Design of a virtual data shelf to effectively explore a large database of 3D medical surface models in VR.

PURPOSE: Medical researchers deal with a large amount of patient data to improve future treatment decisions and come up with new hypotheses. To facilitate working with a large database containing many patients and parameters, we propose a virtual data shelf, displaying the 3D anatomical surface models in an immersive VR environment. METHODS: Thereby, different functionalities such as sorting, filtering and finding similar cases are included. To provide an appropriate layout and arrangement of 3D models that optimally supports working with the database, three layouts (flat, curved and spherical) and two distances are evaluated. A broad audience study with 61 participants was conducted to compare the different layouts based on their ease of interaction, to get an overview and to explore single cases. Medical experts additionally evaluated medical use cases. RESULTS: The study revealed that the flat layout with small distance is significantly faster in providing an overview. Applying the virtual data shelf to the medical use case intracranial aneurysms, qualitative expert feedback with two neuroradiologists and two neurosurgeons was gathered. Most of the surgeons preferred the curved and spherical layouts. CONCLUSION: Our tool combines benefits of two data management metaphors, resulting in an efficient way to work with a large database of 3D models in VR. The evaluation gives insight into benefits of layouts as well as possible use cases in medical research.

Flow Diversion for ICA Aneurysms with Compressive Neuro-Ophthalmologic Symptoms: Predictors of Morbidity, Mortality, and Incomplete Aneurysm Occlusion.

BACKGROUND AND PURPOSE: Flow diversion is an effective treatment for aneurysms of the ICA with compression-related neuro-ophthalmologic symptoms, especially when treatment is initiated early after symptom onset and aneurysm occlusion is complete. However, non-negligible complication rates have been reported. Our aim was to identify risk factors for morbidity/mortality and incomplete aneurysm occlusion. MATERIALS AND METHODS: We performed a secondary analysis of a previous publication, which included all patients treated with flow diversion for an unruptured aneurysm of the ICA with compression-related symptoms. RESULTS: Fifty-four patients with 54 aneurysms (48 women, 88.9%; mean age, 59.2 [SD, 15.9] years; range, 21-86 years) treated with flow diversion were included. We observed morbidity and mortality rates of 7.4% and 3.7%. Increasing age (OR per decade, 3.2; 95% CI, 1.23-8.49; P = .02) and dual-antiplatelet therapy with ticagrelor (OR, 13.9; 95% CI, 1.16-165.97; P = .04) were significantly associated with morbidity/mortality. After a median follow-up of 13.3 [SD, 10.5] months, the rates of complete aneurysm occlusion, neck remnant, and aneurysm remnant were 74%, 14%, and 12%. Incomplete occlusion at follow-up was less frequently observed in aneurysms treated with additional coil embolization (OR, 0.1; 95% CI, 0.01-0.86; P = .04). CONCLUSIONS: Although a promising treatment for compressive ICA aneurysms, flow diversion carries a relevant risk for complications and incomplete aneurysm occlusion. Our results may help identify patients in which flow diversion may not be the ideal treatment method. Additional coil embolization increased the likelihood of complete aneurysm occlusion at follow-up.

True first-pass effect in basilar artery occlusions: First-pass complete reperfusion improves clinical outcome in stroke thrombectomy patients.

BACKGROUND: Complete reperfusion (mTICI 3) in anterior circulation ischemic stroke patients after a single mechanical thrombectomy (MT) pass has been identified as a predictor of favorable outcome (modified Rankin Score 0-2) and defined as true first-pass effect recently. This effect has not yet been demonstrated in posterior circulation ischemic stroke. We hypothesized a true first-pass effect for the subgroup of acute basilar artery occlusions (BAO). METHODS: Consecutive patients with acute thromboembolic occlusions in the posterior circulation, treated between 2010 and 2017, were screened and all BAO patients with complete angiographic reperfusion and known symptom onset included for unmatched and matched analysis after adjustment for multiple confounding factors (demographics, time intervals, stroke severity, posterior circulation Alberta Stroke Program early computed tomography Score and comorbidity. The primary objective was outcome at 90 days between matched cohorts of single pass vs. multi pass complete reperfusion patients. RESULTS: 90 MTs in BAO were analyzed, yielding 56 patients with known symptom onset, in whom we achieved complete reperfusion (mTICI 3), depending on whether complete reperfusion was achieved after a single pass (n = 28) or multiple passes (n = 28). Multivariable analysis of 56 non-matched patients revealed a significant association between first-pass complete reperfusion and favorable outcome (p < 0.01). In matched cohorts (n = 7 vs. n = 7), favorable outcome was only seen if complete reperfusion was achieved after a single pass (86% vs. 0%). CONCLUSION: Single pass complete reperfusion in acute basilar artery occlusion is an independent predictor of favorable outcome. Achieving complete reperfusion after multiple passes might impair favorable patient recovery.

Aneurysm Treatment in Acute SAH with Hydrophilic-Coated Flow Diverters under Single-Antiplatelet Therapy: A 3-Center Experience.

BACKGROUND AND PURPOSE: In certain clinical circumstances, dual-antiplatelet therapy can be problematic in patients with acute SAH. In some aneurysms, however, flow-diverting stents are the ideal therapeutic option. We report our experience with ruptured intracranial aneurysms treated with flow diverters with hydrophilic coating (p48 MW HPC and p64 MW HPC) under single-antiplatelet therapy. MATERIALS AND METHODS: Patients were treated with either flow-diverter placement alone or a flow diverter and additional coiling. Due to the severity of the hemorrhage, the potential for periprocedural rehemorrhage, and the potential for additional surgical interventions, a single-antiplatelet regimen was used in all patients. RESULTS: Thirteen aneurysms were treated in 10 patients. The median age was 62 years; 5 patients were male. All had acute SAH due to aneurysm rupture. Four blood-blister, 2 dissecting, and 7 berrylike aneurysms were treated. Seven aneurysms were adjunctively coiled. Eight of the 10 patients received a single-antiplatelet protocol of aspirin, 1 patient was treated with prasugrel only, and 1 patient was treated with tirofiban first and then switched to the aspirin single-antiplatelet protocol. One device-related complication occurred, a thrombosis of an overstented branch. All stents, however, remained open at DSA, CTA, or MRA follow-up. CONCLUSIONS: The implantation of flow diverters with reduced thrombogenicity due to hydrophilic surface coating under single-antiplatelet therapy seems to be an option in carefully selected cases of SAH due to aneurysm rupture.

Impact of Time on Thrombolysis in Cerebral Infarction Score Results.

PURPOSE: Extended thrombolysis in cerebral infarction (eTICI) score results of 2b or higher are known to be predictors for favorable outcome after acute stroke. Additionally, time is a major factor influencing outcome after ischemic stroke. Until today only little is known about the impact of time on angiographic results regarding the outcome after mechanical thrombectomy; however, this impact might be of interest if an initially unfavorable angiographic result has to be improved. METHODS: Retrospective study of 164 patients with large vessel occlusion of the anterior circulation treated by mechanical thrombectomy. Multiple logistic regression analysis of relevant periprocedural and procedural times in respect to the probability of achieving functional independence at 90 days in respect to different eTICI results was performed to build a time and TICI score-dependent model for outcome prediction in which the influence of time was assumed to be steady among the TICI grades. RESULTS: The probability of achieving a favorable outcome is significantly different between eTICI2b-50, 67, TICI2c and TICI3 results (p < 0.001). The odds for achieving a favorable outcome decrease over time and differ for each TICI category and time point. The individual odds for each patient, time point and TICI grade can be calculated based on this model. CONCLUSION: The impact of periprocedural and procedural times and eTICI reperfusion results adds a new dimension to the decision-making process in patients with primary unfavorable angiographic results.

The problem of strict image-based inclusion criteria for mechanical thrombectomy - an analysis of stroke patients with an initial low CBV-ASPECTS score.

INTRODUCTION: Endovascular treatment for acute ischaemic stroke with large artery occlusion has become the standard of care. However, the question if a subgroup of patients, with a low cerebral blood volume Alberta Stroke Program Early CT score (CBV-ASPECTS) ≤ 7 should be excluded from endovascular treatment remains open. Therefore; we investigated the difference of outcome between patients who were treated by endovascular treatment vs patients who did not receive endovascular treatment. METHODS: We retrospectively analysed our stroke database for all patients who presented within six hours of onset with unfavourable imaging findings and who received endovascular treatment or best medical treatment alone. Unfavourable imaging was defined as a CBV-ASPECTS ≤ 7, which was an exclusion criterion for endovascular treatment at our institution before 2015. RESULTS: From 60 patients with an initial CBV-ASPECTS ≤ 7, 40 received best medical treatment and 20 were treated with endovascular treatment. Arterial hypertension and atrial fibrillation was more present in patients without endovascular treatment, the other baseline characteristics and percentage of patients treated with intravenous recombinant tissue plasminogen activator were not significantly different in both groups. At discharge, 40% of the interventional treated patients had a favourable outcome (eight of 20 (40%) vs six of 40 (15%; p = 0.031). The median values of the National Institute of Health Stroke Score and modified Rankin Scale at discharge were significantly lower in the treated cohort (6.5 (2.5-10.5) vs 16 (9.5-22.5); p = 0.006; 3 (0-5.5) vs 5 (4.5-5.5); p = 0.003). CONCLUSION: Patients with a CBV-ASPECTS ≤ 7 are likely to benefit from therapy and therefore may not be excluded from endovascular treatment. Further randomised trials are warranted to validate the data.

How to Size Intracranial Aneurysms: A Phantom Study of Invasive and Noninvasive Methods.

BACKGROUND AND PURPOSE: Endovascular treatment of intracranial aneurysms has relevantly changed over the past decades. Multiple new devices such as intrasaccular flow diverters have broadened the treatment spectrum but require very exact aneurysm sizing. In this study, we investigated multidetector and flat panel angiographic CT and digital subtraction imaging as well as different postprocessing methods (multiplanar reconstruction, volume-rendering technique, 3D DSA, and conventional 2D angiography) for their ability to exactly size 2 aneurysm models. MATERIALS AND METHODS: Two aneurysm models with known aneurysm sizes were placed inside a human skull. After injection of iodine contrast media, imaging was performed using a 128-slice CT scanner or an Artis Q biplane angiosuite, respectively. Aneurysms were measured for width, neck, and height, and the mean difference from the known sizes was calculated for each technique. The technique with the most exact measurement was defined as the criterion standard. We performed Bland-Altman plots comparing all techniques against the criterion standard. RESULTS: Angiograms adjusted according a previous 3D run with a short object-to-detector distance resulted in the most exact aneurysm measurement: -0.07 ± 0.61 mm for aneurysm 1 and 0.17 ± 0.39 mm for aneurysm 2. Measurements of conventional DSA images were similar, and CT-based images were significantly inferior to the criterion standard. CONCLUSIONS: 2D DSA with a short objective-to-detector distance adjusted according to a previous 3D run resulted in the most exact aneurysm measurement and should therefore be performed before all endovascular aneurysm treatments.

Diagnosing Early Ischemic Changes with the Latest-Generation Flat Detector CT: A Comparative Study with Multidetector CT.

BACKGROUND AND PURPOSE: One-stop management of mechanical thrombectomy-eligible patients with large-vessel occlusion represents an innovative approach in acute stroke treatment. This approach reduces door-to-reperfusion times by omitting multidetector CT, using flat detector CT as pre-mechanical thrombectomy imaging. The purpose of this study was to compare the diagnostic performance of the latest-generation flat detector CT with multidetector CT. MATERIALS AND METHODS: Prospectively derived data from patients with ischemic stroke with large-vessel occlusion and mechanical thrombectomy were analyzed in this monocentric study. All included patients underwent multidetector CT before referral to our comprehensive stroke center and flat detector CT in the angiography suite before mechanical thrombectomy. Diagnosis of early ischemic signs, quantified by the ASPECTS, was compared between modalities using cross tables, the Pearson correlation, and Bland-Altman plots. The predictive value of multidetector CT- and flat detector CT-derived ASPECTS for functional outcome was investigated using area under the receiver operating characteristic curve analysis. RESULTS: Of 25 patients, 24 (96%) had flat detector CT with sufficient diagnostic quality. Median multidetector CT and flat detector CT ASPECTSs were 7 (interquartile range, 5.5-9 and 4.25-8, respectively) with a mean period of 143.6 ± 49.5 minutes between both modalities. The overall sensitivity was 85.1% and specificity was 83.1% for flat detector CT ASPECTS compared with multidetector CT ASPECTS as the reference technique. Multidetector CT and flat detector CT ASPECTS were strongly correlated (r = 0.849, P < .001) and moderately predicted functional outcome (area under the receiver operating characteristic curve, 0.738; P = .007 and .715; P = .069, respectively). CONCLUSIONS: Determination of ASPECTS on flat detector CT is feasible, showing no significant difference compared with multidetector CT ASPECTS and a similar predictive value for functional outcome. Our findings support the use of flat detector CT for emergency stroke imaging before mechanical thrombectomy to reduce door-to-groin time.

Unenhanced Time-of-Flight MR Angiography versus Gadolinium-Enhanced Time-of-Flight MR Angiography in the Follow-Up of Coil-Embolized Aneurysms.

Background and Purpose Coil embolization of ruptured and unruptured aneurysms has emerged as a widely accepted alternative to clipping. Unfortunately, coil-embolized aneurysms need a long-term imaging follow-up to confirm the stability of the occlusion status. We investigated whether contrast-enhanced time-of-flight (ToF) magnetic resonance angiography (MRA) (gadolinium [Gd]-ToF) provides any diagnostic benefit over conventional ToF MRA (nonenhanced [NE]-ToF) in this context. Material and Methods From October 2013 to January 2015, all patients who were regularly scheduled for their follow-up after coil embolization were examined with Gd-ToF and NE-ToF angiography. The general visibility of the occlusion result was compared between the two MRAs as well as with the last digital subtraction angiography (DSA) available. Subgroups of interest (follow-up after stent-assisted coil embolization, cases with already known aneurysm remnants) were also analyzed. Results A total of 70 patients (44 female) harboring 74 treated aneurysms were examined. The reproducibility of the DSA result in terms of therapeutic relevance was 100%. In 10 of 74 cases (14%), the aneurysm status was more difficult to judge in the NE-ToF images (p = 0.02), and the visualization of small vessels was significantly better in the Gd-ToF (p = 0.003). NE-ToF did not fail to show any aneurysm remnants but were more difficult to depict in 35% of the cases (p = 0.09). Regarding the aneurysms that were coiled with stent assistance, there was no significant difference in terms of the visualization (p = 0.1). Conclusion Gd-ToF angiography is in general not superior to NE- ToF for the follow-up of coil-embolized aneurysms.

First-line lesional aspiration in acute stroke thrombectomy using a novel intermediate catheter: Initial experiences with the SOFIA.

INTRODUCTION: Five randomized controlled trials (RCTs) on endovascular therapy (EVT) of stroke have proven a clinical benefit over conservative treatment or IV-thrombolysis alone. Lesional clot aspiration with a dedicated system can achieve revascularization without an additional retriever (a direct-aspiration first-pass technique, ADAPT), and the SOFIA has been shown to be both safe and efficacious in a multicentric retrospective study. We have evaluated a subset of these data acquired in two major stroke centers with regard to using the SOFIA for first-line lesional aspiration. METHODS: Thirty patients with large-vessel occlusions treated with first-line lesional aspiration were identified. Procedural data, clot length, reperfusion success (mTICI), procedural timings, complications, and clinical status at admission, discharge and at 90 days were analyzed. RESULTS: The median baseline NIHSS was 16. IV thrombolysis was administered in 15/30 patients. Ninety-three percent of occlusions were in the anterior circulation. TICI ≥ 2b was achieved in 90% of multimodality treatments; lesional aspiration was successful in 67% within a median time of 20 minutes. The highest first-attempt success rate was in MCA occlusions (median time to recanalization 10 minutes). There were no device-related events. Symptomatic intracerebral hemorrhage (sICH) occurred in 10%, but never with sole lesional aspiration. Embolization to new territories was recorded in 1/30 (3%). Median discharge NIHSS was 7; 30% were mRS ≤ 2 at discharge and 43% at 90-day follow-up. CONCLUSIONS: Lesional aspiration with SOFIA is in line with published data. The SOFIA may be used as a first-line device, aiming at fast recanalization by sole aspiration with good safety and efficacy. If unsuccessful, it converts into part of a stent retriever-based multimodality treatment.

Emergency Stenting of the Extracranial Internal Carotid Artery in Combination with Anterior Circulation Thrombectomy in Acute Ischemic Stroke: A Retrospective Multicenter Study.

BACKGROUND AND PURPOSE: Several small case series reported a favorable clinical outcome for emergency stent placement in the extracranial internal carotid artery combined with mechanical thrombectomy in acute stroke. The rate of postinterventional symptomatic intracranial hemorrhages was reported to be as high as 20%. Therefore, we investigated the safety and efficacy of this technique in a large multicentric cohort. MATERIALS AND METHODS: The data bases of 4 German stroke centers were screened for all patients who received emergency stent placement of the extracranial internal carotid artery in combination with mechanical thrombectomy of the anterior circulation between 2007 and 2014. The primary outcome measure was the rate of symptomatic intracranial hemorrhage according to the European Cooperative Acute Stroke Study III criteria; secondary outcome measures included the angiographic revascularization results and clinical outcome. RESULTS: One hundred seventy patients with a median age of 64 years (range, 25-88 years) were treated. They presented after a median of 98 minutes (range, 52-160 minutes) with a median NIHSS score of 15 (range, 12-19). Symptomatic intracranial hemorrhages occurred in 15/170 (9%) patients; there was no statistically significant difference among groups pertaining to age, sex, intravenous rtPA, procedural timings, and the rate of successful recanalization. In 130/170 (77%) patients, a TICI score of ≥ 2b could be achieved. The in-hospital mortality rate was 19%, and 36% of patients had a favorable outcome at follow-up. CONCLUSIONS: Emergency stent placement in the extracranial internal carotid artery in combination with anterior circulation thrombectomy is effective and safe. It is not associated with a significantly higher risk of symptomatic intracranial hemorrhage compared with published series for mechanical thrombectomy alone.

Single-Layer WEBs: Intrasaccular Flow Disrupters for Aneurysm Treatment­Feasibility Results from a European Study.

BACKGROUND AND PURPOSE: The safety and efficiency of the dual-layer Woven EndoBridge (WEB) device has already been published. However, this international multicenter study sought to evaluate the safety of single-layer devices, which are the newest generation of the WEB intrasaccular flow-disrupter family. They have been designed to offer smaller-sized devices with a lower profile to optimize navigability and delivery, which may, in turn, broaden their range of use. MATERIALS AND METHODS: Data from all consecutive patients treated with a single-layer WEB device, in 10 European centers from June 2013 to May 2014 were included. Clinical presentations, technical details, intra- and perioperative complications, and outcomes at discharge were recorded. Clinical and angiographic data at last follow-up were also analyzed when available. RESULTS: Ninety patients with 98 WEB-treated aneurysms were included in this study. In 93 cases (95%), WEB placement was possible. Complete occlusion at the end of the procedure was obtained in 26 instances (26%). Additional treatment during the procedure (coiling and/or stent placement) was necessary in 12 cases (12.7%). Procedure-related complications occurred in 13 cases, leading to permanent neurologic deficits in 4 patients (4.4%). Early vascular imaging follow-up data were available for 44 patients (57%), with an average time interval of 3.3 months. Treatment-related morbidity and mortality rates at last follow-up were 2.2% and 1.1%, respectively. CONCLUSIONS: In this study, the feasibility and safety of the single-layer WEB device was comparable with that of the double-layer. However, further studies are needed to evaluate long-term efficacies.

Woven EndoBridge Intrasaccular Flow Disrupter for the Treatment of Ruptured and Unruptured Wide-Neck Cerebral Aneurysms: Report of 55 Cases.

BACKGROUND AND PURPOSE: The safety and efficacy of the Woven EndoBridge (WEB) device for the treatment of cerebral aneurysms have been investigated in several studies. Most of these studies focused on specific aneurysms or a certain WEB device. Our objective was to report the experience of 2 German centers with the WEB device, including technical feasibility, safety, and short-term angiographic outcome. MATERIALS AND METHODS: We performed a retrospective study of all ruptured and unruptured aneurysms that were treated with a WEB device (WEB Double-Layer, Single-Layer, and Single-Layer Sphere) between April 2012 and August 2014. Primary outcome measures included the feasibility of the implantation and the angiographic outcome at 3-month follow-up. Secondary outcome measures included the clinical outcome at discharge and procedural complications. RESULTS: Fifty-five aneurysms in 52 patients, including 14 ruptured aneurysms, underwent treatment with the WEB device. The median age of patients was 55 years (range, 30-75 years); 19/55 (37%) were men. The device could be deployed in all patients and was implanted in 51/55 (93%) cases. Procedural complications occurred in 6/51 (12%), comprising 2 thromboembolic events, 2 thrombus formations, 1 high-grade posterior cerebral artery stenosis, and 1 aneurysm rupture. None of these had clinical sequelae. Angiographic follow-up at 3 months was available for 44/51 (86%) aneurysms. A favorable angiographic result at 3 months was achieved in 29/44 (66%) cases, whereas the percentage of good anatomic results increased from 40% in 2012 to 75% in 2014. CONCLUSIONS: The WEB device proved to be safe. Acceptable occlusion rates can be achieved but seem to require wide experience with the device.

Acute Basilar Artery Occlusion with Underlying High-Grade Basilar Artery Stenosis: Multimodal Endovascular Therapy in a Series of Seven Patients.

PURPOSE: Acute basilar artery occlusion is associated with high rates of major morbidity and mortality. In rare cases, the underlying pathology is a high-grade stenosis of the basilar artery. We report on a series of seven cases with occluded high-grade basilar artery stenosis who received endovascular therapy at our center. MATERIAL AND METHODS: Our prospective database since October 2009 until September 2013 was screened for patients with acute basilar artery occlusion and underlying high-grade stenosis who underwent endovascular therapy. Case files were retrospectively reviewed for clinical, outcome, and technical data. RESULTS: Seven patients were identified who suffered from an acute basilar artery occlusion based on a high-grade stenosis between October 2009 and September 2013. These patients were treated with an acute stenting of the basilar artery with or without a preceding mechanical thrombectomy. Median age was 75 (53-83) years; median prethrombectomy National Institute of Health Stroke scale score was 19 (7-28). A successful recanalization result defined as modified Thrombolysis In Cerebral Infarction grade 2b or higher was achieved in all cases. Two of the seven patients had a procedural complication consisting of a vessel dissection after angioplasty. A good clinical outcome according to the Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT) study criteria was achieved in three of the seven patients. One patient died during hospitalization in the acute phase. CONCLUSION: Mechanical thrombectomy combined with acute stenting of the basilar artery is technically feasible and may be an effective therapeutic option in the rare case of an acutely occluded high-grade stenosis of the basilar artery in patients with an otherwise poor prognosis.

M1 is not M1 in ischemic stroke: the disability-free survival after mechanical thrombectomy differs significantly between proximal and distal occlusions of the middle cerebral artery M1 segment.

AIMS: Recent recommendations on the designation of target artery lesions in acute ischemic stroke include the anatomical differentiation between a proximal and a distal occlusion site of the M1 segment of the middle cerebral artery (MCA). The aim of this study was to evaluate whether these occlusion types differ in terms of a disability-free (modified Rankin Scale (mRS) 0 or 1) clinical outcome at 90 days. METHODS: A retrospective analysis was performed of all patients with MCA M1 occlusions who had a successful revascularization result after mechanical thrombectomy between October 2009 and September 2013 and for whom follow-up at 90 days was available. Imaging data were regraded and re-evaluated according to the modified Thrombolysis In Cerebral Infarction (mTICI) scale and the respective vessel occlusion site definitions. Outcome measures included National Institutes of Health Stroke Scale (NIHSS), mRS, Alberta Stroke Program Early CT Score (ASPECTS) scoring and procedural timings. RESULTS: 62 patients were successfully recanalized; follow-up at 90 days was available for 42/62 patients (68%). There were proximal MCA occlusions in 24/42 patients (57%) and distal occlusions in 18/42 (43%). Baseline NIHSS, ASPECTS, procedural timings and final mTICI scores did not differ significantly between proximal and distal M1 occlusions. There was a statistically significant difference between proximal and distal M1 occlusions regarding a disability-free early outcome (mRS 0 or 1) at discharge (p=0.03) and at 90 days (p=0.04). CONCLUSIONS: Proximal occlusions of the M1 segment of the MCA incorporating the lenticulostriate perforators are associated with a poorer clinical outcome than distal M1 occlusions that spare these perforators. Involvement of these perforators might become an additional predictor of clinical outcome after mechanical thrombectomy in ischemic stroke.

ß-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis.

A role of WNT signaling for primary breast cancers of the basal-like subtype and as a predictor of brain metastasis has been described. However, a responsible WNT ligand has not been identified. To further clarify this question, we comparatively investigated 22 human breast cancer brain metastases as well as the highly invasive human breast cancer cell line MDA-MB-231 and the weakly motile MCF-7 as models for the basal-like and the luminal A subtype. WNT5A and B were found overexpressed in MDA-MB-231 cells as compared with MCF-7. This corresponded to reduction of MDA-MB-231 invasiveness by WNT inhibitors, whereas MCF-7 invasion was enhanced by recombinant WNT5B and abolished by WNT and Jun-N-terminal kinase antagonists. Expression and subcellular distribution of ß-catenin remained uninfluenced. Consistently, ß-catenin was not localized in the nuclei of brain metastases while there was strong nuclear c-Jun staining. Similar to MDA-MB-231, metastases showed expression of WNT5A/B and the alternative WNT receptors ROR1 and 2. These findings were validated using external gene expression datasets (Gene Expression Omnibus) of different breast cancer subtypes and brain metastases. Hierarchical cluster analysis yielded a close relation between basal-like cancers and brain metastases. Gene set enrichment analyses confirmed WNT pathway enrichment not only in basal-like primaries but also in cerebral metastases of all subtypes. In conclusion, WNT signaling seems highly relevant for basal-like and other subtypes of breast cancers metastasizing into the brain. ß-catenin-independent WNT signaling, presumably via ROR1-2, plays a major role in this context.