Functional Lung Avoidance for Individualized Radiation Therapy: Results of a Double-Masked, Randomized Controlled Trial.

PURPOSE: To determine whether functional lung avoidance based on 3He magnetic resonance imaging (MRI) improves quality of life (QOL) for patients undergoing concurrent chemoradiotherapy (CCRT) for advanced non-small cell lung cancer. METHODS AND MATERIALS: Patients with stage III non-small cell lung cancer (or oligometastatic disease treated with curative intent) undergoing CCRT with at least a 10 pack-year smoking history were eligible. Patients underwent pretreatment 3He MRI to measure lung ventilation and had 2 radiation therapy (RT) plans created before randomization: a standard plan, which did not make use of the 3He MRI, and an avoidance plan, preferentially sparing well-ventilated lung. All participants were masked to assignment except the physicist responsible for exporting the selected plan. The primary end point was patient-reported QOL measured at 3-months post-RT by the FACT-L lung cancer subscale (LCS); secondary end points included other QOL metrics, toxicity, and survival outcomes. Target accrual was 64. RESULTS: Twenty-seven patients were randomized before the trial was closed due to slower-than-expected accrual, with 11 randomized to the standard arm and 16 to the avoidance arm. Baseline patient characteristics were well-balanced. At 3 months post-RT, the mean ± SD LCS scores were 17.4 ± 2.8 versus 17.3 ± 6.1 for the standard and avoidance arms, respectively (P = .485). A clinically meaningful, prespecified decline of ≥3 points in the LCS score was observed in 50% (4/8) in the standard arm and 33% (4/12) in the avoidance arm (P = .648). Two patients in each arm developed grade ≥2 radiation pneumonitis, with no grade ≥4 toxicities. CONCLUSIONS: Although this trial did not reach full accrual, QOL scores were very similar between arms. Due to the scarcity of 3He MRI, other, more commonly available methods to measure functional lung, such as 4-dimensional computed tomography ventilation mapping, may be considered in the assessment of functional lung avoidance RT, and a larger, multicenter approach would be needed to accrue sufficient patients to test such approaches.

Case Report of a Rare Cystic Mediastinal Lymphangioma Mimicking Recurrent Pleural Effusion.

Mediastinal lymphangiomas are rare benign congenital malformations, but complications can occur, including infection, cystic hemorrhage, superior vena cava syndrome, airway compromise, and chylothorax. Radiologically, lymphangiomas are well-defined masses, with low attenuation ranging from simple to complex fluid and fat. They often encase adjacent mediastinal structures. We present a case of mediastinal lymphangioma in a young female, who presented with recurrent complex pleural effusions, initially thought to represent an empyema and/or necrotic mass. Despite surgical chest tube and interventional radiology drainage, fluid reaccumulated. Upon further review, the interventional and thoracic radiologist concurred that the complex collection was in fact predominantly extra pleural in location. The patient underwent partial resection after it was discovered intraoperatively that the extra pleural cystic mass was contiguous with and extended deeply into the mediastinum. Histopathology confirmed the diagnosis of lymphangioma.

Optimal imaging surveillance after stereotactic ablative radiation therapy for early-stage non-small cell lung cancer: Findings of an International Delphi Consensus Study.

PURPOSE: Imaging after stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer can detect recurrences and second primary lung cancers; however, the optimal follow-up practice of these patients remains unclear. We sought to establish consensus recommendations for surveillance after SABR. METHODS AND MATERIALS: International opinion leaders in thoracic radiation oncology and radiology were invited to participate (n = 31), with 11 accepting (9 radiation oncologists, 2 radiologists). Consensus-building was achieved using a 3-round Delphi process. Participants rated their agreement/disagreement with statements using a 5-point Likert scale. An a priori threshold of ≥75% agreement/disagreement was required for consensus. RESULTS: A 100% response rate was achieved and final consensus statements were approved by all participants. The consensus statements were: (1.1) thoracic computed tomography (CT) scans should be ordered routinely in follow-up; (1.2) if there is a suspicion for local recurrence (LR), fludeoxyglucose positron emission tomography/CT scans are strongly recommended. Otherwise, there is limited evidence to guide routine use of fludeoxyglucose positron emission tomography /CT; (1.3) CT imaging is not recommended at 6 weeks, but is recommended at months 3, 6, and 12 in year 1 and then every 6 months in year 2 and annually in years 3 through 5; (1.4) after 5 years, CT imaging should continue, although no consensus was reached regarding the frequency. (2.1) Response Evaluation Criteria in Solid Tumors 1.1 criteria are not sufficient for detecting LR; (2.2) a formal scoring system, informed by validated data, should be used to classify high-risk imaging features predictive of LR; (2.3) CT findings suspicious for LR include: infiltration into adjacent structures, bulging margins, sustained growth, mass-like growth, spherical growth, craniocaudal growth, and loss of air bronchograms. (3) Salvage therapy without pathologic confirmation of recurrence is acceptable if imaging findings are highly suspicious and a biopsy is not safe/feasible or if an attempted biopsy was nondiagnostic. CONCLUSIONS: These guidelines provide international expert consensus on areas of uncertainty in the management of early-stage non-small cell lung cancer patients after SABR.

Short report: interim safety results for a phase II trial measuring the integration of stereotactic ablative radiotherapy (SABR) plus surgery for early stage non-small cell lung cancer (MISSILE-NSCLC).

A phase II trial was launched to evaluate if neoadjuvant stereotactic ablative radiotherapy (SABR) before surgery improves oncologic outcomes in patients with stage I non-small cell lung cancer (NSCLC). We report a mandated interim safety analysis for the first 10 patients who completed protocol treatment. Operable patients with biopsy-proven T1-2 N0 NSCLC were eligible. SABR was delivered using a risk-adapted fractionation (54Gy/3 fractions, 55/5 or 60/8). Surgical resection was planned 10 weeks later at a high-volume center (>200 lung cancer resections annually). Patients were imaged with dynamic positron emission tomography-computed tomography scans using 18F-fludeoxyglucose (18F-FDG-PET CT) and dynamic contrast-enhanced CT before SABR and again before surgery. Toxicity was recorded using CTCAE version 4.0. Twelve patients were enrolled between 09/2014 and 09/2015. Two did not undergo surgery, due to patient or surgeon preference; neither patient has developed toxicity or recurrence. For the 10 patients completing both treatments, median age was 70 (range: 54-76), 60% had T1 disease, and 60% had adenocarcinoma. Median FEV1 was 73% predicted (range: 54-87%). Median time to surgery post-SABR was 10.1 weeks (range: 9.3-15.6 weeks). Surgery consisted of lobectomy (n = 8) or wedge resection (n = 2). Median follow-up post-SABR was 6.3 months. After combined treatment, the rate of acute grade 3-4 toxicity was 10%. There was no post-operative mortality at 90 days. The small sample size included herein precludes any definitive conclusions regarding overall toxicity rates until larger datasets are available. However, these data may inform others who are designing or conducting similar trials. TRIAL REGISTRATION: NCT02136355 . Registered 8 May 2014.

Unsupervised boundary delineation of spinal neural foramina using a multi-feature and adaptive spectral segmentation.

As a common disease in the elderly, neural foramina stenosis (NFS) brings a significantly negative impact on the quality of life due to its symptoms including pain, disability, fall risk and depression. Accurate boundary delineation is essential to the clinical diagnosis and treatment of NFS. However, existing clinical routine is extremely tedious and inefficient due to the requirement of physicians' intensively manual delineation. Automated delineation is highly needed but faces big challenges from the complexity and variability in neural foramina images. In this paper, we propose a pure image-driven unsupervised boundary delineation framework for the automated neural foramina boundary delineation. This framework is based on a novel multi-feature and adaptive spectral segmentation (MFASS) algorithm. MFASS firstly utilizes the combination of region and edge features to generate reliable spectral features with a good separation between neural foramina and its surroundings, then estimates an optimal separation threshold for each individual image to separate neural foramina from its surroundings. This self-adjusted optimal separation threshold, estimated from spectral features, successfully overcome the diverse appearance and shape variations. With the robustness from the multi-feature fusion and the flexibility from the adaptively optimal separation threshold estimation, the proposed framework, based on MFASS, provides an automated and accurate boundary delineation. Validation was performed in 280 neural foramina MR images from 56 clinical subjects. Our method was benchmarked with manual boundary obtained by experienced physicians. Results demonstrate that the proposed method enjoys a high and stable consistency with experienced physicians (Dice: 90.58% ± 2.79%; SMAD: 0.5657 ± 0.1544 mm). Therefore, the proposed framework enables an efficient and accurate clinical tool in the diagnosis of neural foramina stenosis.

Multi-modal vertebrae recognition using Transformed Deep Convolution Network.

Automatic vertebra recognition, including the identification of vertebra locations and naming in multiple image modalities, are highly demanded in spinal clinical diagnoses where large amount of imaging data from various of modalities are frequently and interchangeably used. However, the recognition is challenging due to the variations of MR/CT appearances or shape/pose of the vertebrae. In this paper, we propose a method for multi-modal vertebra recognition using a novel deep learning architecture called Transformed Deep Convolution Network (TDCN). This new architecture can unsupervisely fuse image features from different modalities and automatically rectify the pose of vertebra. The fusion of MR and CT image features improves the discriminativity of feature representation and enhances the invariance of the vertebra pattern, which allows us to automatically process images from different contrast, resolution, protocols, even with different sizes and orientations. The feature fusion and pose rectification are naturally incorporated in a multi-layer deep learning network. Experiment results show that our method outperforms existing detection methods and provides a fully automatic location+naming+pose recognition for routine clinical practice.

Detection of Local Cancer Recurrence After Stereotactic Ablative Radiation Therapy for Lung Cancer: Physician Performance Versus Radiomic Assessment.

PURPOSE: Stereotactic ablative radiation therapy (SABR) is a guideline-specified treatment option for early-stage lung cancer. However, significant posttreatment fibrosis can occur and obfuscate the detection of local recurrence. The goal of this study was to assess physician ability to detect timely local recurrence and to compare physician performance with a radiomics tool. METHODS AND MATERIALS: Posttreatment computed tomography (CT) scans (n=182) from 45 patients treated with SABR (15 with local recurrence matched to 30 with no local recurrence) were used to measure physician and radiomic performance in assessing response. Scans were individually scored by 3 thoracic radiation oncologists and 3 thoracic radiologists, all of whom were blinded to clinical outcomes. Radiomic features were extracted from the same images. Performances of the physician assessors and the radiomics signature were compared. RESULTS: When taking into account all CT scans during the whole follow-up period, median sensitivity for physician assessment of local recurrence was 83% (range, 67%-100%), and specificity was 75% (range, 67%-87%), with only moderate interobserver agreement (κ = 0.54) and a median time to detection of recurrence of 15.5 months. When determining the early prediction of recurrence within <6 months after SABR, physicians assessed the majority of images as benign injury/no recurrence, with a mean error of 35%, false positive rate (FPR) of 1%, and false negative rate (FNR) of 99%. At the same time point, a radiomic signature consisting of 5 image-appearance features demonstrated excellent discrimination, with an area under the receiver operating characteristic curve of 0.85, classification error of 24%, FPR of 24%, and FNR of 23%. CONCLUSIONS: These results suggest that radiomics can detect early changes associated with local recurrence that are not typically considered by physicians. This decision support system could potentially allow for early salvage therapy of patients with local recurrence after SABR.

Multi-Modality Vertebra Recognition in Arbitrary Views Using 3D Deformable Hierarchical Model.

Computer-aided diagnosis of spine problems relies on the automatic identification of spine structures in images. The task of automatic vertebra recognition is to identify the global spine and local vertebra structural information such as spine shape, vertebra location and pose. Vertebra recognition is challenging due to the large appearance variations in different image modalities/views and the high geometric distortions in spine shape. Existing vertebra recognitions are usually simplified as vertebrae detections, which mainly focuses on the identification of vertebra locations and labels but cannot support further spine quantitative assessment. In this paper, we propose a vertebra recognition method using 3D deformable hierarchical model (DHM) to achieve cross-modality local vertebra location+pose identification with accurate vertebra labeling, and global 3D spine shape recovery. We recast vertebra recognition as deformable model matching, fitting the input spine images with the 3D DHM via deformations. The 3D model-matching mechanism provides a more comprehensive vertebra location+pose+label simultaneous identification than traditional vertebra location+label detection, and also provides an articulated 3D mesh model for the input spine section. Moreover, DHM can conduct versatile recognition on volume and multi-slice data, even on single slice. Experiments show our method can successfully extract vertebra locations, labels, and poses from multi-slice T1/T2 MR and volume CT, and can reconstruct 3D spine model on different image views such as lumbar, cervical, even whole spine. The resulting vertebra information and the recovered shape can be used for quantitative diagnosis of spine problems and can be easily digitalized and integrated in modern medical PACS systems.

Evaluating the impact of a Canadian national anatomy and radiology contouring boot camp for radiation oncology residents.

BACKGROUND: Radiation therapy treatment planning has advanced over the past 2 decades, with increased emphasis on 3-dimensional imaging for target and organ-at-risk (OAR) delineation. Recent studies suggest a need for improved resident instruction in this area. We developed and evaluated an intensive national educational course ("boot camp") designed to provide dedicated instruction in site-specific anatomy, radiology, and contouring using a multidisciplinary (MDT) approach. METHODS: The anatomy and radiology contouring (ARC) boot camp was modeled after prior single-institution pilot studies and a needs-assessment survey. The boot camp incorporated joint lectures from radiation oncologists, anatomists, radiologists, and surgeons, with hands-on contouring instruction and small group interactive seminars using cadaveric prosections and correlative axial radiographs. Outcomes were evaluated using pretesting and posttesting, including anatomy/radiology multiple-choice questions (MCQ), timed contouring sessions (evaluated relative to a gold standard using Dice similarity metrics), and qualitative questions on satisfaction and perceived effectiveness. Analyses of pretest versus posttest scores were performed using nonparametric paired testing. RESULTS: Twenty-nine radiation oncology residents from 10 Canadian universities participated. As part of their current training, 29%, 75%, and 21% receive anatomy, radiology, and contouring instruction, respectively. On posttest scores, the MCQ knowledge scores improved significantly (pretest mean 60% vs posttest mean 80%, P<.001). Across all contoured structures, there was a 0.20 median improvement in students' average Dice score (P<.001). For individual structures, significant Dice improvements occurred in 10 structures. Residents self-reported an improved ability to contour OARs and interpret radiographs in all anatomic sites, 92% of students found the MDT format effective for their learning, and 93% found the boot camp more effective than educational sessions at their own institutions. All of the residents (100%) would recommend this course to others. CONCLUSIONS: The ARC boot camp is an effective intervention for improving radiation oncology residents' knowledge and understanding of anatomy and radiology in addition to enhancing their confidence and accuracy in contouring.

Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial.

BACKGROUND: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial. METHODS/DESIGN: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival. DISCUSSION: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02002052.

Extraspinal findings at lumbar spine CT examinations: prevalence and clinical importance.

PURPOSE: To prospectively determine the prevalence and clinical importance of extraspinal abnormalities in adult outpatients undergoing computed tomography (CT) of the lumbar spine. MATERIALS AND METHODS: Institutional review board approval was obtained for this prospective study. Informed consent was obtained from 400 consecutive adult outpatients (mean age, 49 years; 212 male and 188 female patients) undergoing lumbar spine CT for low back pain and/or radiculopathy. Those with known malignancy were excluded. Dedicated spinal and abdominal full-field-of-view (FOV) images for each patient were reviewed by at least one neuroradiologist and two body radiologists. Extraspinal abnormalities were classified according to the CT Colonography Reporting and Data System (C-RADS). The electronic medical record of the patients with C-RADS E3 and E4 extraspinal findings were reviewed to assess how many of these findings were previously unknown, and the patients were followed up 24-36 months after the initial CT to determine their work-up and outcome. RESULTS: Extraspinal findings were present on images in 162 (40.5%) of 400 lumbar spine CT examinations; 59 (14.8%) patients had indeterminate or clinically important findings requiring clinical correlation or further evaluation. After review of the electronic medical record, the prevalence of clinically important findings was 4.3%, comprising an early-stage renal cell carcinoma and transitional cell carcinoma, chronic lymphocytic leukemia, sarcoidosis, and 13 abdominal aortic aneurysms. Excluding anatomic variants, the full FOV was required to best visualize extraspinal abnormalities in 127 (79.4%) of 160 patients. CONCLUSION: Reviewing the full-FOV images from lumbar spine CT examinations will result in the detection of a small number of substantial extraspinal pathologic findings in addition to many benign incidental findings.

The LxCxE pRb interaction domain of cyclin D1 is dispensable for murine development.

Cyclin D1 is a multifunctional, tumor-associated protein that interacts with pRb via a conserved LxCxE motif, activates a kinase partner, directs the phosphorylation of pRb, activates cyclin E-cyclin-dependent kinase 2 (cdk2) by titrating Cip/Kip cdk inhibitors, and modulates the activity of a variety of transcription factors. It is thought that some of the proproliferative function of cyclin D1 is exerted by LxCxE-dependent binding to the pRb pocket domain, which might interfere with the ability of pRb to repress transcription by recruiting cellular chromatin remodeling proteins to E2F-dependent promoters. To test the importance of the LxCxE domain in vivo, we have generated a "knock-in" mouse by replacing the wild-type cyclin D1 gene with a mutant allele precisely lacking the nucleotides encoding the LxCxE domain. Analysis of this mouse has shown that the LxCxE protein is biochemically similar to wild-type cyclin D1 in all tested respects. Moreover, we were unable to detect abnormalities in growth, retinal development, mammary gland development, or tumorigenesis, all of which are affected by deleting cyclin D1. Although we cannot exclude the presence of subtle defects, these results suggest that the LxCxE domain of cyclin D1 is not necessary for function despite the absolute conservation of this motif in the D-type cyclins from plants and vertebrates.

Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis.

Cyclin D1 is a multifunctional protein that activates CDK4 and CDK6, titrates Cip/Kip CDK inhibitors to increase CDK2 activity, and modulates the function of certain transcription factors. To specifically test the importance of cyclin D1-associated kinase activity, we generated "knockin" mice expressing mutant cyclin D1 deficient in activating CDK4/6. The development of several cyclin D1-dependent compartments, including mammary glands, proceeds relatively normally in these animals, demonstrating that cyclin D1-associated kinase activity is largely dispensable for development of these tissues. Strikingly, knockin mice were resistant to breast cancers initiated by ErbB-2. These results demonstrate a differential requirement for cyclin D1-CDK4/6 kinase activity in development versus tumorigenesis and strongly support cyclin D1-dependent kinase activity as a specific therapeutic target in breast cancer.

Percutaneous management of chronic mesenteric ischemia: outcomes after intervention.

PURPOSE: To assess the efficacy and durability of percutaneous transluminal angioplasty (PTA)/stent placement for treatment of chronic mesenteric ischemia (CMI). MATERIALS AND METHODS: A retrospective review of patients treated from January 1986 to August 2003 was conducted. Twenty-nine patients (mean age, 62 years) were treated for clinical symptoms consistent with CMI. Clinical diagnosis was verified with angiographic assessment and PTA with or without stent placement was performed based on angiographic and/or pressure gradient findings. Outcomes were estimated with the Kaplan-Meier method. RESULTS: A total of 63 interventions were performed in 29 patients during the study period. Of these 63 interventions, 46 PTA and 17 stent implantation procedures were performed. Thirty-four interventions were performed for SMA stenosis/occlusion, 17 interventions for celiac artery stenosis/occlusion, and four interventions were performed on aorto-mesenteric graft stenoses. Technical success was 97%, and clinical success (defined as clinical resolution of symptoms) was 90% (26 of 29 patients). Mean duration of follow-up was 28.3 months. Primary patency for all interventions at 3, 6, and 12 months was 82.7% (95% CI: 68.7-96.7), 78.9% (66.7-91.1), and 70.1% (55.1-85.6), respectively. Primary assisted patency for all interventions at 3, 6, and 12 months was 87.9% (79.0-95.3), 87.9% (79.2-95.1), and 87.9% (77.3-98.3), respectively. An average of 1.9 interventions per patient was required. One major complication occurred (3.4%). There were three minor complications (10.3%). CONCLUSIONS: Percutaneous intervention for CMI is safe with durable early and midterm clinical success. However, repeated intervention is often required for improved primary assisted patency.

Multiple functions of D-type cyclins can antagonize pRb-mediated suppression of proliferation.

The most well understood function of the D-type cyclins is to activate the G(1) kinases, cdk4 and cdk6, and target the retinoblastoma gene product (pRb) for phosphorylation and inactivation. pRb can suppress S phase entry, cause a transient G(1) arrest following DNA damage, and is critical in establishing terminal cell cycle withdrawal in cells exposed to differentiation or senescence-inducing signals. Each of these functions of pRb can be demonstrated in cultured cells derived from human tumors that have suffered RB1 gene inactivation. In such in vitro assays, coexpression of D type cyclins has been shown to inhibit the function of pRb, likely reflecting an oncogenic role of cyclin D1 in vivo. Two regions of cyclin D, the LxCxE pRb-binding motif, and the cyclin box, are thought to be critical for the proper function of cyclin D. Here we show that the LxCxE motif is dispensable in cyclin D1 for all functions tested, but is required by cyclin D2. This observation suggests that there is a functional difference between cyclins D1 and D2 in pRb regulation, and argues against complete functional redundancy of these D cyclins. In addition, the ability of cyclins D1 and D2 to activate cdk partners is required for induction of pRb phosphorylation and S phase entry. However, mutant forms of cyclins D1 and D2 that are incapable of activating kinase partners were still able to prevent pRb-induced senescence. Thus, D cyclins have both kinase-dependent and kinase-independent mechanisms of interfering with proliferation arrest and senescence.