Ironbark: Developing a healthy community program for older Aboriginal people.

ISSUE ADDRESSED: Programs by, with and for Aboriginal older people must be culturally safe and relevant. Successful elements include being Aboriginal specific and group based. Co-design with Aboriginal people and stakeholders is essential. We describe the co-design process of developing the Ironbark: Healthy Community program. METHODS: Aboriginal ways of knowing, being and doing and yarning conversational methods guided the development process, during 2018. A desktop review provided details of current group characteristics and key community stakeholders. Stakeholder engagement regarding views about group operations, participants and benefits also occurred. Aboriginal Elders views of their groups were gathered through yarning circles in New South Wales (NSW). Grounded theory approach was used to ascertain key themes. RESULTS: Initial engagement occurred with 13 different community stakeholders and organisations in three Australian states (NSW, South Australia (SA), Western Australia (WA)). Three yarning circles occurred with Elders from urban (N = 10), regional coastal (N = 10) and regional country (N = 4) groups. Six key themes were organised in three groups according to an Aboriginal ontology. 1. Knowing: groups provide opportunities to share knowledge and connect socially. Adequate program resourcing and sustainability are valued. 2. Being: groups strengthen culture, providing important social, emotional and other forms of support to age well. 3. Doing: previous program experiences inform perceptions for new program operations. Group venues and operational aspects should be culturally safe, acknowledging diversity among Elders, their preferences and community control. Themes were used to develop the program and its resource manual that were finalised with stakeholders, including steering committee approval. CONCLUSIONS: Stakeholder feedback at multiple stages and Aboriginal Elders' perspectives resulted in a new co-designed community program involving weekly yarning circles and social activities. So what?: Co-design, guided by Aboriginal ways of knowing, being and doing, can develop programs relevant for Aboriginal people.

Quantification of hemodynamics of cerebral arteriovenous malformations after stereotactic radiosurgery using 4D flow magnetic resonance imaging.

Stereotactic radiosurgery (SRS) is used to treat cerebral arteriovenous malformations (AVMs). However, early evaluation of efficacy is difficult as structural magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) often does not demonstrate appreciable changes within the first 6 months. The aim of this study was to evaluate the use of four-dimensional (4D) flow MRI to quantify hemodynamic changes after SRS as early as 2 months. This was a retrospective observational study, which included 14 patients with both pre-SRS and post-SRS imaging obtained at multiple time points from 1 to 27 months after SRS. A 3T MRI Scanner was used to obtain T2 single-shot fast spin echo, time-of-flight MRA, and postcontrast 4D flow with three-dimensional velocity encoding between 150 and 200 cm/s. Post-hoc two-dimensional cross-sectional flow was measured for the dominant feeding artery, the draining vein, and the corresponding contralateral artery as a control. Measurements were performed by two independent observers, and reproducibility was assessed. Wilcoxon signed-rank tests were used to compare differences in flow, circumference, and pulsatility between the feeding artery and the contralateral artery both before and after SRS; and differences in nidus size and flow and circumference of the feeding artery and draining vein before and after SRS. Arterial flow (L/min) decreased in the primary feeding artery (mean: 0.1 ± 0.07 vs. 0.3 ± 0.2; p < 0.05) and normalized in comparison to the contralateral artery (mean: 0.1 ± 0.07 vs. 0.1 ± 0.07; p = 0.068). Flow decreased in the draining vein (mean: 0.1 ± 0.2 vs. 0.2 ± 0.2; p < 0.05), and the circumference of the draining vein also decreased (mean: 16.1 ± 8.3 vs. 15.7 ± 6.7; p < 0.05). AVM volume decreased after SRS (mean: 45.3 ± 84.8 vs. 38.1 ± 78.7; p < 0.05). However, circumference (mm) of the primary feeding artery remained similar after SRS (mean: 15.7 ± 2.7 vs. 16.1 ± 3.1; p = 0.600). 4D flow may be able to demonstrate early hemodynamic changes in AVMs treated with radiosurgery, and these changes appear to be more pronounced and occur earlier than the structural changes on standard MRI/MRA. Level of Evidence: 4 Technical Efficacy Stage: 1.

Voxel-level Classification of Prostate Cancer on Magnetic Resonance Imaging: Improving Accuracy Using Four-Compartment Restriction Spectrum Imaging.

BACKGROUND: Diffusion magnetic resonance imaging (MRI) is integral to detection of prostate cancer (PCa), but conventional apparent diffusion coefficient (ADC) cannot capture the complexity of prostate tissues and tends to yield noisy images that do not distinctly highlight cancer. A four-compartment restriction spectrum imaging (RSI4 ) model was recently found to optimally characterize pelvic diffusion signals, and the model coefficient for the slowest diffusion compartment, RSI4 -C1 , yielded greatest tumor conspicuity. PURPOSE: To evaluate the slowest diffusion compartment of a four-compartment spectrum imaging model (RSI4 -C1 ) as a quantitative voxel-level classifier of PCa. STUDY TYPE: Retrospective. SUBJECTS: Forty-six men who underwent an extended MRI acquisition protocol for suspected PCa. Twenty-three men had benign prostates, and the other 23 men had PCa. FIELD STRENGTH/SEQUENCE: A 3 T, multishell diffusion-weighted and axial T2-weighted sequences. ASSESSMENT: High-confidence cancer voxels were delineated by expert consensus, using imaging data and biopsy results. The entire prostate was considered benign in patients with no detectable cancer. Diffusion images were used to calculate RSI4 -C1 and conventional ADC. Classifier images were also generated. STATISTICAL TESTS: Voxel-level discrimination of PCa from benign prostate tissue was assessed via receiver operating characteristic (ROC) curves generated by bootstrapping with patient-level case resampling. RSI4 -C1 was compared to conventional ADC for two metrics: area under the ROC curve (AUC) and false-positive rate for a sensitivity of 90% (FPR90 ). Statistical significance was assessed using bootstrap difference with two-sided α = 0.05. RESULTS: RSI4 -C1 outperformed conventional ADC, with greater AUC (mean 0.977 [95% CI: 0.951-0.991] vs. 0.922 [0.878-0.948]) and lower FPR90 (0.032 [0.009-0.082] vs. 0.201 [0.132-0.290]). These improvements were statistically significant (P < 0.05). DATA CONCLUSION: RSI4 -C1 yielded a quantitative, voxel-level classifier of PCa that was superior to conventional ADC. RSI classifier images with a low false-positive rate might improve PCa detection and facilitate clinical applications like targeted biopsy and treatment planning. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Understanding implementation factors and participant experiences of a cluster randomised controlled trial to prevent falls among older Aboriginal people: a process evaluation protocol.

INTRODUCTION: Process evaluations examining programme implementation are often conducted in conjunction with effectiveness studies. Their inclusion in studies with Aboriginal participants can give an understanding of programme delivery in Aboriginal community contexts. The Ironbark: Standing Strong and Tall programme was codesigned with Aboriginal communities and includes exercise and facilitated 'yarning' discussion about fall risk and prevention strategies. The programme pilot showed favourable outcomes and acceptability for Aboriginal people aged 45 years and over. The Ironbark: Standing Strong and Tall programme is now being compared with a 'Healthy Community' programme in a cluster randomised controlled trial within Aboriginal health and community services. An embedded process evaluation aims to explore relationships between participation and programme outcomes and the quality of programme implementation. METHODS AND ANALYSIS: The process evaluation will use a mixed methods design, guided by Indigenous research methodology. It will evaluate quantitative data (number of completed sessions, site coaching checklist tool, participant and facilitator questionnaire data and a participant habit formation scale), as well as qualitative data (open-ended responses from project and site staff and semistructured interviews using yarning with study participants and site managers). A programme logic model was developed to explain the intended inputs, activities, outputs and outcomes, which guided this process evaluation design. CONCLUSION: This process evaluation of a fall prevention programme for older Aboriginal people using a mixed methods design and data triangulation will allow for a comprehensive understanding of study findings. Multiple study sites allow for generalisability of findings and exploration of variation across sites. TRIAL REGISTRATION NUMBER: ACTRN12619000349145.

The potential for gas-free measurements of absolute oxygen metabolism during both baseline and activation states in the human brain.

Quantitative functional magnetic resonance imaging methods make it possible to measure cerebral oxygen metabolism (CMRO2) in the human brain. Current methods require the subject to breathe special gas mixtures (hypercapnia and hyperoxia). We tested a noninvasive suite of methods to measure absolute CMRO2 in both baseline and dynamic activation states without the use of special gases: arterial spin labeling (ASL) to measure baseline and activation cerebral blood flow (CBF), with concurrent measurement of the blood oxygenation level dependent (BOLD) signal as a dynamic change in tissue R2*; VSEAN to estimate baseline O2 extraction fraction (OEF) from a measurement of venous blood R2, which in combination with the baseline CBF measurement yields an estimate of baseline CMRO2; and FLAIR-GESSE to measure tissue R2' to estimate the scaling parameter needed for calculating the change in CMRO2 in response to a stimulus with the calibrated BOLD method. Here we describe results for a study sample of 17 subjects (8 female, mean age = 25.3 years, range 21-31 years). The primary findings were that OEF values measured with the VSEAN method were in good agreement with previous PET findings, while estimates of the dynamic change in CMRO2 in response to a visual stimulus were in good agreement between the traditional hypercapnia calibration and calibration based on R2'. These results support the potential of gas-free methods for quantitative physiological measurements.

A novel Bayesian approach to accounting for uncertainty in fMRI-derived estimates of cerebral oxygen metabolism fluctuations.

Calibrated blood oxygenation level dependent (BOLD) imaging is a multimodal functional MRI technique designed to estimate changes in cerebral oxygen metabolism from measured changes in cerebral blood flow and the BOLD signal. This technique addresses fundamental ambiguities associated with quantitative BOLD signal analysis; however, its dependence on biophysical modeling creates uncertainty in the resulting oxygen metabolism estimates. In this work, we developed a Bayesian approach to estimating the oxygen metabolism response to a neural stimulus and used it to examine the uncertainty that arises in calibrated BOLD estimation due to the presence of unmeasured model parameters. We applied our approach to estimate the CMRO2 response to a visual task using the traditional hypercapnia calibration experiment as well as to estimate the metabolic response to both a visual task and hypercapnia using the measurement of baseline apparent R2' as a calibration technique. Further, in order to examine the effects of cerebral spinal fluid (CSF) signal contamination on the measurement of apparent R2', we examined the effects of measuring this parameter with and without CSF-nulling. We found that the two calibration techniques provided consistent estimates of the metabolic response on average, with a median R2'-based estimate of the metabolic response to CO2 of 1.4%, and R2'- and hypercapnia-calibrated estimates of the visual response of 27% and 24%, respectively. However, these estimates were sensitive to different sources of estimation uncertainty. The R2'-calibrated estimate was highly sensitive to CSF contamination and to uncertainty in unmeasured model parameters describing flow-volume coupling, capillary bed characteristics, and the iso-susceptibility saturation of blood. The hypercapnia-calibrated estimate was relatively insensitive to these parameters but highly sensitive to the assumed metabolic response to CO2.

Understanding the dynamic relationship between cerebral blood flow and the BOLD signal: Implications for quantitative functional MRI.

Calibrated BOLD imaging, in which traditional measurements of the BOLD signal are combined with measurements of cerebral blood flow (CBF) within a BOLD biophysical model to estimate changes in oxygen metabolism (CMRO2), has been a valuable tool for untangling the physiological processes associated with neural stimulus-induced BOLD activation. However, to date this technique has largely been applied to the study of essentially steady-state physiological changes (baseline to activation) associated with block-design stimuli, and it is unclear whether this approach may be directly extended to the study of more dynamic, naturalistic experimental designs. In this study we tested an assumption underlying this technique whose validity is critical to the application of calibrated BOLD to the study of more dynamic stimuli, that information about fluctuations in venous cerebral blood volume (CBVv) can be captured indirectly by measuring fluctuations in CBF, making the independent measurement of CBVv unnecessary. To accomplish this, simultaneous arterial spin labeling and BOLD imaging were used to measure the CBF and BOLD responses to flickering checkerboards with contrasts that oscillated continuously with frequencies of ~0.02-0.16Hz. The measurements were then fit to a dynamic physiological model of the BOLD response in order to explore the range of consistent CMRO2 and CBVv responses. We found that the BOLD and CBF responses were most consistent with relatively tight dynamic coupling between CBF and CMRO2 and a CBVv response that was an order of magnitude slower than either CBF or CMRO2. This finding suggests that the assumption of tight flow-volume coupling may not be strictly valid, complicating the extension of calibrated BOLD to more naturalistic experimental designs.

The coupling of cerebral blood flow and oxygen metabolism with brain activation is similar for simple and complex stimuli in human primary visual cortex.

Quantitative functional MRI (fMRI) experiments to measure blood flow and oxygen metabolism coupling in the brain typically rely on simple repetitive stimuli. Here we compared such stimuli with a more naturalistic stimulus. Previous work on the primary visual cortex showed that direct attentional modulation evokes a blood flow (CBF) response with a relatively large oxygen metabolism (CMRO2) response in comparison to an unattended stimulus, which evokes a much smaller metabolic response relative to the flow response. We hypothesized that a similar effect would be associated with a more engaging stimulus, and tested this by measuring the primary human visual cortex response to two contrast levels of a radial flickering checkerboard in comparison to the response to free viewing of brief movie clips. We did not find a significant difference in the blood flow-metabolism coupling (n=%ΔCBF/%ΔCMRO2) between the movie stimulus and the flickering checkerboards employing two different analysis methods: a standard analysis using the Davis model and a new analysis using a heuristic model dependent only on measured quantities. This finding suggests that in the primary visual cortex a naturalistic stimulus (in comparison to a simple repetitive stimulus) is either not sufficient to provoke a change in flow-metabolism coupling by attentional modulation as hypothesized, that the experimental design disrupted the cognitive processes underlying the response to a more natural stimulus, or that the technique used is not sensitive enough to detect a small difference.

Calibrating the BOLD response without administering gases: comparison of hypercapnia calibration with calibration using an asymmetric spin echo.

The calibrated BOLD (blood oxygen level dependent) technique was developed to quantify the BOLD signal in terms of changes in oxygen metabolism. In order to achieve this a calibration experiment must be performed, which typically requires a hypercapnic gas mixture to be administered to the participant. However, an emerging technique seeks to perform this calibration without administering gases using a refocussing based calibration. Whilst hypercapnia calibration seeks to emulate the physical removal of deoxyhaemoglobin from the blood, the aim of refocussing based calibration is to refocus the dephasing effect of deoxyhaemoglobin on the MR signal using a spin echo. However, it is not possible to refocus all of the effects that contribute to the BOLD signal and a scale factor is required to estimate the BOLD scaling parameter M. In this study the feasibility of a refocussing based calibration was investigated. The scale factor relating the refocussing calibration to M was predicted by simulations to be approximately linear and empirically measured to be 0.88±0.36 for the visual cortex and 0.93±0.32 for a grey matter region of interest (mean±standard deviation). Refocussing based calibration is a promising approach for greatly simplifying the calibrated BOLD methodology by eliminating the need for the subject to breathe special gas mixtures, and potentially provides the basis for a wider implementation of quantitative functional MRI.

Integrating Overall Survival and Tumor Control Probability Models to Predict Local Progression After Brain Metastasis Radiosurgery.

Purpose: Stereotactic radiosurgery (SRS) for brain metastases is frequently prescribed to the maximum tolerated dose to minimize the probability of local progression. However, many patients die from extracranial disease prior to local progression and may not require maximally aggressive treatment. Recently, improvements in models of SRS tumor control probability (TCP) and overall survival (OS) have been made. We predicted that by combining models of OS and TCP, we could better predict the true risk of local progression after SRS than by using TCP modeling alone. Methods and Materials: Records of patients undergoing SRS at a single institution were reviewed retrospectively. Using established TCP and OS models, for each patient, the probability of 1-year survival [p(OS)] was calculated, as was the probability of 1-year local progression [p(LP)]) for each treated lesion. Joint-probability was used to combine the models [p(LP,OS)=p(LP)*p(OS)]. Analyses were conducted at the individual metastasis and whole-patient levels. Fine-Gray regression was used to model p(LP) or p(LP,OS) on the risk of local progression after SRS, with death as a competing risk. Results: At the patient level, 1-year local progression was 0.08 (95% CI, 0.03-0.15), median p(LP,OS) was 0.13 (95% CI, 0.07-0.2), and median p(LP) was 0.29 (95% CI, 0.22-0.38). At the metastasis level, 1-year local progression was 0.02 (95% CI, 0.01-0.04), median p(LP,OS) was 0.05 (95% CI, 0.02-0.07), and median p(LP) was 0.10 (95% CI, 0.07-0.13). p(LP,OS) was found to be significantly associated with the risk of local progression at the patient level (P = .048) and metastasis level (P = .007); however, p(LP) was not (P = .16 and P = .28, respectively). Conclusions: Simultaneous modeling of OS and TCP more accurately predicted local progression than TCP modeling alone. Better understanding which patients with brain metastases are at risk of local progression after SRS may help personalize treatment to minimize risk without sacrificing efficacy.

A review of calibrated blood oxygenation level-dependent (BOLD) methods for the measurement of task-induced changes in brain oxygen metabolism.

The dynamics of the blood oxygenation level-dependent (BOLD) response are dependent on changes in cerebral blood flow, cerebral blood volume and the cerebral metabolic rate of oxygen consumption. Furthermore, the amplitude of the response is dependent on the baseline physiological state, defined by the haematocrit, oxygen extraction fraction and cerebral blood volume. As a result of this complex dependence, the accurate interpretation of BOLD data and robust intersubject comparisons when the baseline physiology is varied are difficult. The calibrated BOLD technique was developed to address these issues. However, the methodology is complex and its full promise has not yet been realised. In this review, the theoretical underpinnings of calibrated BOLD, and issues regarding this theory that are still to be resolved, are discussed. Important aspects of practical implementation are reviewed and reported applications of this methodology are presented.

Knowledge-based three-dimensional dose prediction for tandem-and-ovoid brachytherapy.

PURPOSE: The purpose of this work was to develop a knowledge-based dose prediction system using a convolution neural network (CNN) for cervical brachytherapy treatments with a tandem-and-ovoid applicator. METHODS: A 3D U-NET CNN was utilized to make voxel-wise dose predictions based on organ-at-risk (OAR), high-risk clinical target volume (HRCTV), and possible source location geometry. The model comprised 395 previously treated cases: training (273), validation (61), test (61). To assess voxel prediction accuracy, we evaluated dose differences in all cohorts across the dose range of 20-130% of prescription, mean (SD) and standard deviation (σ), as well as isodose dice similarity coefficients for clinical and/or predicted dose distributions. We examined discrete Dose-Volume Histogram (DVH) metrics utilized for brachytherapy plan quality assessment (HRCTV D90%; bladder, rectum, and sigmoid D2cc) with ΔDx=Dx,actual-Dx,predicted mean, standard deviation, and Pearson correlation coefficient further quantifying model performance. RESULTS: Ranges of voxel-wise dose difference accuracy (δD¯±σ) for 20-130% dose interval in training (test) sets ranged from [-0.5% ± 2.0% to +2.0% ± 14.0%] ([-0.1% ± 4.0% to +4.0% ± 26.0%]) in all voxels, [-1.7% ± 5.1% to -3.5% ± 12.8%] ([-2.9% ± 4.8% to -2.6% ± 18.9%]) in HRCTV, [-0.02% ± 2.40% to +3.2% ± 12.0%] ([-2.5% ± 3.6% to +0.8% ± 12.7%]) in bladder, [-0.7% ± 2.4% to +15.5% ± 11.0%] ([-0.9% ± 3.2% to +27.8% ± 11.6%]) in rectum, and [-0.7% ± 2.3% to +10.7% ± 15.0%] ([-0.4% ± 3.0% to +18.4% ± 11.4%]) in sigmoid. Isodose dice similarity coefficients ranged from [0.96,0.91] for training and [0.94,0.87] for test cohorts. Relative DVH metric prediction in the training (test) set were HRCTV ΔD¯90±σΔD = -0.19 ± 0.55Gy (-0.09 ± 0.67 Gy), bladder ΔD¯2cc±σΔD = -0.06 ± 0.54Gy (-0.17 ± 0.67 Gy), rectum ΔD¯2cc±σΔD= -0.03 ± 0.36Gy (-0.04 ± 0.46 Gy), and sigmoid ΔD¯2cc±σΔD = -0.01 ± 0.34Gy (0.00 ± 0.44 Gy). CONCLUSIONS: A 3D knowledge-based dose predictions provide voxel-level and DVH metric estimates that could be used for treatment plan quality control and data-driven plan guidance.

Experiences of Older Aboriginal People in Navigating Transport Systems in an Urban Setting: An Indigenous Perspective on Transport Access, a Social Determinant of Health.

BACKGROUND: In Australia, Aboriginal people are underserved by the transport system and are less able to easily get to places they need to go than others. This is a part of a larger pattern of exclusion and inequity for Aboriginal people which affects their health, wellbeing, and social participation. Guided by a decolonising framework, this research explored how older Aboriginal people, whose pivotal roles in their families and communities require their mobility, experience the transportation system, providing an Indigenous-centred view of the accessibility of transportation options in society. METHODS: Interviews drawing from the yarning technique were conducted with ten older Aboriginal people living in Greater Western Sydney and analysed qualitatively. RESULTS: In addition to the cognitive labour required to decipher the rules of the transport system and organise commitments to match the scheduling of transport services, older Aboriginal people in this study experienced stigmatising attitudes and condescending treatment from service professionals and the public when traveling. CONCLUSIONS: This study suggests three potential ways that the current trajectory that underserves older Aboriginal people could be disrupted, relating to service design, the diversity and inclusion agenda, and the social determinants of Indigenous health.

Automated segmentation of multiparametric magnetic resonance images for cerebral AVM radiosurgery planning: a deep learning approach.

Stereotactic radiosurgery planning for cerebral arteriovenous malformations (AVM) is complicated by the variability in appearance of an AVM nidus across different imaging modalities. We developed a deep learning approach to automatically segment cerebrovascular-anatomical maps from multiple high-resolution magnetic resonance imaging/angiography (MRI/MRA) sequences in AVM patients, with the goal of facilitating target delineation. Twenty-three AVM patients who were evaluated for radiosurgery and underwent multi-parametric MRI/MRA were included. A hybrid semi-automated and manual approach was used to label MRI/MRAs with arteries, veins, brain parenchyma, cerebral spinal fluid (CSF), and embolized vessels. Next, these labels were used to train a convolutional neural network to perform this task. Imaging from 17 patients (6362 image slices) was used for training, and 6 patients (1224 slices) for validation. Performance was evaluated by Dice Similarity Coefficient (DSC). Classification performance was good for arteries, veins, brain parenchyma, and CSF, with DSCs of 0.86, 0.91, 0.98, and 0.91, respectively in the validation image set. Performance was lower for embolized vessels, with a DSC of 0.75. This demonstrates the proof of principle that accurate, high-resolution cerebrovascular-anatomical maps can be generated from multiparametric MRI/MRA. Clinical validation of their utility in radiosurgery planning is warranted.

Controversies in Lung Cancer: Heterogeneity in Treatment Recommendations for Stage III NSCLC According to Disease Burden and Oncogenic Driver Alterations.

INTRODUCTION: Therapeutic options for stage III non-small-cell lung cancer (NSCLC) consist of definitive chemoradiation, surgery combined with neoadjuvant/adjuvant chemotherapy, and trimodality therapy. More recently, biologically driven systemic therapy options, including immunotherapy and targeted therapy, have become increasingly available. METHODS: A customized, case-based survey was designed and distributed to members of the International Association for the Study of Lung Cancer (IASLC) to determine practice habits and preferences for NSCLC patients with stage III disease and N2 to N3 nodal involvement. RESULTS: Data were compiled from 87 respondents from 31 countries, including medical oncologists (49%), surgical oncologists (24%), and radiation oncologists (21%). Definitive chemoradiation was more likely to be recommended for stage IIIC (98.2%) or stage IIIB (75.8%) scenarios compared with stage IIIA (59.6%) without actionable driver alterations (P < .0001 and .0003, respectively); and chemoradiation was more likely for stage IIIB (57.7%) compared to stage IIIA (39.9%) with actionable EGFR/ALK alterations (P = .008). Surgery was more likely to be recommended in the presence of an actionable alteration (38.7% vs. 19%, P < .0001). Surgeons were more likely than medical oncologists to recommend surgical approaches in scenarios without actionable alterations (25.6% vs. 11.2%, P < .0001) or with actionable alterations (57.5% vs. 31.1%, P = .0001). DISCUSSION: The dominant recommended strategy for stage III NSCLC was chemoradiation, although respondents were more likely to recommend surgical approaches in the presence of actionable alterations. Despite the lack of reported clinical trial data, many IASLC lung cancer experts favored targeted therapy when actionable driver alterations were present.

Improved Prognosis of Treatment Failure in Cervical Cancer with Nontumor PET/CT Radiomics.

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.

Correcting B0 inhomogeneity-induced distortions in whole-body diffusion MRI of bone.

Diffusion-weighted magnetic resonance imaging (DWI) of the musculoskeletal system has various applications, including visualization of bone tumors. However, DWI acquired with echo-planar imaging is susceptible to distortions due to static magnetic field inhomogeneities. This study aimed to estimate spatial displacements of bone and to examine whether distortion corrected DWI images more accurately reflect underlying anatomy. Whole-body MRI data from 127 prostate cancer patients were analyzed. The reverse polarity gradient (RPG) technique was applied to DWI data to estimate voxel-level distortions and to produce a distortion corrected DWI dataset. First, an anatomic landmark analysis was conducted, in which corresponding vertebral landmarks on DWI and anatomic T2-weighted images were annotated. Changes in distance between DWI- and T2-defined landmarks (i.e., changes in error) after distortion correction were calculated. In secondary analyses, distortion estimates from RPG were used to assess spatial displacements of bone metastases. Lastly, changes in mutual information between DWI and T2-weighted images of bone metastases after distortion correction were calculated. Distortion correction reduced anatomic error of vertebral DWI up to 29 mm. Error reductions were consistent across subjects (Wilcoxon signed-rank p < 10-20). On average (± SD), participants' largest error reduction was 11.8 mm (± 3.6). Mean (95% CI) displacement of bone lesions was 6.0 mm (95% CI 5.0-7.2); maximum displacement was 17.1 mm. Corrected diffusion images were more similar to structural MRI, as evidenced by consistent increases in mutual information (Wilcoxon signed-rank p < 10-12). These findings support the use of distortion correction techniques to improve localization of bone on DWI.

Lymphatic-preserving treatment sequencing with immune checkpoint inhibition unleashes cDC1-dependent antitumor immunity in HNSCC.

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphatics and develop models for regional lymphablation with surgery or radiation. We find that lymphablation eliminates the tumor ICI response, worsening overall survival and repolarizing the tumor- and peripheral-immune compartments. Mechanistically, within tumor-draining lymphatics, we observe an upregulation of conventional type I dendritic cells and type I interferon signaling and show that both are necessary for the ICI response and lost with lymphablation. Ultimately, we provide a mechanistic understanding of how standard oncologic therapies targeting regional lymphatics impact the tumor response to immune-oncology therapy in order to define rational, lymphatic-preserving treatment sequences that mobilize systemic antitumor immunity, achieve optimal tumor responses, control regional metastatic disease, and confer durable antitumor immunity.

Defining the Role of Immunotherapy in the Curative Treatment of Locoregionally Advanced Head and Neck Cancer: Promises, Challenges, and Opportunities.

Recent advancements in the development of immunotherapies have raised the hope for patients with locally-advanced HNSCC (LA-HNSCC) to achieve improved oncologic outcomes without the heavy burden of treatment-related morbidity. While there are several ongoing late phase clinical trials that seek to determine whether immunotherapy can be effectively employed in the definitive setting, initial results from concurrent immuno-radiotherapy therapy trials have not shown strong evidence of benefit. Encouragingly, evidence from preclinical studies and early-phase neoadjuvant studies have begun to show potential pathways forward, with therapeutic combinations and sequences that intentionally spare tumor draining lymphatics in order to maximize the synergy between definitive local therapy and immunotherapy. The intent of this review is to summarize the scientific rationale and current clinical evidence for employing immunotherapy for LA-HNSCC as well as the ongoing efforts and challenges to determine how to optimally deliver and sequence immunotherapy alongside traditional therapeutics. In both the preclinical and clinical settings, we will discuss the application of immunotherapies to both surgical and radiotherapeutic management of HNSCC.

Evaluation of dose differences between intracavitary applicators for cervical brachytherapy using knowledge-based models.

PURPOSE: Currently, there is a lack of patient-specific tools to guide brachytherapy planning and applicator choice for cervical cancer. The purpose of this study is to evaluate the accuracy of organ-at-risk (OAR) dose predictions using knowledge-based intracavitary models, and the use of these models and clinical data to determine the dosimetric differences of tandem-and-ring (T&R) and tandem-and-ovoids (T&O) applicators. MATERIALS AND METHODS: Knowledge-based models, which predict organ D2cc, were trained on 77/75 cases and validated on 32/38 for T&R/T&O applicators. Model performance was quantified using ΔD2cc=D2cc,actual-D2cc,predicted, with standard deviation (σ(ΔD2cc)) representing precision. Model-predicted applicator dose differences were determined by applying T&O models to T&R cases, and vice versa, and compared to clinically-achieved D2cc differences. Applicator differences were assessed using a Student's t-test (p < 0.05 significant). RESULTS: Validation T&O/T&R model precision was 0.65/0.55 Gy, 0.55/0.38 Gy, and 0.43/0.60 Gy for bladder, rectum and sigmoid, respectively, and similar to training. When applying T&O/T&R models to T&R/T&O cases, bladder, rectum and sigmoid D2cc values in EQD2 were on average 5.69/2.62 Gy, 7.31/6.15 Gy and 3.65/0.69 Gy lower for T&R, with similar HRCTV volume and coverage. Clinical data also showed lower T&R OAR doses, with mean EQD2 D2cc deviations of 0.61 Gy, 7.96 Gy (p < 0.01) and 5.86 Gy (p < 0.01) for bladder, rectum and sigmoid. CONCLUSIONS: Accurate knowledge-based dose prediction models were developed for two common intracavitary applicators. These models could be beneficial for standardizing and improving the quality of brachytherapy plans. Both models and clinical data suggest that significant OAR sparing can be achieved with T&R over T&O applicators, particularly for the rectum.