Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.

CONTEXT: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. OBJECTIVE: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. DESIGN: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. RESULTS: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. CONCLUSIONS: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

[Postsurgery meningitis by Staphylococcus aureus: comparison between methicillin-sensitive and resistant strains]. / Estudio comparativo de la meningitis posquirúrgica por Staphylococcus aureus sensible y resistente a meticilina.

BACKGROUND AND OBJECTIVE: In recent years, meningitis caused by methicillin-resistant S. aureus has increased. This study was undertaken to compare the clinical characteristics and prognosis of methicillin-resistant S. aureus (MRSA) postneurosurgical meningitis and methicillin-sensible S. aureus (MSSA) postneurosurgical meningitis. PATIENTS AND METHODS: Twenty-five episodes of postneurosurgical meningitis due to S. aureus (13 methicillin-resistant strains) seen during a ten-year period were retrospectively reviewed. RESULTS: Most common underlying diseases were: intracerebral hemorrhage (50% of MRSA patients and 46% of MSSA patients) and neoplasm (53% of MRSA patients and 33% of MSSA patients). Eleven patients (6 of them with MRSA infection) had received antibiotic treatment previously. Thirteen patients were carriers of intraventricular catheters (8 with MRSA infection), 5 wore a ventriculoperitoneal shunt (4 with infections by MSSA), 5 cases had a CSF leakage (4 with infections by MRSA), and one patient with infection by MSSA wore an epidural catheter. Fifteen patients were cured (7 with MRSA infection), and 8 died due to the infection (27% with MSSA infection and 38% with MRSA infection). CONCLUSIONS: The prognosis of postneurosurgical meningitis by S. aureus does not depend on the presence of resistance to methicillin. Nowadays, the intravenous administration of vancomycin is the treatment of choice in MRSA meningitis.

[Surgical treatment of clival chordomas]. / Tratamiento de los cordomas de clivus.

INTRODUCTION: Clival chordomas are benign neoplastic tumors displaying high morbidity and mortality rates. The difficulties involved in obtaining a total resection and its infiltrative nature explain this aggressiveness. MATERIAL AND METHOD: We present a retrospective clinical series of 8 surgically treated cases of clival chordomas at our department from 1993 to 2006. RESULTS: All 8 patients underwent a total of 14 surgical procedures, 6 of which were anterior approaches (5 transmandibular), 2 subtemporal-preauricular, 2 from the transcondylar lateral edge and 2 transcochlear. In 7 patients the surgery was performed with curative intent. In 2 cases it was necessary to perform the surgery sequentially, in two steps. Total resection was achieved in 58% of patients. Average follow up was 40 months. Two patients died due to local recurrence, one patient died in the postoperative period and another died due to causes which were not related with the tumor. DISCUSSION: The low incidence of clival chordomas makes it difficult to carry out random clinical studies of its management. The treatment of choice is surgery, supplemented by radiotherapy in selected cases. We prefer to use the transmandibular approach, combined with transcondylar lateral edge approach when the occipital condyle is infiltrated. For lateral extensions, we use the subtemporal-preauricular or transpetrosal approaches. New radiotherapy modalities provide an effective treatment of tumoural residues. CONCLUSIONS: Extradural approaches imply anatomical regions which are familiar for otolaryngologists. Specific knowledge about the limitations of each approach is essential in order to avoid unnecessary morbidity and incomplete resections.