Endobronchially Implanted Real-Time Electromagnetic Transponder Beacon-Guided, Respiratory-Gated SABR for Moving Lung Tumors: A Prospective Phase 1/2 Cohort Study.

Purpose: Endobronchial electromagnetic transponder beacons (EMT) provide real-time, precise positional data of moving lung tumors. We report results of a phase 1/2, prospective, single-arm cohort study evaluating the treatment planning effects of EMT-guided SABR for moving lung tumors. Methods and Materials: Eligible patients were adults, Eastern Cooperative Oncology Group 0 to 2, with T1-T2N0 non-small cell lung cancer or pulmonary metastasis ≤4 cm with motion amplitude ≥5 mm. Three EMTs were endobronchially implanted using navigational bronchoscopy. Four-dimensional free-breathing computed tomography simulation scans were obtained, and end-exhalation phases were used to define the gating window internal target volume. A 3-mm expansion of gating window internal target volume defined the planning target volume (PTV). EMT-guided, respiratory-gated (RG) SABR was delivered (54 Gy/3 fractions or 48 Gy/4 fractions) using volumetric modulated arc therapy. For each RG-SABR plan, a 10-phase image-guided SABR plan was generated for dosimetric comparison. PTV/organ-at-risk (OAR) metrics were tabulated and analyzed using the Wilcoxon signed-rank pair test. Treatment outcomes were evaluated using RECIST (Response Evaluation Criteria in Solid Tumours; version 1.1). Results: Of 41 patients screened, 17 were enrolled and 2 withdrew from the study. Median age was 73 years, with 7 women. Sixty percent had T1/T2 non-small cell lung cancer and 40% had M1 disease. Median tumor diameter was 1.9 cm with 73% of targets located peripherally. Mean respiratory tumor motion was 1.25 cm (range, 0.53-4.04 cm). Thirteen tumors were treated with EMT-guided SABR and 47% of patients received 48 Gy in 4 fractions while 53% received 54 Gy in 3 fractions. RG-SABR yielded an average PTV reduction of 46.9% (P < .005). Lung V5, V10, V20, and mean lung dose had mean relative reductions of 11.3%, 20.3%, 31.1%, and 20.3%, respectively (P < .005). Dose to OARs was significantly reduced (P < .05) except for spinal cord. At 6 months, mean radiographic tumor volume reduction was 53.5% (P < .005). Conclusions: EMT-guided RG-SABR significantly reduced PTVs of moving lung tumors compared with image-guided SABR. EMT-guided RG-SABR should be considered for tumors with large respiratory motion amplitudes or those located in close proximity to OARs.

Migration of Calypso beacon transponders for hepatic stereotactic body radiotherapy: a report of two cases.

Background: The Calypso 4-dimensional Localization System allows the delivery of high-dose of radiation to a target guided by the implanted transponders. Calypso beacons are used for prostate and liver tumors treated with stereotactic body radiation therapy (SBRT). Several risks associated with this procedure have been previously observed. Here, we report on two cases where Calypso soft tissue transponders migrated to the lung shortly after implantation in liver. Case Description: Two male patients with hepatocellular carcinoma (HCC) underwent insertion of Calypso beacons in liver under image-guidance in preparation for SBRT. Post-procedure images confirmed the presence of the transponders within the liver. However, few days after implant, further imaging revealed a missing marker, in each patient, that had migrated to the right lung. Patients were asymptomatic and SBRT was delivered uneventfully. Conclusions: This is the first report of migration of Calypso beacons from liver to lung. In order to reduce the risk of migration, a Doppler ultrasound (US) prior to insertion could be performed to ensure that the transponders are at a safe distance from blood vessels. Anchored Calypso beacons, currently approved for insertion in the lung, could be tested as a suitable alternative to soft tissue beacons with a lower risk of migration.

A retrospective study on clinical factors influencing intra-fraction motion using volumetric imaging for spine stereotactic body radiotherapy.

Objectives: Stereotactic body radiation therapy (SBRT) for the spine is challenging due to high-dose gradients sparing the cord in the treatment plans. We present our findings of initial setup error and intrafraction motion from Cone-beam computed tomography (CBCT) imaging. Materials and methods: A total of 47 patients treated with spine SBRT with a total of 154 fractions following a fractionation schedule of 16 Gy in 1, 24 Gy in 2, and 30 Gy in 5 fractions were part of this study. Pre-treatment CBCT was used for localization of the target and couch shifts were applied based on target volume matching to the planning CT image set. Post-treatment CBCT was acquired for all fractions. Intrafraction motion (IFM) was calculated by matching post-treatment CBCT to planning CT for the target volume. Results: The average Intrafraction motion was 1.6 ± 0.9 mm for the study cohort. The average and standard deviation of intrafraction motion were 0.4 ± 1.1 (AP), 0.3 ± 0.9 (SI) and 0.2 ± 1.2 (RL) respectively. The average Initial setup error tabulated from the offline review showed a mean value of 7.8 ± 5.3 mm. The average and standard deviation of the initial setup error were 2.5 ± 5.5 (AP), 2.4 ± 5.3(SI), and 0.8 ± 4.5(RL) respectively. The correlation of intrafraction motion with body mass index (BMI) and the number of consecutive vertebrae levels did not show any statistical significance, however, there was a significant association with gender as women showed more IFM. Conclusions: Our study on intrafraction motion from CBCT images reinforced the importance of immobilization and imaging for positioning spine SBRT patients. Advances in knowledge: The need for CBCT and imagining for positional errors is emphasized while treating with SBRT spine and the need for proper immobilization techniques.

Feasibility study for marker-based VMAT plan optimization toward tumor tracking.

This work investigates the incorporation of fiducial marker-based visibility parameters into the optimization of volumetric modulated arc therapy (VMAT) plans. We propose that via this incorporation, one may produce treatment plans that aid real-time tumor tracking approaches employing exit imaging of the therapeutic beam (e.g., via EPID), in addition to satisfying purely dosimetric requirements. We investigated the feasibility of this approach for a thorax and prostate site using optimization software (MonArc). For a thorax phantom and a lung patient, three fiducial markers were inserted around the tumor and VMAT plans were created with two partial arcs and prescription dose of 48 Gy (4 fractions). For a prostate patient with three markers in the prostate organ, a VMAT plan was created with two partial arcs and prescription dose 72.8 Gy (28 fractions). We modified MonArc to include marker-based visibility constraints ("hard"and "soft"). A hard constraint (HC) imposes full visibility for all markers, while a soft constraint (SC) penalizes visibility for specific markers in the beams-eye-view. Dose distributions from constrained plans (HC and SC) were compared to the reference nonconstrained (NC) plan using metrics including conformity index (CI), homogeneity index (HI), gradient measure (GM), and dose to 95% of planning target volume (PTV) and organs at risk (OARs). The NC plan produced the best target conformity and the least doses to the OARs for the entire dataset, followed by the SC and HC plans. Using SC plans provided acceptable dosimetric tolerances for both the target and OARs. However, OAR doses may be increased or decreased based on the constrained marker location and number of trackable markers. In conclusion, we demonstrate that visibility constraints can be incorporated into the optimization together with dosimetric objectives to produce treatment plans satisfying both objectives. This approach should ensure greater clinical success when applying real-time tracking algorithms, using VMAT delivery.

Constrained optimization towards marker-based tumor tracking in VMAT.

This study proposes that incorporating marker-based visibility constraints into the optimization of volumetric modulated arc therapy (VMAT) will generate treatment plans which not only ensure a higher chance of successfully applying real-time tumor tracking techniques, but also simultaneously satisfy dosimetric objectives. This was applied clinically and investigated for multiple disease sites (10 prostate, 5 liver, and 5 lung) using a radiotherapy optimization software (MonArc), where these new constraints were added to conventional dosimetric constraints. For all the investigated sites, three fiducial markers were located inside or around the planning target volume (PTV), and VMAT plans were created for each patient. We modifiedMonArcto analyze the multi-leaf collimator (MLC) beam's-eye-view at all control points in the gantry arc, while including marker-based visibility constraints of type 'hard' (i.e. requiring 100% visibility of all markers, HC) and 'soft' (i.e. penalizes visibility for one marker [SCI] or two markers [SCII] only) in the optimization process. Dose distributions resulting from the constrained plans (HC, SCI, and SCII) were compared to the non-constrained plan (NC-plans optimized without visibility constraints) using several quantitative dose metrics including the conformity index, homogeneity index, doses to PTV and to organs-at-risk (OAR). Generally, the NC plan produced the best PTV dose conformity and the least OAR doses for the entire patient datasets, followed by the SC and then HC plans, with all the optimization approaches typically achieving acceptable dose metrics. Across the three disease sites, visibility of all three markers in MLC apertures increased from 32% to 100% of available control points as visibility constraints strengthened. Although dose metrics showed some deterioration for constrained plans (-6% for SCIup to -15% for HC using the PTV average index), the required dosimetric objectives were still satisfied in at least 90% of patients. In conclusion, we demonstrated that marker and tumour visibility constraints can be incorporated with dosimetric objectives to produce treatment plans satisfying both objectives, which should ensure greater success when applying real-time tracking for VMAT delivery.

Does Motion Assessment With 4-Dimensional Computed Tomographic Imaging for Non-Small Cell Lung Cancer Radiotherapy Improve Target Volume Coverage?

INTRODUCTION: Modern radiotherapy with 4-dimensional computed tomographic (4D-CT) image acquisition for non-small cell lung cancer (NSCLC) captures respiratory-mediated tumor motion to provide more accurate target delineation. This study compares conventional 3-dimensional (3D) conformal radiotherapy (3DCRT) plans generated with standard helical free-breathing CT (FBCT) with plans generated on 4D-CT contoured volumes to determine whether target volume coverage is affected. MATERIALS AND METHODS: Fifteen patients with stage I to IV NSCLC were enrolled in the study. Free-breathing CT and 4D-CT data sets were acquired at the same simulation session and with the same immobilization. Gross tumor volume (GTV) for primary and/or nodal disease was contoured on FBCT (GTV_3D). The 3DCRT plans were obtained, and the patients were treated according to our institution's standard protocol using FBCT imaging. Gross tumor volume was contoured on 4D-CT for primary and/or nodal disease on all 10 respiratory phases and merged to create internal gross tumor volume (IGTV)_4D. Clinical target volume margin was 5 mm in both plans, whereas planning tumor volume (PTV) expansion was 1 cm axially and 1.5 cm superior/inferior for FBCT-based plans to incorporate setup errors and an estimate of respiratory-mediated tumor motion vs 8 mm isotropic margin for setup error only in all 4D-CT plans. The 3DCRT plans generated from the FBCT scan were copied on the 4D-CT data set with the same beam parameters. GTV_3D, IGTV_4D, PTV, and dose volume histogram from both data sets were analyzed and compared. Dice coefficient evaluated PTV similarity between FBCT and 4D-CT data sets. RESULTS: In total, 14 of the 15 patients were analyzed. One patient was excluded as there was no measurable GTV. Mean GTV_3D was 115.3 cm3 and mean IGTV_4D was 152.5 cm3 (P = .001). Mean PTV_3D was 530.0 cm3 and PTV_4D was 499.8 cm3 (P = .40). Both gross primary and nodal disease analyzed separately were larger on 4D compared with FBCT. D95 (95% isodose line) covered 98% of PTV_3D and 88% of PTV_4D (P = .003). Mean dice coefficient of PTV_3D and PTV_4D was 84%. Mean lung V20 was 24.0% for the 3D-based plans and 22.7% for the 4D-based plans (P = .057). Mean heart V40 was 12.1% for the 3D-based plans and 12.7% for the 4D-based plans (P = .53). Mean spinal cord Dmax was 2517 and 2435 cGy for 3D-based and 4D-based plans, respectively (P = .019). Mean esophageal dose was 1580 and 1435 cGy for 3D and 4D plans, respectively (P = .13). CONCLUSIONS: IGTV_4D was significantly larger than GTV_3D for both primary and nodal disease combined or separately. Mean PTV_3D was larger than PTV_4D, but the difference was not statistically significant. The PTV_4D coverage with 95% isodose line was inferior, indicating the importance of incorporating the true size and shape of the target volume. Relatively less dose was delivered to spinal cord and esophagus with plans based on 4D data set. Dice coefficient analysis for degree of similarity revealed that 16% of PTVs from both data sets did not overlap, indicating different anatomical positions of the PTV due to tumor/nodal motion during a respiratory cycle. All patients with lung cancer planned for radical radiotherapy should have 4D-CT simulation to ensure accurate coverage of the target volumes.

The influence of a novel transmission detector on 6 MV x-ray beam characteristics.

The purpose of this work was to investigate the influence of a new transmission detector on 6 MV x-ray beam properties. The device, COMPASS (IBA Dosimetry, Germany), contains 1600 plane parallel ionization chambers with a detector spacing of 6.5 mm and an active volume of 0.02 cm3. Surface dose measurements were carried out using a Markus chamber and radiochromic film for a range of field sizes and source-to-surface distances (SSDs). The surface dose and dose in the build-up region for COMPASS fields were compared to open fields. For moderately narrow beam geometric conditions, the increase in surface dose was small. For the largest field size investigated (20x20 cm2) at a 90 cm SSD, the surface dose with the detector was 34.9% versus 26.8% in the open field. However, the increase in surface dose in COMPASS fields was less than that observed with a standard block tray in the field (38.7% in the above example). It was found that beyond dmax, the difference in relative dose (profiles and PDDs) between open and COMPASS fields was insignificant. The mean transmission factor of the detector was 0.967 (standard deviation=0.002) measured over a range of field sizes from 3x3 to 20x20 cm2 at SSDs from 70 cm to 90 cm. In summary, the transmission detector was found to increase the relative dose in the buildup region but had a negligible effect on the beam parameters beyond dmax.

Using acetowhite opacity index for detecting cervical intraepithelial neoplasia.

Cervical intraepithelial neoplasia (CIN) exhibits certain morphologic features that can be identified during a colposcopic exam. Immature metaplastic and dysplastic cervical squamous epithelia turn white after application of acetic acid during the exam. The whitening process occurs visually over several minutes and subjectively helps to discriminate between dysplastic and normal tissue. Digital imaging technologies enable us to assist the physician in analyzing acetowhite (acetic-acid-induced) lesions in a fully automatic way. We report a study designed to measure multiple parameters of the acetowhitening process from two images captured with a digital colposcope. One image is captured before the acetic acid application, and the other is captured after the acetic acid application. The spatial change of the acetowhitening is extracted using color and texture information in the post-acetic-acid image; the temporal change is extracted from the intensity and color changes between the post-acetic-acid and pre-acetic-acid images with an automatic alignment. In particular, we propose an automatic means to calculate an opacity index that indicates the grades of temporal change. The imaging and data analysis system is evaluated with a total of 99 human subjects. The proposed opacity index demonstrates a sensitivity and specificity of 94 and 87%, respectively, for discriminating high-grade dysplasia (CIN2+) from normal and low-grade subjects, considering histology as the gold standard.

Automated Image Analysis of Fluorescence Microscopic Images to Identify Protein-protein Interactions.

The identification of protein-protein interactions along with their spatial and temporal localization is vital data for assigning functional information to proteins. Historically, these data sets obtained from fluorescence microscopy, have been analyzed manually, a process that is both time consuming and tedious. The development of an automated system that can measure the location dynamics of the interaction between two proteins inside a live cell is a high priority. This paper describes an automated image analysis system used to identify the interactions between two proteins of interest fused to either GFP or DIV IVA, a bacterial cell division protein that localizes to the cell poles [1]. Upon the induction of DIV IVA fusion protein expression, the GFP-fusion protein will be recruited to the cell poles if a positive interaction occurs. Advanced image processing and feature extraction algorithms are discussed in detail and a statistical feature set used to quantify the image-based information is developed.

Automated Image Analysis of Fluorescence Microscopic Images to Identify Protein-protein Interactions.

The identification of protein-protein interactions along with their spatial and temporal localization is vital data for assigning functional information to proteins. Historically, these data sets obtained from fluorescence microscopy, have been analyzed manually, a process that is both time consuming and tedious. The development of an automated system that can measure the location dynamics of the interaction between two proteins inside a live cell is a high priority. This paper describes an automated image analysis system used to identify the interactions between two proteins of interest fused to either GFP or DIV IVA, a bacterial cell division protein that localizes to the cell poles [1]. Upon the induction of DIV IVA fusion protein expression, the GFP-fusion protein will be recruited to the cell poles if a positive interaction occurs. Advanced image processing and feature extraction algorithms are discussed in detail and a statistical feature set used to quantify the image-based information is developed.