UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy.

The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.

Automation and control of laser wakefield accelerators using Bayesian optimization.

Laser wakefield accelerators promise to revolutionize many areas of accelerator science. However, one of the greatest challenges to their widespread adoption is the difficulty in control and optimization of the accelerator outputs due to coupling between input parameters and the dynamic evolution of the accelerating structure. Here, we use machine learning techniques to automate a 100 MeV-scale accelerator, which optimized its outputs by simultaneously varying up to six parameters including the spectral and spatial phase of the laser and the plasma density and length. Most notably, the model built by the algorithm enabled optimization of the laser evolution that might otherwise have been missed in single-variable scans. Subtle tuning of the laser pulse shape caused an 80% increase in electron beam charge, despite the pulse length changing by just 1%.

Modelling burning thermonuclear plasma.

Considerable progress towards the achievement of thermonuclear burn using inertial confinement fusion has been achieved at the National Ignition Facility in the USA in the last few years. Other drivers, such as the Z-machine at Sandia, are also making progress towards this goal. A burning thermonuclear plasma would provide a unique and extreme plasma environment; in this paper we discuss (a) different theoretical challenges involved in modelling burning plasmas not currently considered, (b) the use of novel machine learning-based methods that might help large facilities reach ignition, and (c) the connections that a burning plasma might have to fundamental physics, including quantum electrodynamics studies, and the replication and exploration of conditions that last occurred in the first few minutes after the Big Bang. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 1)'.

Hypofractionated Radiotherapy in Oesophageal Cancer for Patients Unfit for Systemic Therapy: A Retrospective Single-Centre Analysis.

AIMS: Chemoradiotherapy (CRT) is established as a superior treatment option to definitive radiotherapy in the non-surgical management of oesophageal cancer. For patients precluded from CRT through choice or comorbidity there is little evidence to guide delivery of single-modality radiotherapy. In this study we outline outcomes for patients unfit for CRT who received a hypofractionated radiotherapy (HRT) regimen. MATERIALS AND METHODS: A retrospective UK single-centre analysis of 61 consecutive patients with lower- or middle-third adenocarcinoma (OAC; 61%) or squamous cell carcinoma of the oesophagus managed using HRT with radical intent between April 2009 and 2014. Treatment consisted of 50 Gy in 16 fractions (n = 49, 80.3%) or 50-52.5 Gy in 20 fractions (n = 12, 19.7%). Outcomes were referenced against a contemporaneous comparator cohort of 80 (54% OAC) consecutive patients managed with conventionally fractionated CRT within the same centre. RESULTS: Three-year and median overall survival were, respectively, 56.9% and 29 months with HRT compared with 55.5% and 26 months for CRT; adjusted hazard ratio 0.79 (95% confidence interval 0.48-1.28). Grade 3 and 4 toxicity rates were low at 16.4% (n = 10) for those receiving HRT and 40.2% (n = 32) for the CRT group. In patients with OAC, CRT delivered superior overall survival (hazard ratio 0.46; 95% confidence interval 0.25-0.85) and progression-free survival (hazard ratio 0.45; 95% confidence interval 0.23-0.88) when compared with HRT. CONCLUSIONS: The HRT regimen described here was safe and tolerable in patients unable to receive CRT, and delivered promising survival outcomes. The use of HRT for the treatment of oesophageal cancer, both alone and as a sequential or concurrent treatment with chemotherapy, requires further study. New precision radiotherapy technologies may provide additional scope for improving outcomes in oesophageal cancer using HRT-based approaches and should be evaluated.

UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

Superiority of Deformable Image Co-registration in the Integration of Diagnostic Positron Emission Tomography-Computed Tomography to the Radiotherapy Treatment Planning Pathway for Oesophageal Carcinoma.

AIMS: To investigate the use of image co-registration in incorporating diagnostic positron emission tomography-computed tomography (PET-CT) directly into the radiotherapy treatment planning pathway, and to describe the pattern of local recurrence relative to the PET-avid volume. MATERIALS AND METHODS: Fourteen patients were retrospectively identified, six of whom had local recurrence. The accuracy of deformable image registration (DIR) and rigid registration of the diagnostic PET-CT and recurrence CT, to the planning CT, were quantitatively assessed by comparing co-registration of oesophagus, trachea and aorta contours. DIR was used to examine the correlation between PET-avid volumes, dosimetry and site of recurrence. RESULTS: Positional metrics including the dice similarity coefficient (DSC) and conformity index (CI), showed DIR to be superior to rigid registration in the co-registration of diagnostic and recurrence imaging to the planning CT. For diagnostic PET-CT, DIR was superior to rigid registration in the transfer of oesophagus (DSC=0.75 versus 0.65, P<0.009 and CI=0.59 versus 0.48, P<0.003), trachea (DSC=0.88 versus 0.65, P<0.004 and CI=0.78 versus 0.51, P<0.0001) and aorta structures (DSC=0.93 versus 0.86, P<0.006 and CI=0.86 versus 0.76, P<0.006). For recurrence imaging, DIR was superior to rigid registration in the transfer of trachea (DSC=0.91 versus 0.66, P<0.03 and CI=0.83 versus 0.51, P<0.02) and oesophagus structures (DSC=0.74 versus 0.51, P<0.004 and CI=0.61 versus 0.37, P<0.006) with a non-significant trend for the aorta (DSC=0.91 versus 0.75, P<0.08 and CI=0.83 versus 0.63, P<0.06) structure. A mean inclusivity index of 0.93 (range 0.79-1) showed that the relapse volume was within the planning target volume (PTVPET-CT); all relapses occurred within the high dose region. CONCLUSION: DIR is superior to rigid registration in the co-registration of PET-CT and recurrence CT to the planning CT, and can be considered in the direct integration of PET-CT to the treatment planning process. Local recurrences occur within the PTVPET-CT, suggesting that this is a suitable target for dose-escalation strategies.

A method for scoring treatment time efficiency of Gamma Knife radiosurgical treatment plans for brain metastases.

PURPOSE: In Gamma Knife radiosurgery, an efficient plan is one that achieves dosimetric quality while minimizing treatment time. Although minimization of treatment time to improve throughput and benefit patient comfort is a common and important goal of radiosurgery planning, to date no studies have attempted to specifically quantify efficiency. The aim of this study was to define simple index to score efficiency, and by quantifying time savings achieved by replanning those cases identified as least efficient, so demonstrate the efficacy of the index. METHODS: To quantify efficiency, it is necessary to determine treatment times expected for specified lesions. However, because of numerous case-specifics, efficiency cannot be quantified in terms of treatment times alone. This study defines a new quantity, the attenuation-corrected normalized treatment time-dose rate product, nTRP(corr), to account for differing dose rates, prescriptions, and attenuation. A plan efficiency index (PEI) is then defined for lesions of similar volume and shape in terms of expected and planned nTRP(corr). nTRP(corr) was retrospectively calculated for metastatic lesions of comparable shape. A curve fitted to data describing how nTRP(corr) typically varied with volume for these lesions was then used to determine expected nTRP(corr). For each lesion, PEI was calculated as the ratio of expected-to-planned nTRP(corr). Plans with the lowest PEI were replanned, with the aim of maintaining dosimetric quality while minimizing treatment time. Dosimetric quality was defined in terms of coverage, conformity, and gradient index. Statistical significance of differences between original and replans was quantified via paired t-tests. RESULTS: The mean(standard deviation) PEI of all reviewed lesions was 1.08(0.28). The 14 least efficient plans across the range of investigated volumes (45-19 800 mm(3)) had a mean PEI of 0.64, versus 1.18 when replanned (p < 0.0001). This corresponded to a mean(range) time saving of 42%(19%-62%), [29(8-52) min at date of treatment] with no statistically significant (p > 0.05) change in dosimetric quality. CONCLUSIONS: The PEI is a viable metric for identifying those plans that benefit from a more efficient planning strategy.

An evaluation of four CT-MRI co-registration techniques for radiotherapy treatment planning of prone rectal cancer patients.

OBJECTIVES: MRI is the preferred staging modality for rectal carcinoma patients. This work assesses the CT-MRI co-registration accuracy of four commercial rigid-body techniques for external beam radiotherapy treatment planning for patients treated in the prone position without fiducial markers. METHODS: 17 patients with biopsy-proven rectal carcinoma were scanned with CT and MRI in the prone position without the use of fiducial markers. A reference co-registration was performed by consensus of a radiologist and two physicists. This was compared with two automated and two manual techniques on two separate treatment planning systems. Accuracy and reproducibility were analysed using a measure of target registration error (TRE) that was based on the average distance of the mis-registration between vertices of the clinically relevant gross tumour volume as delineated on the CT image. RESULTS: An automated technique achieved the greatest accuracy, with a TRE of 2.3 mm. Both automated techniques demonstrated perfect reproducibility and were significantly faster than their manual counterparts. There was a significant difference in TRE between registrations performed on the two planning systems, but there were no significant differences between the manual and automated techniques. CONCLUSION: For patients with rectal cancer, MRI acquired in the prone treatment position without fiducial markers can be accurately registered with planning CT. An automated registration technique offered a fast and accurate solution with associated uncertainties within acceptable treatment planning limits.

A mathematical model of muscle containing heterogeneous half-sarcomeres exhibits residual force enhancement.

A skeletal muscle fiber that is stimulated to contract and then stretched from L1 to L2 produces more force after the initial transient decays than if it is stimulated at L2. This behavior has been well studied experimentally, and is known as residual force enhancement. The underlying mechanism remains controversial. We hypothesized that residual force enhancement could reflect mechanical interactions between heterogeneous half-sarcomeres. To test this hypothesis, we subjected a computational model of interacting heterogeneous half-sarcomeres to the same activation and stretch protocols that produce residual force enhancement in real preparations. Following a transient period of elevated force associated with active stretching, the model predicted a slowly decaying force enhancement lasting >30 seconds after stretch. Enhancement was on the order of 13% above isometric tension at the post-stretch muscle length, which agrees well with experimental measurements. Force enhancement in the model was proportional to stretch magnitude but did not depend strongly on the velocity of stretch, also in agreement with experiments. Even small variability in the strength of half-sarcomeres (2.1% standard deviation, normally distributed) was sufficient to produce a 5% force enhancement over isometric tension. Analysis of the model suggests that heterogeneity in half-sarcomeres leads to residual force enhancement by storing strain energy introduced during active stretch in distributions of bound cross-bridges. Complex interactions between the heterogeneous half-sarcomeres then dissipate this stored energy at a rate much slower than isolated cross-bridges would cycle. Given the variations in half-sarcomere length that have been observed in real muscle preparations and the stochastic variability inherent in all biological systems, half-sarcomere heterogeneity cannot be excluded as a contributing source of residual force enhancement.

Thermogenesis, blood metabolites and hormones, and growth of lambs born to ewes supplemented with algae-derived docosahexaenoic acid.

Neonatal lamb mortality is a major factor affecting profitability in the sheep industry, and lamb thermogenesis is a key element in neonatal lamb survival. Increased lamb vigor has been reported when ewes were supplemented during late gestation with algae-derived docosahexaenoic acid (DHA); however, the effects of DHA on lamb thermogenesis and immunocompetence have not been investigated. Eighty twin-bearing Targhee ewes (ages 2 to 5 yr; 68.5 ± 3 kg) were assigned randomly to 1 of 2 supplement treatments to determine the effects of feeding DHA to ewes during late gestation and early lactation on lamb thermogenesis, serum metabolites and hormones, and lamb growth. Supplement treatments were 12 g·ewe(-1)·d(-1) of algae-derived DHA (DHA Gold Advanced Bionutrition Corp., Columbia, MD; algae-derived DHA); and no algae-derived DHA (control). Supplements were individually fed daily during the last 30 d (±7 d) of gestation and pen fed (6 pens/treatment with 6 or 7 ewes/pen) during the first 38 d (±7 d) of lactation. One hour after lambing and before nursing, twin-born lambs were weighed, blood sampled via jugular puncture, and placed in a dry cold chamber for 30 min (0°C), and rectal temperatures were recorded every minute for 30 min. Lambs were removed from the cold chamber, blood sampled, warmed for 15 min, and returned to their dam. Ewes were blood sampled, and colostrum samples were collected 1 h postpartum. Ewe and lamb sera were assayed for glucose, NEFA, cortisol, and leptin. Lamb rectal temperature, glucose, NEFA, cortisol, leptin, and birth weights did not differ between treatments. The BW at 38 d was greater (P = 0.03) for lambs born to control ewes than for lambs born to algae-derived DHA-supplemented ewes; however, the colostrum of algae-derived DHA-supplemented ewes had a greater specific gravity (P = 0.05) than for control ewes. Overall, despite a potentially positive effect on ewe colostral IgG concentrations, supplementation of algae-derived DHA during late gestation and early lactation had a negative effect on lamb BW and did not affect indices of lamb thermogenesis.

Platelet-rich plasma concentrate to augment bone fusion.

Within the foot and ankle literature, there exists only a handful of basic science and clinical articles reporting on the efficacy and clinical utility of platelet-rich plasma (PRP). This article discusses the concept and basic science of PRP, and clinical applications of PRP for the augmentation of bone healing in foot and ankle surgery. The authors also provide a classification system that assesses relative risks for poor bone healing and the need for orthobiologic augmentation.

Effects of late gestation supplementation of rumen undegradable protein, vitamin E, zinc, and chlortetracycline to ewes on indices of immune transfer and productivity.

Late gestation supplementation of feed additives, such as rumen undegradable intake protein (RUIP), vitamin E, Zn, and chlortetracycline, has inconsistently improved ewe/lamb productivity. In 3 experiments, Western white-faced ewes were supplemented for at least 30 d during late gestation with 204 g/(ewe.d) on a DM basis of high (HS; 12.5% RUIP, 880 IU/kg of vitamin E, 176 mg/kg of Zn supplied by an AA complex, and 352 mg/kg of chlortetracycline) or low (LS; 7.56% RUIP and no supplemental vitamin E, Zn, or chlortetracycline) supplements. Ewes of different age (Exp. 1; 3- vs. 6-yr-old; n = 52) and BCS (Exp. 2; good vs. poor BCS; 3.0 and 1.7 +/- 0.5, respectively; n = 40) were supplemented individually in a 2 x 2 factorial arrangement of treatments for 29 d. Thereafter, each ewe was group fed the appropriate supplement until lambing (14 +/- 7 d). Ewe intake, colostral IgG, ewe and lamb parainfluenza type 3 (PI(3)) titers, milk production, ewe BW and BCS change, and lamb production were measured in both experiments. In Exp. 3, approximately 600 ewes were group fed HS or LS over 2 yr. Ewe BW, ewe BCS, lamb production, and lamb survival was measured in Exp. 3 with groups within year as the experimental unit. In Exp. 1, lambs born to 3-yr-old ewes fed the HS had greater (P = 0.01) anti-PI(3) antibody titers than lambs born to 3-yr-old ewes fed the LS. Three-year-old ewes had greater (P < 0.01) DMI than 6-yr-old ewes. In Exp. 1 and 2, d 3 and 10 milk production differences (P

Effects of supplemental safflower and vitamin E during late gestation on lamb growth, serum metabolites, and thermogenesis.

Twin-bearing Targhee ewes (Exp. 1, 1 yr, n = 42) and 1,182 single- and twin-bearing whiteface range ewes (Exp. 2, n = 8 experimental units over 2 yr) were used in a 2 x 2 factorial arrangement of treatments to determine the effect of supplemental energy source and level of vitamin E supplement on lamb serum metabolites and thermogenesis (Exp. 1) and on lamb growth (Exp. 2). During late gestation, ewes were individually fed (Exp. 1) or group-fed (Exp. 2) a daily supplement. Supplements were 226 g/ewe of daily safflower seed (DM basis; SS) with either 350 IU/ewe daily (VE) or no added supplemental (VC) vitamin E; or 340 g/ewe daily of a barley-based grain supplement (DM basis; GC) and either VE or VC. One hour postpartum in Exp. 1, twin-born lambs were placed in a 0 degrees C dry cold chamber for 30 min. Lamb rectal temperature was recorded every 60 s and blood samples were taken immediately before and after cold exposure. In Exp. 2, lambs were weighed at birth, at turnout from confinement to spring range (32 d of age +/- 7; turnout), and at weaning (120 d of age +/- 7). Ewes were weighed at turnout and weaning. In Exp. 1, a level of vitamin E x energy source interaction was detected (P < 0.10) for body temperature and change in NEFA and glucose concentrations. Lambs from SSVC ewes had the lowest (P = 0.01) body temperature and had decreased (P = 0.08) NEFA concentration. The SS lambs tended to have decreased (P < 0.11) concentrations of blood urea N (BUN) and thyroxine at 0 min than did lambs born to GC ewes. After 30 min of cold exposure, SS lambs had increased and GC lambs had decreased BUN, triiodothyronine, and triiodothyronine:thyroxine concentrations (P < 0.10). In Exp. 2, kilograms of lamb per ewe at turnout and weaning and lamb survival at weaning were greater (P < 0.07) for GC than SS lambs. Based on the decreased body temperature in SSVC lambs at birth, the greater change in BUN during the cold exposure for SS than GC lambs, and the decreased survival rate for SS than GC lambs, SSVC-supplemented ewes appeared to give birth to lambs with an apparently decreased energetic capacity. This may compromise the ability of the newborn lamb to adapt to extreme environmental conditions.

The immune system--is it relevant to cancer development, progression and treatment?

The ability of the immune system to effectively respond to human tumours is a matter of long-term controversy. There is an increasing body of recent evidence to support a role for the immune system in eliminating pre-clinical cancers, an old concept termed 'immunosurveillance'. 'Immunoediting' is an updated hypothesis, in which selection pressures applied by the immune response to tumours modulate tumour immunogenicity and growth. Tumour infiltration by immune cells has been shown to have powerful prognostic significance in a host of cancer types. Paradoxically, in some circumstances the immune system can promote tumour development. Cytotoxic therapies, including radiotherapy and chemotherapy, induce potentially immunogenic cell death, releasing tumour-associated antigens in the context of a 'danger' signal to the immune system. An understanding of the interaction between immune cells, tumour cells and treatment modalities will therefore guide the future combination of immunotherapy with conventional therapy to achieve optimal anti-tumour effects.

Comparative pilot study of symptoms and quality of life in cancer patients and patients with end stage renal disease.

BACKGROUND: Patients with advanced renal failure are increasingly opting for conservative treatment, yet little is known of their palliative care needs. METHODS: We performed a cross-sectional study, examining symptom burden and quality of life in patients with advanced renal failure (estimated GFR < 17 mL/min; n = 11). A contemporary cohort with terminal malignancy acted as comparators (n = 11). Symptom burden was scored using an extended Memorial Symptom Assessment Scale Short Form questionnaire. Quality of life was assessed using the Euroqol-5Q questionnaire. Demographic and pathological data, performance status and co-morbidity were also recorded. RESULTS: Baseline characteristics were similar for the two groups. Symptom burden (renal 17; cancer 15; P =NS) and quality of life scores (renal 60; cancer 60; P =NS) were remarkably similar. Both groups reported high levels of psychological distress. CONCLUSIONS: Patients with advanced renal failure experience a symptom burden and impairment of quality of life similar to that of patients with terminal malignancy.

Use of the modified Delphi technique to identify and rate home injury hazard risks and prevention methods for young children.

OBJECTIVE: For children aged 1-5 years, the authors used the Delphi method to determine (1) the most important injury hazards in each area of the home; (2) the most important injury prevention behaviors; and (3) feasible and efficacious safety devices and behaviors to reduce injury risks. DESIGN: The authors used a modified Delphi method to prioritize home injury hazards for children 1-5 years of age. The Delphi method is an indirect, anonymous, iterative process aimed at achieving consensus among experts; in this study, the authors queried key informants electronically. Thirty four key informants, primarily from the United States, participated in at least one of the three rounds of questionnaires. Responses were submitted by email or fax. Participants identified, rated, and ranked home injury hazards and prevention methods. RESULTS: The overall response rate for each survey ranged from 82% to 97%. Initially, 330 unique hazards and prevention behaviors/devices were identified in seven areas of the home. The 126 home injury hazards were rated based on frequency, severity, and preventability of injury; and the 204 behaviors and devices were rated by efficacy and feasibility. These experts rated firearms and pools as the most significant hazards, and smoke alarms and safe water temperature as the most important preventions. CONCLUSIONS: The modified Delphi method of consensus was useful to prioritize home injury hazards and prevention methods for children under the age of 6 years.

Validating self reported home safety practices in a culturally diverse non-inner city population.

OBJECTIVE: To determine the validity of face to face, self reported responses to questions about the presence of safety devices and use of safety practices in the home aimed at preventing unintended injuries to preschool aged children. METHODS: The authors invited families with children enrolling in a medium sized Midwestern US community Head Start program to participate in a randomized study of home safety practices. Participation involved consenting parents (n = 452) completing an initial questionnaire during Head Start enrollment or in their home. Project staff conducted home inspections to confirm parental responses to 16 questions. Only inspections conducted within 34 days of questionnaire completion (n = 259) were included in the validation study. Parents were told that the home visit would assess the need for safety devices, but were not informed of the validation aspect of the study. RESULTS: Sensitivities were generally high for all 16 safety practices, whereas negative predictive value and specificity varied considerably. Positive predictive value was also high for most practices, and did not vary by ethnicity. Answers provided by parents in their home were different and more reliable than those provided by parents interviewed at school (p = 0.001). CONCLUSIONS: Use of safety devices and practices by parents of preschool aged children reported in a face to face interview are generally reliable. Reliability increases if the interview is conducted in the home. Parents may also be more willing to report potential problems if they perceive they may receive corrective assistance.

Supplemental safflower oil affects the fatty acid profile, including conjugated linoleic acid, of lamb.

The objective of this study was to determine whether increasing levels of dietary safflower oil would alter unsaturated fat (especially CLA) and tocopherol content of lamb, animal performance, carcass characteristics, or color stability of lamb muscle tissue. Targhee x Rambouillet wethers (n = 60) were assigned to one of three diets (four pens per treatment with five lambs per pen) in a completely random design. Diets were formulated with supplemental safflower oil at 0 (control), 3, or 6% (as-fed basis) of the diet. Diets containing approximately 80% concentrate and 20% roughage were formulated, on a DM basis, to be isocaloric and isonitrogenous and to meet or exceed NRC requirements for Ca, P, and other nutrients. A subsample of 12 wethers per treatment was selected based on average BW (54 kg) and slaughtered. Carcass data (LM area, fat thickness, and internal fat content) and wholesale cut weight (leg, loin, rack, shoulder, breast, and foreshank), along with fatty acid, tocopherol, and color analysis, were determined on each carcass. The LM and infraspinatus were sampled for fatty acid profile. Increasing safflower oil supplementation from 0 to 3 or 6% increased the proportion of linoleic acid in the diet from 49.93 to 55.32 to 62.38%, respectively, whereas the percentage of oleic acid decreased from 27.94 to 23.80 to 20.73%, respectively. The percentage of oil in the diet did not (P > or = 0.11) alter the growth and carcass characteristics of lambs, nor did it alter the tocopherol content or color stability of meat. Increasing levels of safflower oil in lamb diets decreased (P < 0.01) the weight percentage of oleic acid in the infraspinatus and LM, and increased linoleic acid (P < 0.01). Oil supplementation increased (P < 0.01) the weight percentage of various isomers of CLA in muscle, with the greatest change in the cis-9,trans-11 isomer. Supplementation of sheep diets with safflower oil, up to 6% of the diet, resulted in increasing levels of unsaturated fatty acids and CLA in the lean tissue, without adversely affecting growth performance, carcass characteristics, or color stability of lamb.