Reduced inter-observer and intra-observer delineation variation in esophageal cancer radiotherapy by use of fiducial markers.

Objective: Delineation variation of esophageal tumors remains a large source of geometric uncertainty. In the present study, we investigated the inter- and intra-observer variation in esophageal gross tumor volume (GTV) delineation and the impact of endoscopically implanted fiducial markers on these variations. Material/Methods: Ten esophageal cancer patients with at least two markers endoscopically implanted at the cranial and caudal tumor borders and visible on the planning computed tomography (pCT) were included in this study. Five dedicated gastrointestinal radiation oncologists independently delineated GTVs on the pCT without markers and with markers. The GTV was first delineated on pCTs where markers were digitally removed and next on the original pCT with markers. Both delineation series were executed twice to determine intra-observer variation. For both the inter- and intra-observer analyses, the generalized conformity index (CIgen), and the standard deviation (SD) of the distances between delineated surfaces (i.e., overall, longitudinal, and radial SDs) were calculated. Linear mixed-effect models were used to compare the without and with markers series (α = 0.05). Results: Both the inter- and intra-observer CIgen were significantly larger in the series with markers than in the series without markers (p < .001). For the series without markers vs. with markers, the inter-observer overall SD, longitudinal SD, and radial SD was 0.63 cm vs. 0.22 cm, 1.44 cm vs. 0.42 cm, and 0.26 cm vs. 0.18 cm, respectively (p < .05); moreover, the intra-observer overall SD, longitudinal SD, and radial SD was 0.45 cm vs. 0.26 cm, 1.10 cm vs. 0.41 cm, and 0.22 cm vs. 0.15 cm, respectively (p < .05). Conclusion: The presence of markers at the cranial and caudal tumor borders significantly reduced both inter- and intra-observer GTV delineation variation, especially in the longitudinal direction. Our results endorse the use of markers in GTV delineation for esophageal cancer patients.

Computational Re-Entry Vulnerability Index Mapping to Guide Ablation in Patients With Postmyocardial Infarction Ventricular Tachycardia.

BACKGROUND: Ventricular tachycardias (VTs) in patients with myocardial infarction (MI) are often treated with catheter ablation. However, the VT induction during this procedure does not always identify all of the relevant activation pathways or may not be possible or tolerated. The re-entry vulnerability index (RVI) quantifies regional activation-repolarization differences and can detect multiple regions susceptible to re-entry without the need to induce the arrhythmia. OBJECTIVES: This study aimed to further develop and validate the RVI mapping in patient-specific computational models of post-MI VTs. METHODS: Cardiac magnetic resonance imaging data from 4 patients with post-MI VTs were used to induce VTs in a computational electrophysiological model by pacing. The RVI map of a premature beat in each patient model was used to guide virtual ablations. We compared our results with those of clinical ablation in the same patients. RESULTS: Single-site virtual RVI-guided ablation prevented VT induction in 3 of 9 cases. Multisite virtual ablations guided by RVI mapping successfully prevented re-entry in all cases (9 of 9). Overall, virtual ablation required 15-fold fewer ablation sites (235.5 ± 97.4 vs 17.0 ± 6.8) and 2-fold less ablation volume (5.34 ± 1.79 mL vs 2.11 ± 0.65 mL) than the clinical ablation. CONCLUSIONS: RVI mapping allows localization of multiple regions susceptible to re-entry and may help guide VT ablation. RVI mapping does not require the induction of arrhythmia and may result in less ablated myocardial volumes with fewer ablation sites.

Evaluation of acute esophageal radiation-induced damage using magnetic resonance imaging: a feasibility study in mice.

BACKGROUND: Thoracic and head and neck cancer radiation therapy (RT) can cause damage to nearby healthy organs such as the esophagus, causing acute radiation-induced esophageal damage (ARIED). A non-invasive method to detect and monitor ARIED can facilitate optimizing RT to avoid ARIED while improving local tumor control. Current clinical guidelines are limited to scoring the esophageal damage based on the symptoms of patients. Magnetic resonance imaging (MRI) is a non-invasive imaging modality that may potentially visualize radiation-induced organ damage. We investigated the feasibility of using T2-weighted MRI to detect and monitor ARIED using a two-phased study in mice. METHODS: The first phase aimed to establish the optimal dose level at which ARIED is inducible and to determine the time points where ARIED is detectable. Twenty four mice received a single dose delivery of 20 and 40 Gy at proximal and distal spots of 10.0 mm (in diameter) on the esophagus. Mice underwent MRI and histopathology analysis with esophageal resection at two, three, and 4 weeks post-irradiation, or earlier in case mice had to be euthanized due to humane endpoints. In the second phase, 32 mice received a 40 Gy single dose and were studied at two, three, and 7 days post-irradiation. We detected ARIED as a change in signal intensity of the MRI images. We measured the width of the hyperintense area around the esophagus in all mice that underwent MRI prior to and after irradiation. We conducted a blind qualitative comparison between MRI findings and histopathology as the gold standard. RESULTS/CONCLUSIONS: A dose of 40 Gy was needed to induce substantial ARIED. MRI detected ARIED as high signal intensity, visible from 2 days post-irradiation. Quantitative MRI analysis showed that the hyperintense area around the esophagus with severe ARIED was 1.41 mm wider than with no damage and MRI-only mice. The overall sensitivity and specificity were 56 and 43% respectively to detect any form of ARIED. However, in this study MRI correctly detected 100% of severe ARIED cases. Our two-phased preclinical study showed that MRI has the potential to detect ARIED as a change in signal intensity and width of enhancement around the esophagus.

Optical coherence tomography to detect acute esophageal radiation-induced damage in mice: A validation study.

Radiation therapy for patients with non-small-cell lung cancer is hampered by acute radiation-induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 µm), is able to visualize and monitor acute radiation-induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post-irradiation. In OCT analysis, we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94% and 47%, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post-irradiation. We validate the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans.

Feasibility of using optical coherence tomography to detect acute radiation-induced esophageal damage in small animal models.

Lung cancer survival is poor, and radiation therapy patients often suffer serious treatment side effects. The esophagus is particularly sensitive leading to acute radiation-induced esophageal damage (ARIED). We investigated the feasibility of optical coherence tomography (OCT) for minimally invasive imaging of the esophagus with high resolution (10 µm) to detect ARIED in mice. Thirty mice underwent cone-beam computed tomography imaging for initial setup assessment and dose planning followed by a single-dose delivery of 4.0, 10.0, 16.0, and 20.0 Gy on 5.0-mm spots, spaced 10.0 mm apart in the esophagus. They were repeatedly imaged using OCT up to three months postirradiation. We compared OCT findings with histopathology obtained three months postirradiation qualitatively and quantitatively using the contrast-to-background-noise ratio (CNR). Histopathology mostly showed inflammatory infiltration and edema at higher doses; OCT findings were in agreement with most of the histopathological reports. We were able to identify the ARIED on OCT as a change in tissue scattering and layer thickness. Our statistical analysis showed significant difference between the CNR values of healthy tissue, edema, and inflammatory infiltration. Overall, the average CNR for inflammatory infiltration and edema damages was 1.6-fold higher and 1.6-fold lower than for the healthy esophageal wall, respectively. Our results showed the potential role of OCT to detect and monitor the ARIED in mice, which may translate to humans.

Feasibility of using optical coherence tomography to detect radiation-induced fibrosis and residual cancer extent after neoadjuvant chemo-radiation therapy: an ex vivo study.

Treatment of resectable esophageal cancer includes neoadjuvant chemo-radiation therapy (nCRT) followed by esophagectomy in operable patients. High-risk surgery may have been avoided in patients with a pathological complete response (pCR). We investigated the feasibility of optical coherence tomography (OCT) to detect residual cancer and radiation-induced fibrosis in 10 esophageal cancer patients that underwent nCRT followed by esophagectomy. We compared our OCT findings with histopathology. Overall, OCT was able to differentiate between healthy tissue, fibrotic tissue, and residual cancer with a sensitivity and specificity of 79% and 67%, respectively. Hence, OCT has the potential to add to the assessment of a pCR.

Visibility of fiducial markers used for image-guided radiation therapy on optical coherence tomography for registration with CT: An esophageal phantom study.

PURPOSE: Optical coherence tomography (OCT) is of interest to visualize microscopic esophageal tumor extensions to improve tumor delineation for radiation therapy (RT) planning. Fiducial marker placement is a common method to ensure target localization during planning and treatment. Visualization of these fiducial markers on OCT permits integrating OCT and computed tomography (CT) images used for RT planning via image registration. We studied the visibility of 13 (eight types) commercially available solid and liquid fiducial markers in OCT images at different depths using dedicated esophageal phantoms and evaluated marker placement depth in clinical practice. MATERIALS AND METHODS: We designed and fabricated dedicated esophageal phantoms, in which three layers mimic the anatomical wall structures of a healthy human esophagus. We successfully implanted 13 commercially available fiducial markers that varied in diameter and material property at depths between 0.5 and 3.0 mm. The resulting esophageal phantoms were imaged with OCT, and marker visibility was assessed qualitatively and quantitatively using the contrast-to-background-noise ratio (CNR). The CNR was defined as the difference between the mean intensity of the fiducial markers and the mean intensity of the background divided by the standard deviation of the background intensity. To determine whether, in current clinical practice, the implanted fiducial markers are within the OCT visualization range (up to 3.0 mm depth), we retrospectively measured the distance of 19 fiducial markers to the esophageal lumen on CT scans of 16 esophageal cancer patients. RESULTS: In the esophageal phantoms, all the included fiducial markers were visible on OCT at all investigated depths. Solid fiducial markers were better visible on OCT than liquid fiducial markers with a 1.74-fold higher CNR. Although fiducial marker identification per type and size was slightly easier for superficially implanted fiducial markers, we observed no difference in the ability of OCT to visualize the markers over the investigated depth range. Retrospective distance measurements of 19 fiducial markers on the CT scan of esophageal cancer patients showed that 84% (distance from the closest border of the marker to the lumen) and 53% (distance from the center of the marker to the lumen) of the fiducial markers were located within the OCT visualization range of up to 3.0 mm. CONCLUSIONS: We studied the visibility of eight types of commercially available fiducial markers at different depths on OCT using dedicated esophageal phantoms. All tested fiducial markers were visible at depths ≤3.0 mm and most, but not all, clinically implanted markers were at a depth accessible to OCT. Consequently, the use of fiducial markers as a reference for OCT to CT registration is feasible.