RESUMEN
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas , Neoplasias de la Mama , Glioblastoma , Inmunoconjugados , Recurrencia Local de Neoplasia , Humanos , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Anciano , Inmunoconjugados/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Estudios Prospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismoRESUMEN
The Pipeline Embolization Device™ (PED; Covidien Neurovascular Inc, Irvine, CA, USA) is a flow-diverting stent often used for the endovascular treatment of large or giant, wide-necked intracranial aneurysms of the internal carotid artery. Because of the inherent thrombogenicity of intracranial stents, dual-antiplatelet therapy is initiated after placement, which has been shown to decrease morbidity and mortality related to perioperative ischemic events in neurointerventional procedures. However, in some series, as much as 50% of patients demonstrate clopidogrel non-responsiveness. In these non-responders, alternate agents such as ticagrelor can be used to achieve adequate anticoagulation. Compared with clopidogrel, a prodrug requiring Cytochrome P450 enzymolysis for activation, ticagrelor directly and reversibly inhibits the P2Y12 ADP receptor. The absorption of the prodrug and the formation of its active metabolite is comparatively quicker ( tmax 1.3-2 hours; 1.5-3 hours, respectively). To date, there have been no documented cases of ticagrelor non-responsiveness involving patients undergoing placement of flow-diverting stents or other endovascular neuro-interventional procedures.
Asunto(s)
Adenosina/análogos & derivados , Embolización Terapéutica/instrumentación , Aneurisma Intracraneal/terapia , Inhibidores de Agregación Plaquetaria/uso terapéutico , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Adenosina/uso terapéutico , Anciano , Aspirina/uso terapéutico , Arteria Carótida Interna , Angiografía Cerebral , Clopidogrel , Femenino , Humanos , Ticagrelor , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéuticoRESUMEN
Posterior fossa syndrome (PFS) is a well-known sequela of midline posterior fossa tumor resection. Patients typically exhibit transient behavioral, motor, and oculomotor disturbances that resolve within a few weeks to several months after surgery. The underlying pathophysiology of PFS is not completely understood, but contemporary literature has implicated injury to the dentate nucleus and/or exiting dentatothalamocortical fiber bundles as a causative factor. The authors present a case of a young male who developed a delayed variant of PFS typified by motor deficits and demonstrated diffusion restriction in the ipsilateral superior cerebellar peduncle. Because the correlation between PFS and the superior cerebellar peduncle injury is poorly described in the literature, particularly with regard to relevant radiographic imaging, the authors of this report hope their findings will contribute to that insufficient body of evidence.