Effects of medication intake on the risk of hemorrhage in patients with sporadic cerebral cavernous malformations

Chen, Bixia; Lahl, Kirstin; Saban, Dino; Herten, Annika; Rauschenbach, Laurèl; Santos, Alejandro; Li, Yan; Schmidt, B; Zhu, Yuan; Jabbarli, Ramazan; Wrede, Karsten H.; Kleinschnitz, Christoph; Sure, Ulrich; Dammann, Philipp

doi:10.3389/fneur.2022.1010170

Cited by 4 publications

(6 citation statements)

References 42 publications

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“…IL-8 expression has been previously detected and linked to tumor progression in several types of cancers including breast, colon, ovarian, bladder, and prostate cancers, as well as in melanoma [71][72][73][74] . In GBM especially, studies have focused on describing the role of IL-8 in promoting glioblastoma stem cells 48 , which are also thought to be major drivers of aggressive GBM tumors, cell migration signaling 75 , and angiogenesis 46,50,76 .…”

Section: Discussionmentioning

confidence: 99%

“…It is now known to play key roles in wound healing, angiogenesis, inflammation, and tumor growth 43,44 , and it has been most studied in cancer in the context of epithelial origin tumors 45 . In GBM, IL-8 was reported to be highly expressed and to play a role in regulating GBM stem cells, promoting tumor growth, and promoting angiogenesis [46][47][48][49] . Previous work focused on IL-8's ability to activate vascular mimicry in tumor cells, including after treatment with alkylating chemotherapy temozolomide 50 .…”

Section: Introductionmentioning

confidence: 99%

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IL-8 Instructs Macrophage Identity in Lateral Ventricle Contacting Glioblastoma

Medina,

Brockman,

Cross

et al. 2024

Preprint

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Adult IDH-wildtype glioblastoma (GBM) is a highly aggressive brain tumor with no established immunotherapy or targeted therapy. Recently, CD32+HLA-DRhimacrophages were discovered to have displaced resident microglia in GBM tumors that contact the lateral ventricle stem cell niche. Since these lateral ventricle contacting GBM tumors have especially poor outcomes, identifying the origin and role of these CD32+macrophages is likely critical to developing successful GBM immunotherapies. Here, we identify these CD32+cells as M_IL-8 macrophages and establish that IL-8 is sufficient and necessary for tumor cells to instruct healthy macrophages into CD32+M_IL-8 M2 macrophages. Using a set of 73 GBM tumors, IL-8 protein is shown to be present in GBM tumor cellsin vivoand especially common in tumors contacting the lateral ventricle. Finally, inex vivoexperiments with conditioned medium from primary human tumor cells, inhibitory antibodies to IL-8 blocked the generation of CD32+M_IL-8 cells. These results provide a mechanistic origin for CD32+macrophages that predominate in the microenvironment of the most aggressive GBM tumors. IL-8 and CD32+macrophages should now be explored as targets in combination with GBM immunotherapies, especially for patients whose tumors present with radiographic contact with the ventricular subventricular zone stem cell niche.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL-8 Instructs Macrophage Identity in Lateral Ventricle Contacting Glioblastoma

Medina,

Brockman,

Cross

et al. 2024

Preprint

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“…Neurosurg Focus Volume 55 • October 2023 2 C erebral cavernous malformations (CCMs) are vascular lesions composed of low-flow, clusterorganized capillaries that account for 5%-10% of total cerebral vascular pathologies. 1 Even if a precise measure is difficult, since the majority are clinically silent, the estimated annual incidence in the general population is between 0.4% and 1.0% 2 . Up to 40% are discovered incidentally with an increasing trend over time, 3 so follow-up timing and monitoring strategies have a fundamental role in the clinical and surgical management of these patients.…”

Section: Scerrati Et Almentioning

confidence: 99%

“…8,9 Notably, several drugs, commonly used for different pathologies, have been studied to assess their role in the clinical and radiological evolution of CCMs. Antithrombotic medications have been associated with a reduced risk of bleeding in different studies, 1,3,10,11 thought to be due to the inhibition of the inflammatory mechanism causing rupture. Beta-blockers, specifically propranolol, have been proposed to have a therapeutic effect in causing regression of the CCM and stopping recurrent bleeding.…”

Section: Scerrati Et Almentioning

confidence: 99%

“…12 A randomized controlled trial (RCT) was initiated on the use of propranolol for familial CCMs, 13 but recent studies have found conflicting results regarding a protective role of propranolol in sporadic CCMs. 1,14 Statins have wellknown vessel wall stabilization effects, and a synergistic protective effect has been found when combined with antithrombotic drugs 15 but not when used alone. 1,11,14 Indeed, the role of hemorrhagic factors in general, such as renal or liver disease, labile international normalized ratio (INR), prior major bleeding or predisposition to bleeding, is also not clear.…”

Section: Scerrati Et Almentioning

confidence: 99%

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Bleeding risk evaluation in cerebral cavernous malformation, the role of medications, and hemorrhagic factors: a case-control study

Scerrati,

Mantovani,

Travaglini

et al. 2023

Neurosurgical Focus

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OBJECTIVE Cerebral cavernous malformations (CCMs) are vascular lesions with an overall risk of rupture from 2% to 6% per year, which is associated with significant morbidity and mortality. The diagnostic incidence is increasing, so it is of paramount importance to stratify patients based on their risk of rupture. Data in the literature seem to suggest that specific medications, particularly antithrombotic and cardiovascular agents, are associated with a reduced risk of bleeding. However, the effect of the patient coagulative status on the cumulative bleeding risk remains unclear. The aim of this study was to assess the impact of different radiological, clinical, and pharmacological factors on the bleeding risk of CCMs and to assess the predictive power of an already validated scale for general bleeding risk, the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly). METHOD This was a multicenter retrospective observational study. The authors collected imaging, clinical status, and therapy data on patients with bleeding and nonbleeding CCMs. Univariate analysis and subsequent multivariate logistic regression were performed between the considered variables and bleeding or nonbleeding status to identify potential independent predictors of bleeding. RESULTS The authors collected data on 257 patients (46.7% male, 25.3% with bleeding CCMs). Compared with patients with nonbleeding lesions, those with bleeding CCMs were younger, less frequently had hypertension, and less frequently required antiplatelet drugs and beta-blockers (all p < 0.05). Bleeding lesions, however, had significantly higher median volumes (1050 mm3 vs 523 mm3 , p < 0.001). On multivariate analyses, after adjusting for age, history of hypertension and diabetes, and use of antiplatelet drugs or beta-blockers, lesion volume ≥ 300 mm3 was the only significant predictor of bleeding (adjusted OR 3.11, 95% CI 1.09–8.86). When the diagnostic accuracy of different volume thresholds was explored, volume ≥ 300 mm3 showed a limited sensitivity (36.7%, 95% CI 24.6%–50.0%), but a high specificity 78.2% (95% CI 71.3%–84.2%), with an area under the curve of 0.57 (95% CI 0.51–0.64). CONCLUSIONS This study supports previous findings that the CCM volume is the only factor influencing the bleeding risk. Antithrombotic agents and propranolol seem to have a protective role against the bleeding events. A high HAS-BLED score was not associated with an increased bleeding risk. Further studies are needed to confirm these results.

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Recent novelties in research and management of cerebrospinal cavernous malformations

Rauschenbach,

Dammann,

Sure

2024

Acta Neurochir

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In recent years, knowledge about cerebrospinal cavernomas has grown considerably, leading to the development of initial guidelines and treatment recommendations. However, due to the rarity and heterogeneity of the disease, the level of evidence remains limited, leaving many questions unanswered and subject to ongoing debate. Therefore, an up-to-date review of this field's latest developments and controversies is reasonable.

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Effects of medication intake on the risk of hemorrhage in patients with sporadic cerebral cavernous malformations

Cited by 4 publications

References 42 publications

IL-8 Instructs Macrophage Identity in Lateral Ventricle Contacting Glioblastoma

IL-8 Instructs Macrophage Identity in Lateral Ventricle Contacting Glioblastoma

Bleeding risk evaluation in cerebral cavernous malformation, the role of medications, and hemorrhagic factors: a case-control study

Recent novelties in research and management of cerebrospinal cavernous malformations

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