Feasibility of MV CBCT-based treatment planning for urgent radiation therapy: dosimetric accuracy of MV CBCT-based dose calculations.

Unlike scheduled radiotherapy treatments, treatment planning time and resources are limited for emergency treatments. Consequently, plans are often simple 2D image-based treatments that lag behind technical capabilities available for nonurgent radiotherapy. We have developed a novel integrated urgent workflow that uses onboard MV CBCT imaging for patient simulation to improve planning accuracy and reduce the total time for urgent treatments. This study evaluates both MV CBCT dose planning accuracy and novel urgent workflow feasibility for a variety of anatomic sites. We sought to limit local mean dose differences to less than 5% compared to conventional CT simulation. To improve dose calculation accuracy, we created separate Hounsfield unit-to-density calibration curves for regular and extended field-of-view (FOV) MV CBCTs. We evaluated dose calculation accuracy on phantoms and four clinical anatomical sites (brain, thorax/spine, pelvis, and extremities). Plans were created for each case and dose was calculated on both the CT and MV CBCT. All steps (simulation, planning, setup verification, QA, and dose delivery) were performed in one 30 min session using phantoms. The monitor units (MU) for each plan were compared and dose distribution agreement was evaluated using mean dose difference over the entire volume and gamma index on the central 2D axial plane. All whole-brain dose distributions gave gamma passing rates higher than 95% for 2%/2 mm criteria, and pelvic sites ranged between 90% and 98% for 3%/3 mm criteria. However, thoracic spine treatments produced gamma passing rates as low as 47% for 3%/3 mm criteria. Our novel MV CBCT-based dose planning and delivery approach was feasible and time-efficient for the majority of cases. Limited MV CBCT FOV precluded workflow use for pelvic sites of larger patients and resulted in image clearance issues when tumor position was far off midline. The agreement of calculated MU on CT and MV CBCT was acceptable for all treatment sites

Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clinics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences >5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study. PACS number(s): 87.55.D-, 87.57.C-, 87.57.Q

A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed.Key pointsTo our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases

Pathologic Correlation of PET-CT Based Auto Contouring for Radiation Planning in Lung Cancer

Purpose/Objective(s): Radiation therapy in lung cancer relies on CT and functional imaging (FDG-PET) to delineate tumor volumes. Semi-automatic contouring tools have been developed for PET to improve on the inter-observer bias of manual contouring and intrinsic differences in imaging equipment. A common method involves using a threshold at a given percentage of the max activity, which may be less accurate with smaller tumors and tumors with low source to background ratio. To overcome this deficiency, a gradient algorithm, which detects changes in image counts at the border of the tumor, has been developed. Few studies have correlated these methods to pathological specimens. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

FAD binding, cobinamide binding and active site communication in the corrin reductase (CobR)

Adenosylcobalamin, the coenzyme form of vitamin B12, is one Nature's most complex coenzyme whose de novo biogenesis proceeds along either an anaerobic or aerobic metabolic pathway. The aerobic synthesis involves reduction of the centrally chelated cobalt metal ion of the corrin ring from Co(II) to Co(I) before adenosylation can take place. A corrin reductase (CobR) enzyme has been identified as the likely agent to catalyse this reduction of the metal ion. Herein, we reveal how Brucella melitensis CobR binds its coenzyme FAD (flavin dinucleotide) and we also show that the enzyme can bind a corrin substrate consistent with its role in reduction of the cobalt of the corrin ring. Stopped-flow kinetics and EPR reveal a mechanistic asymmetry in CobR dimer that provides a potential link between the two electron reduction by NADH to the single electron reduction of Co(II) to Co(I)

The trans-activation domain of the sporulation response regulator Spo0A revealed by X-ray crystallography

Sporulation in Bacillus involves the induction of scores of genes in a temporally and spatially co-ordinated programme of cell development. Its initiation is under the control of an expanded two-component signal transduction system termed a phosphorelay. The master control element in the decision to sporulate is the response regulator, Spo0A, which comprises a receiver or phosphoacceptor domain and an effector or transcription activation domain. The receiver domain of Spo0A shares sequence similarity with numerous response regulators, and its structure has been determined in phosphorylated and unphosphorylated forms. However, the effector domain (C-Spo0A) has no detectable sequence similarity to any other protein, and this lack of structural information is an obstacle to understanding how DNA binding and transcription activation are controlled by phosphorylation in Spo0A. Here, we report the crystal structure of C-Spo0A from Bacillus stearothermophilus revealing a single alpha -helical domain comprising six alpha -helices in an unprecedented fold. The structure contains a helix-turn-helix as part of a three alpha -helical bundle reminiscent of the catabolite gene activator protein (CAP), suggesting a mechanism for DNA binding. The residues implicated in forming the sigma (A)-activating region clearly cluster in a flexible segment of the polypeptide on the opposite side of the structure from that predicted to interact with DNA. The structural results are discussed in the context of the rich array of existing mutational data