Cost of cardiac stereotactic body radioablation therapy versus catheter ablation for treatment of ventricular tachycardia.

AIMS: To compare the cost of cardiac stereotactic body radioablation therapy (SBRT) versus catheter ablation for treating ventricular tachycardia (VT). BACKGROUND: Cardiac SBRT is a novel way of treating refractory VT that may be less costly than catheter ablation, owing to its noninvasive, outpatient nature. However, the true costs of either procedure are not well described, which could help inform a more appropriate reimbursement for cardiac SBRT than simply cross-indexing existing procedural rates. METHODS: Process maps were derived for the full patient care cycle of both procedures using time-driven activity-based costing. Step-by-step timestamps were collected prospectively from a 10-patient SBRT cohort and retrospectively from a 59-patient catheter ablation cohort. Individual costs were estimated by multiplying timestamps with capacity cost rates (CCRs) for personnel, space, equipment, consumable, and indirect resources. These were summed into total cost, which for cardiac SBRT was compared with current catheter ablation and single-fraction lung SBRT reimbursements, both potential reference rates for cardiac SBRT. RESULTS: The direct and total procedural costs of cardiac SBRT ($7549 and $10,621) were 49% and 54% less than those of VT ablation ($14,707 and $23,225). These costs were significantly different from current reimbursement for catheter ablation ($22,692) and lung SBRT ($6329). After including hospitalization expenses (≥$15,000), VT ablation costs at least $27,604 more to furnish than cardiac SBRT. CONCLUSIONS: Time-driven activity-based costing (TDABC) can be a helpful tool for assessing healthcare costs, including novel treatment approaches. In addition to its clinical benefits, cardiac SBRT may provide significant cost reduction opportunities for treatment of VT.

Cardiac stereotactic body radiation therapy for ventricular tachycardia: Current experience and technical gaps.

INTRODUCTION: Despite advances in drug and catheter ablation therapy, long-term recurrence rates for ventricular tachycardia remain suboptimal. Cardiac stereotactic body radiotherapy (SBRT) is a novel treatment that has demonstrated reduction of arrhythmia episodes and favorable short-term safety profile in treatment-refractory patients. Nevertheless, the current clinical experience is early and limited. Recent studies have highlighted variable duration of treatment effect and substantial recurrence rates several months postradiation. Contributing to these differential outcomes are disparate approaches groups have taken in planning and delivering radiation, owing to both technical and knowledge gaps limiting optimization and standardization of cardiac SBRT. METHODS AND FINDINGS: In this report, we review the historical basis for cardiac SBRT and existing clinical data. We then elucidate the current technical gaps in cardiac radioablation, incorporating the current clinical experience, and summarize the ongoing and needed efforts to resolve them. CONCLUSION: Cardiac SBRT is an emerging therapy that holds promise for the treatment of ventricular tachycardia. Technical gaps remain, to be addressed by ongoing research and growing clincial experience.

Collagen organization of renal cell carcinoma differs between low and high grade tumors.

BACKGROUND: The traditional pathologic grading for human renal cell carcinoma (RCC) has low concordance between biopsy and surgical specimen. There is a need to investigate adjunctive pathology technique that does not rely on the nuclear morphology that defines the traditional grading. Changes in collagen organization in the extracellular matrix have been linked to prognosis or grade in breast, ovarian, and pancreatic cancers, but collagen organization has never been correlated with RCC grade. In this study, we used Second Harmonic Generation (SHG) based imaging to quantify possible differences in collagen organization between high and low grades of human RCC. METHODS: A tissue microarray (TMA) was constructed from RCC tumor specimens. Each TMA core represents an individual patient. A 5 µm section from the TMA tissue was stained with standard hematoxylin and eosin (H&E). Bright field images of the H&E stained TMA were used to annotate representative RCC regions. In this study, 70 grade 1 cores and 51 grade 4 cores were imaged on a custom-built forward SHG microscope, and images were analyzed using established software tools to automatically extract and quantify collagen fibers for alignment and density assessment. A linear mixed-effects model with random intercepts to account for the within-patient correlation was created to compare grade 1 vs. grade 4 measurements and the statistical tests were two-sided. RESULTS: Both collagen density and alignment differed significantly between RCC grade 1 and RCC grade 4. Specifically, collagen fiber density was greater in grade 4 than in grade 1 RCC (p < 0.001). Collagen fibers were also more aligned in grade 4 compared to grade 1 (p < 0.001). CONCLUSIONS: Collagen density and alignment were shown to be significantly higher in RCC grade 4 vs. grade 1. This technique of biopsy sampling by SHG could complement classical tumor grading approaches. Furthermore it might allow biopsies to be more clinically relevant by informing diagnostics. Future studies are required to investigate the functional role of collagen organization in RCC.

Implementation of the validation testing in MPPG 5.a "Commissioning and QA of treatment planning dose calculations-megavoltage photon and electron beams".

The AAPM Medical Physics Practice Guideline (MPPG) 5.a provides concise guidance on the commissioning and QA of beam modeling and dose calculation in radiotherapy treatment planning systems. This work discusses the implementation of the validation testing recommended in MPPG 5.a at two institutions. The two institutions worked collaboratively to create a common set of treatment fields and analysis tools to deliver and analyze the validation tests. This included the development of a novel, open-source software tool to compare scanning water tank measurements to 3D DICOM-RT Dose distributions. Dose calculation algorithms in both Pinnacle and Eclipse were tested with MPPG 5.a to validate the modeling of Varian TrueBeam linear accelerators. The validation process resulted in more than 200 water tank scans and more than 50 point measurements per institution, each of which was compared to a dose calculation from the institution's treatment planning system (TPS). Overall, the validation testing recommended in MPPG 5.a took approximately 79 person-hours for a machine with four photon and five electron energies for a single TPS. Of the 79 person-hours, 26 person-hours required time on the machine, and the remainder involved preparation and analysis. The basic photon, electron, and heterogeneity correction tests were evaluated with the tolerances in MPPG 5.a, and the tolerances were met for all tests. The MPPG 5.a evaluation criteria were used to assess the small field and IMRT/VMAT validation tests. Both institutions found the use of MPPG 5.a to be a valuable resource during the commissioning process. The validation testing in MPPG 5.a showed the strengths and limitations of the TPS models. In addition, the data collected during the validation testing is useful for routine QA of the TPS, validation of software upgrades, and commissioning of new algorithms.

The impact of a high-definition multileaf collimator for spine SBRT.

PURPOSE: Advanced radiotherapy delivery systems designed for high-dose, high-precision treatments often come equipped with high-definition multi-leaf collimators (HD-MLC) aimed at more finely shaping radiation dose to the target. In this work, we study the effect of a high definition MLC on spine stereotactic body radiation therapy (SBRT) treatment plan quality and plan deliverability. METHODS AND MATERIALS: Seventeen spine SBRT cases were planned with VMAT using a standard definition MLC (M120), HD-MLC, and HD-MLC with an added objective to reduce monitor units (MU). M120 plans were converted into plans deliverable on an HD-MLC using in-house software. Plan quality and plan deliverability as measured by portal dosimetry were compared among the three types of plans. RESULTS: Only minor differences were noted in plan quality between the M120 and HD-MLC plans. Plans generated with the HD-MLC tended to have better spinal cord sparing (3% reduction in maximum cord dose). HD-MLC plans on average had 12% more MU and 55% greater modulation complexity as defined by an in-house metric. HD-MLC plans also had significantly degraded deliverability. Of the VMAT arcs measured, 94% had lower gamma passing metrics when using the HD-MLC. CONCLUSION: Modest improvements in plan quality were noted when switching from M120 to HD-MLC at the expense of significantly less accurate deliverability in some cases.

Integrating Audiovisual Immersion Into Pediatric Radiation Therapy Across Multiple Centers: Methodology, Timeliness, and Cost of the Audiovisual-Assisted Therapeutic Ambience in Radiation Therapy Prospective Multi-Institutional Trial.

Purpose: The Audiovisual-Assisted Therapeutic Ambience in Radiotherapy (AVATAR) trial was a prospective multicenter study (NCT03991156) examining the combination of video immersion with radiation therapy and was successfully conducted through the collaboration of pediatric radiation oncology teams at 10 institutions independent of any pre-existing consortium. We sought to analyze and report the methodology of trial conception and development, process map, and cost. Methods and Materials: The study enrolled patients aged 3 to 10 years preparing to undergo radiation therapy, integrated the combination of AVATAR-based video immersion with radiation therapy at each institution, and offered AVATAR use as an alternative to anesthesia, with rates of anesthesia use and outcomes of serial standardized anxiety and quality-of-life assessments assessed among the 81 children enrolled. A process map was created based on the trial timeline with the following components: study development time (time from conception of the trial to the accrual of the first patient, including design phase, agreement and approval phase, and site preparation phase), and accrual duration time (time from the first to last accrual). Costs and institutional success rates were calculated. Results: Time from inception of study to last accrual was 3.6 years (1313 days). The study development time was 417 days (31.7%), and accrual duration time was 896 days (68.3%), with the final 50% of accrual occurring in <6 months. Equipment cost was approximately $550 per institution and was covered by funding from the lead study institution. All 10 centers were successful with AVATAR implementation, defined as ≥50% of patients able to avoid anesthesia with the use of AVATAR, including centers with both photon and proton therapy. Conclusions: This report elaborates on the methodology and timeline of trial conception and development using data from a previously published supportive care study combining video immersion with radiation therapy among 10 cooperating pediatric oncology institutions. It highlights the potential for multicenter collaborations on prospective trials integrating supportive care therapies with radiation therapy.

Prospective deployment of an automated implementation solution for artificial intelligence translation to clinical radiation oncology.

Introduction: Artificial intelligence (AI)-based technologies embody countless solutions in radiation oncology, yet translation of AI-assisted software tools to actual clinical environments remains unrealized. We present the Deep Learning On-Demand Assistant (DL-ODA), a fully automated, end-to-end clinical platform that enables AI interventions for any disease site featuring an automated model-training pipeline, auto-segmentations, and QA reporting. Materials and methods: We developed, tested, and prospectively deployed the DL-ODA system at a large university affiliated hospital center. Medical professionals activate the DL-ODA via two pathways (1): On-Demand, used for immediate AI decision support for a patient-specific treatment plan, and (2) Ambient, in which QA is provided for all daily radiotherapy (RT) plans by comparing DL segmentations with manual delineations and calculating the dosimetric impact. To demonstrate the implementation of a new anatomy segmentation, we used the model-training pipeline to generate a breast segmentation model based on a large clinical dataset. Additionally, the contour QA functionality of existing models was assessed using a retrospective cohort of 3,399 lung and 885 spine RT cases. Ambient QA was performed for various disease sites including spine RT and heart for dosimetric sparing. Results: Successful training of the breast model was completed in less than a day and resulted in clinically viable whole breast contours. For the retrospective analysis, we evaluated manual-versus-AI similarity for the ten most common structures. The DL-ODA detected high similarities in heart, lung, liver, and kidney delineations but lower for esophagus, trachea, stomach, and small bowel due largely to incomplete manual contouring. The deployed Ambient QAs for heart and spine sites have prospectively processed over 2,500 cases and 230 cases over 9 months and 5 months, respectively, automatically alerting the RT personnel. Discussion: The DL-ODA capabilities in providing universal AI interventions were demonstrated for On-Demand contour QA, DL segmentations, and automated model training, and confirmed successful integration of the system into a large academic radiotherapy department. The novelty of deploying the DL-ODA as a multi-modal, fully automated end-to-end AI clinical implementation solution marks a significant step towards a generalizable framework that leverages AI to improve the efficiency and reliability of RT systems.

Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) System for Anesthesia Avoidance in Pediatric Patients: A Multicenter Trial.

PURPOSE: The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)-compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. METHODS AND MATERIALS: Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. RESULTS: Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P = .04) and private versus public insurance (P < .001). Both patient (P = .008) and parent (P = .006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P < .001), by age (P < .001), and by S versus NS patients (P < .001). CONCLUSIONS: In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P < .001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

Patient specific distortion detection and mitigation in MR images used for stereotactic radiosurgery.

Objective.In MRI-based radiation therapy planning, mitigating patient-specific distortion with standard high bandwidth scans can result in unnecessary sacrifices of signal to noise ratio. This study investigates a technique for distortion detection and mitigation on a patient specific basis.Approach.Fast B0 mapping was performed using a previously developed technique for high-resolution, large dynamic range field mapping without the need for phase unwrapping algorithms. A phantom study was performed to validate the method. Distortion mitigation was validated by reducing geometric distortion with increased acquisition bandwidth and confirmed by both the B0 mapping technique and manual measurements. Images and contours from 25 brain stereotactic radiosurgery patients and 95 targets were analyzed to estimate the range of geometric distortions expected in the brain and to estimate bandwidth required to keep all treatment targets within the ±0.5 mm iso-distortion contour.Main Results.The phantom study showed, at 3 T, the technique can measure distortions with a mean absolute error of 0.12 mm (0.18 ppm), and a maximum error of 0.37 mm (0.6 ppm). For image acquisition at 3 T and 1.0 mm resolution, mean absolute distortion under 0.5 mm in patients required bandwidths from 109 to 200 Hz px-1for patients with the least and most distortion, respectively. Maximum absolute distortion under 0.5 mm required bandwidths from 120 to 390 Hz px-1.Significance.The method for B0 mapping was shown to be valid and may be applied to assess distortion clinically. Future work will adapt the readout bandwidth to prospectively mitigate distortion with the goal to improve radiosurgery treatment outcomes by reducing healthy tissue exposure.

Less Time Is Less Motion: Analysis of Practical Efficiencies Gained With a Modified Workflow Integrating Planar kV Midimaging With CBCT for Spine Stereotactic Body Radiation Therapy.

Purpose: Our purpose was to optimize an image guided radiation therapy (IGRT) workflow to achieve practical setup accuracy in spine stereotactic body radiation therapy (SBRT). We assessed the time-saving efficiencies gained from incorporating planar kV midimaging as a surrogate for cone beam computed tomography (CBCT) for intrafraction motion monitoring. Methods and Materials: We selected 5 thoracic spine SBRT patients treated in 5 fractions and analyzed patient shifts captured by a modified IGRT workflow using planar kV midimaging integrated with CBCT to maintain a tolerance of 1 mm and 1°. We determined the frequency at which kV midimaging captured intrafraction motion as validated on repeat CBCT and assessed the potential time and dosimetric advantages of our modified IGRT workflow. Results: Patient motion, detected as out-of-tolerance shifts on planar kV midimaging, occurred during 6 of 25 fractions (24%) and were validated on repeat CBCT 100% of the time. Observed intrafraction absolute shifts (mean ± standard deviation) for the 25 fractions were 0.39 ± 0.21, 0.56 ± 0.22, and 0.45 ± 0.21 mm for lateral-longitude-vertical translations and 0.38 ± 0.12°, 0.32 ± 0.09°, and 0.47 ± 0.14° for pitch-roll-yaw rotation, which if uncorrected, could have significantly affected target coverage and increased spinal cord dose. The average times for pretreatment imaging, midtreatment verification, and total treatment time were 8.94, 2.81, and 16.21 minutes. Our modified IGRT workflow reduced the total number of CBCTs required from 120 to 35 (70%) and imaging dose from 126.2 to 43.4 cGy (65.6%) while maintaining high fidelity for our patient population. Conclusions: Accurate patient positioning was effectively achieved with use of multiple 2-dimensional-3-dimensional kV images and an average of 1 verification CBCT scan per fraction. Integration of planar kV midimaging can effectively reduce treatment time associated with spine SBRT delivery and minimize the potential dosimetric effect of intrafraction motion on target coverage and spinal cord dose.

Ultrasound-based sensors to monitor physiological motion.

PURPOSE: Medical procedures can be difficult to perform on anatomy that is constantly moving. Respiration displaces internal organs by up to several centimeters with respect to the surface of the body, and patients often have limited ability to hold their breath. Strategies to compensate for motion during diagnostic and therapeutic procedures require reliable information to be available. However, current devices often monitor respiration indirectly, through changes on the outline of the body, and they may be fixed to floors or ceilings, and thus unable to follow a given patient through different locations. Here we show that small ultrasound-based sensors referred to as "organ configuration motion" (OCM) sensors can be fixed to the abdomen and/or chest and provide information-rich, breathing-related signals. METHODS: By design, the proposed sensors are relatively inexpensive. Breathing waveforms were obtained from tissues at varying depths and/or using different sensor placements. Validation was performed against breathing waveforms derived from magnetic resonance imaging (MRI) and optical tracking signals in five and eight volunteers, respectively. RESULTS: Breathing waveforms from different modalities were scaled so they could be directly compared. Differences between waveforms were expressed in the form of a percentage, as compared to the amplitude of a typical breath. Expressed in this manner, for shallow tissues, OCM-derived waveforms on average differed from MRI and optical tracking results by 13.1% and 15.5%, respectively. CONCLUSION: The present results suggest that the proposed sensors provide measurements that properly characterize breathing states. While OCM-based waveforms from shallow tissues proved similar in terms of information content to those derived from MRI or optical tracking, OCM further captured depth-dependent and position-dependent (i.e., chest and abdomen) information. In time, the richer information content of OCM-based waveforms may enable better respiratory gating to be performed, to allow diagnostic and therapeutic equipment to perform at their best.

A bi-institutional multi-disciplinary failure mode and effects analysis (FMEA) for a Co-60 based total body irradiation technique.

BACKGROUND: We aim to assess the risks associated with total body irradiation (TBI) delivered using a commercial dedicated Co-60 irradiator, and to evaluate inter-institutional and inter-professional variations in the estimation of these risks. METHODS: A failure mode and effects analysis (FMEA) was generated using guidance from the AAPM TG-100 report for quantitative estimation of prospective risk metrics. Thirteen radiation oncology professionals from two institutions rated possible failure modes (FMs) for occurrence (O), severity (S), and detectability (D) indices to generate a risk priority number (RPN). The FMs were ranked by descending RPN value. Absolute gross differences (AGD) in resulting RPN values and Jaccard Index (JI; for the top 20 FMs) were calculated. The results were compared between professions and institutions. RESULTS: A total of 87 potential FMs (57, 15, 10, 3, and 2 for treatment, quality assurance, planning, simulation, and logistics respectively) were identified and ranked, with individual RPN ranging between 1-420 and mean RPN values ranging between 6 and 74. The two institutions shared 6 of their respective top 20 FMs. For various institutional and professional comparison pairs, the number of common FMs in the top 20 FMs ranged from 6 to 13, with JI values of 18-48%. For the top 20 FMs, the trend in inter-professional variability was institution-specific. The mean AGD values ranged between 12.5 and 74.5 for various comparison pairs. AGD values differed the most for medical physicists (MPs) in comparison to other specialties i.e. radiation oncologists (ROs) and radiation therapists (RTs) [MPs-vs-ROs: 36.3 (standard deviation SD = 34.1); MPs-vs-RTs: 41.2 (SD = 37.9); ROs-vs-RTs: 12.5 (SD = 10.8)]. Trends in inter-professional AGD values were similar for both institutions. CONCLUSION: This inter-institutional comparison provides prospective risk analysis for a new treatment delivery unit and illustrates the institution-specific nature of FM prioritization, primarily due to operational differences. Despite being subjective in nature, the FMEA is a valuable tool to ensure the identification of the most significant risks, particularly when implementing a novel treatment modality. The creation of a bi-institutional, multidisciplinary FMEA for this unique TBI technique has not only helped identify potential risks but also served as an opportunity to evaluate clinical and safety practices from the perspective of both multiple professional roles and different institutions.

Fibrillar Collagen Quantification With Curvelet Transform Based Computational Methods.

Quantification of fibrillar collagen organization has given new insight into the possible role of collagen topology in many diseases and has also identified candidate image-based bio-markers in breast cancer and pancreatic cancer. We have been developing collagen quantification tools based on the curvelet transform (CT) algorithm and have demonstrated this to be a powerful multiscale image representation method due to its unique features in collagen image denoising and fiber edge enhancement. In this paper, we present our CT-based collagen quantification software platform with a focus on new features and also giving a detailed description of curvelet-based fiber representation. These new features include C++-based code optimization for fast individual fiber tracking, Java-based synthetic fiber generator module for method validation, automatic tumor boundary generation for fiber relative quantification, parallel computing for large-scale batch mode processing, region-of-interest analysis for user-specified quantification, and pre- and post-processing modules for individual fiber visualization. We present a validation of the tracking of individual fibers and fiber orientations by using synthesized fibers generated by the synthetic fiber generator. In addition, we provide a comparison of the fiber orientation calculation on pancreatic tissue images between our tool and three other quantitative approaches. Lastly, we demonstrate the use of our software tool for the automatic tumor boundary creation and the relative alignment quantification of collagen fibers in human breast cancer pathology images, as well as the alignment quantification of in vivo mouse xenograft breast cancer images.

Technical Note: Quality assurance and relative dosimetry testing of a 60 Co total body irradiator using optical imaging.

PURPOSE: The aim of this study was to create an optical imaging-based system for quality assurance (QA) testing of a dedicated Co-60 total body irradiation (TBI) machine. Our goal is to streamline the QA process by minimizing the amount time necessary for tests such as verification of dose rate and field homogeneity. METHODS: Plastic scintillating rods were placed directly on the patient treatment couch of a dedicated TBI 60 Co irradiator. A tripod-mounted intensified camera was placed directly adjacent to the couch. Images were acquired over a 30-s period once the cobalt source was fully exposed. Real-time image filtering was used; cumulative images were flatfield corrected as well as background and darkfield subtracted. Scintillators were used to measure light-radiation field correspondence, dose rate, field homogeneity, and symmetry. Dose rate effects were measured by modifying the height of the treatment couch and scintillator response was compared to ionization chamber (IC) measurements. Optically stimulated luminesce detector (OSLD) used as reference dosimeters during field symmetry and homogeneity testing. RESULTS: The scintillator-based system accurately reported changes in dose rate. When comparing normalized output values for IC vs scintillators over a range of source-to-surface distances, a linear relationship (R2  = 0.99) was observed. Normalized scintillator signal matched OSLD measurements with <1.5% difference during field homogeneity and symmetry testing. Beam symmetry across both axes of the field was within 2%. The light field was found to correspond to 90 ± 3% of the isodose maximum along the longitudinal and latitudinal axis, respectively. Scintillator imaging output results using a single image stack requiring no postexposure processing (needed for OSLD) or repeat manual measurements (needed for IC). CONCLUSION: Imaging of scintillation light emission from plastic rods is a viable and efficient method for carrying out TBI 60 Co irradiator QA. We have shown that this technique can accurately measure field homogeneity, symmetry, light-radiation field correspondence, and dose rate effects.

Collagen Alignment as a Predictor of Recurrence after Ductal Carcinoma In Situ.

Background: Collagen fibers surrounding breast ducts may influence breast cancer progression. Syndecan-1 interacts with constituents in the extracellular matrix, including collagen fibers, and may contribute to cancer cell migration. Thus, the orientation of collagen fibers surrounding ductal carcinoma in situ (DCIS) lesions and stromal syndecan-1 expression may predict recurrence.Methods: We evaluated collagen fiber alignment and syndecan-1 expression in 227 women diagnosed with DCIS in 1995 to 2006 followed through 2014 (median, 14.5 years; range, 0.7-17.6). Stromal collagen alignment was evaluated from diagnostic tissue slides using second harmonic generation microscopy and fiber analysis software. Univariate analysis was conducted using χ2 tests and ANOVA. The association between collagen alignment z-scores, syndecan-1 staining intensity, and time to recurrence was evaluated using HRs and 95% confidence intervals (CIs).Results: Greater fiber angles surrounding DCIS lesions, but not syndecan-1 staining intensity, were related to positive HER2 (P = 0.002) status, comedo necrosis (P = 0.03), and negative estrogen receptor (P = 0.002) and progesterone receptor (P = 0.02) status. Fiber angle distributions surrounding lesions included more angles closer to 90 degrees than normal ducts (P = 0.06). Collagen alignment z-scores for DCIS lesions were positively related to recurrence (HR = 1.25; 95% CI, 0.84-1.87 for an interquartile range increase in average fiber angles).Conclusions: Although collagen alignment and stromal syndecan-1 expression did not predict recurrence, collagen fibers perpendicular to the duct perimeter were more frequent in DCIS lesions with features typical of poor prognosis.Impact: Follow-up studies are warranted to examine whether additional features of the collagen matrix may more strongly predict patient outcomes. Cancer Epidemiol Biomarkers Prev; 27(2); 138-45. ©2017 AACR.

Synthetic CT for MRI-based liver stereotactic body radiotherapy treatment planning.

A technique for generating MRI-derived synthetic CT volumes (MRCTs) is demonstrated in support of adaptive liver stereotactic body radiation therapy (SBRT). Under IRB approval, 16 subjects with hepatocellular carcinoma were scanned using a single MR pulse sequence (T1 Dixon). Air-containing voxels were identified by intensity thresholding on T1-weighted, water and fat images. The envelope of the anterior vertebral bodies was segmented from the fat image and fuzzy-C-means (FCM) was used to classify each non-air voxel as mid-density, lower-density, bone, or marrow in the abdomen, with only bone and marrow classified within the vertebral body envelope. MRCT volumes were created by integrating the product of the FCM class probability with its assigned class density for each voxel. MRCTs were deformably aligned with corresponding planning CTs and 2-ARC-SBRT-VMAT plans were optimized on MRCTs. Fluence was copied onto the CT density grids, dose recalculated, and compared. The liver, vertebral bodies, kidneys, spleen and cord had median Hounsfield unit differences of less than 60. Median target dose metrics were all within 0.1 Gy with maximum differences less than 0.5 Gy. OAR dose differences were similarly small (median: 0.03 Gy, std:0.26 Gy). Results demonstrate that MRCTs derived from a single abdominal imaging sequence are promising for use in SBRT dose calculation.

Second-harmonic generation imaging of cancer.

The last 30 years has seen great advances in optical microscopy with the introduction of sophisticated fluorescence-based imaging methods such as confocal and multiphoton laser scanning microscopy. There is increasing interest in using these methods to quantitatively examine sources of intrinsic biological contrast including autofluorescent endogenous proteins and light interactions such as second-harmonic generation (SHG) in collagen. In particular, SHG-based microscopy has become a widely used quantitative modality for imaging noncentrosymmetric proteins such as collagen in a diverse range of tissues. Due to the underlying physical origin of the SHG signal, it is highly sensitive to collagen fibril/fiber structure and, importantly, to collagen-associated changes that occur in diseases such as cancer, fibrosis, and connective tissue disorders. An overview of SHG physics background and technologies is presented with a focused review on applications of SHG primarily as applied to cancer.

Automated quantification of aligned collagen for human breast carcinoma prognosis.

BACKGROUND: Mortality in cancer patients is directly attributable to the ability of cancer cells to metastasize to distant sites from the primary tumor. This migration of tumor cells begins with a remodeling of the local tumor microenvironment, including changes to the extracellular matrix and the recruitment of stromal cells, both of which facilitate invasion of tumor cells into the bloodstream. In breast cancer, it has been proposed that the alignment of collagen fibers surrounding tumor epithelial cells can serve as a quantitative image-based biomarker for survival of invasive ductal carcinoma patients. Specific types of collagen alignment have been identified for their prognostic value and now these tumor associated collagen signatures (TACS) are central to several clinical specimen imaging trials. Here, we implement the semi-automated acquisition and analysis of this TACS candidate biomarker and demonstrate a protocol that will allow consistent scoring to be performed throughout large patient cohorts. METHODS: Using large field of view high resolution microscopy techniques, image processing and supervised learning methods, we are able to quantify and score features of collagen fiber alignment with respect to adjacent tumor-stromal boundaries. RESULTS: Our semi-automated technique produced scores that have statistically significant correlation with scores generated by a panel of three human observers. In addition, our system generated classification scores that accurately predicted survival in a cohort of 196 breast cancer patients. Feature rank analysis reveals that TACS positive fibers are more well-aligned with each other, are of generally lower density, and terminate within or near groups of epithelial cells at larger angles of interaction. CONCLUSION: These results demonstrate the utility of a supervised learning protocol for streamlining the analysis of collagen alignment with respect to tumor stromal boundaries.

Computational segmentation of collagen fibers from second-harmonic generation images of breast cancer.

Second-harmonic generation (SHG) imaging can help reveal interactions between collagen fibers and cancer cells. Quantitative analysis of SHG images of collagen fibers is challenged by the heterogeneity of collagen structures and low signal-to-noise ratio often found while imaging collagen in tissue. The role of collagen in breast cancer progression can be assessed post acquisition via enhanced computation. To facilitate this, we have implemented and evaluated four algorithms for extracting fiber information, such as number, length, and curvature, from a variety of SHG images of collagen in breast tissue. The image-processing algorithms included a Gaussian filter, SPIRAL-TV filter, Tubeness filter, and curvelet-denoising filter. Fibers are then extracted using an automated tracking algorithm called fiber extraction (FIRE). We evaluated the algorithm performance by comparing length, angle and position of the automatically extracted fibers with those of manually extracted fibers in twenty-five SHG images of breast cancer. We found that the curvelet-denoising filter followed by FIRE, a process we call CT-FIRE, outperforms the other algorithms under investigation. CT-FIRE was then successfully applied to track collagen fiber shape changes over time in an in vivo mouse model for breast cancer.

Molecularly sensitive optical coherence tomography.

Molecular contrast in optical coherence tomography (OCT) is demonstrated by use of coherent anti-Stokes Raman scattering (CARS) for molecular sensitivity. Femtosecond laser pulses are focused into a sample by use of a low-numerical-aperture lens to generate CARS photons, and the backreflected CARS signal is interferometrically measured. With the chemical selectivity provided by CARS and the advanced imaging capabilities of OCT, this technique may be useful for molecular contrast imaging in biological tissues. CARS can be generated and interferometrically measured over at least 600 microm of the depth of field of a low-numerical-aperture objective.