One of the major consequences of the lack of a functional VHL protein in von Hippel-Lindau disease, a rare cancer, is the constitutive activation of the HIF pathway. This activation ends up in the generation of Central Nervous System (CNS) Hemangioblastomas among other tumours along the lifespan of the patient. Nowadays, only surgery has been proven efficient as therapy since the systemic attempts have failed. Propranolol, a non-specific β1-and β2-adrenergic receptor antagonist, was recently designated as the first therapeutic (orphan) drug for VHL disease. Nevertheless, its β1 affinity provokes the decrease in blood pressure, being not recommended for low or regular blood pressure VHL patients. In order to overcome the β1-drawback, the properties of a high specific β2-adrenergic receptor blocker named ICI-118,551 have been studied. ICI-118,551 was able to decrease Hemangioblastomas cell viability in a specific manner, by triggering apoptosis. Moreover, ICI-118,551 also impaired the nuclear internalization of HIF-1α in Hemangioblastomas and hypoxic primary endothelial cells, reducing significantly the activation of HIF-target genes and halting the tumour-related angiogenic processes. In this work, we demonstrate the therapeutical properties of ICI-118,551 in VHL-derived CNS-Hemangioblastoma primary cultures, becoming a promising drug for VHL disease and other HIF-related diseases. Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited genetic disorder with an incidence of 1 per 36,000 individuals in the general population and is considered as a rare disease or rare cancer 1,2. Patients with VHL disease harbour a single mutation allele in the tumour suppressor gene VHL (3p25-p26). VHL protein (pVHL) controls the cytoplasmic levels of the Hypoxia Inducible Factor (HIF) complex. In normoxic conditions, pVHL binds to the previously hydroxylated prolyl residues of HIF-1α and HIF-2α, being ubiquitinated and targeted to the proteasome for rapid degradation. When patients suffer a spontaneous inactivation or loss of the second wild-type VHL allele (loss of heterozygosity), either there is no expression of the pVHL or the mutated form is not functional 3,4. Therefore, in the absence of functional pVHL, HIF-1α and HIF-2α subunits accumulate within the cytoplasm and translocate to the nucleus, triggering the hypoxia program by targeting hypoxia responsive genes, which are normally silenced in normoxia 5. HIF-1α and HIF-2α are involved in cell proliferation, angiogenesis, extracellular matrix degradation, vascular tone, and erythropoiesis, among other processes. Hence, cells from VHL tumours have a constitutively active HIF program (a pseudo-hypoxic state) due to the absence of functional pVHL 6,7. As a consequence of this pseudo-hypoxic state, the clinical manifestations of the disease include multiple benign and malignant tumours that appear throughout the lifespan of the patient: retinal hemangioblastoma,

OBJECTIVEIn the past, the outcome of surgical treatment for thalamic tumor was poor. These lesions were often considered inoperable. However, contemporary microsurgical techniques, together with improvements in neuroimaging that enable accurate presurgical planning, allow resection to be accomplished in a safer way.METHODSThe medical records, imaging studies, and operative and pathology reports obtained for pediatric patients who were treated for thalamic tumors at the authors’ department were reviewed. Neuronavigation and intraoperative monitoring of motor and somatosensory evoked potentials were used. Preoperative tractography, which helped to identify internal capsule fibers, was very important in selecting the surgical strategy. Postoperatively, an MRI study performed within 24 hours was used to assess the extent of tumor resection as partial (≤ 90%), subtotal (> 90%), or gross total (no residual tumor).RESULTSSince 2002, 27 children with thalamic tumors have been treated at the authors’ department. There were 9 patients with unilateral thalamic tumors, 16 with thalamopeduncular tumors, and 2 with a bilateral tumor. These last 2 patients underwent endoscopic biopsy and implantation of a ventriculoperitoneal shunt. Thirty-nine tumor debulking procedures were performed in the remaining 25 patients. Different surgical approaches were chosen according to tumor location and displacement of the posterior limb of the internal capsule (as studied on axial T2-weighted MRI) and corticospinal tract (as studied on diffusion tensor imaging with tractography, after it became available). In 12 cases, multiple procedures were performed; in 7 cases, these were done as part of a planned multistage resection. In the remaining 5 cases, the second procedure was necessary because of late recurrence or regrowth of residual tumor.At the end of the surgical phase, of 25 patients, 15 (60%) achieved a gross-total resection, 4 (16%) achieved a subtotal resection, and 6 (24%) achieved a partial resection. Eighteen patients harbored low-grade tumors in our series. In this group, the mean follow-up was 45 months (range 4–132 months). At the end of follow-up, 1 patient was dead, 12 patients were alive with no evidence of disease, 4 patients were alive with stable disease, and 1 was lost to follow-up. All patients were independent in their daily lives. The outcome of high-grade tumors in 9 patients was very poor: 2 patients died immediately after surgery, 6 died of progressive disease, and 1 was alive with residual disease at the time of this report.CONCLUSIONSThis institutional review seems to offer further evidence in favor of attempts at radical resection in pediatric patients harboring unilateral thalamic or thalamopeduncular tumors. In low-grade gliomas, radical resection in a single or staged procedure can be curative without complementary treatment. Recurrences or residual regrowth can be safely managed surgically. In high-grade tumors, the role of and opportunity for radical or partial resection remains a matter of debate.

Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.

Backgroundvon Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours.MethodsSeven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed.ResultsNumber and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient.ConclusionsPropranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity.Trial registration number2014-003671-30

Sparganosis is a severe parasitic infection caused by the larvae of Spirometra mansoni, also called "sparganum." In human hosts, the Spirometra mansoni larva commonly targets the subcutaneous tissue or muscle. Sometimes it can also migrate into the brain, resulting in cerebral sparganosis, mainly characterized by focal neurological symptoms such as seizures and radiological "wandering lesions" on magnetic resonance images (MRIs). Clinical cases of cerebral sparganosis have been reported worldwide, mainly in Asian countries, but also in North America, South America and Australia. Only two cases have been previously reported in Europe. A 29-year-old male from Bolivia, who lived in Spain, presented to our service for seizures and a multicystic brain lesion, initially suspected to be a dysembryoplastic neuroepithelial tumor (DNET). He underwent gross total resection of the mixed solid/cystic lesion. Pathology revealed gliosis, multiple interconnected cystic cavities with fibrous walls, inflammatory cell infiltration and no necrotizing granulomatous reaction. Inside the cavities, a parasitic form was identified as the larva of the cestode Spirometra mansoni. At 1-year follow-up, the patient had no deficits and was seizure free. Clinicians should be alerted to the possible existence of this rare entity in Europe, especially in patients from endemic areas with a possible infection history as well as "wandering lesions" on the MRI.