Additional file 1: of Patient perceptions regarding physician reimbursements, wait times, and out-of-pocket payments for anterior cruciate ligament reconstruction in Ontario

Survey – Patient Perceptions Surrounding Anterior 441 Cruciate Ligament Reconstruction. (DOCX 13 kb

Parameter generation for the patient-specific biomathematical model.

<p><b>1.</b> Determine radial measurements from serial T1Gd and T2/FLAIR magnetic resonance imaging. <b>2.</b> Compute the invisibility index (D/<i>ρ</i>) from intra-study T1Gd and T2/FLAIR radial measurements. <b>3.</b> Compute the radial velocity () from serial T1Gd or T2/FLAIR radial measurements.</p

Spatial distribution of optimized plans versus the invisibility index.

<p>The radial distance between the 50% isodose radius and the 50% tumor cell isodensity radius versus the invisibility index (<i>D/ρ)</i> for the optimized plans. The horizontal error bars illustrate the range of patient-specific D/p values possible given the observed uncertainty in radial tumor measurements. The vertical error bars represent the minimum and maximum distance from simulations using the expected, minimum and maximum D/p values. The marker is plotted in the center of the range and the center values are positively correlated with Pearson’s correlation r = .98 with p-value = 9e-8, demonstrating that tumors with higher invisibility indices receive optimized doses with shallower gradients and larger high-dose volumes relative to tumor cell density.</p

Optimization Restrictions.

*<p>Patient-specific.</p

Dose-volume histogram showing the total dose delivered to normal brain tissue outside of the T1Gd abnormality for optimized and standard-of-care plans for patient 10.

<p>The lines intersect at 62% of the normal tissue volume, demonstrating that only 2% of the normal tissue receives a higher dose from the optimized plan.</p

Patient Data.

*<p>Extent of Resection.</p>†<p>Still alive.</p>‡<p>Biopsy only.</p>¶<p>Temozolomide.</p>#<p>Subtotal resection.</p>||<p>Carmustine.</p>§<p>Not included in Rockne 2010.</p

Simulated tumor and normal cell densities with clinical and optimized total dose.

<p>Patients are ordered according to tumor diffusivity, from least to greatest and the cell densities are taken at the pre-treatment timepoint. Dose in units Gray is on the left axis while cell density relative to the tumor cell carrying capacity is on the right side. The spatial distribution of the optimized plans is determined primarily by the patient-specific invisibility index (<i>D/ρ</i>), as patients with more nodular tumors (low <i>D/ρ</i>, e.g. Patient 12) receive more peaked optimized doses while those for patients with more diffuse tumors (high <i>D/ρ</i>, e.g. Patient 3) are more spread out along the invasive gradient of the outer edge of the tumor. Patients 2 and 5 show a cell density of zero in the center of the tumor due to subtotal resections.</p

Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma

<div><p>Background</p><p>Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma.</p><p>Methods and Findings</p><p>This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm.</p><p>Conclusions</p><p>Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01310855" target="_blank">NCT01310855</a></p></div

Patient characteristics at baseline for the ITT population.

<p>Patient characteristics at baseline for the ITT population.</p

CONSORT diagram.

<p>CONSORT diagram.</p