RESUMO
OBJECTIVE: The modern management of patients with Koos grade IV vestibular schwannomas (VSs) aims at functional preservation and long-term tumor control. Gross-total resection (GTR) leads to optimal tumor control but frequently also results in permanent facial nerve (FN) palsy. Subtotal resection (STR) or near-total resection (NTR) followed by a wait-and-scan protocol and second-line radiation therapy (RT) in case of progressive residuals yields excellent tumor control rates with less permanent morbidity. METHODS: The authors present the results of their prospective cohort of Koos grade IV VS patients who underwent less-than-total resection followed by a wait-and-scan protocol between January 2009 and December 2019 and discuss the latest evidence on this controversial subject. The cohort was followed up with annual clinical and volumetric outcome analyses after standardized MRI. RESULTS: Forty-eight patients were included in the analysis. The mean extent of resection was 87% (median 91%, range 45%-100%), best fitting into the definition of STR rather than NTR. In 2 cases, the proximal portion of the FN at the brainstem could not be reliably identified and monitored during the initial operation, and a second-stage resection was necessary. At 4.4 years after surgery, 81% (39/48) of the tumor residuals regressed or were stable in size. The percentage of regressive tumor residuals increased over time. Nineteen percent (9/48) of the tumor residuals displayed volumetric progression within a mean time of 35 months (median 36 months, range 14-72 months), resulting in a Kaplan-Meier estimate for progression-free survival of 79% after 4 years; higher postoperative volume showed a linear correlation with higher volumetric progression (factor 1.96, 95% CI 1.67-2.30; p < 0.001). Thirty-four of the 48 (71%) patients continue to undergo a wait-and-scan protocol. Second-line RT was performed in 14 patients (29%) within a mean time of 25 months (median 23 months, range 5-54 months), 12 (86%) of whom responded with post-RT pseudoprogression, resulting in an overall tumor control rate of 96%. At the 4.4-year follow-up from the initial resection, 92% of the patients had a good facial outcome (House-Brackmann [HB] grade I or II), 6% had a fair facial outcome (HB grade III), and 2% had a poor facial outcome (HB grades IV-VI). So far, there has been no need for salvage surgery after RT. CONCLUSIONS: STR followed by observation and second-line RT in cases of progression leads to good facial outcome and an excellent tumor control rate in the longer term.
RESUMO
Diffuse gliomas progress by invading neighboring brain tissue to promote postoperative relapse. Transcription factor SOX2 is highly expressed in invasive gliomas and maps to chromosome region 3q26 together with the genes for PI3K/AKT signaling activator PIK3CA and effector molecules of mitochondria fusion and cell invasion, MFN1 and OPA1. Gene copy number analysis at 3q26 from 129 glioma patient biopsies revealed mutually exclusive SOX2 amplifications (26%) and OPA1 losses (19%). Both forced SOX2 expression and OPA1 inactivation increased LN319 glioma cell invasion in vitro and promoted cell dispersion in vivo in xenotransplanted D. rerio embryos. While PI3 kinase activity sustained SOX2 expression, pharmacological PI3K/AKT pathway inhibition decreased invasion and resulted in SOX2 nucleus-to-cytoplasm translocation in an mTORC1-independent manner. Chromatin immunoprecipitation and luciferase reporter gene assays together demonstrated that SOX2 trans-activates PIK3CA and OPA1. Thus, SOX2 activates PI3K/AKT signaling in a positive feedback loop, while OPA1 deletion is interpreted to counteract OPA1 trans-activation. Remarkably, neuroimaging of human gliomas with high SOX2 or low OPA1 genomic imbalances revealed significantly larger necrotic tumor zone volumes, corresponding to higher invasive capacities of tumors, while autologous necrotic cells are capable of inducing higher invasion in SOX2 overexpressing or OPA1 knocked-down relative to parental LN319. We thus propose necrosis volume as a surrogate marker for the assessment of glioma invasive potential. Whereas glioma invasion is activated by a PI3K/AKT-SOX2 loop, it is reduced by a cryptic invasion suppressor SOX2-OPA1 pathway. Thus, PI3K/AKT-SOX2 and mitochondria fission represent connected signaling networks regulating glioma invasion.