Antonio Nicolato

Introduction: The group of so-called “sellar-region masses” consists of a heterogeneous group of neoplasms and tumor-mimicking lesions, whose differential diagnosis may be challenging due to the overlapping of clinical and radiological features, which can be found both in “common” and “uncommon” lesions. The choice of a correct treatment strategy is still arduous and requires histological analysis. Gamma Knife Radiosurgery (GKRS) has already been reported as a safe and effective treatment in these cases. The objective of this study is to evaluate single-center pre-operative data, post-operative outcomes, and long-term follow-up in patients treated with GKRS for unusual sellar tumors. Methods: We retrospectively identified and analyzed nine patients treated with GKRS from 2004 to 2015, according to a standard protocol. Lesions consist of hypothalamic hamartoma (HH), Rathke’s cleft cist (RCC), Langerhans cell histiocytosis (LCH), spindle cell oncocytoma (SCO), choroid plexus papilloma (CPP), and ossifying fibroma (OF). The diagnosis was histologically confirmed in six patients that underwent surgery, while in three patients, diagnosis was based on characteristic clinical and radiological findings (two HH and one RCC). Pre-operative and post-operative data were retrieved from medical archives, and long-term follow-up was obtained through clinical and neuroradiological periodic examination. Results: In our series, all the “rare” sellar lesions treated, had a successful radiographic and clinical response in a medium-long follow-up period. Conclusions: The long-term follow-up results suggest that GKRS is a safe and effective treatment in rare sellar lesions, with very low toxicity. To the best of our knowledge, this report represents the largest series of unusual sellar lesions treated with GKRS in a single high-volume center, suggesting that GKRS might be an effective non-invasive adjuvant treatment option. Further studies and a larger number of patients are needed to confirm if residuals of these rare sellar lesions might regress on their own without treatment or if other non-invasive treatments could be as effective as GKRS.

Background Drug-resistant epilepsy (DRE) secondary to hypothalamic hamartoma (HH) often requires surgical resection or stereotactic radiosurgery, which frequently fail to provide satisfactory outcomes and are associated with severe side effects. Magnetic resonance-guided focused ultrasound (MRgFUS) may represent a minimally invasive surgical approach to HH by offering precise thermal ablation of sub-millimetric brain targets while sparing surrounding structures. Methods We present the case of a 19-year-old man with HH-associated DRE, who was successfully treated with MRgFUS. The procedure resulted in effective ablation of the hypothalamic interface of the HH, disconnecting the epileptogenic lesion from the surrounding brain tissue. We also reviewed the literature on MRgFUS for DRE. Results The patient experienced a complete resolution of seizures and significant improvements in social and occupational functioning over an 18-month follow-up period. No neurological, cognitive, or endocrinological adverse effects were observed. Conclusion Our case report and literature review suggest that MRgFUS may achieve adequate seizure control in DRE associated with HH without adverse effects. While MRgFUS shows promise for other forms of DRE, data remain preliminary, and some safety concerns persist. Further studies with long-term follow-up are warranted to better support the use of MRgFUS in DRE.

Circulating miRNAs are increasingly studied and proposed as tumor markers with the aim of investigating their role in monitoring the response to therapy as well as the natural evolution of primary or secondary brain tumors. This study aimed to evaluate the modulation of the expression of three miRNAs, miR-21, miR-222 and miR-124-3p, in the serum exosomes of patients with high-grade gliomas (HGGs) and brain metastases (BMs) to verify their usefulness in the differential diagnosis of brain masses; then, it focused on their variations following the surgical and/or radiosurgical treatment of the BMs. A total of 105 patients with BMs from primary lung or breast cancer, or melanoma underwent neurosurgery or radiosurgery treatment, and 91 patients with HGGs were enrolled, along with 30 healthy controls. A significant increase in miR-21 expression in serum exosomes was observed in both HGGs and BMs compared with healthy controls; on the other hand, miR-124-3p was significantly decreased in BMs, and it was increased in HGGs. After the surgical or radiosurgical treatment of patients with BMs, a significant reduction in miR-21 was noted with both types of treatments. This study identified a signature of exosomal miRNAs that could be useful as a noninvasive complementary analysis both in the differential diagnosis of BMs from glial tumors and in providing information on tumor evolution over time.

The immunohistochemical loss of histone H3 trimethylated in lysine 27 (H3K27me3) was recently shown to predict recurrence of meningiomas after surgery. However, its association with tumor progression after stereotactic radiosurgery (SRS) is unexplored. To investigate whether H3K27 methylation status may predict progression-free survival (PFS) after SRS, we assessed H3K27me3 immunoexpression in thirty-nine treatment naïve, intracranial, meningiomas, treated with surgery and subsequent SRS for residual (twenty-three cases) or recurrent (sixteen cases) disease. H3K27me3 immunostaining was lost in seven meningiomas, retained in twenty-seven and inconclusive in five. Six of the seven meningiomas (86%) with H3K27me3 loss had tumor progression after SRS, compared to nine of twenty-seven (33%) with H3K27me3 retention (p = 0.0143). In addition, patients harboring a meningioma with H3K27me3 loss had significantly shorter PFS after SRS (range: 10–81 months; median: 34 months), compared to patients featuring a meningioma with retained H3K27me3 (range: 9–143 months; median: 62 months) (p = 0.0036). Nonetheless, tumor sagittal location was the only significant prognostic variable at multivariate analysis for PFS after SRS (p = 0.0142). These findings suggest a previously unreported role of H3K27me3 as a predictor of meningioma progression after SRS for recurrent or residual disease. Modulation of H3K27 methylation status may represent a novel therapeutic strategy to induce radiosensitization of meningiomas.

The use of adjuvant therapy is controversial in atypical meningiomas with gross total resection. Predictors of recurrence risk could be useful in selecting patients for additional treatments. The aim of this study was to investigate whether molecular features are associated with recurrence risk of atypical meningiomas. According to WHO classification, the diagnosis of atypical meningioma was based on the presence of one major criteria (mitotic activity, brain invasion) or three or more minor criteria. The molecular profile of 22 cases (eight mitotically active, eight brain-invasive, and six with minor criteria) was assessed exploring the mutational status and copy number variation of 409 genes using next generation sequencing. Of the 22 patients with a median follow up of 53.5 months, 13 had recurrence of disease within 68 months. NF2 mutation was the only recurrent alteration (11/22) and was unrelated to clinical-pathological features. Recurring meningiomas featured a significantly higher proportion of copy number losses than non-recurring ones (p = 0.027). Chromosome 18q heterozygous loss or CDKN2A/B homozygous deletion was significantly associated with shorter recurrence-free survival (p = 0.008; hazard ratio: 5.3). Atypical meningiomas could be tested routinely for these genetic alterations to identify cases for adjuvant treatment.

BACKGROUND AND PURPOSE: Intra-arterial DSA has been traditionally used for confirmation of cure following gamma knife radiosurgery for AVMs. Our aim was to evaluate whether 4D arterial spin-labeling MRA and contrast-enhanced time-resolved MRA in combination can be an alternative to DSA for confirmation of AVM obliteration following gamma knife radiosurgery. MATERIALS AND METHODS: In this prospective study, 30 patients undergoing DSA for confirmation of obliteration following gamma knife radiosurgery for AVMs (criterion standard) also underwent MRA, including arterial spin-labeling MRA and contrast-enhanced time-resolved MRA. One dataset was technically unsatisfactory, and the case was excluded. The DSA and MRA datasets of 29 patients were independently and blindly evaluated by 2 observers regarding the presence/absence of residual AVMs. RESULTS: The mean time between gamma knife radiosurgery and follow-up DSA/MRA was 53 months (95% CI, 42–64 months; range, 22–168 months). MRA total scanning time was 9 minutes and 17 seconds. Residual AVMs were detected on DSA in 9 subjects (obliteration rate = 69%). All residual AVMs were detected on at least 1 MRA sequence. Arterial spin-labeling MRA and contrast-enhanced time-resolved MRA showed excellent specificity and positive predictive values individually (100%). However, their sensitivity and negative predictive values were suboptimal due to 1 false-negative with arterial spin-labeling MRA and 2 with contrast-enhanced time-resolved MRA (sensitivity = 88% and 77%, negative predictive values = 95% and 90%, respectively). Both sensitivity and negative predictive values increased to 100% if a composite assessment of both MRA sequences was performed. Diagnostic accuracy (receiver operating characteristic) and agreement (κ) are maximized using arterial spin-labeling MRA and contrast-enhanced time-resolved MRA in combination (area under receiver operating characteristic curve = 1, P < .001; κ = 1, P < .001, respectively). CONCLUSIONS: Combining arterial spin-labeling MRA with contrast-enhanced time-resolved MRA holds promise as an alternative to DSA for confirmation of obliteration following gamma knife radiosurgery for brain AVMs, having provided 100% sensitivity and specificity in the study. Their combined use also enables reliable characterization of residual lesions.

During the past decades, in small-to-medium size vestibular schwannomas, Gamma Knife surgery (GKS) has become a reliable therapeutic option because of either excellent local tumor control or minimal morbidity, with cranial neuropathy becoming increasingly rare. Although still insufficiently analyzed in larger cohorts of patients with long-term follow-ups, adequate chances of hearing preservation and vestibular sparing seem clinically guaranteed. However, deeper investigations are needed in this regard, expanding the number of cases and the follow-up period. A small group of patients with vestibular schwannomas (74 patients, including 41 men and 33 women) treated between 2003 and 2009 using GKS at the authors' institution were analyzed—both before and after GKS—with computerized static stabilometry and electronystagmography for balance disorders, vertigo, and ataxia on 1 side and pure tone average, vocal speech discrimination score, auditory brainstem response, and so forth for hearing impairment and tinnitus on the other side. Eligibility criteria for this prospective study included previously untreated unilateral lesions and a Gardner-Robertson hearing class of I–III. Dosimetry plans had been programmed at the lower effective dosages for these tumors (median surface dose 12.4 Gy, range 10–13 Gy), carefully avoiding even minimal toxic dosages on the most vulnerable targets: the cochlea (never > 6 Gy) and the vestibular canals (< 7.5 Gy). To date, tumor growth control rates remain satisfactory; at a mean follow-up of 50 months, the rate was 96%. The overall level of hearing preservation was 72%, with 81% having Gardner-Robertson Class I hearing. Tinnitus decreased, from 52% to 28% of patients (p < 0.01). Significant improvements were also observed in vestibular symptoms, with computerized static stabilometry abnormalities decreasing from 62% to 32% (p < 0.001) and electronystagmography abnormalities reducing from 48% to 14% (p < 0.001). Using appropriate radiodosimetry planning, GKS seems to guarantee not only adequate tumor growth control rates, but also better levels of hearing preservation, with a documented, long-lasting improvement in vestibular functions.