Local Lysis Research Articles

Catheter-assisted local lysis therapy for submassive pulmonary embolism

Pulmonary embolism is the third most common cardiovascular disease. Interventional treatment options as an alternative to systemic lysis therapy of hemodynamically stable, submassive pulmonary embolisms have received an unprecedented boost in innovation in recent years. The treatment options are heterogeneous and can be roughly divided into local thrombolysis and local thrombectomy. For years in our center we have been carrying out catheter-assisted, locoregional lysis therapy with side-hole lysis catheters and acumulative dose per pulmonary branch of 10 mg alteplase over 15 h for hemodynamically stable, submassive pulmonary emboli. The aim of this retrospective study was to review this therapeutic concept and to collect data on clinical endpoints and possible complications. The study included data from 01/2018-03/2023. For this purpose, the patients were selected based on the OPS codes (8.838.60 and 1‑276.0), and the data was collected using the medical records. Biometric data, data on previous illnesses and vital parameters, laboratory chemistry data, CT diagnostic data, echocardiographic data, data on drug treatment and data on complications were collected anonymously. There was asignificant reduction in the strain on the right heart. Peripheral oxygen saturation also improved significantly and heart rate decreased significantly. The complication rate remained low and was almost exclusively limited to access-related problems. Catheter-assisted, locoregional lysis therapy is asafe and effective treatment method for submassive pulmonary embolism.

Minimally-invasive bedside catheter haematoma aspiration followed by local thrombolysis in spontaneous supratentorial intracerebral haemorrhage: a retrospective single-center study.

The role of surgery in the treatment of intracerebral haemorrhage (ICH) remains controversial. Whereas open surgery has failed to show any clinical benefit, recent studies have suggested that minimal invasive procedures can indeed be beneficial, especially when they are applied at an early time point. This retrospective study therefore evaluated the feasibility of a free-hand bedside catheter technique with subsequent local lysis for early haematoma evacuation in patients with spontaneous supratentorial ICH. Patients with spontaneous supratentorial haemorrhage of a volume of >30 mL who were treated with bedside catheter haematoma evacuation were identified from our institutional database. The entry point and evacuation trajectory of the catheter were based on a 3D-reconstructed CT scan. The catheter was inserted bedside into the core of the haematoma, and urokinase (5,000 IE) was administered every 6 h for a maximum of 4 days. Evolution of haematoma volume, perihaemorrhagic edema, midline-shift, adverse events and functional outcome were analyzed. A total of 110 patients with a median initial haematoma volume of 60.6 mL were analyzed. Haematoma volume decreased to 46.1 mL immediately after catheter placement and initial aspiration (with a median time to treatment of 9 h after ictus), and to 21.0 mL at the end of urokinase treatment. Perihaemorrhagic edema decreased significantly from 45.0 mL to 38.9 mL and midline-shift from 6.0 mm to 2.0 mm. The median NIHSS score improved from 18 on admission to 10 at discharge, and the median mRS at discharge was 4; the latter was even lower in patients who reached a target volume ≤ 15 mL at the end of local lysis. The in-hospital mortality rate was 8.2%, and catheter/local lysis-associated complications occurred in 5.5% of patients. Bedside catheter aspiration with subsequent urokinase irrigation is a safe and feasible procedure for treating spontaneous supratentorial ICH, and can immediately reduce the mass effects of haemorrhage. Additional controlled studies that assess the long-term outcome and generalizability of our findings are therefore warranted. [www.drks.de], identifier [DRKS00007908].

Successful therapy of non-cirrhotic non-malignant portal vein thrombosis (NCNMPT) by interventional therapy using transjugular lysis catheter

NCNMPT is a rare condition with a prevalence of 0.3%. THERAPY: Patient (69 y) with NCNMPT and small bowel ileus received interventional therapy using transjugular local lysis into the superior mesenteric vein. OUTCOME/DISCUSSION: Successful lysis with complete remission. Improved therapeutic efficacy of interventional versus drug therapy alone.

Mechanical aspiration thrombectomy for the treatment of pulmonary embolism: A systematic review and meta-analysis.

There are no randomized trials studying the outcomes of mechanical aspiration thrombectomy (MAT) for management of pulmonary embolism (PE). We performed a systematic review and meta-analysis of existing literature to evaluate the safety and efficacy of MAT in the setting of PE. Inclusion criteria were as follows: studies reporting more than five patients, study involved MAT, and reported clinical outcomes and pulmonary artery pressures. Studies were excluded if they failed to separate thrombectomy data from catheter-directed thrombolysis data. Databases searched include PubMed, EMBASE, Web of Science until April, 2021. Fourteen case series were identified, consisting of 516 total patients (mean age 58.4 ± 13.6 years). Three studies had only high-risk PE, two studies had only intermediate-risk PE, and the remaining nine studies had a combination of both high-risk and intermediate-risk PE. Six studies used the Inari FlowTriever device, five studies used the Indigo Aspiration system, and the remaining three studies used the Rotarex or Aspirex suction thrombectomy system. Four total studies employed thrombolytics in a patient-specific manner, with seven receiving local lysis and 17 receiving systemic lysis, and 40 receiving both. A random-effects meta-analyses of proportions of in-hospital mortality, major bleeding, technical success, and clinical success were calculated, which yielded estimate pooled percentages [95% CI] of 3.6% [0.7%, 7.9%], 0.5% [0.0%, 1.8%], 97.1% [94.8%, 98.4%], and 90.7% [85.5%, 94.3%]. There is significant heterogeneity in clinical, physiologic, and angiographic data in the currently available data on MAT. RCTs with consistent parameters and outcomes measures are still needed.

Transjugular intrahepatic portosystemic shunt, local thrombaspiration, and lysis for management of fulminant portomesenteric thrombosis and atraumatic splenic rupture due to vector-vaccine-induced thrombotic thrombocytopenia: a case report

IntroductionRecombinant adenoviral vector vaccines against severe acute respiratory syndrome coronavirus 2 have been observed to be associated with vaccine-induced immune thrombotic thrombocytopenia. Though vaccine-induced immune thrombotic thrombocytopenia is a rare complication after vaccination with recombinant adenoviral vector vaccines, it can lead to severe complications. In vaccine-induced immune thrombotic thrombocytopenia, the vector vaccine induces heparin-independent production of platelet factor 4 autoantibodies, resulting in platelet activation and aggregation. Therefore, patients suffering from vaccine-induced immune thrombotic thrombocytopenia particularly present with signs of arterial or venous thrombosis, often at atypical sites, but also signs of bleeding due to disseminated intravascular coagulation and severe thrombocytopenia. We describe herein a rare case of fulminant portomesenteric thrombosis and atraumatic splenic rupture due to vaccine-induced immune thrombotic thrombocytopenia.Case summary (main symptoms and therapeutic interventions)This case report presents the diagnosis and treatment of a healthy 29-year-old male Caucasian patient suffering from an extended portomesenteric thrombosis associated with atraumatic splenic rupture due to vaccine-induced immune thrombotic thrombocytopenia after the first dose of an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 [ChAdOx1 nCoV-19 (AZD1222)]. Therapeutic management of vaccine-induced immune thrombotic thrombocytopenia initially focused on systemic anticoagulation avoiding heparin and the application of steroids and intravenous immune globulins as per the recommendations of international societies of hematology and hemostaseology. Owing to the atraumatic splenic rupture and extended portomesenteric thrombosis, successful management of this case required splenectomy with additional placement of a transjugular intrahepatic portosystemic shunt to perform local thrombaspiration, plus repeated local lysis to reconstitute hepatopetal blood flow.ConclusionThe complexity and wide spectrum of the clinical picture in patients suffering from vaccine-induced immune thrombotic thrombocytopenia demand an early interdisciplinary diagnostic and therapeutic approach. Severe cases of portomesenteric thrombosis in vaccine-induced immune thrombotic thrombocytopenia, refractory to conservative management, may require additional placement of a transjugular intrahepatic portosystemic shunt, thrombaspiration, thrombolysis, and surgical intervention for effective management.

Modified donor blood flow-preserved cross-leg anterolateral thigh flap procedure for complex lower extremity reconstruction

BackgroundComplex lower limb reconstruction due to severe trauma remains a challenge for reconstructive surgeons. Here, we introduce a modified donor blood flow-preserved cross-leg anterolateral thigh flap procedure and evaluate its clinical efficacy.MethodsBetween January 2013 and December 2019, 22 patients (range 10 to 64 years old) with unilateral lower limb injury underwent modified donor blood flow-preserved cross-leg anterolateral thigh flap procedures. Among them, 16 cases were traffic accidents, 5 cases were persistent ulcers, and 1 case was a degloving injury. The arterial pedicle of the flap was prepared in a Y-shaped fashion and microanastomosed to the posterior tibial artery of intact leg in a flow-through style. A split-thickness skin graft was applied to wrap the vascular pedicle after anastomosis. The flap was designed in a single or bilobed fashion according to the shape of the tissue defect. The operation time, the intraoperative blood loss and the length of hospital stays were recorded. The vascular pedicle was divided 4 weeks after anastomosis. Doppler ultrasound was performed to evaluate the blood flow of the donor posterior tibial artery during postoperative follow-up.ResultsAll 22 flaps survived. The tissue defects ranged from 12 × 6 to 21 × 18 cm2. The flap sizes ranged from 14 × 7.5 to 24 × 21 cm2. The average operation time, intraoperative blood loss and length of hospital stays were 6.73 ± 1.49 h, 280.95 ± 59.25 ml and 30.55 ± 2.52 days, respectively. Eighteen flaps were designed in a single fashion, while four were in bilobed fashion. Twenty patients underwent fasciocutaneous flap transplantations, while two underwent musculocutaneous flap transplantations. Two cases developed local lysis of the flap which healed after further debridement. Direct suture of the incision after flap harvest was performed in 16 cases, while additional full-thickness skin grafting was performed in the remaining 6 cases. Further bone transport procedures were performed in 15 patients who had severe tibia bone defects. The blood flow of donor posterior tibial artery was confirmed in all patients during follow-ups. All patients recovered flap sensation at the final follow-up. The postoperative follow-ups ranged from 18 to 84 months, and no long-term complications were observed.ConclusionsThe modified donor blood flow-preserved cross-leg anterolateral thigh flap procedure is an ideal method to repair severe lower limb trauma with tibial artery occlusion which avoids sacrificing the major artery of the uninjured lower limb.

Acute left ventricular insufficiency in a Burkitt Lymphoma patient with myocardial involvement and extensive local tumor cell lysis: a case report

BackgroundBurkitt lymphoma (BL) is a rare disease with the sporadic variant accounting for less than 1% of adult non-Hodgkin lymphomas. BL usually presents with an abdominal bulk, but extranodal disease affecting the bone marrow and central nervous system is common. Cardiac manifestations, however, are exceedingly rare, with less than 30 cases reported in the literature.Case presentationWe report on a 54-year-old male patient with a six week-long history of paranasal sinus swelling, fatigue and dyspnea on exertion. Stage IV sporadic BL with extensive lymphonodal and cardiovascular involvement was diagnosed. Manifestations included supra- and infradiaphragmatic lymphadenopathy as well as infiltration of the aortic root, the pericardium, the right atrium and the right ventricle. EBV-reactivation was detected, which is uncommon in the sporadic subtype. After initial full-dose chemotherapy with very good BL control, the patient developed acute, but fully reversible cardiac insufficiency. Myocardial lymphoma involvement receded completely during the following two therapy cycles, while cardiac function periodically deteriorated shortly after chemotherapy administration and quickly recovered thereafter. Interestingly, the decline in cardiac function lessened with decreasing myocardial lymphoma manifestation. Once the cardiovascular BL infiltration was resolved, cardiac function remained stable throughout further treatment. Following seven cycles of chemotherapy and mediastinal radiation, the patient is now in continued complete remission.ConclusionsAlthough rare, cardiac involvement in BL can quickly become life-threatening due to rapid lymphoma doubling time and should therefore be considered at initial diagnosis. This case suggests an association between myocardial infiltration, chemotherapy associated tumor cell lysis and transient deterioration of cardiac function until the damage caused by the underlying lymphoma could be restored. While additional studies are needed to further elucidate the mechanisms of acute cardiac insufficiency due to lymphoma lysis in the infiltrated structures, prompt BL control and full recovery of the patient supports courageous treatment start despite extensive cardiovascular involvement.

Medical gas plasma promotes blood coagulation via platelet activation

Major blood loss still is a risk factor during surgery. Electrocauterization often is used for necrotizing the tissue and thereby halts bleeding (hemostasis). However, the carbonized tissue is prone to falling off, putting patients at risk of severe side effects, such as dangerous internal bleeding many hours after surgery. We have developed a medical gas plasma jet technology as an alternative to electrocauterization and investigated its hemostatic (blood clotting) effects and mechanisms of action using whole human blood. The gas plasma efficiently coagulated anticoagulated donor blood, which resulted from the local lysis of red blood cells (hemolysis). Image cytometry further showed enhanced platelet aggregation. Gas plasmas release reactive oxygen species (ROS), but neither scavenging of long-lived ROS nor addition of chemically-generated ROS were able to abrogate or recapitulate the gas plasma effect, respectively. However, platelet activation was markedly impaired in platelet-rich plasma when compared to gas plasma-treated whole blood that moreover contained significant amounts of hemoglobin indicative of red blood cell lysis (hemolysis). Finally, incubation of whole blood with concentration-matched hemolysates phenocopied the gas plasmas-mediated platelet activation. These results will spur the translation of plasma systems for hemolysis into clinical practice.

Acute peripheral ischemia in healthy female patient: an indirect and unanticipated diagnosis of spontaneous thrombus in the aortic arch

BackgroundIn this case we discuss the management of a pediculated floating thrombus in the aortic arch which led to peripheral embolization and acute ischemia oft he left leg.Case presentationA healthy 46 year old female patient presented with pain in her left leg and progressive numbness. Computed Tomography Angiography (CTA) showed an acute ischemia of the left leg (Rutherford 2 B) with a 2 cm thrombus distal of the aortic bifurcation. Emergency operation with embolectomy, selective thrombembolectomy and patch plasty on the tibioperoneal trunk and local lysis was performed. As part of a further diagnostic examination a thoracic CT scan has been performed revealing a pediculated-floating 2 cm thrombus in the aortic arch. Four days after the initial operation thrombus excision via a minimally invasive access way has been performed. After initiation of the extracorporeal circulation, selective unilateral antegrade cerebral perfusion has been established in mild (30–32 °C) systemic hypothermia. Patients postoperative course was uneventful. Histological evaluation of the mass demonstrated thrombotic material without evidence of infection or malignacy.ConclusionA pediculated spontaneous thrombus may develop in aortic arch in patients without traditional risk factors or family history of embolic events. Two stage operation was feasible and safe.

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.

PECULIARITIES OF MORPHOLOGICAL CHANGES OF TISSUES AFTER HERNOPLASTIC DURING RECURRENCE OF POSTOPERATIVE VENTRAL HERNIAS

Considering the results of surgical treatment of postoperative ventral hernias, a significant number of relapses, comprising 4.3-46 %, should be noted, and for large and giant postoperative ventral hernias reaches 80 %. The lack of clear criteria for assessing the local response of the tissues of the anterior abdominal wall to the implantation of various types of mesh implants and the associated early wound postoperative complications and relapses prompts further study of the morphological features of the anterior abdominal wall tissue responses in patients with primary and postoperative ventral hernias. Aim of the study: to establish morphological patterns of the restructuring of the tissues of the anterior abdominal wall in patients with recurrent ventral hernia. Material and methods. An in-depth comprehensive clinical, instrumental and laboratory examination of 1419 patients with primary and postoperative ventral hernia was performed. There were 250 patients with recurrent ventral hernia (17.62 %). Results and conclusions. The use of a “light mesh” in patients with recurrent postoperative ventral hernia in the presence of concomitant NDCT appears to be significantly less lymphohistiocytic and leukocyte infiltration for the surrounding tissue, and reduces the likelihood of postoperative complications. Morphological changes in the tissue of the anterior abdominal wall with NDCT strongly indicate a disorder of its architectonics. It is clinically reflected in the formation of postoperative and recurrent hernias. Separate muscle fibers lose cross striation. In the muscular aponeurotic component without signs of connective tissue dysplasia, the application of various types of nets leads to the formation of elastic and collagen fibers, with minor changes in their architectonics and minimal cell infiltration of the immune inflammation of the extracellular matrix. Disintegration, destructive-dystrophic changes in the architectonics of the connective tissue were observed in patients with signs of NDCT in relapses. When using the “heavy” mesh, significant disorientation, collagenolysis, reduced synthesis of all types of collagens, the phenomenon of thickening of elastic fibers and elastolysis were observed. Inflammatory infiltration, triggered by immune inflammation cells, increased mucoid and fibrinoid edema, which led to homogenization, local lysis, and focal tissue destruction.

ОСОБЛИВОСТІ МОРФОЛОГІЧНИХ ЗМІН ТКАНИН ПІСЛЯ ІМПЛАНТАЦІЙНОЇ ГЕРНІОПЛАСТИКИ ПРИ РЕЦИДИВАХ ПІСЛЯОПЕРАЦІЙНИХ ВЕНТРАЛЬНИХ ГРИЖ

Considering the results of surgical treatment of postoperative ventral hernias, a significant number of relapses, comprising 4.3-46 %, should be noted, and for large and giant postoperative ventral hernias reaches 80 %. The lack of clear criteria for assessing the local response of the tissues of the anterior abdominal wall to the implantation of various types of mesh implants and the associated early wound postoperative complications and relapses prompts further study of the morphological features of the anterior abdominal wall tissue responses in patients with primary and postoperative ventral hernias. Aim of the study: to establish morphological patterns of the restructuring of the tissues of the anterior abdominal wall in patients with recurrent ventral hernia. Material and methods. An in-depth comprehensive clinical, instrumental and laboratory examination of 1419 patients with primary and postoperative ventral hernia was performed. There were 250 patients with recurrent ventral hernia (17.62 %). Results and conclusions. The use of a “light mesh” in patients with recurrent postoperative ventral hernia in the presence of concomitant NDCT appears to be significantly less lymphohistiocytic and leukocyte infiltration for the surrounding tissue, and reduces the likelihood of postoperative complications. Morphological changes in the tissue of the anterior abdominal wall with NDCT strongly indicate a disorder of its architectonics. It is clinically reflected in the formation of postoperative and recurrent hernias. Separate muscle fibers lose cross striation. In the muscular aponeurotic component without signs of connective tissue dysplasia, the application of various types of nets leads to the formation of elastic and collagen fibers, with minor changes in their architectonics and minimal cell infiltration of the immune inflammation of the extracellular matrix. Disintegration, destructive-dystrophic changes in the architectonics of the connective tissue were observed in patients with signs of NDCT in relapses. When using the “heavy” mesh, significant disorientation, collagenolysis, reduced synthesis of all types of collagens, the phenomenon of thickening of elastic fibers and elastolysis were observed. Inflammatory infiltration, triggered by immune inflammation cells, increased mucoid and fibrinoid edema, which led to homogenization, local lysis, and focal tissue destruction.

Gall Wasp Transcriptomes Unravel Potential Effectors Involved in Molecular Dialogues With Oak and Rose.

To gain insight into wasp factors that might be involved in the initial induction of galls on woody plants, we performed high throughput (454) transcriptome analysis of ovaries and venom glands of two cynipid gall wasps, Biorhiza pallida and Diplolepis rosae, inducing galls on oak and rose, respectively. De novo assembled and annotated contigs were compared to sequences from phylogenetically related parasitoid wasps. The relative expression levels of contigs were estimated to identify the most expressed gene sequences in each tissue. We identify for the first time a set of maternally expressed gall wasp proteins potentially involved in the interaction with the plant. Some genes highly expressed in venom glands and ovaries may act to suppress early plant defense signaling. We also identify gall wasp cellulases that could be involved in observed local lysis of plant tissue following oviposition, and which may have been acquired from bacteria by horizontal gene transfer. We find no evidence of virus-related gene expression, in contrast to many non-cynipid parasitoid wasps. By exploring gall wasp effectors, this study is a first step toward understanding the molecular mechanisms underlying cynipid gall induction in woody plants, and the recent sequencing of oak and rose genomes will enable study of plant responses to these factors.

Abstract B083: Defective transcription elongation in a subset of cancers confers immunotherapy resistance

Abstract Immunogenicity of most cancer types is a result of either neoantigenic mutational load, which stokes up an adaptive immune response, or due to oncogenic stress pathways, which elicit an innate antitumor response. There have been exponential gains made in recent times using numerous strategies to reactivate the host antitumor immunity including the development of immune checkpoint inhibitors. Nonetheless, the promise of a cure and durable response in select patients does not refute the low response rates in advanced cases, most of which also relapse. These observations shore up the possibility of other mechanisms beyond the inactivation of local lymphocyte infiltrates that might also play in tumor cell evasion of antitumor immune response. Through comprehensive computational and follow-up experimental validations, we have found that a subset of cancers (~15-20% of all cancers) are characterized by severe defects in almost the entire epigenetic and transcriptional apparatus. These defects result in genome-wide deregulation of histone modifications, mRNA transcription elongation, and mRNA processing and nuclear export, especially in the long genes which we term as Transcriptional Elongation Deficient: TEdef. As such, cancer cells with TEdef suppressed the expression of the pathways enriched for long genes, such as proinflammatory signaling pathways (FasL response, TNF/NF-kB signaling, interferon signaling) at both mRNA and protein levels, and had diminished response to interferon and TNF stimuli. Remarkably, in renal cell carcinoma and metastatic melanoma patients in four cohorts, the TEdef phenotype significantly correlated with poor response and unfavorable outcome to immunotherapy, but not to chemo- or targeted therapy. Importantly, forced induction of TEdef in tumor cells impaired the expression of, and signaling through, the proinflammatory pathways, and imposed a resistance to the innate and adaptive antitumor immune responses and to immune checkpoint inhibitor therapy in vivo. Tumor lymphocyte infiltration (TIL) and somatic neoepitope load (SNL) are some of the best markers of immunotherapy response in the clinic. However, TEdef tumors were characterized by a higher rate of immune cell infiltration, but paradoxically, less immune-mediated local tumor cell lysis, further supporting the notion that TEdef is a tumor cell-autonomous mechanism of immune resistance. As such, combining TIL or SNL with TEdef had superior power in predicting the progression-free and overall survival of melanoma patients treated with the anti-CTLA4 and anti-PD-1 therapy. Overall, TEdef is a novel epigenetic mechanism of resistance to antitumor immune attack, which warrants its assessment in cancer patients undergoing immunotherapy. Citation Format: Vishnu Modur. Defective transcription elongation in a subset of cancers confers immunotherapy resistance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B083.

Interventional Treatment of Acute Portal Vein Thrombosis.

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. 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. 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. 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. · Pharmacomechanic thrombectomy in combination with local thrombolysis is a feasible approach. · The transjugular transhepatic approach seems to be a safe procedure. · TIPSS and dual catheter lysis may support flow management. · Wolter K, Decker G, Kuetting D et al. Interventional Treatment of Acute Portal Vein Thrombosis. Fortschr Röntgenstr 2018; 190: 740 - 746.

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.

Localized Electroporation With Dielectrophoretic Field Flow Fractionation: Toward Removal of Circulating Tumour Cells From Human Blood.

This paper presents the design and experimental performance of a microelectrode-based device to selectively lyse cells in a flow in a microfluidic channel. Localized cell lysis is achieved by utilizing "irreversible electroporation," in which cells are exposed to high magnitude electric pulses. Localized cell lysis in a flow has research applications and may allow for the removal of harmful cells, such as circulating tumor cells from blood. Due to the dependence of this technique on the magnitude of the applied electric field, lethal electric field regions can be localized in the channel by the calibration of the applied voltage. Dielectrophoresis field flow fractionation is used to levitate target cancer cells in the lethal region of the device microchannel. Experiments are performed to demonstrate the localized lysis of MCF7 cancer cells in a mixture of blood cells. Due to their larger size, these circulating tumor cell analogues levitate to a greater height in the channel than erythrocytes. MCF7 lysis is observed to increase from 4.6% in control experiments to 57.3% in active experiments. Leukocyte viability was unaffected in active experiments. These results demonstrate the feasibility of localizing cell lysis in a microfluidic flow environment.

Endovascular Therapy of Chronic Venous Outflow Obstruction

Current national and international guidelines recommend endovascular therapy of iliofemoral thromboses in young patients, as a treatment option to avoid the post-thrombotic syndrome. Possible techniques include endovascular local lysis therapy, as well as pharmacomechanical or purely mechanical procedures. Endovascular therapy of chronic obstruction of the inferior V.cava or pelvic veins is an effective therapy for patients suffering from post-thrombotic syndrome. If there is involvement of the V.femoralis communis, hybrid operations may be considered in which an AV fistula is formed or endophlebectomy is carried out.

Structural modifications of macrophages initiated by tick-borne encephalitis virus

Macrophages are cells of natural immunity and play a key role in pathogenesis of viral infections. Results of ultrastructural research on macrophages infected with tick-borne encephalitis virus (TBEV), an agent that causes dangerous infections affecting nervous system in human beings and belongs to the Flaviviridae family, were shown here. Using virology methods, it was ascertained that the TBEV is consumed by macrophages and multiplies in them. Ultrastructural research showed that the virus penetrates into the cytoplasm by means of local plasmalemma lysis and newly synthesized virus particles escape from the cell by the same path. At the same time, induration of the perinuclear space of cytoplasm was observed, where ribosomes, microfilaments, ribonucleoprotein threats, and virus-specific structures, namely, nucleocapsids, tube formations, and viroplasts, were found in large quantities. On the surface of viroplasts, newly synthesized virus particles were visualized. Thus, evidence was presented that microphages can play certain role in spreading of TBEV and are the target of the virus. Like active antigen-presenting cells, such macrophages can modulate the protective response of an organism and affect the pathogenesis of tick-borne encephalitis.

Abstract B33: Loss of transcriptional fidelity in cancers confers immunotherapy resistance

Abstract Most cancers are immunogenic, either due to neo-antigenic mutational load that makes them susceptible to rejection by the adaptive immune system, or due to oncogenic stress pathways that makes them vulnerable to innate anti-tumor responses. The therapeutic strategies to reactivate the host anti-tumor immunity have a great promise for cancer therapy. However, despite the unprecedented promise of a cure and durable disease management in select patients, the response rates are still low in advanced cases, most of which also relapse. These findings reflect the multitude of mechanisms of tumor cell evasion of anti-tumor immunity, and that mechanisms beyond inactivation of local lymphocyte infiltrates might also play a role. Through comprehensive computational and follow-up experimental validations, we have found that a subset of cancers (~15-20% of all cancers) is characterized by severe defects in almost the entire epigenetic and transcriptional apparatus, resulting in genome-wide deregulation of histone modifications, mRNA transcription elongation, splicing and processing (Loss of Transcriptional Fidelity: LTF). LTF impaired the transcription of long genes in the genome at both mRNA and protein levels; and the pathways that are primarily regulated by long genes, such as immune-related (FasL response, TNF/NF-kB signaling, interferon signaling), MAP kinase and tyrosine kinase signaling pathways, were significantly suppressed in LTF+ (i.e. those with LTF) tumors. We validated the LTF phenotype and associated epigenetic and transcriptional defects in some cancer cell lines, and showed that severe loss of transcriptional fidelity can confer resistance to pro-inflammatory anti-tumor mechanisms in vitro, and suppress immune-mediated tumor rejection in vivo. As such, we found that LTF predicted poor response to immunotherapeutic, but not to chemo- or targeted therapy, agents in the clinic, including immune checkpoint inhibitors, in 3 different cohorts. Therefore, LTF is a previously unknown global phenotype in cancer cells that confers cell-autonomous resistance to anti-tumor immune attacks. Tumor lymphocyte infiltration is one of the best markers of immunotherapy response in the clinic. However, LTF+ tumors were characterized by a higher rate of immune cell infiltration, but paradoxically, less immune-mediated local tumor cell lysis, further supporting the notion that LTF is a tumor cell-autonomous mechanism of immune resistance. As such, combining tumor lymphocyte infiltration with LTF had superior power in predicting the progression-free and overall survival of melanoma patients treated with the anti-CTLA4 antibody ipilimumab. This study uncovers a major phenotype in cancers that dictates global transcriptional and signaling state in the cell, and response to immunotherapeutic agents in the clinic. Further, this study warrants assessment of markers of LTF in immunotherapy-candidate patients, especially given that LTF+ kidney cancer patients had significantly better response to targeted therapy agents. Citation Format: Navneet Singh, Vishnu Modur, Vakul Mohanty, Kwangmin Choi, Edith M. Janssen, Lisa Privette-Vinnedge, Gang Huang, Kakajan Komurov. Loss of transcriptional fidelity in cancers confers immunotherapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B33.