Predicting Survival with Brain Metastases in the Stereotactic Radiosurgery Era: are Existing Prognostic Scores Still Relevant? Or Can we do Better?

Predicting survival is essential to tailoring treatment for patients diagnosed with brain metastases. We have evaluated the performance of widely used, validated prognostic scoring systems (Graded Prognostic Assessment and diagnosis-specific Graded Prognostic Assessment) in over 1000 'real-world' patients treated with stereotactic radiosurgery to the brain, selected according to National Health Service commissioning criteria. Survival outcomes from our dataset were consistent with those predicted by the prognostic systems, but with certain cancer subtypes showing a significantly better survival than predicted. Although performance status remains the simplest tool for prediction, total brain tumour volume emerges as an independent prognostic factor, and a new, improved, prognostic scoring system incorporating this has been developed.

Clinical Implementation of Robust Multi-isocentric Volumetric Modulated Arc Radiotherapy for Craniospinal Irradiation.

AIMS: To determine if multi-isocentric volumetric modulated arc radiotherapy for craniospinal irradiation (CSI-VMAT) can be implemented safely and accurately using robust optimisation in a commercially available treatment planning system. Our initial clinical experience is reported for the first 20 patients treated with the technique. MATERIALS AND METHODS: Patients received between 23.4 and 39.6 Gy (mode 23.4 Gy) in 13-22 fractions with CSI-VMAT. The heart mean dose was 4.2-10.3 Gy (median 5.3 Gy) for patients prescribed up to 24 Gy and 6.5-16.3 Gy (median 10.1 Gy) for patients receiving 35 Gy or more. The lung mean dose was 5.5-7.6 Gy (median 6.8 Gy) for patients prescribed up to 24 Gy and 6.9-11.1 Gy (median 10.0 Gy) for patients receiving 35 Gy or more. The robustness of the planning target volume D0.1cm3 and D99% to systematic errors in the isocentre superoinferior position of up to 5 mm was evaluated. These remained acceptable but were correlated to the length of the available beam overlap through the neck. RESULTS: As of January 2021, one patient was deceased after 508 days and one patient was lost to follow-up after completing treatment. The median follow-up was 399 days (range 175-756 days) and progression-free survival was 131 days (34-490 days). Acute toxicities at Common Terminology Criteria for Adverse Events v5.0 grade 3+ included lowered white blood cell count (16/20), decreased platelet count (8/20), nausea (5/20), vomiting (2/20), pharyngeal mucositis (1/20) and oral mucositis (1/20). Three patients developed grade 4 neutropenia or decreased white blood cell count. CONCLUSIONS: CSI-VMAT can be implemented safely and accurately using robust optimisation functions in a commercially available treatment planning system.

The hidden dangers of staying home: a London trauma unit experience of lockdown during the COVID-19 virus pandemic.

INTRODUCTION: The COVID-19 pandemic resulted in reconfiguration of the NHS. Elective services were stopped and trauma services focused on decreasing patient-clinician interactions and managing injuries nonoperatively wherever possible. The everyday life of the general public changed dramatically with the introduction of a national lockdown to prevent the spread of COVID-19. This paper looks at the experience of a South West London trauma unit. MATERIALS AND METHODS: All patients reviewed in fracture clinic and by the orthopaedic on-call team between 23 March to 23 April 2020 were included. Data on the mechanism of injury and whether this was a usual activity, the injury sustained and its management were collected. RESULTS: A total of 167 trauma injuries were seen, compared with 735 new patients with injuries in the previous month. The number of trauma operations completed decreased by 38%; 55% of injuries occurred inside the home and 44% outside the home during daily exercise. Some 31% of injuries were secondary to a new activity taken up during lockdown. Three open fractures and two polytrauma cases were seen that would have normally been managed at the local major trauma centre. CONCLUSION: Overall, both the number of injuries seen and trauma operations completed during the enforced lockdown decreased. This is probably due to a change in the way the general public are living their lives, and the reconfigurations within the NHS in response to the COVID-19 pandemic. This is an interesting time within trauma and orthopaedic departments, as they continue to adapt to the changing injuries and working environment.

Evolving concepts in ventral hernia repair and physical therapy: prehabilitation, rehabilitation, and analogies to tendon reconstruction.

PURPOSE: The abdominal wall and musculoskeletal tendons share many anatomic, physiologic, and functional characteristics. This review aims to highlight these similar characteristics and to present a rationale why the treatment principles of successful musculoskeletal tendon reconstruction, including principles of surgical technique and physical therapy, can be used in the treatment of complex abdominal wall reconstruction or ventral hernia repair. METHODS: The MEDLINE/PubMed database was used to identify published literature relevant to the purpose of this review. CONCLUSIONS: There are several anatomical and functional similarities between the linea alba and musculoskeletal tendons. Because of this reason, many of the surgical principles for musculoskeletal tendon repair and ventral hernia repair overlap. Distribution of tension is the main driving principle for both procedures. Suture material and configuration are chosen to maximize tension distribution among the tissue edges, as seen in the standard of care multistrand repairs for musculoskeletal tendons, as well as in the small bites for laparotomy technique described in the STITCH trial. Physical therapy is also one of the mainstays of tendon repair, but surprisingly, is not routine in ventral hernia repair. The evidence surrounding physical therapy prehabilitation and rehabilitation protocols in other disciplines is significant. This review challenges the fact that these protocols are not routinely implemented for ventral hernia repair, and presents the rationale and feasibility for the routine practice of physical therapy in ventral hernia repair.

Scars Matter: The Importance of Incision Decisions in Bariatric Patients.

This study aims to determine if cosmetic outcomes play an important role for patients undergoing bariatric surgery, when considering a surgical approach. A video-animation describing open, conventional laparoscopic, and reduced incision magnetic assisted surgery was shown. The patient's perceptions of the surgical approaches were recorded using an anonymous survey. Fifty-one patients completed the survey. The median age was 45 (IQR: 36-51), and 38 (74.5%) were women. Cosmesis was found to be an important factor (77%) for selecting a surgical approach. Ninety percent of the patients believe that reduced incision magnet-assisted surgery provides superior cosmesis. Cosmetic results may play a determinant role when choosing a surgical approach.

Hypofractionated Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Tumours in Children and Young Adults.

AIMS: Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population. MATERIALS AND METHODS: We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged <25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented. RESULTS: Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5-20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2-49.5 months). The median follow-up was 3.4 years (range 0.28-6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8-82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04). CONCLUSION: Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

AIMS: A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. RESULTS: Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. CONCLUSIONS: The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

Stereotactic radiosurgery planning of vestibular schwannomas: Is MRI at 3 Tesla geometrically accurate?

PURPOSE: MRI is a mandatory requirement to accurately plan Stereotactic Radiosurgery (SRS) for Vestibular Schwannomas. However, MRI may be distorted due not only to inhomogeneity of the static magnetic field and gradients but also due to susceptibility-induced effects, which are more prominent at higher magnetic fields. We assess geometrical distortions around air spaces and consider MRI protocol requirements for SRS planning at 3 T. METHODS: Hardware-related distortion and the effect of incorrect shimming were investigated with structured test objects. The magnetic field was mapped over the head on five volunteers to assess susceptibility-related distortion in the naso-oro-pharyngeal cavities (NOPC) and around the internal ear canal (IAC). RESULTS: Hardware-related geometric displacements were found to be less than 0.45 mm within the head volume, after distortion correction. Shimming errors can lead to displacements of up to 4 mm, but errors of this magnitude are unlikely to arise in practice. Susceptibility-related field inhomogeneity was under 3.4 ppm, 2.8 ppm, and 2.7 ppm for the head, NOPC region and IAC region, respectively. For the SRS planning protocol (890 Hz/pixel, approximately 1 mm3 isotropic), susceptibility-related displacements were less than 0.5 mm (head), and 0.4 mm (IAC and NOPC). Large displacements are possible in MRI examinations undertaken with lower receiver bandwidth values, commonly used in clinical MRI. Higher receiver bandwidth makes the protocol less vulnerable to sub-optimal shimming. The shimming volume and the CT-MR co-registration must be considered jointly. CONCLUSION: Geometric displacements can be kept under 1 mm in the vicinity of air spaces within the head at 3 T with appropriate setting of the receiver bandwidth, correct shimming and employing distortion correction.

p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFß signaling.

Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-ß and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

Neurocognitive function after (chemo)-radiotherapy for head and neck cancer.

Radical radiotherapy has a pivotal role in the treatment of head and neck cancer (HNC) and cures a significant proportion of patients while simultaneously sparing critical normal organs. Some patients treated with radical radiotherapy for HNC receive significant radiation doses to large volumes of brain tissue. In fact, intensity-modulated radiotherapy techniques for HNC have been associated with a net increase in irradiated brain volumes. The increasing use of chemoradiotherapy for HNC has additionally exposed this patient population to potential neurotoxicity due to cytotoxic drugs. Patients with HNC may be particularly at risk for adverse late brain effects after (chemo)-radiotherapy, such as impaired neurocognitive function (NCF), as risk factors for the development of HNC, such as smoking, excess alcohol consumption and poor diet, are also associated with impaired NCF. The relatively good survival rates with modern treatment for HNC, and exposure to multiple potentially neurotoxic factors, means that it is important to understand the impact of (chemo)-radiotherapy for HNC on NCF, and to consider what measures can be taken to minimise treatment-related neurotoxicity. Here, we review evidence relating to the late neurotoxicity of radical (chemo)-radiotherapy for HNC, with a focus on studies of NCF in this patient population.

VEGFA and tumour angiogenesis.

In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.

Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age.

Advances in neonatal care have resulted in increased survival of children born extremely pre-term (EP). Nevertheless the incidence of bronchopulmonary dysplasia and long-term respiratory morbidity remains high. We investigated the nature of pathophysiological changes at 11 yrs of age to ascertain whether respiratory morbidity in EP children primarily reflects alterations in the lung periphery or more centralised airway function in this population. Spirometry, plethysmography, diffusing capacity, exhaled nitric oxide, multiple-breath washout, skin tests and methacholine challenge were used during laboratory-based assessments in a subgroup of the 1995 EPICure cohort and in controls. Results were obtained in 49 EP and 52 control children. Lung function abnormalities were found in 78% of EP children, with evidence of airway obstruction, ventilation inhomogeneity, gas trapping and airway hyperresponsiveness. Levels of atopy and exhaled nitric oxide were similar between the groups. Prior wheeze was associated with significant reductions in forced flows and volumes. By contrast, abnormalities of the lung periphery appear to be mediated primarily through EP birth per se. The prevalence of lung function abnormalities, which is largely obstructive in nature and likely to have long-term implications, remains high among 11-yr-old children born EP. Spirometry proved an effective means of detecting these persistent abnormalities.

Reference equations for specific airway resistance in children: the Asthma UK initiative.

Plethysmographic specific airway resistance (sR(aw)) is a useful research method for discriminating lung disease in young children. Its use in clinical management has, however, been limited by lack of consensus regarding equipment, methodology and reference data. The aim of our study was to collate reference data from healthy children (3-10 yrs), document methodological differences, explore the impact of these differences and construct reference equations from the collated dataset. Centres were approached to contribute sR(aw) data as part of the Asthma UK initiative. A random selection of pressure-flow plots were assessed for quality and site visits elucidated data collection and analysis protocols. Five centres contributed 2,872 measurements. Marked variation in methodology and analysis excluded two centres. sR(aw) over-read sheets were developed for quality control. Reference equations and recommendations for recording and reporting both specific effective and total airway resistance (sR(eff) and sR(tot), respectively) were developed for White European children from 1,908 measurements made under similar conditions. Reference sR(aw) data collected from a single centre may be misleading, as methodological differences exist between centres. These preliminary reference equations can only be applied under similar measurement conditions. Given the potential clinical usefulness of sR(aw), particularly with respect to sR(eff), methodological guidelines need to be established and used in prospective data collection.

Embryonic stem cell models in vascular biology.

Embryonic stem cells have become an established tool in vascular biology to study the details of vasculogenesis as well as angiogenesis. There is also a future potential in using embryonic stem cell-derived endothelial cells for therapeutic purposes. It is important to evaluate this model by comparing features of endothelial cells derived from differentiating stem cells and their responsiveness to external stimuli to those of primary endothelial cells and to in vivo models. Through culture of mouse embryonic stem cell we discovered that differentiating stem cells are highly amenable to analyzing biochemical and cell biologic processes that are independent of flow. Endothelial cell function can be studied in the context of mutations or deletions that are embryonically lethal in vivo. Many, if not all, of the features of sprouting angiogenesis in differentiating stem cells closely mimic the in vivo process.

The EPICure study: comparison of pediatric spirometry in community and laboratory settings.

RATIONALE: Accuracy of spirometry testing is a prerequisite for its use as an objective outcome measure in large epidemiological studies. We compared spirometry measurements obtained by trained pediatricians in a variety of school settings with those obtained in the laboratory by respiratory physiologists. METHODS: Following a 3-day training course, three pediatricians carried out spirometry in children born extremely preterm (EP) and age matched controls in schools across the UK and Ireland (The EPICure study). A subgroup had repeated measurements in the laboratory. Spirometric flows and volumes were expressed as Z-scores. Bland-Altman analysis was used to calculate within-subject differences. RESULTS: Fifty children (40% boys), 37 (74%) of whom were born EP, with a mean age 10.8 years had paired spirometry results (average interval between tests: 20.3 weeks). There was no statistically significant difference between any of the outcome variables: mean (95% CI of difference) in Z-scores [school-laboratory]) being 0.0 (-0.1; 0.1) for FEV(1), 0.1 (-0.1; 0.3) for FVC, -0.1 (-0.3; 0.1) for FEF(25-75), and 0.0 (-0.3; 0.1) for FEV(1)/FVC. Within individuals, the 95% limits of agreement for repeated measures were within +/- 1 Z-score for FEV(1) and FVC, and within +/- 1.5 Z-score for FEF(25-75) and FEV(1)/FVC. CONCLUSION: With appropriate training, quality control, and support, pediatric spirometry can reliably be performed outside the lung function laboratory.

Molecular structure of fd (f1, M13) filamentous bacteriophage refined with respect to X-ray fibre diffraction and solid-state NMR data supports specific models of phage assembly at the bacterial membrane.

Filamentous bacteriophage (Inovirus) is a simple and well-characterized model system. The phage particle, or virion, is about 60 angstroms in diameter and several thousand angstrom units long. The virions are assembled at the bacterial membrane as they extrude out of the host without killing it, an example of specific transport of nucleoprotein assemblages across membranes. The Ff group (fd, f1 and M13) has been especially widely studied. Models of virion assembly have been proposed based on a molecular model of the fd virion derived by X-ray fibre diffraction. A somewhat different model of the fd virion using solid-state NMR data has been proposed, not consistent with these models of assembly nor with the X-ray diffraction data. Here we show that reinterpreted NMR data are also consistent with the model derived from X-ray fibre diffraction studies, and discuss models of virion assembly.