Identification of CT radiomic features robust to acquisition and segmentation variations for improved prediction of radiotherapy-treated lung cancer patient recurrence.

The primary objective of the present study was to identify a subset of radiomic features extracted from primary tumor imaged by computed tomography of early-stage non-small cell lung cancer patients, which remain unaffected by variations in segmentation quality and in computed tomography image acquisition protocol. The robustness of these features to segmentation variations was assessed by analyzing the correlation of feature values extracted from lesion volumes delineated by two annotators. The robustness to variations in acquisition protocol was evaluated by examining the correlation of features extracted from high-dose and low-dose computed tomography scans, both of which were acquired for each patient as part of the stereotactic body radiotherapy planning process. Among 106 radiomic features considered, 21 were identified as robust. An analysis including univariate and multivariate assessments was subsequently conducted to estimate the predictive performance of these robust features on the outcome of early-stage non-small cell lung cancer patients treated with stereotactic body radiation therapy. The univariate predictive analysis revealed that robust features demonstrated superior predictive potential compared to non-robust features. The multivariate analysis indicated that linear regression models built with robust features displayed greater generalization capabilities by outperforming other models in predicting the outcomes of an external validation dataset.

Multicentric development and evaluation of [18F]FDG PET/CT and CT radiomic models to predict regional and/or distant recurrence in early-stage non-small cell lung cancer treated by stereotactic body radiation therapy.

PURPOSE: To develop machine learning models to predict regional and/or distant recurrence in patients with early-stage non-small cell lung cancer (ES-NSCLC) after stereotactic body radiation therapy (SBRT) using [18F]FDG PET/CT and CT radiomics combined with clinical and dosimetric parameters. METHODS: We retrospectively collected 464 patients (60% for training and 40% for testing) from University Hospital of Liège and 63 patients from University Hospital of Brest (external testing set) with ES-NSCLC treated with SBRT between 2010 and 2020 and who had undergone pretreatment [18F]FDG PET/CT and planning CT. Radiomic features were extracted using the PyRadiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Clinical, radiomic, and combined models were trained and tested using a neural network approach to predict regional and/or distant recurrence. RESULTS: In the training (n = 273) and testing sets (n = 191 and n = 63), the clinical model achieved moderate performances to predict regional and/or distant recurrence with C-statistics from 0.53 to 0.59 (95% CI, 0.41, 0.67). The radiomic (original_firstorder_Entropy, original_gldm_LowGrayLevelEmphasis and original_glcm_DifferenceAverage) model achieved higher predictive ability in the training set and kept the same performance in the testing sets, with C-statistics from 0.70 to 0.78 (95% CI, 0.63, 0.88) while the combined model performs moderately well with C-statistics from 0.50 to 0.62 (95% CI, 0.37, 0.69). CONCLUSION: Radiomic features extracted from pre-SBRT analog and digital [18F]FDG PET/CT outperform clinical parameters in the prediction of regional and/or distant recurrence and to discuss an adjuvant systemic treatment in ES-NSCLC. Prospective validation of our models should now be carried out.

Development and prospective validation of a spatial dose pattern based model predicting acute pulmonary toxicity in patients treated with volumetric arc-therapy for locally advanced lung cancer.

INTRODUCTION: (Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment's compliance and patients' quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the posterior right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arctherapy (VMAT) and to validate our findings prospectively. METHODS: For the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for n = 10.000 permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (p < 0.05) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A prediction model (Pmap-Model) was then built using a neural network approach and then applied to an observational prospective cohort for validation. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). RESULTS: 165 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.4% and 19.1%. In the training cohort, a cluster of voxels (Pmap-region) was identified in the posterior right lung. In the training cohort, the Pmap-Model combining 11 features among which the mean dose to the Pmap-region resulted in an AUC of 0.99 and a Bacc of 99.2 using an 8% probability threshold. Using the same voxel cluster on the validation cohort, the Pmap-model resulted in an AUC of 0.81 and a Bacc of 82.0. CONCLUSION: Our APT-prediction model was successfully validated in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints, opening the possibility of easily implementable adaptive dosimetry planning.

Radiation Therapy Planning of Thoracic Tumors: A Review of Challenges Associated With Lung Toxicities and Potential Perspectives of Gallium-68 Lung PET/CT Imaging.

Despite the introduction of new radiotherapy techniques, such as intensity modulated radiation therapy or stereotactic body radiation therapy, radiation induced lung injury remains a significant treatment related adverse event of thoracic radiation therapy. Functional lung avoidance radiation therapy is an emerging concept in the treatment of lung disease to better preserve lung function and to reduce pulmonary toxicity. While conventional ventilation/perfusion (V/Q) lung scintigraphy is limited by a relatively low spatial and temporal resolution, the recent advent of 68Gallium V/Q lung PET/CT imaging offers a potential to increase the accuracy of lung functional mapping and to better tailor lung radiation therapy plans to the individual's lung function. Lung PET/CT imaging may also improve our understanding of radiation induced lung injury compared to the current anatomical based dose-volume constraints. In this review, recent advances in radiation therapy for the management of primary and secondary lung tumors and in V/Q PET/CT imaging for the assessment of functional lung volumes are reviewed. The new opportunities and challenges arising from the integration of V/Q PET/CT imaging in radiation therapy planning are also discussed.

Germline mutations in BRCA1 and BRCA2 incidentally revealed in a biobank research study: experiences from re-contacting mutation carriers and relatives.

Once an incidental finding (IF) is discovered in the course of genomic research, the researchers are faced with the question of whether or not that finding should be reported back to the study participant. A large number of hypothetical studies and policy documents on this issue have been published, but there are very few empirical studies to inform the bioethics debate. Within a biobank research study of somatic mutations in breast carcinomas, ten germline BRCA1/2 mutations were incidentally detected. After thorough discussions within a group of experts, the mutation carriers (n = 7) or relatives of deceased carriers (n = 3) were re-contacted and informed about the findings. Eight out of ten accepted to receive the information and underwent confirmatory testing. One year later, semi-structured interviews were undertaken with three of the study participants. All of them felt that BRCA mutations discovered in the course of research should be reported back to the individual study participants. In this paper, we report our step-by-step experiences of the re-contacting process. We hope that our detailed reporting will be helpful for other researchers and clinicians that are faced with similar situations. The results of our study lend empirical support to opinion that IFs that meet the three baseline criteria of analytic validity, clinical significance, and actionability should be reported back to the individual study participants.

Aesthetic result after breast-conserving therapy is associated with quality of life several years after treatment. Swedish women evaluated with BCCT.core and BREAST-Q™.

PURPOSE: A gold standard for evaluation of aesthetic outcome after breast-conserving therapy (BCT) is still lacking. The BCCT.core software has been developed to assess aesthetic result in a standardised way. We aimed to study how the result of BCCT.core after BCT is associated with quality of life, measured with the BREAST-Q™, a validated questionnaire. METHODS: Women eligible for BCT were consecutively recruited between February 1st 2008 and January 31st 2012 (n = 653). Photographs of 310 women, taken one year after BCT, were evaluated using the BCCT.core software. The postoperative BCT module of the BREAST-Q™ questionnaire was administered by mail and 348 questionnaires were returned (median 5.5 years after BCT). In all, 216 women had both BCCT.core results and completed BREAST-Q™ questionnaires available. RESULTS: The results from the BCCT.core evaluation were: excellent n = 49 (15.8%); good n = 178 (57.4%); fair n = 73 (23.5%); poor n = 10 (3.2%). The median BREAST-Q™ score for satisfaction with breasts was 66 [interquartile range (IQR) 57-80] and for psychosocial well-being 82 (IQR 61-100). Poor/fair results on BCCT.core were associated with Q-scores below median for both satisfaction with breasts [odds ratio (OR) 3.4 (confidence interval (CI) 1.7-6.8)] as well as for psychosocial well-being [OR 2.2 (CI 1.1-4.2)]. CONCLUSIONS: A statistically significant association between BCCT.core results one year after BCT and quality of life ratings using BREAST-Q™ several years later is shown in this study. This implies that the BCCT.core may be valuable in BCT follow-up and used as a standardised instrument in the evaluation of aesthetic results.

Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer.

Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast cancer patients from the well-characterized, population-based, single-site All Breast Cancer in Malmö (ABiM) study. The patients were diagnosed with breast cancer during the years 2007 through 2009. Out of 20 mutation carriers identified, 13 fulfilled Swedish criteria at time of diagnosis. Thus, the efficacy of these criteria was 65%. Excluding three patients in whom a mutation was already known at time of diagnosis, only 3/17 had been identified in the clinical routine, corresponding to an effectiveness of 18%. Here we detail the reasons why mutation carriers in our cohort were not detected though routine health care. In conclusion, effectiveness of BRCA testing criteria was much lower than efficacy. Our results indicate that current testing criteria and procedures associated with BRCA1 and BRCA2 testing are insufficient. There is room for improvement of their efficacy, but even more so regarding effectiveness. Clinical BRCA testing routines need to be critically revised.

Patients Undergoing Breast-Conserving Surgery Can Benefit from the Opportunity to Participate in Choosing Their Surgical Technique.

BACKGROUND: Shared decision-making is increasingly advocated in many countries. The aims of this study were to investigate whether patients receiving breast-conserving surgery at Skåne University Hospital Malmö, Sweden, perceived an offered possibility to join in the decision-making process regarding the surgical method; to identify potential determinants for not having perceived such an offer; and to study how this perception of being offered an opportunity to take part in the decision-making process affected satisfaction with the aesthetic outcome. METHODS: Women offered breast-conserving surgery were consecutively recruited over a period of 4 years. In all, 324 women completed a study-specific questionnaire. RESULTS: A majority of the women (53 %) perceived that they had not, or had only partly, been offered a possibility to take part in the decision-making process. Patients who reported that they had received enough preoperative information regarding the expected aesthetic result were more likely to have perceived such an offer (odds ratio (OR) 5.44; confidence interval (CI) 2.83-10.43). Women who had perceived an opportunity to be involved were more satisfied with the aesthetic result (OR 2.71; CI 1.18-6.25) and more likely to have had their expectations met regarding the aesthetic result (OR 5.91; CI 2.01-17.38). CONCLUSION: When deciding on a suitable surgical approach for women with early breast cancer, physicians could try to more clearly communicate to the women that they can choose whether or not to participate in the decision-making regarding surgical technique. This might improve satisfaction. An important part of patient involvement is sufficient preoperative information.

Determinants for patient satisfaction regarding aesthetic outcome and skin sensitivity after breast-conserving surgery.

BACKGROUND: With the development of new surgical techniques in breast cancer, such as oncoplastic breast surgery, increased knowledge of risk factors for poor satisfaction with conventional breast-conserving surgery (BCS) is needed in order to determine which patients to offer these techniques to. The aim of this study was to investigate patient satisfaction regarding aesthetic result and skin sensitivity in relation to patient, tumour, and treatment factors, in a consecutive sample of patients undergoing conventional BCS. METHODS: Women eligible for BCS were recruited between February 1, 2008 and January 31, 2012 in a prospective setup. In all, 297 women completed a study-specific questionnaire 1 year after conventional BCS and radiotherapy. Potential risk factors for poor satisfaction were investigated using logistic regression analysis. RESULTS: The great majority of the women, 84%, were satisfied or very satisfied with the overall aesthetic result. The rate of satisfaction regarding symmetry between the breasts was 68% and for skin sensitivity in the operated breast it was 67%. Excision of more than 20% of the preoperative breast volume was associated with poor satisfaction regarding overall aesthetic outcome, as was axillary clearance. A high BMI (≥30 kg/m2) seemed to affect satisfaction with symmetry negatively. Factors associated with less satisfied patients regarding skin sensitivity in the operated breast were an excision of ≥20% of preoperative breast volume, a BMI of 25-30 kg/m2, axillary clearance, and radiotherapy. Re-excision and postoperative infection were associated with lower rates of satisfaction regarding both overall aesthetic outcome and symmetry, as well as with skin sensitivity. CONCLUSIONS: Several factors affect patient satisfaction after BCS. A major determinant of poor satisfaction in this study was a large excision of breast volume. If the percentage of breast volume excised is estimated to exceed 20%, other techniques, such as oncoplastic breast surgery, with or without contralateral surgery, or mastectomy with reconstruction, may be considered.

GM6001 Increases Anastomotic Leakage following Colonic Obstruction Possibly by Impeding Epithelialization.

BACKGROUND: Emergency operations performed on an obstructed colon are accompanied by an increased risk of anastomotic insufficiency. Tissue-destructive matrix metalloproteinase (MMP) activity is elevated in the obstructed colon and contributes to a loss of suture-holding submucosal collagen, which may be mediated by tumor necrosis factor (TNF)-α. Our aim was to study the effect of the non-selective MMP and TNF-α converting enzyme (TACE) inhibitor GM6001 (30 mg/kg) on anastomosis repair in obstructed left colon. GM6001 has been proved to be highly efficacious in elective anastomosis rodent models. METHODS: A partial obstruction of the distal colon was induced in male Sprague-Dawley rats. After 4 d the obstructed colonic segment was resected, and an end-to-end anastomosis was constructed. Seven days later, the anastomoses were evaluated for clinical leakage. Histopathological and immunohistochemical assessments were also performed. Finally, the direct effect of GM6001 on epithelialization was studied in cultured colonic epithelial cells. RESULTS: Unlike the robust beneficial effect on anastomosis under uncomplicated conditions, here GM6001 had a negative impact on anastomotic wound healing following colonic obstruction and substantially (p=0.004) more rats in the GM6001 group (75%) than in the control group (11%) had developed anastomotic leakage. In the anastomotic wounds, the myofibroblast abundance and cell proliferation were similar in the two groups. Histologically, GM6001 treatment resulted in wider and minimally epithelialized wounds that were commonly necrotic on the luminal side and infiltrated with numerous granulocytes. In vitro, GM6001 also delayed (p=0.026) epithelialization of denuded intestinal epithelium grown on type I collagen. CONCLUSIONS: Non-selective MMP/TACE inhibition with GM6001 increased the anastomotic complications following colon obstruction. Inhibition of epithelialization is one possible mechanism responsible for the increased leakage following GM6001 treatment.

Rapid morphological changes and loss of collagen following experimental acute colonic obstruction.

PURPOSE: Anastomosis of an acutely obstructed colon is associated with an increased risk of dehiscence. In experimental models, acute obstruction decreases collagen in the colonic wall, but the time course and propagation along the colon of the biochemical changes are unknown. Furthermore, there is a paucity of information on the correlation between these biochemical changes and histological features. METHODS: Forty male Sprague Dawley rats were subjected to partial obstruction by placing a silicone ring around the left colon 30 mm above the reflection. Obstruction was maintained for 0, 1, 2, 3 or 4 days. Samples from five different locations along the colon were analysed on circumference, tissue water content, collagen concentration and histomorphology. Neutrophil and macrophage infiltration was characterized immunohistochemically. RESULTS: The colonic circumference and water content increased (p < 0.001), while the collagen concentration decreased by 48 % (p < 0.01) proximal to the obstruction already after 1 day. The degree of dilation and collagen reduction did not change significantly over the subsequent 3 days of obstruction, whereas the water content normalized by day 3. Mucosal and submucosal oedema and the relative neutrophil infiltration were highest after 1 day in the colonic segment proximal to the stenosis while the macrophage population continued to increase to day 4. Muscular necrosis in addition to ganglionitis and neuritis in the nervous plexus increased with duration of obstruction. CONCLUSIONS: The pronounced and rapid changes of the composition of cells and the extracellular matrix of the colonic wall following acute obstruction may be of guidance for present surgical treatments and future pharmacological interventions.

Sound retrieval and ranking using sparse auditory representations.

To create systems that understand the sounds that humans are exposed to in everyday life, we need to represent sounds with features that can discriminate among many different sound classes. Here, we use a sound-ranking framework to quantitatively evaluate such representations in a large-scale task. We have adapted a machine-vision method, the passive-aggressive model for image retrieval (PAMIR), which efficiently learns a linear mapping from a very large sparse feature space to a large query-term space. Using this approach, we compare different auditory front ends and different ways of extracting sparse features from high-dimensional auditory images. We tested auditory models that use an adaptive pole-zero filter cascade (PZFC) auditory filter bank and sparse-code feature extraction from stabilized auditory images with multiple vector quantizers. In addition to auditory image models, we compare a family of more conventional mel-frequency cepstral coefficient (MFCC) front ends. The experimental results show a significant advantage for the auditory models over vector-quantized MFCCs. When thousands of sound files with a query vocabulary of thousands of words were ranked, the best precision at top-1 was 73% and the average precision was 35%, reflecting a 18% improvement over the best competing MFCC front end.

Doxycycline-coated sutures improve mechanical strength of intestinal anastomoses.

BACKGROUND AND AIMS: After resection and repair of the intestines, tissue degradation leads to weakening of the repair site and risk of postoperative leakage. Matrix metalloproteinases (MMPs) are thought to be responsible for collagenolysis in the direct vicinity of surgical sutures in many tissues. Several experimental studies show that MMP inhibitors administered systemically alleviate postoperative weakening of intestinal anastomoses. We hypothesised that local delivery of MMP inhibitors would achieve a similar effect. MATERIALS AND METHODS: Implementing a novel method for the coating of biomaterials, we coated sutures with a cross-linked fibrinogen film and bound the MMP inhibitor doxycycline into this film. The sutures were then used in a standard rat model for evaluating mechanical properties of colonic anastomoses 3 days after surgery. RESULTS: The breaking strength of the anastomoses on the critical third day after operation was 17% higher with doxycycline-coated sutures compared to controls (P = 0.026). Energy uptake at failure was enhanced by 20% (P = 0.047). CONCLUSION: Drug delivery by means of MMP-inhibitor-coated sutures appears to improve tissue integrity during anastomotic repair and may reduce postoperative complications.

A network that uses few active neurones to code visual input predicts the diverse shapes of cortical receptive fields.

Computational models of primary visual cortex have demonstrated that principles of efficient coding and neuronal sparseness can explain the emergence of neurones with localised oriented receptive fields. Yet, existing models have failed to predict the diverse shapes of receptive fields that occur in nature. The existing models used a particular "soft" form of sparseness that limits average neuronal activity. Here we study models of efficient coding in a broader context by comparing soft and "bard" forms of neuronal sparseness. As a result of our analyses, we propose a novel network model for visual cortex. The model forms efficient visual representations in which the number of active neurones, rather than mean neuronal activity, is limited. This form of hard sparseness also economises cortical resources like synaptic memory and metabolic energy. Furthermore, our model accurately predicts the distribution of receptive field shapes found in the primary visual cortex of cat and monkey.

Attractor dynamics in a modular network model of neocortex.

Starting from the hypothesis that the mammalian neocortex to a first approximation functions as an associative memory of the attractor network type, we formulate a quantitative computational model of neocortical layers 2/3. The model employs biophysically detailed multi-compartmental model neurons with conductance based synapses and includes pyramidal cells and two types of inhibitory interneurons, i.e., regular spiking non-pyramidal cells and basket cells. The simulated network has a minicolumnar as well as a hypercolumnar modular structure and we propose that minicolumns rather than single cells are the basic computational units in neocortex. The minicolumns are represented in full scale and synaptic input to the different types of model neurons is carefully matched to reproduce experimentally measured values and to allow a quantitative reproduction of single cell recordings. Several key phenomena seen experimentally in vitro and in vivo appear as emergent features of this model. It exhibits a robust and fast attractor dynamics with pattern completion and pattern rivalry and it suggests an explanation for the so-called attentional blink phenomenon. During assembly dynamics, the model faithfully reproduces several features of local UP states, as they have been experimentally observed in vitro, as well as oscillatory behavior similar to that observed in the neocortex.