Improving hybrid image and structure-based deformable image registration for large internal deformations.

Objective.Deformable image registration (DIR) is a widely used technique in radiotherapy. Complex deformations, resulting from large anatomical changes, are a regular challenge. DIR algorithms generally seek a balance between capturing large deformations and preserving a smooth deformation vector field (DVF). We propose a novel structure-based term that can enhance the registration efficacy while ensuring a smooth DVF.Approach.The proposed novel similarity metric for controlling structures was introduced as a new term into a commercially available algorithm. Its performance was compared to the original algorithm using a dataset of 46 patients who received pelvic re-irradiation, many of which exhibited complex deformations.Main results.The mean Dice Similarity Coefficient (DSC) under the improved algorithm was 0.96, 0.94, 0.76, and 0.91 for bladder, rectum, colon, and bone respectively, compared to 0.69, 0.89, 0.62, and 0.88 for the original algorithm. The improvement was more pronounced for complex deformations.Significance.With this work, we have demonstrated that the proposed term is able to improve registration accuracy for complex cases while maintaining realistic deformations.

Deep Learning for Radiotherapy Outcome Prediction Using Dose Data - A Review.

Artificial intelligence, and in particular deep learning using convolutional neural networks, has been used extensively for image classification and segmentation, including on medical images for diagnosis and prognosis prediction. Use in radiotherapy prognostic modelling is still limited, however, especially as applied to toxicity and tumour response prediction from radiation dose distributions. We review and summarise studies that applied deep learning to radiotherapy dose data, in particular studies that utilised full three-dimensional dose distributions. Ten papers have reported on deep learning models for outcome prediction utilising spatial dose information, whereas four studies used reduced dimensionality (dose volume histogram) information for prediction. Many of these studies suffer from the same issues that plagued early normal tissue complication probability modelling, including small, single-institutional patient cohorts, lack of external validation, poor data and model reporting, use of late toxicity data without taking time-to-event into account, and nearly exclusive focus on clinician-reported complications. They demonstrate, however, how radiation dose, imaging and clinical data may be technically integrated in convolutional neural networks-based models; and some studies explore how deep learning may help better understand spatial variation in radiosensitivity. In general, there are a number of issues specific to the intersection of radiotherapy outcome modelling and deep learning, for example translation of model developments into treatment plan optimisation, which will require further combined effort from the radiation oncology and artificial intelligence communities.

The Long and the Short of it: the Role of Short-course Radiotherapy in the Neoadjuvant Management of Rectal Cancer.

Total mesorectal excision is the cornerstone of treatment for rectal cancer. Multiple randomised trials have shown a reduction in local recurrence rates with the addition of preoperative radiotherapy, either as a 1-week hypofractionated short-course (SCRT) or a conventionally fractionated long-course (LCRT) schedule with concurrent chemotherapy. There is also increasing interest in the addition of neoadjuvant chemotherapy to radiotherapy with the aim of improving disease-free survival. The relative use of SCRT and LCRT varies considerably across the world. This is reflected in, and is probably driven in part by, disparity between international guideline recommendations. In addition, different approaches to treatment may exist both between and within countries, with variation related to patient, disease and treatment centre and financial factors. In this review, we will specifically focus on the use of SCRT for the treatment of rectal cancer. We will discuss the literature base and current guidelines, highlighting the challenges and controversies in clinical application of this evidence. We will also discuss potential future applications of SCRT, including its role in optimisation and intensification of treatment for rectal cancer.

Intensity-modulated Radiotherapy for Rectal Cancer in the UK in 2020.

AIMS: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance. MATERIALS AND METHODS: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out. RESULTS: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres. CONCLUSION: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance.

Image-Guided Radiotherapy for Pelvic Cancers: A Review of Current Evidence and Clinical Utilisation.

The meticulous selection and utilisation of image-guided radiotherapy (IGRT) are essential for optimal radiotherapy treatment delivery when using highly conformal treatment techniques in pelvic radiotherapy. Pelvic IGRT has several general IGRT issues to consider (such as choice of match strategy, prioritisation between multiple treatment targets and margin estimates) as well as issues specific to pelvic radiotherapy, in particular large inter-fraction organ variation. A range of interventions, including adaptive treatment strategies, have been developed to address these challenges. This review covers general considerations for the clinical implementation of pelvic IGRT in routine practice and provides an overview of current knowledge regarding pelvic inter-fraction organ motion. Published IGRT evidence for each of the major tumour sites (gynaecological, prostate, bladder, rectal and anal cancer) is summarised, as are state-of-the-art adaptive approaches. General recommendations for the implementation of an institutional pelvic IGRT strategy include. •Ensuring consistency between treatment intent and the IGRT approach utilised. •Ensuring minimum national and international IGRT guidance is followed while considering the benefit of daily volumetric IGRT. •Ensuring the appropriate allied health professionals (namely therapy radiographers/radiation therapists) lead on undertaking IGRT. •Ensuring the IGRT workflow procedure is clear and includes an escalation process for difficult set-ups. •Ensuring a robust IGRT service is in place before implementing advanced adaptive approaches.

Prediction of outcome in anal squamous cell carcinoma using radiomic feature analysis of pre-treatment FDG PET-CT.

PURPOSE: Incidence of anal squamous cell carcinoma (ASCC) is increasing, with curative chemoradiotherapy (CRT) as the primary treatment of non-metastatic disease. A significant proportion of patients have locoregional treatment failure (LRF), but distant relapse is uncommon. Accurate prognostication of progression-free survival (PFS) would help personalisation of CRT regimens. The study aim was to evaluate novel imaging pre-treatment features, to prognosticate for PFS in ASCC. METHODS: Consecutive patients with ASCC treated with curative intent at a large tertiary referral centre who underwent pre-treatment FDG-PET/CT were included. Radiomic feature extraction was performed using LIFEx software on baseline FDG-PET/CT. Outcome data (PFS) was collated from electronic patient records. Elastic net regularisation and feature selection were used for logistic regression model generation on a randomly selected training cohort and applied to a validation cohort using TRIPOD guidelines. ROC-AUC analysis was used to compare performance of a regression model encompassing standard clinical prognostic factors (age, sex, tumour and nodal stage-model A), a radiomic feature model (model B) and a combined radiomic/clinical model (model C). RESULTS: A total of 189 patients were included in the study, with 145 in the training cohort and 44 in the validation cohort. Median follow-up was 35.1 and 37. 9 months, respectively for each cohort, with 70.3% and 68.2% reaching this time-point with PFS. GLCM entropy (a measure of randomness of distribution of co-occurring pixel grey-levels), NGLDM busyness (a measure of spatial frequency of changes in intensity between nearby voxels of different grey-level), minimum CT value (lowest HU within the lesion) and SMTV (a standardized version of MTV) were selected for inclusion in the prognostic model, alongside tumour and nodal stage. AUCs for performance of model A (clinical), B (radiomic) and C (radiomic/clinical) were 0.6355, 0.7403, 0.7412 in the training cohort and 0.6024, 0.6595, 0.7381 in the validation cohort. CONCLUSION: Radiomic features extracted from pre-treatment FDG-PET/CT in patients with ASCC may provide better PFS prognosis than conventional staging parameters. With external validation, this might be useful to help personalise CRT regimens in the future.

Penetration of linezolid into synovial fluid and muscle tissue after elective arthroscopy.

Objectives: Penetration of antibiotics into synovial fluid is crucial to combat septic arthritis efficiently. Since linezolid may be used for treatment of septic arthritis when methicillin-resistant bacterial strains are suspected, we investigated its target-site concentrations in synovial fluid. Patients and methods: Ten patients undergoing elective knee arthroscopy were included in this study. Subjects received a single dose of 600 mg of linezolid intravenously and linezolid concentrations were measured in plasma and by using microdialysis in muscle tissue and synovial fluid. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing ability were performed using CLSI breakpoints and MIC90 for clinical isolates. Results: All 10 subjects tolerated linezolid well. As indicated by AUCtissue/AUCfree plasma ratios of 0.76 ±âŸ0.34 (synovial fluid) and 0.98 ±âŸ0.62 (muscle tissue) linezolid penetrated well into the knee gap and tissue. In synovial fluid AUC0-24/MIC ratios for bacteria with an MIC of 1, 2 and 4 mg/L were 86.8 ±âŸ47.0, 43.4 ±âŸ23.5 and 21.7 ±âŸ11.8, respectively. Conclusions: Linezolid may be used to treat septic arthritis caused by bacterial strains with an MIC ≤1 mg/L. Assuming a pharmacokinetic/pharmacodynamic target of > 50 for AUC0-24/MIC, when treating strains with an MIC >1 mg/L treatment surveillance is warranted. However, pharmacokinetic/pharmacodynamic targets for tissue are poorly understood and clinical data are needed to verify our assumptions.

Pharmacokinetics of Cefuroxime in Synovial Fluid.

Cefuroxime is frequently used as preoperative antibiotic prophylaxis and may be used for the treatment of septic arthritis. A prerequisite for successful treatment of septic arthritis is the ability of an antibiotic agent to penetrate into the target site. Therefore, the concentration of cefuroxime in synovial fluid was evaluated. Ten patients who underwent elective knee arthroscopy were included in this study. Patients were treated with a single dose of 1,500 mg cefuroxime intravenously, and subsequently, the concentrations in plasma, the interstitial fluid of muscle tissue, and synovial fluid were measured by using microdialysis. Pharmacokinetic/pharmacodynamic calculations to predict bacterial killing were performed using the epidemiologically defined MIC90 for clinical isolates and CLSI breakpoints. Cefuroxime penetrated excellently into muscle tissue (ratio of the area under the concentration-time curve [AUC] for muscle tissue/AUC for free plasma, 1.79) and synovial fluid (ratio of the AUC for synovial fluid/AUC for free plasma, 1.94). The cefuroxime concentration was greater than the MIC90 for Staphylococcus aureus and S. epidermidis strains (≤2 mg/liter) over the complete dosing interval (the percentage of the dosing interval during which the free cefuroxime concentration exceeded the MIC for the pathogen [fTMIC]). CLSI defines staphylococci with MICs of ≤8 mg/liter to be susceptible to cefuroxime. For staphylococci with MICs of ≤8 mg/liter, the fTMIC in plasma was 52.5%, while the fTMIC in muscle tissue and synovial fluid was 93.6% and 96.3%, respectively. Cefuroxime may be used to treat septic arthritis caused by susceptible bacterial strains (MIC ≤ 8 mg/liter). The activity of cefuroxime in septic arthritis might be underestimated when relying exclusively on plasma concentrations.

KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer.

BACKGROUND: We investigated the clinical implications of KRAS and BRAF mutations detected in both archival tumor tissue and plasma cell-free DNA in metastatic colorectal cancer patients treated with irinotecan monotherapy. METHODS: Two hundred and eleven patients receiving second-line irinotecan (350 mg m(-2) q3w) were included in two independent cohorts. Plasma was obtained from pretreatment EDTA blood-samples. Mutations were detected in archival tumour and plasma with qPCR methods. RESULTS: Mutation status in tumor did not correlate to efficacy in either cohort, whereas none of the patients with mutations detectable in plasma responded to therapy. Response rate and disease control rate in plasma KRAS wt patients were 19 and 66% compared with 0 and 37%, in patients with pKRAS mutations, (P=0.04 and 0.01). Tumor KRAS status was not associated with PFS but with OS in the validation cohort. Plasma BRAF and KRAS demonstrated a strong influence on both PFS and OS. The median OS was 13.0 mo in pKRAS wt patients and 7.8 in pKRAS-mutated, (HR=2.26, P<0.0001). PFS was 4.6 and 2.7 mo, respectively (HR=1,69, P=0.01). Multivariate analysis confirmed the independent prognostic value of pKRAS status but not KRAS tumor status. CONCLUSION: Tumor KRAS has minor clinical impact, whereas plasma KRAS status seems to hold important predictive and prognostic information.

Modern hypofractionation schedules for tangential whole breast irradiation decrease the fraction size-corrected dose to the heart.

AIMS: Hypofractionation of postoperative radiotherapy for breast cancer has been evaluated in a number of large randomised clinical trials, but concerns remain over the late cardiac toxicity. In this study, we examined the predictions of the linear quadratic model on the estimated fraction size-corrected dose to the heart for four evidence-based hypofractionation regimens. MATERIALS AND METHODS: Dose plans for 60 left-sided breast cancer patients were analysed. All patients were planned with tangential fields for whole breast irradiation. Dose distributions were corrected to the equivalent dose in 2 Gy fractions (EQD(2)) using the linear quadratic model for five different fractionation schedules (50 Gy/25 fractions and four hypofractionation regimens) and for a range of α/ß values (0-5 Gy). The mean EQD(2) to the heart ( [Formula: see text] ) and the volume receiving 40 Gy ( [Formula: see text] ), both as calculated from the EQD(2) dose distributions, were compared between schedules. RESULTS: For α/ß = 3 Gy, [Formula: see text] favours hypofractionation for 40 Gy/15 fractions, 39 Gy/13 fractions and 42.5 Gy/16 fractions, but not for 41.6 Gy/13 fractions. All of the hypofractionation schedules result in lower [Formula: see text] compared with normofractionation. These results hold as long as α/ߠ≳ 1.5 Gy. If the heart is blocked from the treatment beam, the fraction size-corrected dose is lower for the first three hypofractionation schedules, compared with normofractionation, even for α/ß = âˆ¼1 Gy. CONCLUSION: For standard tangential field whole breast irradiation, most of the examined hypofractionation schedules are estimated to spare the heart when compared with normofractionation. The dose to the heart, adjusted for fraction size using the linear quadratic model, will generally be lower after hypofractionated compared with normofractionated schedules, even for very low values of α/ß.

[Solid body augmentation for comminuted calcaneal fractures : development and biomechanical testing of a hybrid osteosynthesis technique]. / Festkörperaugmentation bei Kalkaneustrümmerfrakturen : Entwicklung und biomechanische Testung einer Hybridosteosynthesetechnik.

BACKGROUND: Comminuted calcaneal fractures are a consequence of high impact trauma to the foot. Stable fixation and anatomically correct repositioning of the joint surfaces are often a problem. To improve fracture treatment, surgical techniques in combination with new augmentation materials have been tested. METHODS: This study presents a new concept of osteosynthesis of complex calcaneal fractures in combination with an alternative augmentation technique. Solid body augmentation was developed and mechanically tested against standard techniques. The solid body was used for augmentation of a central fracture void in combination with conventional plating. RESULTS: The results show a statistically significant higher stability of the new hybrid osteosynthesis concept against conventional plating techniques under in-vitro conditions. CONCLUSIONS: This work investigated a new concept of internal support of multifragmentary calcaneal fractures. Augmentation of defect voids in the calcaneus with a mechanically stable solid body implant in combination with stable screw anchorage in this implant leads to a higher stability compared to plate-fixation and augmentation with cancellous bone under in-vitro conditions.

[Precision of guidewire placement--can it be improved by applying the new, isocentric aiming principle?]. / Können Führungsdrähte durch ein neues isozentrisches Zielverfahren präziser platziert werden?

BACKGROUND: Exact placement of a guidewire is difficult for the less experienced surgeon as this complex 3D task usually is controlled by means of 2D fluoroscopic projections. The new isocentric aiming principle presented here splits up the 3D task into two planar, 2D steps. Movements of the guidewire to achieve correct placement are limited to one plane per step and can therefore be exactly controlled by fluoroscopy. The fluoroscopic projection needs to be changed only once in between the two steps. METHODS: The isocentric aiming principle became applicable to the proximal femur region by means of a mechanical aiming device. We have done an experimental study in order to compare the new isocentric aiming principle to the freehand aiming technique which is routinely applied. We documented the precision of guidewire placement achieved (angular deviation of the guidewire in two projections, linear deviation of the actual from the intended entry point), number of fluoroscopic controls, and procedure time when guidewire placement is done by an experienced and by an inexperienced surgeon. RESULTS: When applying the isocentric aiming principle the inexperienced surgeon succeeded in fixing the entry angle of the guidewire more precisely both in the AP [1.3 degrees (0.0-2.0 degrees ) versus 2.3 degrees (0.0-9.0 degrees ), p=0.034] as well as in the axial view [1.0 degrees (0.0-2.5 degrees ) versus 6.5 degrees (0.0-12.0 degrees ), p=0.036]. Linear displacement was not significantly different between the two methods: 4.4 (0.7-9.6) mm deviation with the isocentric aiming principle versus 3.9 (1.6-5.7) mm, p=0.406, when the freehand technique is applied. When applying the isocentric aiming principle for guidewire placement the experienced surgeon achieved less precise angulation in the AP view [2.5 degrees (0.0-4.0 degrees ) versus 1.8 degrees (0.0-3.5 degrees ), p=0.061], improved precision in the axial view [2.0 degrees (1.0-3.0 degrees ) versus 3.0 degrees (0.0-5.0 degrees ), p=0.074], and a slightly worsened linear displacement [2.5 (1.0-4.2) mm versus 2.0 (1.0-2.6) mm, p=0.131]. Both surgeons needed less fluoroscopic controls when using the isocentric aiming principle instead of the freehand aiming method: inexperienced surgeon: 8.0 controls (7.0-16.0) instead of 13.0 controls (7.0-16.0), p=0.043; experienced surgeon: 14.5 controls (8.0-26.0) instead of 16.5 controls (12.0-33.0), p=0.282. However due to the additional time needed to fix and align the aiming device to the bone both surgeons required increased procedure time when using the isocentric aiming principle: 4.3 (3.0-6.9) min instead of 2.6 (2.2-4.0) min, p=0.005, for the inexperienced surgeon and 3.3 (2.3-4.3) min instead of 1.9 (1.4-2.8) min, p=0.001, for the experienced surgeon. CONCLUSIONS: Based on the experimental results we would suggest clinical application of the isocentric aiming principle especially for the less experienced surgeon. Increased precision would outweigh the drawback of a slightly prolonged procedure time. X-ray exposure may also be reduced when using the isocentric aiming principle for guidewire placement. However our results have to be verified by a clinical study beforehand. The isocentric aiming principle can also be applied in other situations that allow for two orthogonal projections for guidewire placement.

Biomechanical evaluation of a new augmentation method for enhanced screw fixation in osteoporotic proximal femoral fractures.

A biomechanical investigation on eight pairs of human cadaver proximal femurs was performed to evaluate the impact of a new augmentation method on the internal fixation of osteoporotic proximal femur fractures. The study focused on enhancing implant purchase to reduce the incidence of implant cut-out in osteoporotic bone. In a left-right comparison, a conventional hip screw fixation (control) was compared to the new cement augmentation method. After bone bed preparation through high pressure irrigation to remove fat, blood, and bone debris, the bones were augmented with low viscosity polymethylmethacrylate (PMMA) cement. Step-wise fatigue testing was performed by cyclically loading the femoral heads in a physiological manner, beginning at 1,500 N and increasing 500 N every 5,000 cycles to 4,000 N, and continuously monitoring head displacement. Failure was defined as >5.0 mm head displacement. The head displacement at 2,000 N was significantly smaller (p=0.018) for the augmented group as compared to the conventionally treated bones (0.09+/-0.01 mm vs. 0.90+/-0.32 mm; mean+/-SEM). The displacement rate at the second load step was significantly higher (p=0.018) for the conventionally treated bones as compared to the augmented ones. All of the nonaugmented specimens failed during testing, where 50% of the augmented specimens did not fail. The promising results of these experiments suggest that this new standardized irrigation/augmentation method enhances the implant anchorage and offers a potential solution to the problem of implant cut-out in osteoporotic metaphyseal bone.