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Dimitrios Varrias,1,2,* Michail Spanos,3,* Damianos G Kokkinidis,4 Panagiotis Zoumpourlis,1,2 Dimitrios Rafail Kalaitzopoulos5 1Department of Medicine, Jacobi Medical Center, Bronx, NY, 10461, USA; 2Albert Einstein College of Medicine, Bronx, NY, 10461, USA; 3Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; 4Section of Cardiovascular Medicine, Yale University School of Medicine, Yale New Haven Hospital, New Haven, CT, USA; 5Department of Gynecology and Obstetrics, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland*These authors contributed equally to this workCorrespondence: Dimitrios Varrias, Jacobi NYCHHC, 1400 Pelham Parkway South, 3N1, Bronx, NY, 10461, USA, Tel +1 7189185000, Email varriasd@nychhc.orgAbstract: Venous thromboembolism (VTE) is a serious medical condition that can lead to severe morbidity and mortality, making it a significant public health concern. VTE is a multifactorial condition that results from the interaction of genetic, acquired, and environmental factors. Physiological changes during pregnancy increase the risk of VTE as they express Virchow’s triad (increased coagulation factors, decreased fibrinolysis, trauma, and venous stasis). Moreover, pregnancy-related risk factors, such as advanced maternal age, obesity, multiple gestations, and cesarean delivery, further increase the risk of VTE. Managing VTE in pregnancy is challenging due to the complexity of balancing the risks and benefits of anticoagulant therapy for both the mother and the fetus. A multidisciplinary approach involving obstetricians, hematologists, and neonatologists, is necessary to ensure optimal outcomes for both the mother and baby. This review aims to discuss the current challenges associated with VTE in pregnancy and identify potential solutions for improving outcomes for pregnant women at risk for VTE.Keywords: venous embolism, thrombosis, pregnancy, VTE, anticoagulation

Leptomeningeal Metastases (LM) is a turning point in terms of prognosis and quality of life of patients with breast cancer (BC). Intrathecal therapy is largely used for the treatment of breast cancer LM. In this metanalysis with meta-regression, we gathered data on intrathecal (IT) trastuzumab administration in patients with HER2 positive breast cancer with LM. A total of 24 articles (58 patients) were included in the study and intrathecal trastuzumab was used in all patients. The mean age at IT administration was 50.7 years (SD 11.4, range 24-80) and the mean total dose of IT trastuzumab was 711.9 mg (SD 634.9, median 450). IT trastuzumab was used both alone (n = 20) and in combination with systemic pharmacotherapy (n = 37). No serious adverse events were reported in 87.9% of cases. In this selected population a significant clinical improvement was observed in 55.0% of cases while stabilization was reported in 14% of cases. CSF response was observed in 55.6% of the cases. MRI was improved or stable in 70.8% of the cases. Interestingly, the CNS-PFS was 5.2 months and the median OS was 13.2 months. A clinical improvement (HR 0.13, 95% CI 0.03-0.49) and CSF response (HR 0.13, 95% CI 0.03-0.58) were associated with a longer CNS-PFS. The association of longer CNS-PFS with radio- or neurosurgery prior to the administration of IT trastuzumab did not reach statistical significance. This metanalysis with meta-regression indicates that IT trastuzumab in patients with HER2 positive breast cancer LM might be a safe and effective treatment, but further prospective studies are needed to definitively prove such a point.