Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition.

BACKGROUND: Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. METHODS: Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. RESULTS: Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. CONCLUSIONS: These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

[Vagal nerve stimulation treatment in patients with drug resistant epilepsy: Son Espases University Hospital experience]. / Tratamiento con estimulación del nervio vago en pacientes con epilepsia resistente a los fármacos: experiencia en el Hospital Universitario Son Espases.

OBJECTIVE: To present our experience in treating drug-resistant epilepsy with vagal nerve stimulation in our centre, evaluating its impact on disease control and on different aspects related to the patients and main caretakers' quality of life. MATERIALS AND METHODS: This was a retrospective analysis of patients operated from January 2004 until December 2012. Interviews and tests completed by outpatients and principle caretakers were evaluated. RESULTS: Fifteen patients were included, with a mean postoperative follow-up of 4.41 (0.5-8) years. Mean age at implantation was 25 (10-50) years. Over 66% of the patients perceived a reduction greater than 25% of their crisis intensity. Forty-seven percent of the patients experienced a decrease greater than 50% in the number of crises. As undesired adverse events, one patient presented persistent dysphonia, another self-limited cough and cervical discomfort and another, persistent cervical discomfort. The device had to be removed in 2 patients due to refractory headaches. There were no complications derived from the surgical procedure. CONCLUSIONS: Vagal nerve stimulation is an effective treatment for reducing crisis frequency and intensity. The patients as well as their caretakers experience a subjective improvement in their quality of life. Despite its economic cost, it seems to reduce their care needs to a certain degree and its use may therefore be justified.