Genevieve Maquilan

A Functional Role for Transposases in a Large Eukaryotic Genome

Editing the Genome The ciliate Oxytricha trifallax has an unusual genome with the coding regions of genes (the exons) scattered through the genome. The exons are then somehow knitted together following transcription prior to their translation into proteins. As part of this process Oxytricha eliminates all transposable elements, stripping the genome down to 5% of the original germline DNA during development. Nowacki et al. (p. 935, published online 16 April) show that germline-limited transposases appear to be important for these large-scale DNA rearrangements. The ciliate Oxytricha expresses transposase genes to influence thousands of DNA rearrangements required for proper development. Despite comprising much of the eukaryotic genome, few transposons are active, and they usually confer no benefit to the host. Through an exaggerated process of genome rearrangement, Oxytricha trifallax destroys 95% of its germline genome during development. This includes the elimination of all transposon DNA. We show that germline-limited transposase genes play key roles in this process of genome-wide DNA excision, which suggests that transposases function in large eukaryotic genomes containing thousands of active transposons. We show that transposase gene expression occurs during germline-soma differentiation and that silencing of transposase by RNA interference leads to abnormal DNA rearrangement in the offspring. This study suggests a new important role in Oxytricha for this large portion of genomic DNA that was previously thought of as junk.

Stereotactic body radiation therapy for early-stage lung cancer

Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy, is a technique of external beam radiation that delivers precisely targeted, ablative doses to extracranial sites. It has become an integral component of the management of early-stage non-small cell lung cancer (NSCLC). In this review, we discuss the technology and techniques used in treatment planning and delivery, the efficacy and toxicity of SBRT for medically inoperable early-stage NSCLC, and the preliminary investigations into the role of SBRT for operable early-stage NSCLC.

Acute toxicity profile of patients with low-grade gliomas and meningiomas receiving proton therapy.

Objectives:Proton therapy is an emerging treatment modality. We studied its acute side effects on patients with low-grade gliomas and meningiomas. Materials and Methods:Twenty-three patients diagnosed with low-grade gliomas or meningiomas enrolled in an Institutional Review Board-approved prospective proton treatment protocol (NCT01024907) were treated and followed between April 2010 and August 2011. Patients received 54 Gy (relative biological effectiveness) in 1.8 Gy (relative biological effectiveness) per fraction and were assessed at the time of consult, weekly during treatment, and at 1, 3, 6, and 9 months posttreatment. At each clinic visit, nursing completed a “Symptom Assessment/Grading” table. Symptoms were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Results:Fatigue: At on-treatment visit (OTV) week 6, 13 patients had grade 1 and 6 patients had grade 2 fatigue. At 1-month follow-up, 3 patients had grade 1 and 1 patient had grade 2 fatigue. At each timepoint, 1 patient had grade 3 fatigue. Nausea: At OTV week 3, 5 patients experienced grade 1 nausea. At OTV week 6, 3 patients experienced grade 1 nausea. Headache: At OTV week 3, 10 patients had grade 1 headaches. At OTV week 6, 4 patients experienced grade 1 headaches and 1 patient by follow-up month 1. One to 2 patients experienced grade 2 headaches at each timepoint. At OTV week 3, 1 patient experienced a grade 3 headache. Conclusions:Our results suggest that proton therapy for patients with low-grade gliomas and meningiomas has a favorable acute toxicity profile—most patients experienced mild fatigue, headache, and insomnia that largely resolved by 1-month posttreatment.

Minimal mask immobilization with optical surface guidance for head and neck radiotherapy

Abstract Purpose Full face and neck thermoplastic masks provide standard‐of‐care immobilization for patients receiving H&N IMRT. However, these masks are uncomfortable and increase skin dose. The purpose of this pilot trial was to investigate the feasibility and setup accuracy of minimal face and neck mask immobilization with optical surface guidance. Methods Twenty patients enrolled onto this IRB‐approved protocol. Patients were immobilized with masks securing only forehead and chin. Shoulder movement was restricted by either moldable cushion or hand held strap retractors. Positional information, including isocenter location and CT skin contours, were imported to a commercial surface image guidance system. Patients typically received standard‐of‐care IMRT to 60–70 Gy in 30–33 fractions. Patients were first set up to surface markings with optical image guidance referenced to regions of interest (ROIs) on simulation CT images. Positioning was confirmed by in‐room CBCT. Following six‐dimensional robotic couch correction, a new optical real‐time surface image was acquired to track intrafraction motion and to serve as a reference surface for setup at the next treatment fraction. Therapists manually recorded total treatment time as well as couch shifts based on kV imaging. Intrafractional ROI motion tracking was automatically recorded by the optical image guidance system. Patient comfort was assessed by self‐administered surveys. Results Setup error was measured as six‐dimensional shifts (vertical/longitudinal/lateral/rotation/pitch/roll). Mean error values were −0.51 ± 2.42 mm, −0.49 ± 3.30 mm, 0.23 ± 2.58 mm, −0.15 ± 1.01o, −0.02 ± 1.19o, and 0.06 ± 1.08o, respectively. Average treatment time was 21.6 ± 8.4 mins). Subjective comfort during surface‐guided treatment was confirmed on patient surveys. Conclusion These pilot results confirm feasibility of minimal mask immobilization combined with commercially available optical image guidance. Patient acceptance of minimal mask immobilization has been encouraging. Follow‐up validation, with direct comparison to standard mask immobilization, appears warranted.

Accurate segmenting of cervical tumors in PET imaging based on similarity between adjacent slices

Because in PET imaging cervical tumors are close to the bladder with high capacity for the secreted 18FDG tracer, conventional intensity-based segmentation methods often misclassify the bladder as a tumor. Based on the observation that tumor position and area do not change dramatically from slice to slice, we propose a two-stage scheme that facilitates segmentation. In the first stage, we used a graph-cut based algorithm to obtain initial contouring of the tumor based on local similarity information between voxels; this was achieved through manual contouring of the cervical tumor on one slice. In the second stage, initial tumor contours were fine-tuned to more accurate segmentation by incorporating similarity information on tumor shape and position among adjacent slices, according to an intensity-spatial-distance map. Experimental results illustrate that the proposed two-stage algorithm provides a more effective approach to segmenting cervical tumors in 3D18FDG PET images than the benchmarks used for comparison.

Analysis of the Relationship Between Response to Chemotherapy and Response to Radiation Therapy in Patients With Non–Small Cell Lung Cancer Receiving Sequential Treatment

Objectives: We examine whether induction chemotherapy response predicts thoracic radiotherapy response in locally advanced or oligometastatic non–small cell lung cancer. Materials and Methods: Between January 2001 to August 2010, 25 consecutive patients were identified who received systemic dose chemotherapy followed by definitive thoracic radiotherapy alone. All patients had measurable disease after chemotherapy that was evaluable for response to radiotherapy. Response to each modality was scored by RECIST as stable disease (SD), progressive disease (PD), partial response (PR), or complete response (CR). Results: Patients had adenocarcinoma (n=13), squamous cell carcinoma (n=8), or other histologies (n=4). They had stage IIIA (n=6), IIIB (n=14), and IV (n=5) disease. Patients received 2 to 6 cycles (median 4) of platinum-based chemotherapy followed by radiotherapy (median 66.6/1.8 Gy [range 50 to 84 Gy]). Median time between chemotherapy end and radiotherapy start was 6.7 weeks (range, 1.6 to 53.4 wk). Twelve patients responded to chemotherapy (all were PRs) and 13 did not (SD+PD). Fifteen patients responded to radiotherapy (7 CR, 8 PR) and 10 did not (SD+PD). Of the 12 patients who responded to chemotherapy, 8 also responded to radiotherapy (4 CR, 4 PR). Of the 13 chemotherapy nonresponders, 7 responded to radiotherapy (3 CR, 4 PR). &khgr;2 analysis did not find any association between chemotherapy and radiotherapy response (P=0.513). Regression analysis also failed to identify any correlation between chemotherapy and radiotherapy response (r2=0.008). Conclusions: This study suggests that response to chemotherapy does not predict response to radiotherapy in locally advanced or oligometastatic non–small cell lung cancer. Lack of response to chemotherapy, therefore, should not preclude treatment with definitive radiotherapy.

Shell feature: a new radiomics descriptor for predicting distant failure after radiotherapy in non-small cell lung cancer and cervix cancer

Distant failure is the main cause of human cancer-related mortalities. To develop a model for predicting distant failure in non-small cell lung cancer (NSCLC) and cervix cancer (CC) patients, a shell feature, consisting of outer voxels around the tumor boundary, was constructed using pre-treatment positron emission tomography (PET) images from 48 NSCLC patients received stereotactic body radiation therapy and 52 CC patients underwent external beam radiation therapy and concurrent chemotherapy followed with high-dose-rate intracavitary brachytherapy. The hypothesis behind this feature is that non-invasive and invasive tumors may have different morphologic patterns in the tumor periphery, in turn reflecting the differences in radiological presentations in the PET images. The utility of the shell was evaluated by the support vector machine classifier in comparison with intensity, geometry, gray level co-occurrence matrix-based texture, neighborhood gray tone difference matrix-based texture, and a combination of these four features. The results were assessed in terms of accuracy, sensitivity, specificity, and AUC. Collectively, the shell feature showed better predictive performance than all the other features for distant failure prediction in both NSCLC and CC cohorts.

Automatic PET cervical tumor segmentation by deep learning with prior information.

Cervical tumor segmentation on 3D 18FDG PET images is a challenging task due to the proximity between cervix and bladder. Since bladder has high capacity of 18FDG tracers, bladder intensity is similar to cervical tumor intensity in the PET image. This inhibits traditional segmentation methods based on intensity variation of the image to achieve high accuracy. We propose a supervised machine learning method that integrates a convolutional neural network (CNN) with prior information of cervical tumor. In the proposed prior information constraint CNN (PIC-CNN) algorithm, we first construct a CNN to weaken the bladder intensity value in the image. Based on the roundness of cervical tumor and relative positioning information between bladder and cervix, we obtain the final segmentation result from the output of the network by an auto-thresholding method. We evaluate the performance of the proposed PIC-CNN method on PET images from 50 cervical cancer patients whose cervix and bladder are abutting. The PIC-CNN method achieves a mean DSC value of 0.84 while transfer learning method based on fully convolutional neural networks (FCN) achieves 0.77 DSC. In addition, traditional segmentation methods such as automatic threshold and region-growing method only achieve 0.59 and 0.52 DSC values, respectively. The proposed method provides a more accurate way for segmenting cervical tumor in 3D PET image.

SU-F-J-18: Feasibility of Open Mask Immobilization with Optical Imaging Guidance (OIG) for H&N Radiotherapy

PURPOSE Full face and neck thermoplastic masks provide standard-of-care immobilization for patients receiving H&N IMRT. However, these masks are uncomfortable and increase skin dose. The purpose of this pilot study was to investigate the feasibility and setup accuracy of open face and neck mask immobilization with OIG. METHODS Ten patients were consented and enrolled to this IRB-approved protocol. Patients were immobilized with open masks securing only forehead and chin. Standard IMRT to 60-70 Gy in 30 fractions were delivered in all cases. Patient simulation information, including isocenter location and CT skin contours, were imported to a commercial OIG system. On the first day of treatment, patients were initially set up to surface markings and then OIG referenced to face and neck skin regions of interest (ROI) localized on simulation CT images, followed by in-room CBCT. CBCTs were acquired at least weekly while planar OBI was acquired on the days without CBCT. Following 6D robotic couch correction with kV imaging, a new optical real-time surface image was acquired to track intrafraction motion and to serve as a reference surface for setup at the next treatment fraction. Therapists manually recorded total treatment time as well as couch shifts based on kV imaging. Intrafractional ROI motion tracking was automatically recorded. RESULTS Setup accuracy of OIG was compared with CBCT results. The setup error based on OIG was represented as a 6D shift (vertical/longitudinal/lateral/rotation/pitch/roll). Mean error values were -0.70±3.04mm, -0.69±2.77mm, 0.33±2.67 mm, -0.14±0.94 o, -0.15±1.10o and 0.12±0.82o, respectively for the cohort. Average treatment time was 24.1±9.2 minutes, comparable to standard immobilization. The amplitude of intrafractional ROI motion was 0.69±0.36 mm, driven primarily by respiratory neck motion. CONCLUSION OGI can potentially provide accurate setup and treatment tracking for open face and neck immobilization. Study accrual and patient/provider satisfaction survey collection remain ongoing. This study is supported by VisionRT, Ltd.