Deoptimized influenza virus for treatment of TNBC and induction of anticancer immunity in the EMT6 mouse model.

e13109 Background: Triple negative breast cancer (TNBC) is resistant to classical hormone-based therapy, prone to relapse and aggressive metastasis. Oncolytic viruses (OVs) when injected into the tumor, can promote local lysis of tumor cells and drive presentation of tumor antigens, thereby making tumors visible to the immune system. CodaLytic is a re-coded influenza A virus that has a high frequency of disfavored codons and codon pairs which attenuate the virus yet preserve all antigens and immune stimulation properties of the wild type influenza virus. CodaLytic is produced from the same master virus seed as CodaVax, a universal influenza vaccine candidate currently in Phase I clinical trials under a US IND. Methods: BALB/c mice were implanted with EMT6 mouse TNBC cells into a mammary fat pad. Six days post-implantation, when tumors became palpable, treatment was initiated by intratumoral administration of PBS (mock) or CodaLytic (108 PFU in 50 µL). Mice were treated three times a week for a total of three weeks. Tumor growth was monitored daily for 33 days and animals were euthanized if the tumor volume exceeded 500 mm3. Survivors were challenged via flank or intravenous (IV) injection of EMT6 cells. Two weeks after IV challenge, lungs were removed and compared to the lungs of control mice. Results: At the end of the initial experiment (day 33), 80% of CodaLytic-treated mice were alive with 70% of survivors being tumor-free as compared to mock, of which none survived. Survivors on day 33 had a median decrease in tumor size of 75%. CodaLytic stimulated lasting anti-tumor immunity as 100% of CodaLytic-treated survivors failed to establish tumors following challenge with EMT6 cells via flank injection. To model metastasis, surviving treated mice were also challenged with EMT6 cells delivered 2x104 cells IV. IV challenged mice had over 10-fold fewer nodules in their lungs as compared to naïve controls and 40% of the animals remained tumor free, whereas 100% of the control animals developed tumors. Additionally, CodaLytic-treated survivors showed no weight loss after IV re-challenge compared to controls which lost an average of 12% body mass. Conclusions: CodaLytic OV treatment of TNBC increased survival, led to complete tumor clearance in the EMT6 mouse model, and induced systemic anti-tumor immunity that has potential for preventing and treating metastatic disease.

Interventional Treatment of Acute Portal Vein Thrombosis

Background Acute portal vein thrombosis is a potentially fatal condition. In symptomatic patients not responding to systemic anticoagulation, interventional procedures have emerged as an alternative to surgery. This study sought to retrospectively evaluate initial results of interventional treatment of acute portal vein thrombosis (aPVT) using a transjugular interventional approach. Materials and Methods Between 2014 and 2016, 11 patients were treated because of aPVT (male: 7; female: 4; mean age: 41.06 years). All patients presented a rapid onset of symptoms without collateralization of portal flow as assessed by a CT scan at the time of admittance. The patients showed thrombotic occlusion of the main portal vein (11/11), the lienal vein (10/11) and the superior mesenteric vein (10/11). Different techniques for recanalization were employed: catheter thromboaspiration (1/9), AngioJet device (7/9), local-lysis-only (1/9) and TIPSS (7/9). Local lysis was administered using a dual (4/9) or single (5/9) catheter technique. The mean follow-up was 24.32 months. Results In 9 patients transhepatic access was successful. Initially reduction of thrombus load and recanalization were achieved in all 9 cases with residual thrombi in PV (n = 3), SMV (n = 7), and IL (n = 5). In the collective undergoing interventional procedures (n = 9) rethrombosis and continuous abdominal pain were seen in one patient, and thrombus progression after successful recanalization was seen in another. Freedom from symptoms could be achieved in 6 patients. One patient developed peritoneal and pleural effusion, respiratory insufficiency and portosystemic collaterals. Both patients who could not undergo an interventional procedure developed a cavernous transformation of the portal vein. One of them also had continuous intermittent abdominal pain. Conclusion Interventional percutaneous approaches are able to improve patient outcome in patients with aPVT. It appears to be of utmost importance to not only remove/reduce the thrombotic material but to establish sufficient inflow and outflow by TIPS and simultaneous multi-catheter thrombolysis. Key Points: Citation Format

Renal Function Salvage After Delayed Endovascular Revascularization of Acute Renal Artery Occlusion in Patients With Fenestrated-Branched Endovascular Aneurysm Repair or Visceral Debranching

Purpose: To analyze the renal function and outcome after delayed (>6 hours) endovascular revascularization of acute renal artery occlusion (RAO) in patients with fenestrated-branched endovascular aneurysm repairs (EVARs) or open visceral debranching. Methods: A single-center retrospective analysis was conducted involving 7 patients (mean age 61 years, range 49–72; 5 women) with 9 RAOs treated with endovascular revascularization between December 2014 and March 2017. Three patients had a solitary kidney with chronic renal insufficiency; 1 patient had bilateral occlusions as the acute event. Initial aortic surgery included 5 branched and 1 fenestrated EVAR as well as 1 open visceral debranching operation. Revascularization of the RAO was performed using aspiration thrombectomy, local lysis therapy, and stent-graft relining. The median time between initial aortic surgery and RAO was 10 months (range 0.5–17). Results: Median renal ischemic time to revascularization was 24 hours (range 7–168). Technical success was 100%, with 1 procedure-related access complication. Temporary dialysis dependency occurred in 4 patients. Mean in-hospital stay was 17 days (range 7–32) with 1 postoperative death at day 10 due to cardiac arrest of unknown cause. Mean follow-up was 10.3 months (range 1.5–27) in 5 of 6 discharged patients. During follow-up, 1 reintervention for recurrent occlusion was performed. At follow-up imaging, all renal arteries were patent. No permanent dialysis dependency occurred. Conclusion: Renal function can be salvaged by delayed revascularization for RAO with prolonged renal ischemia. The endovascular approach with aspiration thrombectomy, local lysis, and stent-graft relining is a feasible technique for revascularization after RAO in patients with fenestrated-branched EVAR or open visceral debranching.

Treatment of acute limb ischemia with focus on endovascular techniques

Acute limb ischemia is still the most frequent cause of major limb loss. Timely and fast revascularization is the key for limb salvage and patient survival. Large randomized trials showed equivalency of surgical and endovascular revascularization by means of local lysis with urokinase (TOPAS, STILE). New lytic agents and their modified application such as via a pulse spray catheter or combined with an ultrasound catheter and the combination with glycoprotein IIb/IIIa receptor antagonists have increased the efficacy and speed of thrombolysis. Recently, mechanical thrombectomy devices have become more widespread because intervention time and bleeding complications can be reduced. This review article summarizes the clinical presentation of and the treatment options for acute arterial occlusive disease caused either by embolism or local thrombosis.

The N- and C-Terminal Portions of theAgrobacterium VirB1 Protein Independently Enhance Tumorigenesis

ABSTRACT Genetic transformation of plants by Agrobacterium tumefaciens is mediated by a virulence (vir)-specific type IV secretion apparatus assembled from 11 VirB proteins and VirD4. VirB1, targeted to the periplasm by an N-terminal signal peptide, is processed to yield VirB1*, comprising the C-terminal 73 amino acids. The N-terminal segment, which shares homology with chicken egg white lysozyme as well as lytic transglycosylases, may provide local lysis of the peptidoglycan cell wall to create channels for transporter assembly. Synthesis of VirB1* followed by its secretion to the exterior of the cell suggests that VirB1* may also have a role in virulence. In the present study, we provide evidence for the dual roles of VirB1 in tumorigenesis as well as the requirements for processing and secretion of VirB1*. Complementation of a virB1 deletion strain with constructs expressing either the N-terminal lysozyme-homologous region or VirB1* results in tumors intermediate in size between those induced by a wild-type strain and a virB1 deletion strain, suggesting that each domain has a unique role in tumorigenesis. The secretion of VirB1* translationally fused to the signal peptide indicates that processing and secretion are not coupled. When expressed independently of all other vir genes, VirB1 was processed and VirB1* was secreted. When restricted to the cytoplasm by deletion of the signal peptide, VirB1 was neither processed nor secreted and did not restore virulence to the virB1 deletion strain. Thus, factors that mediate processing of VirB1 and secretion of VirB1* are localized in the periplasm or outer membrane and are not subject tovir regulation.