The technique of crossing the limbs of bifurcated modular stent grafts for endovascular aneurysm repair (EVAR) is often employed in the face of splayed aortic bifurcations to facilitate cannulation and prevent device kinking. However, little has been reported about the implications of cross-limb EVAR, especially in comparison to conventional EVAR. Previous computational fluid dynamics studies of conventional EVAR grafts have mostly utilized simplified planar stent graft geometries. We herein examined the differences between conventional and cross-limb EVAR by comparing their hemodynamic flow fields (i.e., in the "direct" and "cross" configurations, respectively). We also added a "planar" configuration, which is commonly found in the literature, to identify how well this configuration compares to out-of-plane stent graft configurations from a hemodynamic perspective. A representative patient's cross-limb stent graft geometry was segmented using computed tomography imaging in Mimics software. The cross-limb graft geometry was used to build its direct and planar counterparts in SolidWorks. Physiologic velocity and mass flow boundary conditions and blood properties were implemented for steady-state and pulsatile transient simulations in ANSYS CFX. Displacement forces, wall shear stress (WSS), and oscillatory shear index (OSI) were all comparable between the direct and cross configurations, whereas the planar geometry yielded very different predictions of hemodynamics compared to the out-of-plane stent graft configurations, particularly for displacement forces. This single-patient study suggests that the short-term hemodynamics involved in crossing the limbs is as safe as conventional EVAR. Higher helicity and improved WSS distribution of the cross-limb configuration suggest improved flow-related thrombosis resistance in the short term. However, there may be long-term fatigue implications to stent graft use in the cross configuration when compared to the direct configuration.

BackgroundSitravatinib, a tyrosine kinase inhibitor that targets TYRO3, AXL, MERTK and the VEGF receptor family, is predicted to increase the M1 to M2-polarized tumor-associated macrophages ratio in the tumor microenvironment and have synergistic antitumor activity in combination with anti-programmed death-1/ligand-1 agents. SNOW is a window-of-opportunity study designed to evaluate the immune and molecular effects of preoperative sitravatinib and nivolumab in patients with oral cavity squamous cell carcinoma.MethodsPatients with newly-diagnosed untreated T2-4a, N0-2 or T1 >1 cm-N2 oral cavity carcinomas were eligible. All patients received sitravatinib 120 mg daily from day 1 up to 48 hours pre-surgery and one dose of nivolumab 240 mg on day 15. Surgery was planned between day 23 and 30. Standard of care adjuvant radiotherapy was given based on clinical stage. Tumor photographs, fresh tumor biopsies and blood samples were collected at baseline, at day 15 after sitravatinib alone, and at surgery after sitravatinib–nivolumab combination. Tumor flow cytometry, multiplex immunofluorescence staining and single-cell RNA sequencing (scRNAseq) were performed on tumor biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing and circulating tumor DNA and cell-free DNA were evaluated at each time point.ResultsTen patients were included. Grade 3 toxicity occurred in one patient (hypertension); one patient required sitravatinib dose reduction, and one patient required discontinuation and surgery delay due to G2 thrombocytopenia. Nine patients had clinical-to-pathological downstaging, with one complete response. Independent pathological treatment response (PTR) assessment confirmed a complete PTR and two major PTRs. With a median follow-up of 21 months, all patients are alive with no recurrence. Circulating tumor DNA and cell-free DNA dynamics correlated with clinical and pathological response and distinguished two patient groups with different tumor biological behavior after sitravatinib alone (1A) versus sitravatinib–nivolumab (1B). Tumor immunophenotyping and scRNAseq analyses revealed differential changes in the expression of immune cell populations and sitravatinib-targeted and hypoxia-related genes in group 1A vs 1B patients.ConclusionsThe SNOW study shows sitravatinib plus nivolumab is safe and leads to deep clinical and pathological responses in oral cavity carcinomas. Multi-omic biomarker analyses dissect the differential molecular effects of sitravatinib versus the sitravatinib–nivolumab and revealed patients with distinct tumor biology behavior.Trial registration numberNCT03575598.

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Purpose: Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT. Experimental Design: A window-of-opportunity, phase II randomized trial was performed in stage IB-IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic. Results: Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4% to 34.2%) ± SD 16.9% after 1 week of metformin, compared to an average increase of 4.7% (29.1% to 33.8%) ±11.5% for the 3 controls (p = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival (DFS) was 67% for the metformin arm vs 33% for controls (p=0.09). Conclusions: Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor.

For multicenter clinical studies, characterizing the robustness of image-derived radiomics features is essential. Features calculated on PET images have been shown to be very sensitive to image noise. The purpose of this work was to investigate the efficacy of a relatively simple harmonization strategy on feature robustness and agreement. A purpose-built texture pattern phantom was scanned on 10 different PET scanners in 7 institutions with various different image acquisition and reconstruction protocols. An image harmonization technique based on equalizing a contrast-to-noise ratio was employed to generate a “harmonized” alongside a “standard” dataset for a reproducibility study. In addition, a repeatability study was performed with images from a single PET scanner of variable image noise, varying the binning time of the reconstruction. Feature agreement was measured using the intraclass correlation coefficient (ICC). In the repeatability study, 81/93 features had a lower ICC on the images with the highest image noise as compared to the images with the lowest image noise. Using the harmonized dataset significantly improved the feature agreement for five of the six investigated feature classes over the standard dataset. For three feature classes, high feature agreement corresponded with higher sensitivity to the different patterns, suggesting a way to select suitable features for predictive models.

6569 Background: Sitravatinib (receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) is predicted to increase M1-type tumor-associated macrophages (TAMs) and decrease MDSCs in the tumor microenvironment. SNOW is a window-of-opportunity study evaluating the immunogenic and antitumor effects of preoperative sitravatinib and nivolumab in patients (pts) with OCC. Early results demonstrated the combination was safe and active (Oliva et al, SITC 2019). Biomarker analyses and updated results are presented. Methods: Pts with untreated T2-4a, N0-2 or T1>1cm-N2 OCC are eligible. All pts receive oral sitravatinib 120mg daily from day (D) 1 up to 48h pre-surgery and 1 dose of Nivolumab 240mg on D15. Surgery planned between D23-D30. Standard of care adjuvant radiotherapy given based on clinical stage. Tumor pictures, fresh tumor biopsies, blood samples taken at baseline, D15 and pre-surgery. Tumor flow cytometry and multiplex immunofluorescence staining performed on all biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing (WES) performed on baseline biopsies. Results: As of Jan 31st 2020, 10 out of 12 planned pts were enrolled. Study treatment was well-tolerated: only 1 pt had grade (G) >3 toxicity (hypertension) and 1 pt required surgery delay due to G2 thrombocytopenia. None had intraoperative complications. 1 pt had wound infection and tracheostomy bleeding 11 days post-surgery, possibly-related to study drugs. All pts had tumor reduction, 9/10 had pathological downstaging, including 1 complete response (Table). All had clear margins with no extranodal extension; none required adjuvant chemotherapy. All pts are alive with no recurrence (median follow-up= 69 weeks). Lower % of MDSCs and increased % of M1-TAMs and M1:M2 ratio trend was seen at D15 and pre-surgery, with stronger effect in major responders. Best responders (Pts S1-S2) had higher % of PD-L1+ TAMs at baseline. Tumor WES revealed an HRAS G12D mutation in pt S2 and a BLM mutation (DNA repair) in pt S6 (no downstaging). Conclusions: Pharmacodynamic analyses support the antitumor and immune effects of sitravatinib and nivolumab in OCC. Immune pathological response assessment and transcriptomics are on-going. Clinical trial information: NCT03575598 . [Table: see text]