Our experimental data provide novel insights into the nonfibrinolytic properties of the fibrinolytic system and emphasize plasminogen activator inhibitor-1 as a promising target for the prevention and treatment of I/R injury.

Objective— Neutrophil infiltration of the postischemic tissue considerably contributes to organ dysfunction on ischemia/reperfusion injury. Beyond its established role in fibrinolysis, tissue-type plasminogen activator (tPA) has recently been implicated in nonfibrinolytic processes. The role of this serine protease in the recruitment process of neutrophils remains largely obscure. Approach and Results— Using in vivo microscopy on the postischemic cremaster muscle, neutrophil recruitment and microvascular leakage, but not fibrinogen deposition at the vessel wall, were significantly diminished in tPA −/− mice. Using cell transfer techniques, leukocyte and nonleukocyte tPA were found to mediate ischemia/reperfusion-elicited neutrophil responses. Intrascrotal but not intra-arterial application of recombinant tPA induced a dose-dependent increase in the recruitment of neutrophils, which was significantly higher compared with stimulation with a tPA mutant lacking catalytic activity. Whereas tPA-dependent transmigration of neutrophils was selectively reduced on the inhibition of plasmin or gelatinases, neutrophil intravascular adherence was significantly diminished on the blockade of mast cell activation or lipid mediator synthesis. Moreover, stimulation with tPA caused a significant elevation in the leakage of fluorescein isothiocyanate dextran to the perivascular tissue, which was completely abolished on neutrophil depletion. In vitro, tPA-elicited macromolecular leakage of endothelial cell layers was abrogated on the inhibition of its proteolytic activity. Conclusions— Endogenously released tPA promotes neutrophil transmigration to reperfused tissue via proteolytic activation of plasmin and gelatinases. As a consequence, tPA on transmigrating neutrophils disrupts endothelial junctions allowing circulating tPA to extravasate to the perivascular tissue, which, in turn, amplifies neutrophil recruitment through the activation of mast cells and release of lipid mediators.

Our objective was to predict the outcome of Y radioembolization in patients with intrahepatic tumors from pretherapeutic baseline parameters and to identify predictive variables using a machine-learning approach based on random survival forests. In this retrospective study, 366 patients with primary ( = 92) or secondary ( = 274) liver tumors who had received Y radioembolization were analyzed. A random survival forest was trained to predict individual risk from baseline values of cholinesterase, bilirubin, type of primary tumor, age at radioembolization, hepatic tumor burden, presence of extrahepatic disease, and sex. The predictive importance of each baseline parameter was determined using the minimal-depth concept, and the partial dependency of predicted risk on the continuous variables bilirubin level and cholinesterase level was determined. Median overall survival was 11.4 mo (95% confidence interval, 9.7-14.2 mo), with 228 deaths occurring during the observation period. The random-survival-forest analysis identified baseline cholinesterase and bilirubin as the most important variables (forest-averaged lowest minimal depth, 1.2 and 1.5, respectively), followed by the type of primary tumor (1.7), age (2.4), tumor burden (2.8), and presence of extrahepatic disease (3.5). Sex had the highest forest-averaged minimal depth (5.5), indicating little predictive value. Baseline bilirubin levels above 1.5 mg/dL were associated with a steep increase in predicted mortality. Similarly, cholinesterase levels below 7.5 U predicted a strong increase in mortality. The trained random survival forest achieved a concordance index of 0.657, with an SE of 0.02, comparable to the concordance index of 0.652 and SE of 0.02 for a previously published Cox proportional hazards model. Random survival forests are a simple and straightforward machine-learning approach for prediction of overall survival. The predictive performance of the trained model was similar to a previously published Cox regression model. The model has revealed a strong predictive value for baseline cholinesterase and bilirubin levels with a highly nonlinear influence for each parameter.

In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. Recently, intravascularly adherent leukocytes have been reported to shape the blood flow in their immediate vascular environment. Whether these rheological effects are relevant for microvascular thrombogenesis remains elusive. Employing multi-channel in vivo microscopy, analyses in microfluidic devices, and computational modeling, we identified a previously unanticipated role of leukocytes for microvascular clot formation in inflamed tissue. For this purpose, neutrophils adhere at distinct sites in the microvasculature where these immune cells effectively promote thrombosis by shaping the rheological environment for platelet aggregation. In contrast to larger (lower-shear) vessels, this process in high-shear microvessels does not require fibrin generation or extracellular trap formation, but involves GPIbα-vWF and CD40-CD40L-dependent platelet interactions. Conversely, interference with these cellular interactions substantially compromises microvascular clotting. Thus, leukocytes shape the rheological environment in the inflamed venular microvasculature for platelet aggregation thereby effectively promoting the formation of blood clots. Targeting this specific crosstalk between the immune system and the hemostatic system might be instrumental for the prevention and treatment of microvascular thromboembolic pathologies, which are inaccessible to invasive revascularization strategies.

Background and Purpose— Large vessel occlusion stroke leads to highly variable hyperacute infarction growth. Our aim was to identify clinical and imaging parameters associated with hyperacute infarction growth in patients with an large vessel occlusion stroke of the anterior circulation. Methods— Seven hundred twenty-two consecutive patients with acute stroke were prospectively included in our monocentric stroke registry between 2009 and 2017. We selected all patients with a large vessel occlusion stroke of the anterior circulation, documented times from symptom onset, and CT perfusion on admission for our analysis (N=178). Ischemic core volume was determined with CT perfusion using automated thresholds. Hyperacute infarction growth was defined as ischemic core volume divided by times from symptom onset, assuming linear progression during times from symptom onset to imaging on admission. For collateral assessment, the regional leptomeningeal collateral score (rLMC) was used. Clinical data included the National Institutes of Health Stroke Scale score on admission and cardiovascular risk factors. Regression analysis was performed to adjust for confounders. Results— Median ischemic core volume was 34.4 mL, and median hyperacute infarction growth was 0.27 mL/min. In regression analysis including age, sex, National Institutes of Health Stroke Scale, clot burden score, diabetes mellitus, smoking, hypercholesteremia, hypertension, Alberta Stroke Program Early CT Score, and rLMC scores, only the rLMC score had a significant, independent association with hyperacute infarction growth (adjusted β=−0.35; P <0.001). Trichotomizing patients by rLMC scores yielded 65 patients with good (rLMC >15), 67 with intermediate (rLMC 11–15) and 46 with poor collaterals (rLMC <11) with an infarction growth of 0.17 mL/min, 0.26 mL/min, and 0.41 mL/min, respectively. Conclusions— Hyperacute infarction growth strongly depends on collaterals. In primary stroke centers, hyperacute infarction growth may be extrapolated to estimate the stroke progression during transfer times to thrombectomy centers and to support decisions on which patients to transfer.

Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the related supratentorial region. Our aim was to analyze its influence on morphologic and functional outcome in acute ischemic stroke. Subjects with stroke caused by a large vessel occlusion of the anterior circulation were selected from an initial cohort of 1644 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Two experienced readers evaluated the posterior fossa in terms of CCD absence (CCD-) or presence (CCD+). A total of 156 patients formed the study cohort with 102 patients (65.4%) categorized as CCD- and 54 (34.6%) as CCD+. In linear and logistic regression analyses, no significant association between CCD and final infarction volume (β = -0.440, p = 0.972), discharge mRS ≤ 2 (OR = 1.897, p = 0.320), or 90-day mRS ≤ 2 (OR = 0.531, p = 0.492) was detected. CCD+ patients had larger supratentorial cerebral blood flow deficits (median: 164 ml vs. 115 ml; p = 0.001) compared to CCD-patients. Regarding complications, CCD was associated with a higher rate of parenchymal hematomas (OR = 4.793, p = 0.035). In conclusion, CCD is frequently encountered in acute ischemic stroke caused by large vessel occlusion of the anterior circulation. CCD was associated with the occurrence of parenchymal hematoma in the ipsilateral cerebral infarction but did not prove to significantly influence patient outcome.

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient’s own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with 18F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

WB-CTP provides added diagnostic value for the early identification of patients at risk for MCE development in acute cerebellar stroke.