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Background Breast cancer has been associated with activation of the WNT signaling pathway, although no driver mutations in WNT genes have been found yet. Instead, a high expression of the alternative WNT receptor ROR2 was observed, in particular in breast cancer brain metastases. However, its respective ligand and downstream signaling in this context remained unknown. Methods We modulated the expression of ROR2 in human breast cancer cells and characterized their gene and protein expression by RNA-Seq, qRT-PCR, immunoblots and reverse phase protein array (RPPA) combined with network analyses to understand the molecular basis of ROR2 signaling in breast cancer. Using co-immunoprecipitations, we verified the interaction of ROR2 with the identified ligand, WNT11. The functional consequences of WNT11/ROR2 signaling for tumor cell aggressiveness were assessed by microscopy, impedance sensing as well as viability and invasion assays. To evaluate the translational significance of our findings, we performed gene set enrichment, expression and survival analyses on human breast cancer brain metastases. Results We found ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. ROR2 overexpression induced a BRCAness-like phenotype in a cell-context specific manner and rendered cells resistant to PARP inhibition. High levels of ROR2 were furthermore associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. On a molecular level, ROR2 overexpression upregulated several non-canonical WNT ligands, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 indeed interacts with the cysteine-rich domain of ROR2 and triggers its invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Conclusions Taken together, our study revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.

Objective Glioblastoma with multiple foci (mGBM) and multiple brain metastases share several common features on magnetic resonance imaging (MRI). A reliable preoperative diagnosis would be of clinical relevance. The aim of this study was to explore the differences and similarities between mGBM and multiple brain metastases on MRI. Methods We performed a retrospective analysis of 50 patients with mGBM and compared them with a cohort of 50 patients with multiple brain metastases (2–10 lesions) histologically confirmed and treated at our department between 2015 and 2020. The following imaging characteristics were analyzed: lesion location, distribution, morphology, (T2-/FLAIR-weighted) connections between the lesions, patterns of contrast agent uptake, apparent diffusion coefficient (ADC)-values within the lesion, the surrounding T2-hyperintensity, and edema distribution. Results A total of 210 brain metastases and 181 mGBM lesions were analyzed. An infratentorial localization was found significantly more often in patients with multiple brain metastases compared to mGBM patients (28 vs. 1.5%, p  < 0.001). A T2-connection between the lesions was detected in 63% of mGBM lesions compared to 1% of brain metastases. Cortical edema was only present in mGBM. Perifocal edema with larger areas of diffusion restriction was detected in 31% of mGBM patients, but not in patients with metastases. Conclusion We identified a set of imaging features which improve preoperative diagnosis. The presence of T2-weighted imaging hyperintensity connection between the lesions and cortical edema with varying ADC-values was typical for mGBM.

BackgroundThe management of small unruptured incidentally discovered intracranial aneurysms (SUIAs) is still controversial. The aim of this study is to assess the safety of a management protocol of SUIAs, where selected cases with SUIAs are observed and secured only if signs of instability (growth) are documented.MethodsA prospective consecutive cohort of 292 patients (2006–2014) and 368 SUIAs (anterior circulation aneurysms (ACs) smaller than 7 mm and posterior circulation aneurysms smaller than 4 mm without previous subarachnoid haemorrhage) was observed (mean follow-up time of 3.2 years and 1177.6 aneurysm years). Factors associated with aneurysm growth were systematically reviewed from the literature.ResultsThe aneurysm growth probability was 2.6±0.1% per year. The rate of unexpected aneurysm rupture before treatment was 0.24% per year (95% CI 0.17% to 2.40%). The calculated rate of aneurysm rupture after growth was 6.3% per aneurysm-year (95% CI 1% to 22%). Aneurysms located in the posterior circulation and aneurysms with lobulation were more likely to grow. Females or patients suffering hypertension were more likely to have an aneurysm growing. The probability of aneurysms growth increased with the size of the dome and was proportional to the number of aneurysms diagnosed in a patient.ConclusionsIt is safe to observe patients diagnosed with SUIAs using periodic imaging. Intervention to secure the aneurysm should be performed after growth is observed.

To evaluate whether tumour-derived microvesicles (T-MV), originating from the plasma membrane, represent suitable cancer biomarkers, we isolated MV from peripheral blood samples of cancer patients with locally advanced and/or metastatic solid tumours (n = 330, including 79 head & neck cancers, 74 lung cancers, 41 breast cancers, 28 colorectal cancers and 108 with other cancer forms) and controls (n = 103). Whole MV preparations were characterised using flow cytometry. While MV carrying the tumour-associated proteins MUC1, EGFR and EpCAM were found to be enhanced in a tumour-subtype-specific way in patients' blood, expression of the matrix metalloproteinase inducer EMMPRIN was increased independent of tumour type. Higher levels of EMMPRIN + -MV correlated significantly with poor overall survival, whereas the other markers were prognostic only in specific tumour subgroups. By combining all four tumour-associated antigens, cancer patients were separated from healthy controls with an AUC of up to 0.85. Ex vivo, whole MV preparations from cancer patients, in contrast to those of controls, induced a tumour-supporting phenotype in macrophages and increased tumour cell invasion, which was dependent on the highly glycosylated isoform of EMMPRIN. In conclusion, the detection of T-MV in whole blood, even in minor amounts, is feasible with standard techniques, proves functionally relevant and correlates with clinical outcome.

Purpose Differentiating between glioblastoma (GB) with multiple foci (mGB) and multifocal central nervous system lymphoma (mCNSL) can be challenging because these cancers share several features at first appearance on magnetic resonance imaging (MRI). The aim of this study was to explore morphological differences in MRI findings for mGB versus mCNSL and to develop an interpretation algorithm with high diagnostic accuracy. Methods In this retrospective study, MRI characteristics were compared between 50 patients with mGB and 50 patients with mCNSL treated between 2015 and 2020. The following parameters were evaluated: size, morphology, lesion location and distribution, connections between the lesions on the fluid-attenuated inversion recovery sequence, patterns of contrast enhancement, and apparent diffusion coefficient (ADC) values within the tumor and the surrounding edema, as well as MR perfusion and susceptibility weighted imaging (SWI) whenever available. Results A total of 187 mCNSL lesions and 181 mGB lesions were analyzed. The mCNSL lesions demonstrated frequently a solid morphology compared to mGB lesions, which showed more often a cystic, mixed cystic/solid morphology and a cortical infiltration. The mean measured diameter was significantly smaller for mCNSL than mGB lesions ( p  < 0.001). Tumor ADC ratios were significantly smaller in mCNSL than in mGB (0.89 ± 0.36 vs. 1.05 ± 0.35, p  < 0.001). The ADC ratio of perilesional edema was significantly higher ( p  < 0.001) in mCNSL than in mGB. In SWI / T2*-weighted imaging, tumor-associated susceptibility artifacts were more often found in mCNSL than in mGB ( p  < 0.001). Conclusion The lesion size, ADC ratios of the lesions and the adjacent tissue as well as the vascularization of the lesions in the MR-perfusion were found to be significant distinctive patterns of mCNSL and mGB allowing a radiological differentiation of these two entities on initial MRI. A diagnostic algorithm based on these parameters merits a prospective validation.

Background Multimodality treatment suites for patients with cerebral arteriovenous malformations (AVM) have recently become available. This study was designed to evaluate feasibility, safety and impact on treatment of a new intraoperative flat-panel (FP) based integrated surgical and imaging suite for combined endovascular and surgical treatment of cerebral AVM. Methods Twenty-five patients with AVMs to treat with combined endovascular and surgical interventions were prospectively enrolled in this consecutive case series. The hybrid suite allows combined endovascular and surgical approaches with intraoperative scanner-like imaging (XperCT®) and intraoperative 3D rotational angiography (3D-RA). The impact of intraoperative multimodal imaging on feasibility, workflow of combined interventions, surgery, and unexpected imaging findings were analyzed. Results Twenty-five patients (mean age 38 ± 18.6 year) with a median Spetzler-Martin grade 2 AVM (range 1–4) underwent combined endovascular and surgical procedures. Sixteen patients presented with a ruptured AVM and nine with an unruptured AVM. In 16 % ( n  = 4) of cases, intraoperative imaging visualized AVM remnants ≤3 mm and allowed for completion of the resections in the same sessions. Complete resection was confirmed in all n  = 16 patients who had follow-up angiography one year after surgery so far. All diagnostic and therapeutical steps, including angiographic control, were performed without having to move the patients Conclusion The hybrid neurointerventional suite was shown to be a safe and useful setup which allowed for unconstrained combined microsurgical and neuroradiological workflow. It reduces the need for extraoperative angiographic controls and subsequent potential surgical revisions a second time, as small AVM remnants can be detected with high security.

IntroductionRobotic guidance (RG) and computer-assisted navigation (NV) have seen increased adoption in instrumented spine surgery over the last decade. Although there exists some evidence that these techniques increase radiological pedicle screw accuracy compared with conventional freehand (FH) surgery, this may not directly translate to any tangible clinical benefits, especially considering the relatively high inherent costs. As a non-randomised, expertise-based study, the European Robotic Spinal Instrumentation Study aims to create prospective multicentre evidence on the potential comparative clinical benefits of RG, NV and FH in a real-world setting.Methods and analysisPatients are allocated in a non-randomised, non-blinded fashion to the RG, NV or FH arms. Adult patients that are to undergo thoracolumbar pedicle screw instrumentation for degenerative pathologies, infections, vertebral tumours or fractures are considered for inclusion. Deformity correction and surgery at more than five levels represent exclusion criteria. Follow-up takes place at 6 weeks, as well as 12 and 24 months. The primary endpoint is defined as the time to revision surgery for a malpositioned or loosened pedicle screw within the first postoperative year. Secondary endpoints include patient-reported back and leg pain, as well as Oswestry Disability Index and EuroQOL 5-dimension questionnaires. Use of analgesic medication and work status are recorded. The primary analysis, conducted on the 12-month data, is carried out according to the intention-to-treat principle. The primary endpoint is analysed using crude and adjusted Cox proportional hazards models. Patient-reported outcomes are analysed using baseline-adjusted linear mixed models. The study is monitored according to a prespecified monitoring plan.Ethics and disseminationThe study protocol is approved by the appropriate national and local authorities. Written informed consent is obtained from all participants. The final results will be published in an international peer-reviewed journal.Trial registration numberClinical Trials.gov registry NCT03398915; Pre-results, recruiting stage.

Background According to microsurgical principles, the access to deep-seated cerebral lesions should be as atraumatic as possible. Temporary brain retraction is acceptable in certain situations and may be indispensable when the view of the lesion is obstructed. Method The utility of this method is illustrated in a case of a ruptured middle cerebral artery (MCA) aneurysm. Two temporary aneurysm clips were connected by a braided suture, thus forming a band with two points of attachment. The Sylvian fissure was opened in a standard fashion. Using one clip, the adventitia and arachnoid over the superficial Sylvian vein were grasped firmly enough to mobilize the superficial Sylvian vein. The distal clip was then attached to surrounding drapes, thus granting a direct view of the aneurysm in the depth of the fissure. Retraction with spatula was not necessary. Patency of the superficial Sylvian vein was demonstrated using idocyanine green angiography. Results We present a simple method for minimally traumatic brain retraction using aneurysm clips attached to the adventitia of Sylvian veins and held back by sutures. Conclusion The use of clips attached to the adventitia of the superficial Sylvian may be of help in retracting the Sylvian fissure. By virtue of enlarging the field of view into the deep Sylvian fissure, it may be of help in performing retractorless aneurysm surgery.

Background Robotic assistance for the placement of pedicle screws has been established as a safe technique. Nonetheless rare instances of screw misplacement have been reported.The aim of the present retrospective study is to assess whether experience and time affect the accuracy of screws placed with the help of the SpineAssist™ robot system. Methods Postoperative computed tomography (CT) scans of 258 patients requiring thoracolumbar pedicle screw instrumentation from 2008 to 2013 were reviewed. Overall, 13 surgeons performed the surgeries. A pedicle breach of >3 mm was graded as a misplacement. Surgeons were dichotomised into an early and experienced period in increments of five surgeries. Results In 258 surgeries, 1,265 pedicle screws were placed with the aid of the robot system. Overall, 1,217 screws (96.2 %) were graded as acceptable. When displayed by surgeon, the development of percent misplacement rates peaked between 5 and 25 surgeries in 12 of 13 surgeons. The overall misplacement rate in the first five surgeries was 2.4 % (6/245). The misplacement rate rose to 6.3 % between 11 and 15 surgeries (10/158; p  = 0.20), and reached a significant peak between 16 and 20 surgeries with a rate of 7.1 % (8/112; p  = 0.03). Afterwards, misplacement rates declined. Conclusions A major peak in screw inaccuracies occurred between cases 10 and 20, and a second, smaller one at about 40 surgeries. One potential explanation could be a transition from decreased supervision (unskilled but aware) to increased confidence of a surgeon (unskilled but unaware) who adopts this new technique prior to mastering it (skilled). We therefore advocate ensuring competent supervision for new surgeons at least during the first 25 procedures of robotic spine surgery to optimise the accuracy of robot-assisted pedicle screws.

PurposeSpinal augmentation procedures (SAP) are standard procedures for vertebral compression fractures. Often, SAPs are carried out in a minimally invasive, percutaneous way. Certain anatomic conditions such as small pedicles or kyphotic deformities resulting from a significant collapse of the vertebral body might render the operation more difficult and increase the risk of complications. Thus, robot assistance might be useful to optimize the trajectory and to reduce procedure-associated complications. In this study robot-assisted percutaneous SAPs are compared with conventional fluoroscopy-guided percutaneous SAP. MethodsA retrospective observational analysis was carried out. Standard demographic parameters were analyzed. Procedural data including radiation dosage records were screened. Biomechanical data were recorded. Cement volumes were analyzed. The precision of the pedicular trajectory was reviewed, and misplaced trajectories were categorized. Procedure-associated complications were analyzed and evaluated for their clinical significance. ResultsA total of 130 procedures were reviewed, and 94 patients were finally included. Osteoporotic fractures (OF) were the main indication (60.7%; OF 2–44%, OF 4–33%). Demographic parameters and clinically relevant complications were equally distributed between the two groups. Duration of surgery was significantly longer in robot-assisted procedures (p < 0.001). Intraoperative radiation exposure was equally distributed. Injected cement volume was similar in both groups. There was no significant difference in pedicle trajectory deviation. ConclusionThe use of robot assistance in SAP seems not to be superior with regard to accuracy, radiation exposure and the rate of complications when compared to fluoroscopy-guided SAP.