validation to select the best model hyperparameters, optimizing for area under the receiver operating characteristic curve (AUC). RESULTS: The average (out of sample) performance based on the repeated cross validation using the ONESE model yielded an AUC of 0.60±0.2. Shape-based features were the most prominent in the model. CONCLUSION: The development of a radiomics hypoxia model using T2 weighted MR images, standard in the staging of prostate cancer, is possible.

Evaluation of the quality of fit of flexible bolus material created using 3D printing technology.

AIMS: To retrospectively evaluate the quality of fit of 3D printed bolus over four different treatment sites to determine whether certain sites favor a 3D printed approach and if the quality of fit changes over the course of treatment. MATERIALS AND METHODS: A retrospective analysis of the first 60 cases treated using 3D printed bolus in our radiotherapy center was undertaken. All boluses were printed using flexible thermoplastic polyurethane (TPU) material. We developed a system of rating the quality of fit using four quality categories. The analysis of 60 patients consisted of a review of a total 627 treatment fractions for head and neck (H&N), scalp, pelvis, and extremity treatment sites. RESULTS: Out of 627 fractions evaluated, 75.1% were rated either "good" or "excellent", 20.6% were rated as "acceptable" and 4.3% were rated "poor". H&N, scalp, and extremity treatment regions were found to favor a 3D printed approach. However, pelvis cases had a higher proportion of "acceptable" and "poor" ratings. Trend analysis showed no notable change in the quality of 3D printed bolus fit over the course of treatment, except for pelvis cases which tended to change categories more than other treatment sites. CONCLUSION: This evaluation demonstrates that 3D printed bolus, created using semi-flexible materials such as TPU, is an effective and practical bolus choice for radiotherapy. In particular, using a 3D printed approach for H&N, scalp, and extremities was found to have a highly conformal fit.

Prevalence of Hip Ultrasound Abnormalities in Newborns With a Hip Click.

A hip click on examination of the newborn hip is believed to be the result of a ligament or myofascial structure and thought to be benign. Some studies suggest a link between hip clicks and developmental dysplasia of the hip. The purpose of our study is to estimate the prevalence of ultrasound hip abnormalities in newborns with a hip click and an otherwise normal physical examination. Results. Ninety patients meeting inclusion criteria of a hip click with an otherwise normal physical examination underwent diagnostic ultrasound with a 17.8% prevalence of hip abnormalities found (95% confidence interval ±7.9% [range of 9.9% to 25.7%]). Our study had 64 (71%) females and 26 (29%) males. The prevalence of hip pathology for females was 18.8% (12 of 64 patients) and for males was 15.4% (4 of 26 patients). Thirty-three patients were found to have bilateral hip clicks on presentation, with 21.2% (7 of 33) of those patients found to have hip pathology on ultrasound (3 of the 7 had pathology of both hips). Six patients had a family history of hip dysplasia and 1 of these patients (16.7%) had pathology on ultrasound. The average age to hip sonography was 6.6 weeks. Conclusions. In all, 17.8% of newborns with a hip click were found to have hip abnormalities on ultrasound. The prevalence of hip pathology, on ultrasound, suggests that additional larger, prospective studies are needed to clarify the association between a hip click and abnormal ultrasound found at 6 weeks of age or greater.

Conversion of a Conference Room into a Low-Acuity Inpatient Medical Unit: A Creative Response to Influenza-Related Surge.

The 2017-2018 influenza season was associated with high demand for both emergency department (ED) care and inpatient acute care for influenza-like illness (ILI). This high demand resulted in increased numbers of inpatients and ED patients, including prolonged ED length of stay. A large, urban, academic medical center in a cold-weather region was limited in its ability to expand its footprint to create de novo locations of care, such as temporary outbuildings or tents. As such, a large conference room was rapidly converted and placed in service as a temporary inpatient unit for adults requiring inpatient admission. LOGISTICS AND IMPLEMENTATION: The logistical, infection prevention, safety, information technology, staffing, and other concerns of creating a clinical environment during a high demand scenario is challenging. However, the lessons learned in this study are reproducible despite the complexity of this issue. CONCLUSION: This is believed to be the first published account of successful conversion of a nonclinical area to an operational clinical unit in response to a surge in demand for hospital care and admission. This may be a valid option for hospitals of all sizes as part of a surge or disaster plan.

Decreasing Unplanned Office Visits Due to Cast Problems in the Pediatric Population.

INTRODUCTION: Unplanned office visits due to cast-related problems in the pediatric orthopedic office are common. Decreasing problems associated with the use of a cast would improve patient safety, increase office productivity, and decrease inconvenience to the child and family. METHODS: Pediatric patients treated with a cast in our office were included in the study if they returned for an unplanned office visit due to a cast-related problem. Group 1 received verbal cast care instruction. Group 2 had the same verbal instruction in addition to a written handout identical to the verbal instructions. Group 3 was provided the same verbal instructions and a revised handout limiting the number of instructions and focused on keeping the cast away from water. RESULTS: The study included 550 patients with 146 in group 1, 124 in group 2, and 280 in group 3. Comparing group 1 (10.3%) and group 2 (10.5%), there was almost no difference in the rate of unplanned office visits due to cast-related problems. Combining the revised handout with verbal instructions in group 3, the percentage of patients returning for an unplanned visit was 6%. There was a relative decrease in office visits by 55% and an absolute decrease of 4.5% when comparing group 2 and group 3. CONCLUSIONS: There was a decrease in the number of unplanned office visits due to cast problems utilizing a handout focused on keeping the cast dry in collaboration with verbal cast care instructions. However, the decrease was not statistically significant.

Musculoskeletal Injuries Associated With Hoverboard Use in Children.

Hoverboards burst onto the scene with wide popularity only to be quickly deemed unsafe and banned in many arenas. We conducted a retrospective cohort study of 35 patients seen in our outpatient pediatric orthopedic office over a 1-year period. The mean age of injured patients was 11.14 years; 18 patients were male (51.4%), and 17 were female (48.5%). The highest number of injuries occurred in children 10 to 14 years old who had 57.1% of the injuries. There were a total of 31 fractures in 27 patients. Most of the fractures were in the upper extremities (93.6 %). Also, 9 soft-tissue injuries were found in 8 patients; 88.9 % of injuries occurred in the upper extremities. Most of the injuries were secondary to a fall (94.3%). We found that the most common injury was upper-extremity fracture. We suggest restricting riding <16 years and encourage protective equipment, especially elbow and wrist guards.

Personal reflections on the inspections of the Defence Medical Services by the Healthcare Commission and Care Quality Commission.

The Defence Medical Services (DMS) have been inspected by the Healthcare Commission and by the Care Quality Commission. Both inspections reported a mixed picture: high quality in some areas, particularly those concerned with operational casualties, but room for improvement in other areas, particularly the infrastructure of home-base primary care. The DMS valued the external validation of their own systems of quality assurance, and the findings of the inspectors have supported progress in areas where resource constraints have been difficult to overcome. Other findings have encouraged attention to areas of practice that needed improvement. The benefit of these inspections cannot be realised unless the organisation is prepared to accept adverse observations not as criticism but as opportunities for improvement. The inspections also benefitted the inspectors, providing a different and interesting clinical environment, and some benchmarking for future inspections of civilian general practice.

Preventable childhood injuries.

BACKGROUND: This is a literature review generated from The Committee on Trauma and Prevention of Pediatric Orthopaedic Society of North America to bring to the forefront 4 main areas of preventable injuries in children. METHODS: Literature review of pertinent published studies or available information of 4 areas of childhood injury: trampoline and moonbouncers, skateboards, all-terrain vehicles, and lawn mowers. RESULTS: Much literature exists on these injuries. CONCLUSIONS: Preventable injuries occur at alarming rates in children. By arming the orthopaedist with a concise account of these injuries, patient education and child safety may be promoted. LEVEL OF EVIDENCE: 3.

Subsurface interactions of Fe(II) with humic acid or landfill leachate do not control subsequent iron(III) (hydr)oxide production at the surface.

At least 93% of Fe(II) remained free, as defined by ferrozine assay under anoxic conditions in the presence of humic acid (HA) and two simulated landfill leachates of different maturities. However, tangential flow ultrafiltration showed a weaker but more extensive interaction of Fe with organic carbon (OC); 90% of Fe associated with the less mature leachate. Despite the existence of this weak interaction under anoxic conditions, there was no difference in iron(III) (hydr)oxide production whether HA was added prior to or coincident with the oxidation of Fe(II) on exposure to oxic conditions. Under oxic conditions ferrozine showed that more Fe(II) bound to OC, up to 50% to HA. However, this occurs via oxidation of Fe(II) to Fe(III), which is bound and then thermally reduced. This affinity for Fe(III) and the ability to carry out thermal reduction both increase with the maturity of the OC. The rate at which ferrozine-defined free Fe(II) was lost on exposure to dissolved oxygen was also enhanced by the more mature OC, while it was slowed by acetogenic leachate. The slowing must be a consequence of the filtration-defined Fe(II)/OC interaction.

Impact of fractures on school attendance.

BACKGROUND: The purpose of this study was to determine the average prevalence of children across the nation who experience difficulty in attending school after an acute orthopaedic injury. METHODS: A survey was created to obtain information on school absence for children with acute orthopaedic injuries. All members of the Pediatric Orthopaedic Society of North America were invited to complete the survey. RESULTS: The survey was sent by e-mail to 936 members of the Pediatric Orthopaedic Society of North America. A total of 283 surgeons from 45 states responded to the survey, which resulted in a response rate of 30.2%. The survey found a correlation with difficulty in attending school with a cast and the size of the population served. Communities with the larger populations are less likely to permit children to attend school with a cast. The most common reasons given by schools for a child not being permitted to attend school with a cast were concern for the safety of the child and inability to accommodate the needs of the child. CONCLUSIONS: Most physicians participating in the survey reported no difficulty with their patients attending school with a cast. There was more difficulty with children in attending school with a cast in metropolitan areas and in communities with greater than 1 million people. To decrease or to eliminate absence from school, it may be best to identify schools in a physician's community that do not allow attendance of children with a cast. Once individual schools are identified, advocacy can be targeted. At the very least, when it is known which schools are involved, the surgeon can anticipate difficulties and plan accordingly. As a child's absence from school has substantial negative consequences, we strongly support intervention to enable injured children to appropriately return to a regular educational setting in a timely manner. Future studies with school participation would help to identify reasons for school absence after a musculoskeletal injury. LEVEL OF EVIDENCE: Level V, Prognostic.

Therapeutic applications of hyaluronan.

Hyaluronan (HA), a multifunctional, high molecular weight glycosaminoglycan, is a component of the majority of extracellular matrices. HA is synthesised in a unique manner by a family of hyaluronan synthases, degraded by hyaluronidases and exerts a biological effect by binding to families of cellular receptors, the hyaladhedrins. Receptor binding activates signal pathways in endothelial cells leading to proliferation, migration and differentiation collectively termed angiogenesis. HA and associated enzymes are implicated in the aetiology of cardiovascular disease and cancer and manipulation of HA expression offers a therapeutic target. HA microspheres have been developed as drug delivery agents to deliver HA to sites of disease and also in diagnosis. In this review we discuss some of the recent therapeutic applications of hyaluronan in tissue repair, as a drug delivery system and the synthesis, application and delivery of hyaluronan nanoparticles to target drugs to sites of disease.

Use of the Gartland classification system for treatment of pediatric supracondylar humerus fractures.

The extension-type pediatric supracondylar humerus fracture accounts for nearly two-thirds of all pediatric hospitalizations due to elbow trauma. The Gartland classification guides the standard of care for treatment of this entity. Type I injuries are treated with cast immobilization while type II and III injuries are treated operatively. The reported interobserver reliability ranges from moderate to full agreement, which is on par with other frequently referenced classification systems such as Lauge-Hansen for adult ankle fractures. In this study, 4 fellowship-trained pediatric orthopedic surgeons reviewed radiographs of 72 pediatric supracondylar fractures and classified them based on Gartland's system. They recommended their preferred treatment of cast immobilization for type I fractures and of closed reduction and pinning in the operating room for type II and type III fractures. The interobserver and intraobserver reliability for each set of radiographs was then analyzed. There was moderate agreement comparing all fractures and comparing types I and II fractures, while there was full agreement for type III fractures. There was full agreement for the intraobserver reliability. The preferred treatment (casting vs operative intervention) differed in 35% of patients, if based on the fracture classification.

Tibia fractures in children sustained on a playground slide.

BACKGROUND: The purpose of this study is to investigate the relationship between children who sustain tibia fractures on a playground slide and the mechanism of injury. METHODS: This retrospective review included the chart and radiographs of all children diagnosed with a tibia fracture, over an 11-month period. All patients were originally seen in either the emergency room of a level 1 trauma center or the treating physician's office. RESULTS: During the period of study, 58 fractures of the tibia were found. Eight (13.8%) of the tibia fractures were sustained while playing on a playground slide. The 8 fractures identified are the focus of this study. The tibia fractures were nondisplaced, diaphyseal, with an intact fibula. There were 5 female and 6 male children included in the study. The age range of the patients with a tibia fracture sustained while going down a slide was 14 months to 32 months; the average age of the 8 children in this study was 20.6 months. The average age of boys sustaining a tibia fracture on a playground slide was found to be 20.7 months and the average age of girls was found to be 20.6 months. All tibia fractures associated with playing on a slide were sustained while going down the slide on the lap of an adult. None of the 8 children studied went down the slide alone. CONCLUSIONS: Children at risk for tibia fractures sustained while going down a playground slide, on the lap of an adult, were found to be less than 32 months of age. Many parents believe they are increasing the safety of their young child by placing the child on their lap while going down a playground slide. Parents should be educated not to go down a slide with a child on their lap. If the child is unable to use the slide independently, another activity would be more appropriate. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Stilbene glycosides are natural product inhibitors of FGF-2-induced angiogenesis.

BACKGROUND: Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with pathological processes, in particular tumour development, and is a target for the development of new therapies. We have investigated the anti-angiogenic potential of two naturally occurring stilbene glycosides (compounds 1 and 2) isolated from the medicinal plant Boswellia papyriferai using large and smallvessel-derived endothelial cells. Compound 1 (trans-4',5'-dihydroxy-3-methoxystilbene-5-O-{alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->6)}-beta-D-glucopyranoside was the more hydrophilic and inhibited FGF-2-induced proliferation, wound healing, invasion in Matrigel, tube formation and angiogenesis in large and small vessel-derived endothelial cells and also in the chick chorioallantoic membrane assay. Using a binding assay we were able to show compound 1 reduced binding of FGF-2 to fibroblast growth factor receptors-1 and -2. In all cases the concentration of compound 1 which caused 50% inhibition (IC50) was determined. The effect of compound 1 on EGF and VEGF-induced proliferation was also investigated. RESULTS: Compound 1 inhibited all stages of FGF-2 induced angiogenesis with IC50 values in the range 5.8 +/- 0.18 - 48.90 +/- 0.40 microM but did not inhibit EGF or VEGF-induced angiogenesis. It also inhibited FGF-2 binding to FGF receptor-1 and -2 with IC50 values of 5.37 +/- 1.04 and 9.32 +/- 0.082 muM respectively and with concommotant down-regulation of phosphorylated-ERK-1/-2 expression. Compound 2 was an ineffective inhibitor of angiogenesis despite its structural homology to compound 1. CONCLUSION: Compound 1 inhibited FGF-2 induced angiogenesis by binding to its cognate receptors and is an addition to the small number of natural product inhibitors of angiogenesis.

Oxidation state and size of Fe controlled by organic matter in natural waters.

In a well mixed-stream, in which the iron/organic carbon (OC) ratio varied from 0.333 to 0.05 with sampling point and discharge, 40-70% of the Fe load was found to be present as lightly bound Fe(II). In laboratory simulations of streamwater, after 24 h of aeration at pH 6.5, and with an Fe/OC concentration ratio of 0.417, 97% of Fe(II) was converted to Fe(III) (hydr)oxides, while at a ratio of 0.083, 87% of Fe(ll) remained unoxidized. The particle size distribution of Fe contained < 0.2 microm fractions only when OC was present and comparison of Fe and OC size distributions suggested that there was more than one mechanism by which colloidal Fe was produced. At high Fe/ OC ratios, < 0.2 microm fractions may be predominantly Fe(III) (hydr)oxides stabilized by OC, but at low ratios, they must consist of otherwise soluble Fe(ll) attached to < 0.2 microm OC. The recognition in the field of the consequences of processes demonstrated in the laboratory suggests that OC may be a predominant control of both size and oxidation state of Fe in many natural waters.

The normal cellular prion protein and its possible role in angiogenesis.

Cellular Prion Protein (PrPc) is a ubiquitous glycoprotein present on the surface of endothelial cells. Resting vascular endothelial cells show minimum expression of PrPc and can constitutively release PrPc. PrPc participates in cell survival, differentiation and angiogenesis. During development, neonatal brain endothelial cells transiently express PrPc. Our group recently reported upregulation of PrPc in microvessels from ischemic brain regions in stroke patients. Ischemia/hypoxia induces PrPc expression through the activation of extracellular signal-regulated kinase (ERK). All these data suggest that PrPc plays an important role in angiogenic responses. In addition, PrPc participates in cellular function in the central nervous system, since PrPc is also highly expressed in neurons. PrPc binds copper, suggesting a role in copper metabolism. PrPc also protects cells against oxidative stress and it seems to be involved in neuroprotection. Several studies have demonstrated that PrPc prevents cells from apoptosis and subsequent tissue damage. Moreover, PrPc plays an important role in the immune response. Here, we review the multiple functions of PrPc with a special attention to its recently reported role in angiogenesis.

Dynamin and perforin are associated with neovascularisation in advanced carotid plaques.

Intimal plaque neovascularization is associated with the development of symptomatic disease and thrombosis, with new 'leaky' fragile microvessels prone to haemorrhage. Perforin or pore forming protein is involved in vascular cell death by forming pores in target cells. Enzymes, in particular, granzyme B are secreted by immune infiltrates present in inflammatory plaque regions and have been shown to induce endothelial cell apoptosis. Similarly, dynamin-2 is a GTPase which mediates oxidised low density lipoprotein-induced apoptosis and is also required for granzyme B-mediated exocytosis and apoptosis. Our pilot studies identified increased expression of these proteins in complicated atherosclerotic plaques. Here we demonstrate by immunohistochemistry that both proteins are over-expressed in angiogenic regions of complicated carotid plaques. Dynamin-2 was extensively localised around microvessels and in immune infiltrating cells whilst perforin was localised in immune infiltrating cells, endothelial cells and smooth muscle cells. Over-expression of these proteins may contribute to plaque destabilisation by increasing cellular apoptosis in vulnerable atherosclerotic plaques.