Yuan-Chyuan Lo

Hyperspectral imaging for early detection of oxygenation and perfusion changes in irradiated skin

Studies examining acute oxygenation and perfusion changes in irradiated skin are limited. Hyperspectral imaging (HSI), a method of wide-field, diffuse reflectance spectroscopy, provides noninvasive, quantified measurements of cutaneous oxygenation and perfusion. This study examines whether HSI can assess acute changes in oxygenation and perfusion following irradiation. Skin on both flanks of nude mice (n=20) was exposed to 50 Gy of beta radiation from a strontium-90 source. Hyperspectral images were obtained before irradiation and on selected days for three weeks. Skin reaction assessment was performed concurrently with HSI. Desquamative injury formed in all irradiated areas. Skin reactions were first seen on day 7, with peak formation on day 14, and resolution beginning by day 21. HSI demonstrated increased tissue oxygenation on day 1 before cutaneous changes were observed (p<0.001). Further increases over baseline were seen on day 14, but returned to baseline levels by day 21. For perfusion, similar increases were seen on days 1 and 14. Unlike tissue oxygenation, perfusion was decreased below baseline on day 21 (p<0.002). HSI allows for complete visualization and quantification of tissue oxygenation and perfusion changes in irradiated skin, and may also allow prediction of acute skin reactions based on early changes seen after irradiation.

Volume Modulated Arc Therapy (VMAT) for pulmonary Stereotactic Body Radiotherapy (SBRT) in patients with lesions in close approximation to the chest wall

Purpose: Chest wall pain and discomfort has been recognized as a significant late effect of radiation therapy in historical and modern treatment models. Stereotactic Body Radiotherapy (SBRT) is becoming an important treatment tool in oncology care for patients with intrathoracic lesions. For lesions in close approximation to the chest wall with motion management, SBRT techniques can deliver high dose to the chest wall. As an unintended target of consequence, there is possibility of imposing significant chest wall pain and discomfort as a late effect of therapy. The purpose of this paper is to evaluate the potential role of Volume Modulated Arc Therapy (VMAT) technologies in decreasing chest wall dose in SBRT treatment of pulmonary lesions in close approximation to the chest wall. Materials and Methods: Ten patients with pulmonary lesions of various sizes and tomography in close approximation to the chest wall were selected for retrospective review. All volumes including tumor target, chest wall, ribs, and lung were contoured with maximal intensity projection maps and four-dimensional computer tomography planning. Radiation therapy planning consisted of static techniques including Intensity Modulated Radiation Therapy compared to VMAT therapy to a dose of 60 Gy in 12 Gy fraction dose. Dose volume histogram to rib, chest wall, and lung were compared between plans with statistical analysis. Results: In all patients, dose and volume were improved to ribs and chest wall using VMAT technologies compared to static field techniques. On average, volume receiving 30 Gy to the chest wall was improved by 74%; the ribs by 60%. In only one patient did the VMAT treatment technique increase pulmonary volume receiving 20 Gy (V20). Conclusions: VMAT technology has potential of limiting radiation dose to sensitive chest wall regions in patients with lesions in close approximation to this structure. This would also have potential value to lesions treated with SBRT in other body regions where targets abut critical structures.

Miniature Multileaf Collimator as an Alternative to Traditional Circular Collimators for Stereotactic Radiosurgery and Stereotactic Radiotherapy

Purpose: To evaluate the miniature multileaf collimator (MMLC) as an alternative to traditional circular collimators for radiosurgery. Materials and Methods: ‘Circular’ fields were created with the Radionics MMLC (leaf width 3.53 mm at isocenter). Beam data, including tissue maximum ratios, output factors, penumbrae and isodose distributions of these fields were measured. These were compared to the Radionics circular collimators traditionally used for radiosurgery. The MMLC data were input to the XKnife Treatment Planning System. Treatment plans were completed and evaluated using both the MMLC ‘circular’ fields and the circular collimators. Results: MMLC fields using 3, 5, 7, 9, 11, and 13 leaves on each side of the Radionics MMLC were created to approximate circular fields. The TMRs are essentially identical to those of comparable-size circular collimators. Measured at isocenter at 5-cm depth for 6 MV, the 80–20% penumbra widths are comparable to circular collimators, but are increased by as much as 1 mm at the leaf intersections (steps) where scalloping occurs. Isodose distributions were matched to those of circular collimators with comparable 50% isodose widths. Treatment plans for the MMLC ‘circular’ fields with four arcs (totaling 360Conclusions: With the MMLC simulating circular fields, dose distributions may be obtained which are essentially identical to comparable-size circular collimators. The mechanical accuracy of the MMLC is as good as that of the circular collimators, and the leakage dose is less. The diameter of ‘circular’ fields is limited by the MMLC leaf width to 1 cm and greater in increments of 7 mm. Attention needs to be paid to mechanical collisions because the MMLC is bulkier than the circular collimators.

Dosimetric impact of the AeroForm tissue expander in postmastectomy radiation therapy: An ex vivo analysis

PURPOSE To evaluate the effect of the AeroForm (AirXpanders Inc, Palo Alto, CA) tissue expander on the dose distribution in a phantom from a simulated postmastectomy radiation treatment for breast cancer. METHODS AND MATERIALS Experiments were conducted to determine the effect on the dose distribution with the metallic reservoir irradiated independently and with the entire AeroForm tissue expander placed on a RANDO phantom (The Phantom Laboratory, Salem, NY). The metallic reservoir was irradiated on a block of solid water with film at various depths ranging from 0 to 8.2 cm from the surface. The intact 400 cc AeroForm was inflated to full capacity and irradiated while positioned on a RANDO phantom, with 12 optically stimulated luminescent dosimeters (OSLDs) placed at clinically relevant expander-tissue interface points. RESULTS Film dosimetry with the reservoir perpendicular to film reveals 40% transmission at a depth of 0.7 cm, which increases to 60% at a depth of 8.2 cm. In the parallel position, the results vary depending on which area under the reservoir is examined, indicating that the reservoir is not a uniformly dense object. Testing of the intact expander on the phantom revealed that the average percent difference (measured vs expected dose) was 2.7%, σ = 6.2% with heterogeneity correction and 3.7%, σ = 2.4% without heterogeneity correction. The only position where the OSLD readings were consistently higher than the calculated dose by >5% was at position 1, just deep to the canister at the expander-phantom interface. At this position, the readings varied from 5.2% to 14.5%, regardless of heterogeneity correction. CONCLUSIONS Film dosimetry demonstrated beam attenuation in the shadow of the metallic reservoir in the expander. This decrease in dose was not reproduced on the intact expander on the phantom designed to replicate a clinical setup.

External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site.

Background: External volume expansion prepares recipient sites to improve outcomes of fat grafting. For patients receiving radiotherapy after mastectomy, results with external volume expansion vary, and the relationship between radiotherapy and expansion remains unexplored. Thus, the authors developed a new translational model to investigate the effects in chronic skin fibrosis after radiation exposure. Methods: Twenty-four SKH1-E mice received 50 Gy of &bgr;-radiation to each flank and were monitored until fibrosis developed (8 weeks). External volume expansion was then applied at −25 mmHg to one side for 6 hours for 5 days. The opposite side served as the control. Perfusion changes were assessed with hyperspectral imaging. Mice were euthanized at 5 (n = 12) and 15 days (n = 12) after the last expansion application. Tissue samples were analyzed with immunohistochemistry for CD31 and Ki67, Masson trichrome for skin thickness, and picrosirius red to analyze collagen composition. Results: All animals developed skin fibrosis 8 weeks after radiotherapy and became hypoperfused based on hyperspectral imaging. Expansion induced edema on treated sides after stimulation. Perfusion was decreased by 13 percent on the expansion side (p < 0.001) compared with the control side for 5 days after stimulation. Perfusion returned to control-side levels by day 15. Dermal vasculature increased 38 percent by day 15 (p < 0.01) in expansion versus control. No difference was found in collagen composition. Conclusions: External volume expansion temporarily reduces perfusion, likely because of transient ischemia or edema. Together with mechanotransduction, these effects encourage a proangiogenic and proliferative environment in fibrotic tissue after radiotherapy in the authors’ mouse model. Further studies are needed to assess these changes in fat graft retention.

Hyperspectral Imaging as an Early Biomarker for Radiation Exposure and Microcirculatory Damage.

Background Radiation exposure can lead to detrimental effects in skin microcirculation. The precise relationship between radiation dose received and its effect on cutaneous perfusion still remains controversial. Previously, we have shown that hyperspectral imaging (HSI) is able to demonstrate long-term reductions in cutaneous perfusion secondary to chronic microvascular injury. This study characterizes the changes in skin microcirculation in response to varying doses of ionizing radiation and investigates these microcirculatory changes as a possible early non-invasive biomarker that may correlate with the extent of long-term microvascular damage. Methods Immunocompetent hairless mice (n = 66) were exposed to single fractions of superficial beta-irradiation in doses of 0, 5, 10, 20, 35, or 50 Gy. A HSI device was utilized to measure deoxygenated hemoglobin levels in irradiated and control areas. HSI measurements were performed at baseline before radiation exposure and for the first 3 days post-irradiation. Maximum macroscopic skin reactions were graded, and histological assessment of cutaneous microvascular densities at 4 weeks post-irradiation was performed in harvested tissue by CD31 immunohistochemistry. Results CD31 immunohistochemistry demonstrated a significant correlation (r = 0.90, p < 0.0001) between dose and vessel density reduction at 4 weeks. Using HSI analysis, early changes in deoxygenated hemoglobin levels were observed during the first 3 days post-irradiation in all groups. These deoxygenated hemoglobin changes varied proportionally with dose (r = 0.98, p < 0.0001) and skin reactions (r = 0.98, p < 0.0001). There was a highly significant correlation (r = 0.91, p < 0.0001) between these early changes in deoxygenated hemoglobin and late vascular injury severity assessed at the end of 4 weeks. Conclusion Radiation dose is directly correlated with cutaneous microvascular injury severity at 4 weeks in our model. Early post-exposure measurement of cutaneous deoxygenated hemoglobin levels may be a useful biomarker for radiation dose reconstruction and predictor for chronic microvascular injury.

SU‐FF‐T‐164: Radiochromic EBT Film Characterization and Applicability for IMRT QA Verification

Purpose: Characterization of ISPs new EBT radiochromic film for clinical dosimetry, with emphasis on the usefulness for routine QA of IMRT treatments. Method and Materials: EBT is a new formulation of radiochromic film by ISP. Sheets were exposed to 6 MV and 18 MV photons from a Varian 2300C/D accelerator over clinically useful dose ranges. Density was measured by scanning the film in a Vidar VXR‐16 Dosimetry Pro scanner and the data analyzed using RIT113 v4 software. The reproducibility, stability, and temperature sensitivity were investigated. Dose distributions for IMRT treatments delivered with a Millinieum 120 leaf MLC were measured with the EBT film and compared to those of Kodak EDR2 film and to the predictions of the Eclipse treatment planning system. Results: EBT films from the same batch have a consistent response to doses ranging from 50 to 500 cGy for 6 MV and 18 MV photons. The density readings are stable from 1 to 75 hours post exposure when stored in the dark at room temperature. Beyond 75 hours, the density slowly increases. The film is insensitive to cold, but shows significant degradation when exposed to 60 C for as little as two hours. For IMRT dose distributions where the dose is below 200 cGy, the EBT film has similar responses as Kodaks EDR2 film and very close agreement to the Eclipse predictions. In regions of IMRT doses greater than 200 cGy, the EBT film loses sensitivity as compared to EDR2 film and to the Eclipse calculations. Conclusion: ISPs EBT radiochromic film is reproducible and stable under normal clinical conditions. For IMRT dose verification, the EBT film is in close agreement with calculations and EDR2 film for doses less than 200 cGy. Further research is needed to understand the reduced response of EBT to IMRT doses above 200 cGy.

Reply: External Volume Expansion in Irradiated Tissue

Reply: External Volume Expansion in irradiated Tissue: Effects on the Recipient Site Sir: We thank Dr. Klinger et al. for their enthusiastic and supportive comments regarding our recently published study, “External Volume Expansion in Irradiated Tissue: Effects on the Recipient Site.”1 We are pleased and encouraged to hear that their department has found autologous fat grafting to be clinically efficacious for breasts that have undergone postmastectomy and postlumpectomy radiation therapy. It is interesting to note in their cited studies that they hypothesize that tissue expansion from the fat grafting process itself may have contributed to modulation of pain.2,3 In our previous work, the lead author (M.S.C.) demonstrated that mechanical skin stretch induces regulation of neuropeptides, including substance P and calcitonin gene-related peptide.4 In addition, the introduction of adipocyte stem cells and growth factors, and the stimulation of mechanosensitive nociceptors, may also be playing a role in the reduction of pain found in patients treated with fat grafting. In agreement with our external volume expansion findings that cite hypoxia and mechanotransduction as potential stimuli for angiogenesis, Dr. Klinger et al.’s Breast Unit protocol (which includes preexpansion with tissue expanders) likely relies on a similar angiogenic phenomena.5 However, we propose that external preexpansion in the clinical setting may confer the additional benefits of being less invasive, minimizing the need for an additional surgical procedure and any associated complications. second-stage breast reconstruction with the expander totally inflated and during second-stage breast reconstruction, confirming how expanded tissues can be positively injected with fat with good survival although previously treated with radiation therapy. In conclusion, we consider that data described by Chin et al. can sustain on the murine model our positive clinical findings on the effectiveness of our Breast Unit protocol that we believe could efficiently reduce the complication rate of irradiated breasts after first-stage breast reconstruction. DOI: 10.1097/PRS.0000000000002871

Association between cumulative radiation dose, adverse skin reactions, and changes in surface hemoglobin among women undergoing breast conserving therapy

Introduction Radiation therapy is crucial to effective cancer treatment. Modern treatment strategies have reduced possible skin injury, but few clinical studies have addressed the dose relationship between radiation exposure and skin reaction. This prospective clinical study analyzes skin oxygenation/perfusion in patients undergoing fractionated breast conserving therapy via hyperspectral imaging (HSI). Methods Forty-three women undergoing breast conserving therapy were enrolled in this study. Optically stimulated luminescent dosimeters (OSLDs) measured radiation exposure in four sites: treatment breast, lumpectomy scar, medial tattoo and the control breast. The oxygenation/perfusion states of these sites were prospectively imaged before and after each treatment fraction with HSI. Visual skin reactions were classified according to the RTOG system. Results 2753 observations were obtained and indicated a dose-response relationship between radiation exposure and oxygenated hemoglobin (OxyHb) after a 600 cGy cumulative dose threshold. There was a relatively weak association between DeoxyHb and radiation exposure. Results suggest strong correlations between changes in mean OxyHb and skin reaction as well as between radiation exposure and changes in skin reaction. Conclusion HSI demonstrates promise in the assessment of skin dose as well as an objective measure of skin reaction. The ability to easily identify adverse skin reactions and to modify the treatment plan may circumvent the need for detrimental treatment breaks.

SU‐FF‐T‐444: Variability of EDR2 Dose Calibration Films Taken for IMRT Dose Verification

Purpose: To report the consistency of EDR2 calibration films taken for IMRT absolute dose verification. Method and Materials: 180 sets of dose‐optical (OD) calibration films for IMRT dose validation were taken on 4 Linacs on two campuses using Kodak EDR2 film from Nov. 2005 to Dec. 2006. Each calibration datum contained at least 5 dose points (i.e. 0 cGy, 60 cGy, 120 cGy, 180 cGy and 240 cGy). All calibration films were processed on the same Kodak film processor, were scanned with the same Vidar 1600Pro film scanner, and analyzed using RIT dosimetrysoftware. A second order polynomial function was applied to create the H‐D curve using averaged dose‐OD data from each Linac separately. The range of dose variation (maximum, minimum and standard deviation) was determined. Results: Overall, one standard deviation of the OD corresponded to ±5.3 cGy at 60 cGy, ±8.1 cGy at 120 cGy, ±11.1 cGy at 180 cGy, and ±11.7 cGy at 240 cGy. The maximum and minimum recorded OD numbers of 180 cGy dose point corresponded to 221.4 cGy and 152.5 cGy respectively. Variability was greater for the films taken at one campus and transported (usually overnight) to the main campus for processing and analysis. Had a single dose point film (e.g. 180 cGy) been taken, dose errors (2 SD) of ±24.4 cGy at 240 cGy and ±16.5 cGy at 120 cGy would have occurred. There was no correlation of consistency with processor service. Conclusions: The OD calibration curves with EDR2 film varied significantly, not only in absolute OD value but also in curvature. In order to achieve +/−3% accuracy for IMRT dose verification films, EDR2 calibration films must be taken for each set of IMRT films.