Background  Despites advances in radiation technology, skull base osteoradionecrosis (ORN) continues to be a rare, devastating, and hard to treat complication of radiotherapy. We present three cases of anterior skull base ORN in a cohort treated with intensity-modulated radiation therapy (IMRT). Case Series  Three patients developed anterior skull base ORN after receiving at least one round of IMRT. ORN was diagnosed through either nasal endoscopy or imaging findings. The first was a 59-year-old woman with a sinonasal squamous cell carcinoma. Her chemoradiation history was notable for reirradiation and a high dose of radiation (143.3 Gy). The second was a 55-year-old man with recurrent nasopharyngeal carcinoma, whose history was notable for a high dose of radiation (∼140 Gy) and for being reirradiated. The final patient was a 37-year-old woman with an unremarkable history who received radiotherapy (65.0 Gy) for an esthesioneuroblastoma. One patient was asymptomatic and did not receive ORN-specific therapy. The other two were treated with a combination of medical and surgical intervention with successful short-term outcomes (no evidence of infection). Conclusion  Anterior skull base ORN can be treated through conservative and surgical means to achieve successful short-term outcomes. Further investigation of long-term outcomes is warranted.

Purpose

Missing or discrepant imaging volume is a common challenge in deformable image registration (DIR). To minimize the adverse impact, we train a neural network to synthesize cropped portions of head and neck CT's and then test its use in DIR.

Methods

Using a training dataset of 409 head and neck CT's, we trained a generative adversarial network to take in a cropped 3D image and output an image with synthesized anatomy in the cropped region. The network used a 3D U-Net generator along with Visual Geometry Group (VGG) deep feature losses. To test our technique, for each of the 53 test volumes, we used Elastix to deformably register combinations of a randomly cropped, full, and synthetically full volume to a single cropped, full, and synthetically full target volume. We additionally tested our method's robustness to crop extent by progressively increasing the amount of cropping, synthesizing the missing anatomy using our network, and then performing the same registration combinations. Registration performance was measured using 95% Hausdorff distance across 16 contours.

Results

We successfully trained a network to synthesize missing anatomy in superiorly and inferiorly cropped images. The network can estimate large regions in an incomplete image, far from the cropping boundary. Registration using our estimated full images was not significantly different from registration using the original full images. The average contour matching error for full image registration was 9.9 mm, whereas our method was 11.6, 12.1, and 13.6 mm for synthesized-to-full, full-to-synthesized, and synthesized-to-synthesized registrations, respectively. In comparison, registration using the cropped images had errors of 31.7 mm and higher. Plotting the registered image contour error as a function of initial preregistered error shows that our method is robust to registration difficulty. Synthesized-to-full registration was statistically independent of cropping extent up to 18.7 cm superiorly cropped. Synthesized-to-synthesized registration was nearly independent, with a -0.04 mm of change in average contour error for every additional millimeter of cropping.

Conclusions

Different or inadequate in scan extent is a major cause of DIR inaccuracies. We address this challenge by training a neural network to complete cropped 3D images. We show that with image completion, the source of DIR inaccuracy is eliminated, and the method is robust to varying crop extent.

Stereotactic body radiation therapy (SBRT) is a promising new method for non-invasive management of life-threatening ventricular arrhythmias. Numerous case reports and case series have provided encouraging short-term results suggesting good efficacy and safety, but randomized data and long-term outcomes are not yet available. The primary hypothesis as to the mechanism of action for SBRT relates to the development of cardiac fibrosis in arrhythmogenic myocardial substrate; however, limited animal model data offer conflicting insights into this theory. The use of SBRT for patients with refractory ventricular arrhythmias is rapidly increasing, but ongoing translational science work and randomized clinical trials will be critical to address many outstanding questions regarding this novel therapy.

Purpose/objective(s)

To communicate our institutional experience with single isocenter radiosurgery treatments for multiple brain metastases, including challenges with determining planning target volume (PTV) margins and resulting consequences, image-guidance translational and rotational tolerances, intra-fraction patient motion, and prescription considerations with larger PTV margins.

Materials/methods

Eight patient treatments with 51 targets were planned with various margins using Elements Multiple Brain Mets SRS treatment planning software (Brainlab, Munich, Germany). Forty-eight plans with 0 mm, 1 mm and 2 mm margins were created, including plans with variable margins, where targets more than 6 cm away from the isocenter were planned with larger margins. The dosimetric impact of the margins were analyzed with V5Gy, V8Gy, V10Gy, V12Gy values. Additionally, 12 patient motion data were analyzed to determine both the impact of the repositioning threshold and the distributions of the patient translational and rotational movements.

Results

The V5Gy, V8Gy, V10Gy, V12Gy volumes approximately doubled when margins change from 0 to 1 mm and tripled when change from 0 to 2 mm. With variable margins, the aggregated results are similar to results from plans using the lower of two margins, since only 12.2% of the targets were more than 6 cm away from the isocenter. With 0.5 mm re-positioning threshold, 57.4% of the time the patients are repositioned. Reducing the threshold to 0.25 mm results in 91.7% repositioning rate, due to limitations of the fusion algorithm and actual patient motion. The 90th percentile of translational movements in all directions is 0.7 mm, while the 90th percentile of rotational movements in all directions is 0.6 degrees. Median translations and rotations are 0.2 mm and 0.2 degrees, respectively.

Conclusions

Based on the data presented, we have switched our modus operandi from 2 to 1 mm PTV margins, with an eventual goal of using 0.5 and 1.0 mm variable margins when an automated margin assignment method becomes available. The 0.5 mm and 0.5 degrees repositioning thresholds are clinically appropriate with small residual patient movements.

Purpose

The practice of deliberately sparing the ipsilateral parotid gland with intensity modulated radiation therapy (IMRT) in patients with node-positive head and neck cancer is controversial. We sought to compare the clinical outcomes among consecutive cohorts of patients with head and neck cancer who were treated with differing strategies to spare the parotid gland that is ipsilateral to the involved neck using IMRT.

Methods and materials

A total of 305 patients were treated with IMRT for node-positive squamous cell carcinoma of the head and neck. The first 139 patients were treated with IMRT whereby the ipsilateral parotid gland was delineated and intentionally designated as an avoidance structure during planning. The subsequent 166 patients were treated by IMRT without the deliberate sparing of the ipsilateral parotid gland.

Results

The 2-year estimates of overall survival, local-regional control, and distant metastasis-free survival were 84%, 73%, and 87%, respectively. The 2-year estimates of overall survival were 77% and 86% among patients who were treated by IMRT with and without the sparing of the ipsilateral parotid gland, respectively (P = .01). The respective rates of 2-year regional control were 76% and 90% (P < .001). A trend was observed between increased nodal burden in the ipsilateral cervical neck and the likelihood of regional failure for both groups. A spatial evaluation revealed a significantly higher incidence of marginal failures and true misses in the cohort of patients who underwent IMRT with the sparing of the ipsilateral parotid gland.

Conclusion

Caution is urged when using IMRT to spare patients' parotid gland on the involved side of neck disease. Our study showed a significantly higher preponderance of regional failure, which highlights the need for careful patient selection and consideration of clinical and pathological factors that influence the likelihood of disease recurrence in the ipsilateral neck.

Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2. We generated mice that were either deficient or hypomorphic for SREBP-2. SREBP-2 deficiency generally caused death during embryonic development. Analyses of Srebf2(-/-) embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2(-/-) mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specific manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue.

Purpose

A previously developed ordinary differential equation (ODE) that models the dynamic interaction and distinct radiosensitivity between cancer stem cells (CSC) and differentiated cancer cells (DCC) was used to explain the definitive treatment failure in Glioblastoma Multiforme (GBM) for conventionally and hypo-fractionated treatments. In this study, optimization of temporal dose modulation based on the ODE equation is performed to explore the feasibility of improving GBM treatment outcome.

Methods

A non-convex optimization problem with the objective of minimizing the total cancer cell number while maintaining the normal tissue biological effective dose (BEDnormal) at 100 Gy, equivalent to the conventional 2 Gy × 30 dosing scheme was formulated. With specified total number of dose fractions and treatment duration, the optimization was performed using a paired simulated annealing algorithm with fractional doses delivered to the CSC and DCC compartments and time intervals between fractions as variables. The recurrence time, defined as the time point at which the total tumor cell number regrows to 2.8×109 cells, was used to evaluate optimization outcome. Optimization was performed for conventional treatment time frames equivalent to currently and historically utilized fractionation schemes, in which limited improvement in recurrence time delay was observed. The efficacy of a super hyperfractionated approach with a prolonged treatment duration of one year was therefore tested, with both fixed regular and optimized variable time intervals between dose fractions corresponding to total number of fractions equivalent to weekly, bi-weekly, and monthly deliveries (n = 53, 27, 13). Optimization corresponding to BEDnormal of 150 Gy was also obtained to evaluate the possibility in further recurrence delay with dose escalation.

Results

For the super hyperfractionated schedules with dose fraction number equivalent to weekly, bi-weekly, and monthly deliveries, the recurrence time points were found to be 430.5, 423.9, and 413.3 days, respectively, significantly delayed compared with the recurrence time of 250.3 days from conventional fractionation. Results show that optimal outcome was achieved by first delivering infrequent fractions followed by dense once per day fractions in the middle and end of the treatment course, with sparse and low dose treatments in the between. The dose to the CSC compartment was held relatively constant throughout while larger dose fractions to the DCC compartment were observed in the beginning and final fractions that preceded large time intervals. Dose escalation to BEDnormal of 150 Gy was shown capable of further delaying recurrence time to 452 days.

Conclusion

The development and utilization of a temporal dose fractionation optimization framework in the context of CSC dynamics have demonstrated that substantial delay in GBM local tumor recurrence could be achieved with a super hyperfractionated treatment approach. Preclinical and clinical studies are needed to validate the efficacy of this novel treatment delivery method.

Central neurocytoma (CN) typically presents as an intraventricular mass causing obstructive hydrocephalus. The first line of treatment is surgical resection with adjuvant conventional radiotherapy. Stereotactic radiosurgery (SRS) was proposed as an alternative therapy for CN because of its lower risk profile. The objective of this systematic analysis is to assess the efficacy of SRS for CN. A systematic analysis for CN treated with SRS was conducted in PubMed. Baseline patient characteristics and outcomes data were extracted. Heterogeneity and publication bias were also assessed. Univariate and multivariate linear regressions were used to test for correlations to the primary outcome: local control (LC). The estimated cumulative rate of LC was 92.2% (95% confidence interval: 86.5-95.7%, p<0.001). Mean follow-up time was 62.4 months (range 3-149 months). Heterogeneity and publication bias were insignificant. The univariate linear regression models for both mean tumor volume and mean dose were significantly correlated with improved LC (p<0.001). Our data suggests that SRS may be an effective and safe therapy for CN. However, the rarity of CN still limits the efficacy of a quantitative analysis. Future multi-institutional, randomized trials of CN patients should be considered to further elucidate this therapy.

Purpose: To analyze geometric discrepancy and dosimetric impact in using contours generated by auto-segmentation (AS) against manually segmented (MS) clinical contours. Methods: A 48-subject prostate atlas was created and another 15 patients were used for testing. Contours were generated using a commercial atlas-based segmentation tool and compared to their clinical MS counterparts. The geometric correlation was evaluated using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). Dosimetric relevance was evaluated for a subset of patients by assessing the DVH differences derived by optimizing plan dose using the AS and MS contours, respectively, and evaluating with respect to each. A paired t-test was employed for statistical comparison. The discrepancy in plan quality with respect to clinical dosimetric endpoints was evaluated. The analysis was repeated for head/neck (HN) with a 31-subject atlas and 15 test cases. Results: Dice agreement between AS and MS differed significantly across structures: from (L:0.92/R: 0.91) for the femoral heads to seminal vesical of 0.38 in the prostate cohort, and from 0.98 for the brain, to 0.36 for the chiasm of the HN group. Despite the geometric disagreement, the paired t-tests showed the lack of statistical evidence for systematic differences in dosimetric plan quality yielded by the AS and MS approach for the prostate cohort. In HN cases, statistically significant differences in dosimetric endpoints were observed in structures with small volumes or elongated shapes such as cord (p = 0.01) and esophagus (p = 0.04). The largest absolute dose difference of 11 Gy was seen in the mean pharynx dose. Conclusion: Varying AS performance among structures suggests a differential approach of using AS on a subset of structures and focus MS on the rest. The discrepancy between geometric and dosimetric-end-point driven evaluation also indicates the clinical utility of AS contours in optimization and evaluating plan quality despite of suboptimal geometrical accuracy.

This study evaluates the potential for tumor dose escalation in recurrent head and neck cancer (rHNC) patients with automated non-coplanar volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) planning (HyperArc). Twenty rHNC patients are planned with conventional VMAT SBRT to 40 Gy while minimizing organ-at-risk (OAR) doses. They are then re-planned with the HyperArc technique to match these minimal OAR doses while escalating the target dose as high as possible. Then, we compare the dosimetry, tumor control probability (TCP), and normal tissue complication probability (NTCP) for the two plan types. Our results show that the HyperArc technique significantly increases the mean planning target volume (PTV) and gross tumor volume (GTV) doses by 10.8 ± 4.4 Gy (25%) and 11.5 ± 5.1 Gy (26%) on average, respectively. There are no clinically significant differences in OAR doses, with maximum dose differences of <2 Gy on average. The average TCP is 23% (± 21%) higher for HyperArc than conventional plans, with no significant differences in NTCP for the brainstem, cord, mandible, or larynx. HyperArc can achieve significant tumor dose escalation while maintaining minimal OAR doses in the head and neck-potentially enabling improved local control for rHNC SBRT patients without increased risk of treatment-related toxicities.