Mutational Status and Clinical Outcomes Following Systemic Therapy with or without Focal Radiation for Resected Melanoma Brain Metastases.

BACKGROUND: Brain metastases occur frequently in advanced melanoma and traditionally require surgery and radiation therapy. New evidence demonstrates that systemic therapies are effective for controlling metastatic melanoma brain metastases. This study evaluated outcomes after resection of melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy. METHODS: All patients received immunotherapy or BRAF/MEK inhibitors preoperatively or in the immediate 3 months postoperatively. Resection cavity failure, distant central nervous system progression, and adverse radiation effects were reported in the presence and absence of focal radiotherapy using the Kaplan-Meier method. RESULTS: Between 2011 and 2020, 37 resection cavities in 29 patients met criteria for analysis. Of lesions, 22 (59%) were treated with focal radiotherapy, and 15 (41%) were treated with targeted therapy or immunotherapy alone. The 12- and 24-month freedom from local recurrence was 64.8% (95% confidence interval [CI] 42.1%-99.8%) and 46.3% (95% CI 24.5%-87.5%), respectively, for systemic therapy alone and 93.3% (95% CI 81.5%-100%) at both time points for focal radiotherapy (P = 0.01). On univariate analysis, focal radiotherapy was the only significant factor associated with reduction of local recurrence risk (hazard ratio 0.10, 95% CI 0.01-0.85; P = 0.04). There were no significant differences in central nervous system progression-free survival or overall survival between patients who received systemic therapy plus focal radiotherapy compared with systemic therapy alone. BRAF mutation status was reviewed for either the brain metastasis (n = 9 patients, 31%) or the primary site (n = 20 patients, 69%), and patients harboring BRAFV600E mutations had worse progression-free survival (P = 0.043). CONCLUSIONS: Focal radiotherapy with systemic therapy for resected melanoma brain metastases significantly decreased resection cavity recurrence compared with systemic therapy alone. BRAF mutation status correlated with poorer outcomes.

Investigating focal spot position drift in a mobile imaging system equipped with a monobloc-based x-ray generator.

BACKGROUND: Misalignment or double-contouring artifacts can appear in high-resolution 3D cone beam computed tomography (CBCT) images, potentially indicating geometric accuracy issues in the projection data. Such artifacts may go unnoticed in low-resolution images and could be associated with changes in the focal spot (FS) position. PURPOSE: High-resolution 3D-CBCT imaging by a mobile imaging device with a large gantry clearance offers more versatility for clinical workflows in image-guided brachytherapy (IGBT), intraoperative radiation therapy (IORT), and spinal, as well as maxillofacial surgery. However, misalignment or double-contouring artifacts hinder workflow advancements in these domains. This paper introduces intrinsic calibration and geometrical correction methods as extensions to a well-established technique for addressing geometrical deviations resulting from factors such as gravity or mechanical inconsistencies. These extensions cover shifts and drifts of the FS depending on FS size selection, temperature, tube current, and tube potential. The proposed methods effectively mitigate artifacts in high-resolution CBCT images stemming from geometrical inaccuracies in projection data, without requiring additional equipment like a pinhole device. METHODS: Geometrical offsets and drifts of the x-ray tube FS were characterized on a mobile multi-purpose imaging system, the ImagingRing-m. A pinhole-like experiment was simulated by adjusting the movable collimation unit to a small rectangular aperture within the FS size range. The influence of filament selection, that is, FS size, temperature, the relatively low tube currents, as well as tube potential settings have been studied on two different monobloc types sharing the same x-ray tube insert. The Catphan 504 and an Alderson head phantom were used to assess resulting image artifacts. RESULTS: Switching the FS size to one different from what was used for geometrical (gravitation, mechanical variations) calibration induced the most notable position changes of the x-ray FS, resulting in double-contouring artifacts and blurring of high-resolution 3D-CBCT images. Incorporating these shifts into a geometrical correction method effectively minimized these artifacts. Thermal drifts exhibited the second largest geometrical changes, comparable to FS size shifts across the thermal operating conditions of the x-ray system. The proposed thermal drift compensation markedly reduced thermal drift effects. Tube current and potential had little impact within the range of available tube currents, eliminating the need for compensation in current applications. CONCLUSIONS: Augmenting the geometrical calibration pipeline with proposed FS drift compensations yielded significant enhancements in image quality for high-resolution reconstructions. While compensation for thermal effects posed challenges, it proved achievable. The roles of tube current and potential were found to be negligible.

Whole brain radiation therapy plus focal boost may be a suitable strategy for brain metastases in SCLC patients: a multi-center study.

BACKGROUND: The treatment for brain metastases in small cell lung cancer (SCLC) is still controversial. The purpose of this study was to compare different brain radiotherapy treatments on SCLC patients with brain metastases. METHODS: In this multi-center retrospective study, SCLC patients who had undergone whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases from January 2012 to December 2018 were retrospectively screened. RESULTS: A total of 263 eligible SCLC patients were included in this study, among whom, 73 were women and 190 were men. According to accepted brain radiotherapy, the remaining patients were divided into WBRT plus focal radiation boost (WBRT+boost), WBRT, and SRS groups. In pairwise comparisons of the overall survival (OS), WBRT+boost group led to longer survival than did WBRT both in all patients (17.9 vs 8.7 months; P < 0.001) and 140 matched patients (17.9 vs 11.7 months; P = 0.045). There were no significant differences in OS between WBRT+boost and SRS groups in all patients (17.9 vs 14.5 months; P = 0.432). Among 74 matched patients between WBRT+boost and SRS groups, however, patients who received WBRT+boost led to a longer survival than did SRS alone (21.8 vs 12.9 months; P = 0.040). In pairwise comparison of the intracranial progression-free survival time (iPFS), WBRT+boost group also showed survival advantages over WBRT (10.8 vs 6.5 months; P = 0.005) and SRS groups (10.8 vs 7.5 months; P = 0.032). CONCLUSION: Due to the SCLC-derived multiple brain metastases and better survival time, focal radiation boost combined with adjuvant WBRT may be a preferred strategy for SCLC patients with brain metastases.

Periosteal Mesenchymal Progenitor Dysfunction and Extraskeletally-Derived Fibrosis Contribute to Atrophic Fracture Nonunion.

Atrophic nonunion represents an extremely challenging clinical dilemma for both physicians and fracture patients alike, but its underlying mechanisms are still largely unknown. Here, we established a mouse model that recapitulates clinical atrophic nonunion through the administration of focal radiation to the long bone midshaft 2 weeks before a closed, semistabilized, transverse fracture. Strikingly, fractures in previously irradiated bone showed no bony bridging with a 100% nonunion rate. Radiation triggered distinct repair responses, separated by the fracture line: a less robust callus formation at the proximal side (close to the knee) and bony atrophy at the distal side (close to the ankle) characterized by sustained fibrotic cells and type I collagen-rich matrix. These fibrotic cells, similar to human nonunion samples, lacked osteogenic and chondrogenic differentiation and exhibited impaired blood vessel infiltration. Mechanistically, focal radiation reduced the numbers of periosteal mesenchymal progenitors and blood vessels and blunted injury-induced proliferation of mesenchymal progenitors shortly after fracture, with greater damage particularly at the distal side. In culture, radiation drastically suppressed proliferation of periosteal mesenchymal progenitors. Radiation did not affect hypoxia-induced periosteal cell chondrogenesis but greatly reduced osteogenic differentiation. Lineage tracing using multiple reporter mouse models revealed that mesenchymal progenitors within the bone marrow or along the periosteal bone surface did not contribute to nonunion fibrosis. Therefore, we conclude that atrophic nonunion fractures are caused by severe damage to the periosteal mesenchymal progenitors and are accompanied by an extraskeletal, fibro-cellular response. In addition, we present this radiation-induced periosteal damage model as a new, clinically relevant tool to study the biologic basis of therapies for atrophic nonunion. © 2018 American Society for Bone and Mineral Research.

Focal radiation therapy for limited brain metastases is associated with high rates of local control and low subsequent whole brain radiation therapy.

BACKGROUND: Assess clinical outcomes of focal radiotherapy (RT) in patients with limited brain metastasis (LBM) with whole brain RT (WBRT) avoidance. METHODS: Patients diagnosed with LBM were entered into a database between January 2010 and February 2017. Patients were recommended WBRT avoidance with focal therapy and three-monthly magnetic resonance imaging. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, initial-site failure (ISF), distant brain relapse (DBF), leptomeningeal disease and rate of WBRT. Analysis involved Kaplan-Meier survival estimate with log-rank tests and Cox-regression analysis. RESULTS: One hundred and sixty-six patients were managed with median follow-up of 13 months and median overall survival of 15 months (95% confidence interval (CI) 10.8-19.2). Eighty-three patients had central nervous system (CNS) relapse with median progression-free survival of 11 months (95% CI 6.7-15.3), of which most failures were DBF (83.1%) with 27 ISF (32.5%). Of the ISFs, 12 (43%) had surgery alone, six had chemotherapy alone and nine received RT. Surgery or chemotherapy alone compared with RT had a significantly higher incidence of ISF with a hazard ratio of 4.96 (P < 0.0001, 95% CI 2.10-11.83) and 6.54 (P = 0.001, 95% CI 2.26-18.87), respectively. WBRT was utilized in only 24 patients, with 83% patients free of WBRT at 12 months. On univariate analysis, number of metastases (P = 0.04), symptomatic extracranial disease (P = 0.04) and early CNS relapse within 6 months (P < 0.01) had worse survival. No grade 3-4 toxicity events were noted in 129 patients undergoing RT. CONCLUSION: Focal RT has a low rate of ISF with low toxicity in patients with LBMs. CNS progression was mainly DBF with low rates of salvage WBRT.

Monte Carlo analysis of beam blocking grid design parameters: Scatter estimation and the importance of electron backscatter.

PURPOSE: Beam blocking grids provide a simple and direct measurement of the scattered photon signal which degrades image quality in x-ray imaging systems, such as cone-beam CT (CBCT). This study evaluates the scatter estimation accuracy of the beam blocking method to optimize the design parameters of the grid system (e.g., grid thickness, source-to-grid distance (SGD), septa width, air interspace, and grid ratio) using Monte Carlo (MC) simulations. METHOD: A MC model of a CBCT imaging system with a beam blocking grid in place is made using code based on EGSnrc, with the x-ray tube portion of the simulation including electron backscatter between the anode and cathode. The inclusion of the electron backscatter allowed a more complete model of the contamination signal to be estimated. The contamination signal consists of the off-focal radiation (OFR) and source component scatter (photon scatter in source components such as tube housing, filters, and collimators). The MC model was validated against measurements collected on a bench top imaging system with a grid in place. The MC model was used to simulate 11 different grid design configurations in addition to a case with no grid. For each design a simulated projection with and without a phantom in place was computed. The simulated projections were then used to estimate the scatter and contamination portion of the signal using the signal behind the grid septa. The estimated signals from the grid data were compared to the actual signals labeled during the MC simulation. RESULTS: Simulated results showed good agreeance with measured results with the importance of including electron backscatter resulting in off-focal radiation in the simulation being highlighted. When the source was free of contamination photons all grids performed with an error less than 8% when estimating just the scatter from the object. When the contamination photons were included in the simulation, the error in estimating both the scatter and contamination signal rose by a factor of 4 on average. In the case when both signals are present, increasing the grid thickness, changing the SGD, and reducing septa width and air interspace sizes all showed the ability to improve the grid-based estimates of the object scatter and contamination portion signal. CONCLUSIONS: The inclusion of the contamination signal in MC simulations of x-ray imaging systems is important in the design, validation, and evaluation of measurement-based scatter methods. Beam blocking grids show potential not only in object scatter estimation but in the estimation of the contamination signal, but appropriate interpolation functions must be used to account for higher frequencies found in contamination signal.