Cancer and stroke : commonly encountered by clinicians, but little evidence to guide clinical approach

The association between stroke and cancer is well-established. Because of an aging population and longer survival rates, the frequency of synchronous stroke and cancer will become even more common. Different pathophysiologic mechanisms have been proposed how cancer or cancer treatment directly or via coagulation disturbances can mediate stroke. Increased serum levels of D-dimer, fibrin degradation products, and CRP are more often seen in stroke with concomitant cancer, and the clot retrieved during thrombectomy has a more fibrin- and platelet-rich constitution compared with that of atherosclerotic etiology. Multiple infarctions are more common in patients with active cancer compared with those without a cancer diagnosis. New MRI techniques may help in detecting typical patterns seen in the presence of a concomitant cancer. In ischemic stroke patients, a newly published cancer probability score can help clinicians in their decision-making when to suspect an underlying malignancy in a stroke patient and to start cancer-screening studies. Treating stroke patients with synchronous cancer can be a delicate matter. Limited evidence suggests that administration of intravenous thrombolysis appears safe in non-axial intracranial and non-metastatic cancer patients. Endovascular thrombectomy is probably rather safe in these patients, but probably futile in most patients placed on palliative care due to their advanced disease. In this topical review, we discuss the epidemiology, pathophysiology, and prognosis of ischemic and hemorrhagic strokes as well as cerebral venous thrombosis and concomitant cancer. We further summarize the current evidence on acute management and secondary preventive therapy.Peer reviewe

Serotonergic modulation of the ventral pallidum by 5HT1A, 5HT5A, 5HT7 AND 5HT2C receptors

Introduction: Serotonin's involvement in reward processing is controversial. The large number of serotonin receptor sub-types and their individual and unique contributions have been difficult to dissect out, yet understanding how specific serotonin receptor sub-types contribute to its effects on areas associated with reward processing is an essential step. Methods: The current study used multi-electrode arrays and acute slice preparations to examine the effects of serotonin on ventral pallidum (VP) neurons. Approach for statistical analysis: extracellular recordings were spike sorted using template matching and principal components analysis, Consecutive inter-spike intervals were then compared over periods of 1200 seconds for each treatment condition using a student’s t test. Results and conclusions: Our data suggests that excitatory responses to serotonin application are pre-synaptic in origin as blocking synaptic transmission with low-calcium aCSF abolished these responses. Our data also suggests that 5HT1a, 5HT5a and 5HT7 receptors contribute to this effect, potentially forming an oligomeric complex, as 5HT1a antagonists completely abolished excitatory responses to serotonin application, while 5HT5a and 5HT7 only reduced the magnitude of excitatory responses to serotonin. 5HT2c receptors were the only serotonin receptor sub-type tested that elicited inhibitory responses to serotonin application in the VP. These findings, combined with our previous data outlining the mechanisms underpinning dopamine's effects in the VP, provide key information, which will allow future research to fully examine the interplay between serotonin and dopamine in the VP. Investigation of dopamine and serotonins interaction may provide vital insights into our understanding of the VP's involvement in reward processing. It may also contribute to our understanding of how drugs of abuse, such as cocaine, may hijack these mechanisms in the VP resulting in sensitization to drugs of abuse

EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients (EVA-TRISP) registry: basis and methodology of a pan-European prospective ischaemic stroke revascularisation treatment registry.

PURPOSE The Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration was a concerted effort initiated in 2010 with the purpose to address relevant research questions about the effectiveness and safety of intravenous thrombolysis (IVT). The collaboration also aims to prospectively collect data on patients undergoing endovascular treatment (EVT) and hence the name of the collaboration was changed from TRISP to EVA-TRISP. The methodology of the former TRISP registry for patients treated with IVT has already been published. This paper focuses on describing the EVT part of the registry. PARTICIPANTS All centres committed to collecting predefined variables on consecutive patients prospectively. We aim for accuracy and completeness of the data and to adapt local databases to investigate novel research questions. Herein, we introduce the methodology of a recently constructed academic investigator-initiated open collaboration EVT registry built as an extension of an existing IVT registry in patients with acute ischaemic stroke (AIS). FINDINGS TO DATE Currently, the EVA-TRISP network includes 20 stroke centres with considerable expertise in EVT and maintenance of high-quality hospital-based registries. Following several successful randomised controlled trials (RCTs), many important clinical questions remain unanswered in the (EVT) field and some of them will unlikely be investigated in future RCTs. Prospective registries with high-quality data on EVT-treated patients may help answering some of these unanswered issues, especially on safety and efficacy of EVT in specific patient subgroups. FUTURE PLANS This collaborative effort aims at addressing clinically important questions on safety and efficacy of EVT in conditions not covered by RCTs. The TRISP registry generated substantial novel data supporting stroke physicians in their daily decision making considering IVT candidate patients. While providing observational data on EVT in daily clinical practice, our future findings may likewise be hypothesis generating for future research as well as for quality improvement (on EVT). The collaboration welcomes participation of further centres willing to fulfill the commitment and the outlined requirements

Supplemental material for Endovascular treatment of acute ischemic stroke in the posterior circulation

<p>Supplemental material for Endovascular treatment of acute ischemic stroke in the posterior circulation by Alexandros Rentzos, Jan-Erik Karlsson, Christer Lundqvist, Lars Rosengren, Mikael Hellström and Gunnar Wikholm in Interventional Neuroradiology</p

The impact of occlusion location and bridging therapy in patients affected by acute ischemic stroke in determining the total number of passes required to remove the clot and the final revascularization outcome

Purpose Our purpose was to assess the impact of occlusion location in patients suffering from Acute Ischemic Stroke (AIS) on the total number of passes (attempts) necessary to retrieve the clot and on final revascularization outcome. Moreover, we analysed the impact of bridging-therapy, i.e. the concomitant use of IV tPA (intravenous tissue plasminogen activator) and mechanical thrombectomy (MT) on the different categories of occlusion locations. Methods 550 mechanically extracted thrombi were collected from four partner hospitals: Beaumont (Dublin) Sahlgrenska (Gothenburg), National Institute of Clinical Neurosciences (Budapest) and Metropolitan Hospital (Piraeus). In the vast majority of the cases (311 patients, 56.5%) the thrombus was located in the Middle Cerebral Artery (MCA), followed by Carotid Terminus/Internal Carotid Artery (ICA) in 89 cases (16.2%) and by vertebral/basilar artery (45 patients, 8.2%). In 65 cases (11.8%) a tandem occlusion, i.e. the occlusion of both ICA and MCA was found, while a dual occlusion occurred in 26 cases (4.7%). 248 patients (45.1%) underwent bridging-therapy, while 291 patients (52.9%) were treated with MT alone. For 11 patients (2%) we have no information whether tPA was administered or not. Recanalization rate was defined by using the modified Thrombolysis In Cerebral Infarction (mTICI) score. Non-parametric Kruskal-Wallis test using IBM SPSS-25 software was used for statistical analysis. Results Occlusion location had a significant impact on the total number of passes required to retrieve the clot as well as on final revascularization outcome. The cases with tandem and dual occlusion showed higher number of procedural passes and lower percentage of complete revascularizations (mTICI=3, Table 1). Bridging-therapy did not significantly reduce the total number of passes or improve the recanalization rates for patients with singular occlusion. On the other hand, bridging-therapy significantly lowered the total number of passes to remove the clot in patients with dual and tandem occlusion (N=87, mean for MT+tPA= 2.63±1.73, MT alone=3.80±2.14, H1=7.608, p=0.006*), but had no statistically significant effect on the final mTICI score (N=87, H1=0.266, p=0.606). Conclusion This study suggests that occlusion location significantly influences the total number of procedural passes in MT procedures as well as the final revascularization outcome. Furthermore, bridging-therapy lowers the number of procedural passes in cases of tandem and dual occlusion without having significant effect on final mTICI score. Funding: Science Foundation Ireland (Grant Number 13/RC/2073) and Cerenovus.Science Foundation Ireland (Grant Number 13/RC/2073) and Cerenovus.non-peer-reviewe

Histological characterization of white clots retrieved by mechanical thrombectomy from acute ischemic stroke patients

Introduction: Advances in mechanical thrombectomy have created the unique opportunity to study the acute ischemic stroke clot material. However, there is a lack of uniformity in the histopathologic characterization of thrombi. Many clots are mainly red in colour and predominantly composed of Red Blood Cells and Fibrin. In this context, white clots represent a less common entity and their histological composition is largely unknown. We investigated the histopathological features of 21 white clots retrieved by thrombectomy. To our knowledge, this is the first series reported to date. Methods: Twenty one mechanically extracted white thrombi were collected from two partner hospitals: Beaumont Hospital and Sahlgrenska University Hospital. Clots were immediately formalin-fixed and subsequently embedded in paraffin. For each case, serial sections of 3-µm thickness were cut and stained with Hematoxylin & Eosin and Martius Scarlett Blue (MSB) for the identification of main clot components. The MSB-stained slide underwent whole slide scanning (Olympus VS120) and histologic quantification was performed using Orbit Image Analysis Software (Orbit Image Analysis, Idorsia Ltd.). Von Kossa staining was performed to confirm calcification when suspected. The presence of specific components was assessed by immunostaining for platelets (CD42b), von Willebrand Factor (vWF) and fatty-acid binding protein (FABP4) for adipocytes. Results: The quantification identified the Platelets as the major component in white clots accounting for up to 90% of their composition. The main components showed mean values of 75.67% for Platelets, 13.36% for Fibrin, 5.07% for Red Blood cells and 3.75% for White Blood Cells Immunostaining confirmed the presence of CD42b and vWF in all cases. Collagen and calcification were present in one case. Interestingly, adipocytes represented the main component in two cases. Conclusions: Platelets are the key component of white clots . Calcification and adipocytes are also found occasionally. Increased levels of platelets and calcium confer resistance to thrombolysis and may render clots stiffer and less accessible for stent retrievers leading to low recanalization rates. The presence of adipocytes may represent a histological marker of fat embolism when suspected or a vulnerable atherosclerotic plaque, especially if associated with collagen.Science Foundation Ireland (Grant Number 13/RC/2073) and Industrial partners Cerenovu

Does bridging therapy in mechanical thrombectomy increase recanalization rates in ischemic stroke patients affected by acute large vessel occlusion?

Both intravenous thrombolysis with tissue plasminogen activator (IV-rtPA) and mechanical thrombectomy (MT) increase recanalization rates. We assessed if bridging-therapy (the concomitant use of rtPA and MT) could increase the recanalization rates and reduce the number of procedural passes in patients suffering from acute ischemic stroke (AIS) when compared to MT alone. Analysis of type of device used, stentriever or aspiration catheter, is also reported. 334 mechanically extracted thrombi were collected from two partner hospitals: Beaumont (Dublin) and Sahlgrenska (Gothenburg). 158 patients (47.3%) were treated with bridging-therapy, while 176 (52.7%) underwent MT alone. Recanalization rate was defined by using the modified Thrombolysis In Cerebral Infarction (mTICI) score. Non-parametric Kruskal-Wallis test was used for statistical analysis. Bridging-therapy reduced the total number of passes to remove the clot (mean for MT+rtPA=2.27±2.10, MT alone=2.63±1.88, H1=4.376, p=0.036*). Analysing the device, rtPA lowered the overall number of passes using stentriever devices (mean for MT+rtPA=1.57±1.12, MT alone=2.36±1.48, H1=8.303, p=0.004*), but not for aspiration (mean for MT+rt-PA=1.78±1.22, MT alone=2.03±1.47, for H1=0.795, p=0.372). Also, when using both devices no significant reduction of number of passes was observed (mean for MT+rtPA=3.29±2.90, MT alone=3.83±2.20, H1=3.027, p=0.082). There was no significant effect on final mTICI score using bridging-therapy when compared to MT alone (H1=1.163, p=0.281). This small study suggests that bridging-therapy lowers the number of procedural passes in MT procedures, specifically when using stentriever devices. However, this did not have a significant effect on final mTICI score. Funding: Science Foundation Ireland (Grant Number 13/RC/2073) and Cerenovus.Funding: Science Foundation Ireland (Grant Number 13/RC/2073) and Cerenovus.non-peer-reviewe

Platelet-rich emboli are associated with von Willebrand factor levels and have poorer revascularization outcomes

Background and aims Platelets and von Willebrand factor (vWF) are key factors in thrombosis and thus are likely key components of acute ischemic stroke (AIS) emboli. We aimed to characterize platelet and vWF levels in AIS emboli and to assess associations between their expression levels and clinical and procedural information. Materials and method Histopathological and immunohistochemical analysis of emboli collected as part of the multi-institutional RESTORE registry was performed. The composition of the emboli was quantified using Orbit Image Analysis machine learning software. Correlations between clot components and clinical and procedural information were assessed using the χ2 test. Results Ninety-one emboli samples retrieved from 63 patients were analyzed in the study. The mean platelet (CD42b) content of the clots was 33.9% and the mean vWF content of the clots was 29.8%. There was a positive correlation between platelet and vWF levels (ρ=0.564, p<0.001*, n=91). There was an inverse correlation between both platelets and vWF levels and percentage of red blood cells (RBCs) in the emboli (CD42b vs RBC: ρ=−0.535, p<0.001*, n=91; vWF vs RBC: ρ=−0.366, p<0.001*, n=91). Eighty-one percent of patients in the low platelet group had a good revascularization outcome (Thrombolysis in Cerebral Infarction 2c/3) compared with 58% in the high platelet group (χ2=5.856, p=0.016). Conclusion Platelet and vWF levels in AIS emboli correlate with each other and both have an inverse relationship with RBC composition. Patients with platelet-rich clots have poorer revascularization outcomes.peer-reviewe