Malignant meningiomas.

Malignant meningiomas are WHO Grade III meningiomas representing 1% of all meningiomas. They are comprised of three histologic types: anaplastic, rhabdoid, and papillary. They can arise de novo or as a result of biologic progression of meningiomas of lower histologic grades. The overall survival of patients with WHO grade III meningiomas is 2-3 years. Surgery is the main treatment, while radiotherapy is thought to slow tumor growth. Multiple trials have been attempted on chemotherapeutic agents, hormonal therapies, small molecule and anti-angiogenic agents without robust evidence of efficacy. The rarity of these tumors is the main reason for our patchy understanding of the natural history and lack of effective treatment options. There is an urgent need to develop alternative therapies given the significantly increased risk of complication and co-mordibity associated with repeated surgeries in this population.

MR-guided laser interstitial thermal therapy in the treatment of recurrent intracranial meningiomas.

OBJECTIVE: Recurrent meningiomas can prove problematic for treatment, especially if anaplastic, as options are limited primarily to surgery and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive technique for achieving immediate cytoreduction. This study seeks to determine the utility of LITT in the setting of recurrent meningiomas. MATERIALS AND METHODS: Patients undergoing LITT for tumor treatment at our institution between November 2014 and February 2016 were identified. Those with biopsy-confirmed meningiomas were reviewed with attention to ablation volume, survival, demographic data, and complications. Data from imaging performed at set intervals post-operatively were available for all. RESULTS: Four patients were identified, three of whom had successful treatment with a total of four ablations. The one case that did not result in a successful ablation was due to problems with stereotactic placing of the laser catheter. One patient had a grade 1 meningioma, with the other two being Grade 3. Immediate ablation volumes averaged 75% of preoperative tumor volume and increased to 97% at 2 weeks before dropping to 65% at 3 months. One patient had acute hemiparesis with speech difficulty, which resolved after 6 months. At date of last follow-up, two of three had progression at an average of nine weeks, and one had no progression at 28 weeks. CONCLUSION: LITT appeared to be a potentially viable treatment for recurrent meningiomas. Ablation volumes increased over time, but not beyond the initial meningioma volume. Larger studies are needed to better determine complications and outcomes. Lasers Surg. Med. 51:245-250, 2019. © 2018 Wiley Periodicals, Inc.

Infiltrated Embolization of Meningioma with Dilute Cyanoacrylate Glue.

We describe the efficacy and technical aspects of infiltrated preoperative embolization of meningioma by penetration of very dilute glue. In this method, a 13% n-butyl-cyanoacrylate (NBCA)-lipiodol mixture is injected extremely slowly from the middle meningeal artery (MMA) in a similar manner to plug and push injection of ethylene vinyl alcohol copolymer mixed with tantalum and dimethyl sulfoxide (Onyx®) after the tortuous side feeders are proximally embolized. The glue is infiltrated into small tumor arteries and extends to inaccessible feeders from deep meningeal arteries. Since 2011, we have used this technique in the embolization of 32 cases preoperatively diagnosed with meningioma. Intratumoral embolization was possible in 30 cases (94%), and a greater than 50% reduction in contrast area of contrast-enhanced T1-weighted MR imaging (T1-WI) was achieved in 18 cases (56%). Two cases achieved complete devascularization, showing a remarkable shrinkage in tumor size after embolization. If excessive reflux of embolization and the resulting migration of glue into normal arteries is achieved, this method provides extremely effective devascularization on surgical extirpation. It might also be applicable to surgically untreatable meningiomas as a semi-radical treatment option.

Checkpoint inhibition in meningiomas.

Meningiomas are increasingly appreciated to share similar features with other intra-axial central nervous system neoplasms as well as systemic cancers. Immune checkpoint inhibition has emerged as a promising therapy in a number of cancers, with durable responses of years in a subset of patients. Several lines of evidence support a role for immune-based therapeutic strategies in the management of meningiomas, especially high-grade subtypes. Meningiomas frequently originate juxtaposed to venous sinuses, where an anatomic conduit for lymphatic drainage resides. Multiple populations of immune cells have been observed in meningiomas. PD-1/PD-L1 mediated immunosuppression has been implicated in high-grade meningiomas, with association between PD-L1 expression with negative prognostic outcome. These data point to the promise of future combinatorial therapeutic strategies in meningioma.

Medical Management of Meningiomas: Current Status, Failed Treatments, and Promising Horizons.

Meningiomas are benign tumors of the central nervous system, with low recurrence risk for World Health Organization (WHO) grade I lesions but a high risk for WHO grade II and III lesions. Current standard treatments include maximum safe surgical resection when indicated and radiation. Only three systemic therapies alpha-interferon, somatostatin receptor agonists, and vascular endothelial growth factor inhibitors are currently recommended by the National Comprehensive Cancer Network for treatment of recurrent meningioma. This paper aims to review medical approaches in the treatment of meningiomas.

Treatment recommendations for primary extradural meningiomas.

Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas and are often encountered by non-neurosurgeons. These lesions typically present as enlarging, painless, benign masses that can be surgically cured. Imaging is critical for defining involvement of adjacent structures; however, diagnosis depends on classic histologic patterns. Treatment for benign PEMs (WHO I) consists of resection with wide margins, whereas adjuvant therapy after resection of atypical (WHO II) or malignant (WHO III) PEMs should be considered. By using the collective experience from our comprehensive cancer center, including neuro-oncologists, neuroradiologists, and neurosurgeons, in addition to a complete literature review, the authors have established treatment guidelines not previously reported. This manuscript describes key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs (n = 163), and provides salient treatment guidelines to surgeons unfamiliar with these challenging tumors.

Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma.

Stereospecific radiation treatment offers a distinct opportunity for temporal and spatial regulation of gene expression at tumor sites by means of inducible promoters. To this end, a plasmid, pCArG-U2, was constructed by incorporating nine CArG elements (in tandem) of EGR1 gene upstream to uPA and uPAR siRNA oligonucleotides in a pCi-neo vector. Radiation-induced siRNA expression was detected in a meningioma cell line (IOMM-Lee). Immunoblotting and RT-PCR analyses confirmed downregulation of uPA and uPAR. A similar effect was observed in transfected cells followed by H2O2 treatment. Moreover, pre-treatment of transfected cells with N-acetyl L-cysteine blocked the silencing of uPA and uPAR, which further confirmed the oxidative damage-mediated downregulation. Cell proliferation assays and Western blot analysis for apoptotic molecules confirmed cell death in a radiation-inducible fashion. Migration and matrigel invasion assays also revealed a marked decrease in migration and invasion. Immunocytochemistry showed a marked decrease in uPA and uPAR levels in transfected and irradiated cells. H&E staining revealed a decrease in the pre-established tumor volume among the animals treated with pCArG-U2 and radiation. Immunohistochemistry of the brain sections established with intracranial tumors also revealed a marked decrease in uPA and uPAR in a radiation-inducible fashion. Taken together, our data suggest pCArG-U2 as a suitable candidate for radiation-inducible gene therapy.

Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2.

PURPOSE: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. EXPERIMENTAL DESIGN: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. RESULTS: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. CONCLUSIONS: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics.

Benign adult brain tumors: an evidence-based medicine review.

BACKGROUND: Benign adult brain tumors can be managed conservatively or using surgery, radiation, or medicines. While randomized comparisons assessing tumor recurrence, quality of life, or survival are the ideal means of comparing treatments, it can be difficult to recruit patients to such trials and lengthy follow-up periods are needed because of the slowly progressive natural history of these tumors. METHODS: Review of the literature on benign adult brain tumors using evidence-based standards and focusing on meningiomas, pituitary adenomas, and vestibular schwannomas, which together represent the majority of WHO grade 1 adult brain tumors. RESULTS: Nearly all studies of benign adult brain tumors were of relatively poor quality (level 3 or poorer). These studies enable grade C recommendations. The safety of meningioma surgery in the elderly varies with institution, radiosurgery is a reliable alternative to surgery in small to medium-sized meningiomas, and the efficacy of drugs in therapy of meningiomas recurring after surgery is difficult to interpret due to a lack of uniform criteria in the studies. Radiosurgery is effective in nonfunctional pituitary adenomas recurring after surgery, while phototherapy is a newer treatment modality with potential benefits in pituitary adenomas that fail surgery or radiation. Vestibular schwannomas can be conservatively managed, but there are no reliable predictors of growth, so serial imaging is important. Radiosurgery has proven to be a reliable alternative to surgery for small to medium-sized vestibular schwannomas, but followup has been relatively short in most studies to date. CONCLUSIONS: While randomized clinical trials comparing conservative management, surgery, radiation, and medical management of benign adult benign tumors are unlikely to occur, there is some level 3 evidence that can assist in their treatment.

Immunohistochemical study of anaplastic meningioma with special reference to the phenotypic change of intermediate filament protein.

The phenotypic changes in the transformation of classic or atypical meningioma to anaplastic meningioma were investigated. Among nine patients with anaplastic meningioma, four men and five women ranging in age from 32 to 75 years, four cases were identified as anaplastic meningioma at the first operation (de novo type), while five cases were identified as classic or atypical meningioma at the first operation but at recurrence had transformed to anaplastic meningioma (secondary type). Immunohistochemical analysis was performed with the avidin-biotin complex method using monoclonal antibodies for glial fibrillary acidic protein, cytokeratin, alpha-internexin, neurofilament proteins (70 kd, 168 kd, and 200 kd), desmin, vimentin, CD34, Ki-67, epithelial membrane antigen, and S-100 protein. Immunohistochemical analysis showed positive immunoreactivity for cytokeratin, alpha-internexin, neurofilament proteins, vimentin, and glial fibrillary acidic protein during the course of progression. Expression of epithelial membrane antigen decreased with malignant progression. Marked expression of cytokeratin was observed in anaplastic meningioma. Ki-67 labeling index increased at every recurrence of both the de novo and secondary types. The major phenotypic changes in the transformation of meningioma from the classic to the anaplastic type are loss of meningioma architecture, decreased expression of epithelial membrane antigen, increased expression of vimentin, and metaplastic expression of alpha-internexin and neurofilament triplet proteins.

Erythropoietin-augmented isovolemic hemodilution in skull-base surgery. Case report.

Human erythropoietin in concert with intraoperative hemodilution, tumor embolization, and surgical staging was used to manage a red blood cell mass in an anemic Jehovah's Witness patient with a hypervascular meningioma. Erythropoietin (3000 U thrice weekly) and oral iron (1300 mg daily) were given for 1 month prior to surgery, raising the hemoglobin level from 11.8 to 14.1 gm/100 ml. A posterior fossa craniectomy combined with a temporal craniectomy was then performed so that partial petrosectomy, section of the transverse sinus, incision of the tentorium, and exposure of the lesion could be carried out. The first stage of the surgery was terminated immediately prior to tumor mobilization. Isovolemic hemodilution was initiated just before the skin incision. Postoperatively, the hemoglobin concentration dropped to 11.5 gm/100 ml. The erythropoietin dose was doubled and administration of oral iron continued, leading to a hemoglobin level of 14.0 gm/100 ml at 1 month after the first operation. The tumor was embolized using superselective catheterization. The next day, at the second stage of the surgery, the tumor was extirpated, again employing isovolemic hemodilution. By the 4th postoperative day, the hemoglobin level had dropped to 9.4 gm/100 ml. The patient made an uncomplicated recovery. Erythropoietin therapy contributed substantially to the successful outcome of this case. Since erythropoietin has the potential to augment all other forms of autologous banking, its role in elective neurosurgery may become increasingly important in an era of heightened concern about heterologous transfusion.

[Embolization of meningiomas using liquid embolizing agents]. / Meningeomembolisationen mit flüssigen Embolisaten.

In 25 patients with meningiomas, the tumours were embolised with liquid embolising materials following angiography. Nine subselective flow-guided Ethibloc embolisations were performed, four selective Ethibloc embolisations and 16 selective Histoacryl embolisations. The physical properties and pathophysiological behaviour make liquid embolising materials superior to particles. The use of micro-catheter systems introduced as far as possible into the feeding vessels makes Histoacryl embolisation an uncomplicated, effective and painless method for obliterating the vascular bed of the tumour.

Optic nerve sheath meningioma: diagnostic features and therapeutic alternatives.

Twenty-two cases of optic nerve sheath meningioma were reviewed. The clinical features included slowly progressive visual loss in every case. Orbital signs of limited ocular movements and mild proptosis were present in only a third of cases; gaze-evoked amaurosis occurred in 3 cases. The disc was abnormal in every case, usually swollen if vision was 6/12 or better, atrophic if the vision worse than 6/12. Optociliary shunt vessels occurred in 5 patients and were of diagnostic significance. The diagnosis was made by a high-resolution CT scan of the orbits showing tubular expansion of the optic nerve sheath. Calcification of the optic nerve was present in 12 cases. Tubular expansion of the optic nerve sheath may occur in raised intracranial pressure, optic nerve glioma, granuloma, lymphoma or metastatic disease. In the absence of calcification these alternative diagnoses must be considered. Surgery, undertaken for the intracranial component of the tumour, did not halt progressive visual loss.

Radiation therapy for brain tumors.

Results of radiation therapy obtained at the University of California, San Francisco over the last 25 years for various adult types of brain tumors are presented. Included are astrocytomas, ependymomas, pineal and suprasellar tumors, meningiomas, and malignant gliomas. For each tumor type considered, the disease-free survival rate appeared to be improved when subtotal resection was followed by irradiation. The lack of improvement in survival with malignant gliomas has prompted investigation into more aggressive multimodality therapies. These are discussed along with a new program using high-activity iodine 125 sources to deliver high-dose radiotherapy to malignant gliomas. It is possible that this new approach will lead to improved survival rates and be applicable to many tumors within the central nervous system.