Citations

Abstract With mean survival from glioblastoma multiforme (GBM) barely edging over 15 months, it become imperative to develop novel tools informing on both progression and treatment efficacy. As the aggressive growth of GBM outstrips available resources, regions of hypoxia develop. Hypoxia can be clinically assessed through [18F]-flouromisonidazole (FMISO) PET. However, PET imaging suffers from low resolution and reconstruction artifact. We present the comparative and predictive results of a multi-stage model utilizing the mathematical biology of cancer and the physics of PET imaging. Our mathematical model of GBM characterizes cancer cells into the interacting phenotypes of normoxic, hypoxic, and necrotic cells supported by vasculature. The pharmacokinetic activity of FMISO is induced in the simulated tissue then acquired and reconstructed by an analytic simulator of the PET process. This multi-stage process creates a patient-specific virtual PET images with characteristic of the clinical PET scan. Extending previous work, we model the full three-dimensional dynamics of tumor progression, pharmacokinetic activity, and FMISO PET for the tumor kinetics of six GBM patients. Virtual and clinical FMISO PET images are compared. Overall hypoxic burden and spatial distribution show strong correspondence between virtual and clinical FMISO PET images for all six patients. Simulated FMISO PET dynamics, with tumor kinetics derived from routine clinical MRI scans, provide a unique and evolving tool giving insight into the biological connections between magnetic resonance and molecular imaging. Citation Format: Joshua Jacobs, Andrea Hawkins-Darrud, Robert Harrison, Sandra Johnston, Paul Kinahan, Kristin Swanson. Correlating magnetic resonance and molecular imaging using three dimensional untreated virtual control. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A10.

Abstract Purpose: Investigate the utility of patient-specific spatial predictions of tumor cell density from a bio-mathematical model. Introduction: Glioblastomas (GBMs) are the most malignant of all primary brain tumors. While it is known there is always a non-detectable portion of the tumor, current techniques of monitoring GBM progression, imaging and initial histological assessment, are not able to reliably estimate the tumor invasion past the enhancing region on T2-Weighted (T2W) imaging. Over the last two decades, a large effort has been made to create a simple patient-specific mathematical model of gliomas. The resulting model, referred to as the Proliferation-Invasion (PI) model, is based on two key parameters, the net growth rate, ρ, and the dispersal coefficient, D. In this model, the ratio of D/ρ is related to degree of invasion and the product D*ρ, is related to the speed of growth. The intuitive understanding provided by this model has been able to provide patient-specific understanding of disease kinetics enabling prediction of outcomes following surgical resection, radiation and the development of a prognostic response metric. Previous literature utilizing this model has been based on the assumption that what is seen on the pretreatment T1-Weighted contrast-enhanced (T1Gd) and T2W, images correspond to an 80% and 16% tumor cell density threshold respectively. This assumption allows for an estimate of D/ρ from a single time point of imaging. While these values were based on extensive experience, for ethical and technical reasons, they have never been rigorously investigated histologically. Recent technological advances have made it possible for surgeons to use an MRI to guide the acquisition of tissue making it possible to know with a good degree of accuracy where on the MR image the histological specimen comes from. Methods: Model Calibration : To estimate D/ρ for each patient, we assume abnormalities on the T1Gd and T2W images correspond to an 80% and 16% tumor cell density threshold respectively. We then utilize a Bayesian calibration approach based on adaptive grid refinement while holding the velocity constant to find the most likely value of D/ρ to match the observed radial measurements. Three-Dimensional Density Maps : Given a gray/white segmentation and an estimate for D/ρ, we can build a tumor cell density prediction in the patient's anatomy using the Eikonal equations and the modified Fast Marching Method (FMM) algorithm presented by Konukoglu et al. Patient Cohort : Eighteen patients were recruited with clinically suspected GBM undergoing preoperative stereotactic MRI for surgical resection with IRB approval Barrow Neurological Institute and Mayo Clinic in Arizona. Surgical Biopsy : Pre-operative conventional MRI, including T1Gd and T2W, was utilized to guide stereotactic biopsies. An average of 5–6 tissue specimens were acquired from each tumor by using stereotactic surgical localization, following the smallest possible diameter craniotomies to minimize brain shift. Histological Analysis : 4 μm tissue sections were stained with hematoxylin and eosin (H&E) for neuropathology review. H&E slides were reviewed by a neuropathologist. The percent tumor nuclei in the field was estimated. Results and Conclusion: Our analysis showed that the intuitive ordering of diffuse to nodular tumor profiles from the PI model is consistent with the histologic data. Further, utilizing the histologic data, limitations to a universal threshold cutoff of the T2/FLAIR region are specified and a better threshold cutoff value is suggested. We hope that this paper will lead to more studies of this kind resulting in more accurate ways to predict the spatial distribution of GBM tumor cells from medical imaging. Such advances could revolutionize surgical procedures and radiation therapy and may enable additional insights into tumor kinetic differences meaningful for treatment. Citation Format: Andrea Hawkins-Daarud, Lauren DeGirolamo, Joshua Jacobs, Kamala Clark-Swanson, Jennifer M. Eschbacher, Kris A. Smith, Peter Nakaji, Leslie C. Baxter, John P. Karis, Teresa Wu, J. Ross Mitchell, Jing Li, Leland Hu, Kristin R. Swanson. Histologic evidence for a bio-mathematical model of glioblastoma invasion. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A08.

125 Background: Treatment for locally advanced esophageal carcinoma is radiation and chemotherapy, with or without surgery. Radiation has traditionally been delivered with 3D conformal radiation therapy (3D CRT). This study evaluates late toxicity in patients treated with IMRT as well as early outcomes and acute toxicity. Methods: This is a retrospective review of 32 patients with esophageal carcinoma treated with IMRT at Mayo Clinic Florida from 2008 -2012. Pathology includes squamous cell and adenocarcinomas. Tumor sites include middle and lower thoracic and GE junction. Clinical stages are TX-T3, N0-3, M0-1. All patients received at least one cycle of concurrent chemotherapy. IMRT dose was 50.4 Gy in 28 fractions prescribed to a target volume including the tumor and regional lymphatics. IMRT plans utilized coplaner beams in a 7-9 beam arrangement or volumetric modulated arc therapy. Results: Median follow-up is 8.9 months (range 2.4-23.0) for all patients and 13.1 months (range 2.8-23.0 months) in surviving patients. Median patient age is 69 (range 46-87). Trimodality treatment was completed in 20 patients (62.5%). Surgery was either an open or minimally invasive esophagogastrectomy. The incidence of grade 3 or greater late toxicity at 1 year was 48% in surgery patients and 26% in non-surgery patients. The most common grade 3 or higher toxicity was esophageal strictures in 25%. The incidence of any grade 3 or greater acute toxicity was 65% in the surgery patients and 75% in the non-surgery patients. Overall survival (OS) for all patients at 18 months is 57% (CI 37-86%) and progression-free survival (PFS) is 60% (36-99%). OS and PFS for trimodality therapy at 12 months is 83% (66-100%) and 81% (63-100%) respectively and for bimodality therapy is 34% (12-93%) and 70% (33-100%) respectively. Conclusions: Increased late toxicity occurs in surgery patients, and increased acute toxicity in non-surgery patients. Lower survival in non-surgery patients may be due to early progression, morbidities which preclude surgery or improved survival with surgery. Overall, IMRT is a feasible treatment modality, which may be equally efficacious to 3D CRT for the treatment of esophageal carcinoma.

211 Background: The current standard of care for locally advanced esophageal cancer includes chemoradiotherapy with or without surgery. Radiation is usually delivered via a 3D technique. IMRT has been utilized in the treatment of multiple tumors and demonstrated similar efficacy while offering the possibility of decreased toxicity. Methods: Thirty-six patients were treated with IMRT and chemotherapy. Twenty-one patients underwent surgical resection. Eleven underwent open surgery and the remainder underwent minimally invasive surgery. Chemotherapy consisted primarily of 5-FU with oxaliplatin or cisplatin. All but two patients received 50.4 Gy; one patient received 41.4 Gy without surgery and one patient discontinued treatment after 25.2 Gy. Eleven patients required a treatment break during radiotherapy. The median age was 69 (range 46-87). Approximately two-thirds of tumors were adenocarcinomas located in the lower thorax. Two thirds of patients were staged as T3 and had positive lymph nodes. The median tumor size was 5 cm (range 2-13). Results: With a median follow-up of 21.3 months (range 2.4-44.8) and 33.9 months for survivors (range 3.7-44.8), overall survival at 24 months was 55%. The 24 month overall survival was 75% vs 24% for surgical and non-surgical patients, respectively. Seven patients had a complete pathologic response. Twenty-four patients experienced grade 3 or higher acute toxicity and there was one grade 5 toxicity. Acute toxicity was similar between surgery and non-surgery patients. Fourteen patients experienced grade 3 or higher late toxicity; 9 surgery and 5 non-surgery patients. The most frequent late toxicity was grade 3 stricture (21%). On multivariate analysis, advanced age (RR [10 year increase] 2.01, p=0.032) and heart maximum dose >55 Gy (RR 3.73, p=0.011) were associated with decreased survival. Conclusions: Patients who undergo surgery after chemoradiotherapy demonstrate improved survival; however, this may be related to underlying comorbidities that preclude surgery. IMRT appears to be a reasonable treatment option that may reduce complications from radiotherapy. Careful attention should be given to heart dose during treatment planning.

284 Background: Frameless stereotactic radiosurgery (SRS) is single fraction radiation therapy delivered to an intracranial lesion. Rather than with a rigid head frame, frameless SRS uses a thermoplastic mask for immobilization. The benefit of this mask includes the ability to simulate and treat the patient at different times, ease of patient set-up and improved patient comfort. Clinically, frameless SRS is used for primary brain tumors and metastatic lesions. The length of the treatments may vary based on a number of factors, including total treatment dose, number of monitor units, number and arrangement of beams, and equipment manipulations. This is a single institution review of patients treated with SRS with positional checks made before, during and at the completion of treatment to evaluate intrafraction motion. Methods: Patients were treated with SRS at Mayo Clinic Florida between 2010 and 2011. All patients were immobilized with a thermoplastic mask and treated on a Varian IX Clinac. KV Cone beam CT was taken prior to the initiation of treatment to verify the treatment position. Cone beam CT’s were also performed at the midpoint and conclusion of treatment. The same physician analyzed all cone beam CT’s. Adjustments were recorded in each dimension and analyzed to determine intrafraction motion. Results: Intrafraction motion was evaluated during six separate SRS cases. The mean displacements at mid-treatment were 0.67±0.52 mm, 0.50±0.55 mm, 0.83±0.75 mm, and 1.35±0.78 mm in the medial/lateral, superior/inferior, anterior/posterior, and vectoral direction, respectively. The mean post-treatment displacements were 0.17±0.41 mm, 0.67±0.82 mm, 0.50±0.84 mm, and 1.11±0.96 mm in the medial/lateral, superior/inferior, anterior/posterior, and vectoral direction, respectively. Estimated overall margins to accommodate intrafraction motion in 90% of patients were 2.63 mm and 2.69 mm at mid-treatment and post-treatment, respectively. Conclusions: The majority of intrafraction motion occurred during the first portion of treatment. Intrafraction motion during the course of frameless SRS treatment is not negligible and approximately a 2.5 mm margin should be taken into account during the planning process.

LBA2000 Background: Formalin-fixed, paraffin embedded GBM tumor tissue, adequate for conventional MGMT methylation analyses, was required for entry onto the RTOG 0525 clinical trial. Methods: Four prognostic biomarkers were evaluated on a training set of 220 retrospectively obtained GBM samples, consisting of IDH1 mutation, the glioma-CpG island methylator phenotype (G-CIMP), a microarray-based mRNA panel and a novel MGMT promoter methylation assay. For each biomarker, 2 (IDH1 and mRNA) or 3 subgroups (G-CIMP and MGMT) were defined based on associations with overall survival. All combinations (36 possible) of each of the 4 biomarker-derived subgroups were then defined and compared with survival data and then consolidated into 4 risk groups. Once created in the training set, this model was applied to the RTOG 0525 samples (n=763) for external validation. Results: Application of the molecular risk classification to RTOG 0525 samples (left table) showed a highly significant survival association (p<0.001). When compared to the recursive partitioning analysis (RPA, table on right), this composite molecular classifier better identified patients with long term survival and appears to improve resolution by revealing an additional distinct risk group. The molecular classifier was prognostic in each of the treatment arms individually. Conclusions: Four distinct biomarkers or biomarker panels were tested in GBM. These biomarkers were compared with clinical outcome in a training set to optimize a method to combine them into a classifier. This classifier was then validated on a large sample set from a large phase III clinical trial. This composite panel may represent an improvement over the existing RPA with respect to risk stratification of patients for GBM. Additionally, it has the potential to impact future clinical trial designs and provide enhanced opportunities for personalization of therapy for GBM. Support: NCI U10 CA2121661, U10 CA37422, P50 CA127001. [Table: see text]

Background: Total knee arthroplasty (TKA) with a rotating-hinge prosthesis is considered a salvage procedure. While excellent immediate stability is achieved, the historically high failure rate has tempered its use. The goal of this study was to determine clinical outcomes, radiographic results, and survivorship after TKA with contemporary rotating-hinge components. Methods: We identified 408 consecutive TKAs performed with rotating-hinge components for nononcologic indications from 2002 to 2012 at a single academic institution. Two hundred and sixty-four knees (65%) had rotating-hinge TKA components implanted for aseptic etiologies, while 144 knees (35%) were managed with the components in 2-stage reimplantation following infection. Rotating-hinge TKA implants were used for complex primary procedures in 74 knees (18%) and as a revision construct in 334 knees (82%). Clinical outcomes were assessed with the Knee Society scoring system, survivorship analyses, and cumulative incidence of revision. The mean age of the patients at the time of the index arthroplasty was 69 years, and the mean duration of follow-up was 4 years (range, 2 to 12 years). Results: At the most recent follow-up, the mean Knee Society knee score had increased from 51 points preoperatively to 81 points (p < 0.0001), and the mean Knee Society functional score had increased from 26 to 36 points (p < 0.0001). At a mean of 4 years, loosening of components was observed in 13 (3.7%) of 349 knees. At the most recent follow-up, 59 revision procedures and 25 reoperations had been performed. The cumulative incidence of any revision was 9.7% at 2 years and 22.5% at 10 years. The cumulative incidence of revision for aseptic loosening was 1.7% at 2 years and 4.5% at 10 years. Metaphyseal cones were used in 114 knees (28%). Survivorship analysis revealed a trend toward a lower risk of revision (hazard ratio [HR] = 0.69; 95% confidence interval [CI] = 0.39 to 1.22; p = 0.20) and reoperation (HR = 0.51; 95% CI = 0.22 to 1.19; p = 0.12) in patients with metaphyseal cones, despite their use in the most severe of bone defects. Conclusions: Contemporary rotating-hinge TKA implants had a low 10-year cumulative incidence of revision for aseptic loosening of 4.5%. Greater use of metaphyseal fixation has aided this improvement. Patients can expect substantial improvements in clinical outcomes with this revision strategy. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Study Design. Retrospective analysis of prospectively collected data. Objective. The aim of this study was to determine whether 1-year patient-reported outcomes (PROs) can accurately assess effective care for patients undergoing surgery for degenerative lumbar spine disease. Summary of Background Data. Prospective longitudinal PROs registries provide a means to accurately assess outcomes and determine the relative effectiveness of various spine treatments. Obtaining long-term PROs can be costly and challenging. Methods. Patients enrolled into a prospective registry who underwent lumbar spine surgery for degenerative disease were included. Baseline, 1-year, and 2-year Oswestry Disability Index (ODI) scores were captured. Previously published minimum clinically important difference (MCID) for ODI (14.9) was used. Multivariable linear regression model was created to derive model-estimated 2-year ODI scores. Absolute differences between 1-year and 2-year ODI were compared to absolute differences between 2-year and model-estimated 2-year ODI. Concordance rates in achieving MCID at 1-year and 2-year and predictive values were calculated. Results. A total of 868 patients were analyzed. One-year ODI scores differed from 2-year scores by an absolute difference of 9.7 ± 8.9 points and predictive model-estimated 2-year scores differed from actual 2-year scores by 8.8 ± 7.3 points. The model-estimated 2-year ODI was significantly different than actual 1-year ODI in assessing actual 2-year ODI for all procedures ( P = 0.001) except for primary ( P = 0.932) and revision microdiscectomy ( P = 0.978) and primary laminectomy ( P = 0.267). The discordance rates of achieving or not achieving MCID for ODI ranged from 8% to 27%. Concordance rate was about 90% for primary and revision microdiscectomy. The positive and negative predictive value of 1-year ODI to predict 2-year ODI was 83% and 67% for all procedures and 92% and 67% for primary and 100% and 86% for revision microdiscectomy respectively. Conclusion. One-year disability outcomes can potentially estimate 2-year outcomes for patient populations, but cannot reliably predict 2-year outcomes for individual patients, except for patients undergoing primary and revision microdiscectomy. Level of Evidence: 4