Recurrent Malignant Meningioma Research Articles

The FGF6 amplification mutation plays an important role in the progression and treatment of malignant meningioma

Meningioma is a benign tumor with slow growth and long course. However, patients with recurrent malignant meningioma still face a lack of effective treatment. Here, we report a rare case of primary mediastinal malignant meningioma with lung and bone metastases, who benefited from the treatment of apatinib (≥33 months) and anlotinib (until the publication date). Retrospective molecular analysis revealed the frequent amplification of FGF6 in primary and metastatic lesions. Then we constructed the FGF6 over-expressed IOMM-LEE and CH157MN malignant meningioma cell lines, and in vitro and vivo experiments showed that overexpression of FGF6 can promote the proliferation, migration and invasion of malignant meningioma cells. Based on the Western analysis, we revealed that FGF6 can promote the phosphorylation of FGFR, AKT, and ERK1/2, which can be inhibited by anlotinib. Together, we were the first to verify that overexpression of FGF6 promotes the progression of malignant meningiomas by activating FGFR/AKT/ERK1/2 pathway and pointed out that anlotinib may effectively inhibit the disease progression of patients with FGF6 amplification.

Case report and literature review: exploration of molecular therapeutic targets in recurrent malignant meningioma through comprehensive genetic analysis with Todai OncoPanel

Case report and literature review: exploration of molecular therapeutic targets in recurrent malignant meningioma through comprehensive genetic analysis with Todai OncoPanel

Brachytherapy as an Adjuvant for Recurrent Atypical and Malignant Meningiomas

Brachytherapy as an Adjuvant for Recurrent Atypical and Malignant Meningiomas

Brachytherapy as an Adjuvant for Recurrent Atypical and Malignant Meningiomas.

Recurrent atypical and malignant meningiomas have poor outcomes with surgical therapy alone. Neither adjuvant chemotherapy nor postoperative radiation therapy remedies this problem. To evaluate our experience with the treatment of 15 patients treated with I-125 or Cs-131 brachytherapy radiation seeds as an adjuvant in these difficult cases. Patients with high-grade recurrent meningioma who underwent resection and intraoperative placement of brachytherapy seeds at our institution from 2002 to 2014 were identified and studied by retrospective chart review. Fifteen patients with median age of 68.8 yr were treated with I-125 (n=13) or Cs-131 (n=2) brachytherapy seeds for cases of recurrent, grade II (n=8), or grade III (n=7) meningioma at our institution from 2002 to 2014. These lesions originated from a variety of locations including, convexity (3), falcine (3), frontal (2), occipital (1), parietal (2), 2 sphenoid wing (2), and temporal (2), based recurrent meningiomas. Patients had a median of 2 prior open surgical interventions and received local radiation therapy with a median dose of 55 Gy prior to brachytherapy. Survival at 2.5 yr was 56% for grade II and 17% for grade III lesions. Survival was significantly associated with patient age but not tumoral pathology. Forty percent of patients required reoperations for wound complications following brachytherapy. Brachytherapy with implantation of permanent radiation seeds provides a viable alternative treatment for recurrent meningioma while carrying a significant clinical risk of wound infection and need for reoperation.

Initial Experience with Intraoperative Phosphorous-32 Brachytherapy During Resection of Malignant Spinal Tumors

Brachytherapy is a major adjuvant modality for neoplasms, but few have trialed its use for spinal tumors. This study examines perioperative and oncologic outcomes of patients with malignant spinal tumors who underwent resection with intraoperative phosphorous-32 (P32) brachytherapy. Consecutive adult patients who underwent P32 brachytherapy during malignant spinal tumor resection were retrospectively identified from 2014 to 2015. Complications, tumor recurrence, and survival were reviewed. A comprehensive review of the literature was performed. A total of 8 patients were included. Average age was 54.3 years, and 25.0% were males. Tumor types included metastatic leiomyosarcoma, chordoma, multifocal recurrent ependymomas, breast metastasis, malignant meningioma, and myxofibrosarcoma. One-half of patients underwent en bloc tumor resection. P32 plaques were applied to 2 sites per patient for mean 13.1 minutes per site with a goal penetration of 10 Gy to 1-mm depth. Perioperative complications occurred in 3 patients (37.5%), including a persistent cerebral spinal fluid leak, deep infection requiring reoperation, and sacral insufficiency fracture. At a mean 25.6 months follow-up, local recurrence rate was 25.0%, and overall survival was 75.0%. Mean time to recurrence was 14.4 months. Survival at 6, 12, 18, and 24 months was 100.0%, 100.0%, 85.7%, and 71.4%, respectively. The use of P32 is safe and feasible. P32 intraoperative brachytherapy does not seem to increase the rate of complications. The sample size of this series is small with heterogeneity in tumor type, but recurrence and survival outcomes seem promising compared with previous reports. Further clinical trials are needed.

Expanded Endoscopic Transsphenoidal Resection of Tuberculum Sella Meningioma Invading the Optic Canal.

A 61-year-old male patient presented with recurrent malignant meningioma involving the left optic canal and decreased vision from the left eye. The patient had undergone orbital exenteration on the right 2 years ago. The decision to treat the patient was made based on the significant vision deterioration and rapid tumor growth. Endoscopic transsphenoidal approach considered the most suitable route due to the inferomedial invasion of the optic canal. Gross total removal was achieved and the patient's vision improved postoperatively. The patient developed hydrocephalus 4 weeks postoperatively and cerebrospinal fluid (CSF) leak. Ventriculoperitoneal shunt placement corrected both hydrocephalus and CSF leak. The link to the video can be found at: https://youtu.be/2cOF0pf5gAk .

Surgical Resection and Interstitial Iodine-125 Brachytherapy for High-Grade Meningiomas: A 25-Year Series.

Atypical and malignant meningiomas can recur despite resection and radiation. To determine outcomes of patients with recurrent atypical or malignant meningioma treated with repeat resection and permanent iodine-125 ( 125 I) brachy-therapy. Charts of patients who underwent surgical resection and 125 I brachyther-apy implantation for atypical and malignant meningiomas between 1988 and 2013 were retrospectively reviewed. The Kaplan-Meier actuarial method was used to calculate progression-free and overall survival. The log-rank test was used to compare groups. Significance was set at P < .05. Forty-two patients underwent 50 resections with 125 I brachytherapy im-plantations. All patients had undergone previous resections and 85% had previously undergone radiation. Median follow-up was 7.5years after diagnosis and 2.3years after brachytherapy. Median time to progression after resection with 125 I brachytherapy was 20.9months for atypical meningioma, 11.4months for malignant meningioma, and 11.4months for the combined groups. Median survival after re-resection and 125 I brachytherapy was 3.5years for atypical meningioma, 2.3years for malignant menin-gioma, and 3.3years for all subjects. Median overall survival after diagnosis was 11.1years for atypical meningioma, 9.1years for malignant meningioma, and 9.4years for all subjects. Complications occurred in 17 patients and included radiation necrosis (n = 8, 16%), wound breakdown (n = 6, 12%), hydrocephalus (n = 4, 8%), infection (n=3, 6%), and a pseudomeningocele (n = 2, 5%). This is the largest experience with adjuvant 125 I brachytherapy for recurrent high-grade meningiomas. The outcomes support the use of adjuvant brachytherapy as an option for these aggressive tumors.

MNGO-16ESTABLISHMENT OF A PATIENT - DERIVED ORTHOTOPIC MALIGNANT MENINGIOMA MODEL FOR THE DEVELOPMENT OF TARGETED THERAPY

The majority of meningiomas are benign (WHO Grade I) and can be cured by surgery alone. However, 20% are non-benign meningioma (NBM) including atypical (Grade II) and malignant meningioma (Grade III), and pose a clinical problem due to their high recurrence rates after treatment. Preclinical development of novel therapeutics requires disease model that is representative of human NBM. However, patient-derived tumor models that recapitulate the genotype and phenotype of NBM are lacking. We established an orthotopic xenograft model from a patient with recurrent malignant meningioma that is based on tumor-sphere culture. Subdural implantation of the cultured cells in SCID mice reproducibly generated meningiomas that are lethal within 3 months, and excised tumors were serially transplantable for at least 7 generations. Pathological analysis of xenografts showed hypercellularity with whorl formations, and exhibited frequent mitotic figures, high proliferation index (Ki67 labeling 25%) and invasion to the brain parenchyma, hallmarks of malignant meningioma. The patient tumor, xenografts and cultured cells had strong expression of vimentin, a mesenchymal marker. Western blot analysis revealed that the original tumor and xenografts are NF2 (Merlin) negative, and sequencing verified NF2 mutation. This novel tumor model set a stage for us to test targeted and biological therapeutics for NBM. Our preliminary investigations in vitro include the use of dual PI3K and mTOR inhibitors, focal adhesion kinase (FAK) inhibitor, and oncolytic herpes simplex virus (oHSVs) (G47Δ and MG18L). MTS cell viability assay showed PI3K and mTOR inhibitors and oHSVs efficiently killed the tumor cells, while FAK inhibitor was ineffective. Thus our novel patient-derived orthotopic NBM model has NF2 deletion, faithfully recapitulates the human disease, and is reproducible and lethal. This model provides us with superb opportunities to develop much needed targeted therapeutics for treatment-refractory NBM, and currently studies examining oHSV efficacy in orthotopic tumor model are ongoing.

I-125 Brachytherapy for Recurrent Atypical and Malignant Skull Base Meningiomas: Complications and Outcomes

I-125 Brachytherapy for Recurrent Atypical and Malignant Skull Base Meningiomas: Complications and Outcomes

Clinical image: rare localization of a giant recurrent malignant meningioma

Meningiomas are the most common benign brain tumors. Malignant meningioma is a rare subtype with a high recurrence rate and poor prognosis. Most meningiomas grow intracranially, whereas extracranial growth of meningiomas has been rarely reported. We herein report a rare case of a giant malignant meningioma with multiple recurrences. A 56-year old man presented with a forehead swelling. He had a history of repeated craniotomy for a frontal sinus invasion. The tumor recurred one year after the last surgery on the forehead and was classified as a giant meningioma at admission to our hospital. Neurosurgeons performed total resection of the giant meningioma and reconstructed the defect. However, six months after the surgery, the tumor recurred at the same site. The patient refused surgery and underwent cyber-knife treatment. An hydroxyurea treatment was initiated after radiotherapy, but the tumor progressed. Temozolomide and cisplatin treatment was started. A valuable clinical improvement was observed after the initiation of the first cycle. After completion of two cycles of systemic chemotherapy, the patient will be assessed clinically and radiologically.

Drug therapy for recurrent, progressive, atypical, and malignant meningiomas

Till date, no breakthrough for systemic therapy of recurrent meningiomas has been achieved. The multitude of optional drugs shows that none of them so far could become a standard of care. On the other hand, although the disease is rare, each neurooncological centre has some patients with unmet treatment needs. Cohort studies should be able to answer the question whether meningiomas occur more rarely or do not become symptomatic in individuals undergoing treatment with statins, glitazones, or calcium channel blockers. If found effective, such drugs would be suitable as first line treatment in patients with grade I recurrent meningiomas, because for these indications most probably the long treatment periods appear necessary. For patients who recur with such drugs, targeted therapies could represent further treatment options, whereas cytotoxic drugs with severe side effects such as trabectedin could perhaps be investigated for recurrent malignant meningiomas after all other options.

Targeting different types of human meningioma and glioma cells using a novel adenoviral vector expressing GFP-TRAIL fusion protein from hTERT promoter

ObjectiveThe objective of this study was to evaluate the anti-tumor effects of Ad/gTRAIL (an adenoviral vector in which expression of GFP and TRAIL is driven by a human telomerase reverse transcriptase promoter, hTERT) on malignant meningiomas and gliomas.BackgroundGliomas and meningiomas are the two most common types of human brain tumors. Currently there is no effective cure for recurrent malignant meningiomas or for gliomas. Ad/gTRAIL has been shown to be effective in killing selected lung, colon and breast cancer cells, but there have been no studies reporting its antitumor effects on malignant meningiomas. Therefore, we tested the antitumor effect of Ad/gTRAIL for the first time in human malignant meningioma and glioma cell lines, and in intracranial M6 and U87 xenografts.MethodsMaterials and Methods: Human malignant meningioma and glioma cells were infected with adenoviruses, Ad/gTRAIL and Ad/CMV-GFP. Cell viability was determined by proliferation assay. FACS analysis and quantification of TRAIL were used to measure apoptosis in these cells. We injected Ad/gTRAIL viruses in intracranial M6 and U87 xenografts, and measured the brain tumor volume, quantified apoptosis by TUNEL assay in the brain tumor tissue.ResultsOur studies demonstrate that in vitro/in vivo treatment with Ad/gTRAIL virus resulted in significant increase of TRAIL activity, and elicited a greater tumor cell apoptosis in malignant brain tumor cells as compared to treatment with the control, Ad/CMV-GFP virus without TRAIL activity.ConclusionsWe showed for the first time that adenovirus Ad/gTRAIL had significant antitumor effects against high grade malignant meningiomas as well as gliomas. Although more work needs to be done, our data suggests that Ad/gTRAIL has the potential to be useful as a tool against malignant brain tumors.

Stereotactic LINAC radiosurgery for incompletely resected or recurrent atypical and anaplastic meningiomas

The optimal management of subtotally resected or recurrent malignant meningiomas remains controversial. We evaluated the efficacy of linear accelerator (LINAC) radiosurgery for atypical and anaplastic meningiomas after incomplete resection or treatment of recurrences. Between August 1990 and December 2003, 16 patients with 28 meningiomas WHO II and III were treated by stereotactic LINAC radiosurgery at our institution. The median radiological follow-up was 60.3 months, respectively (range: 7.2-173.9 months). Fourteen tumors in nine patients were classified as WHO II and 14 tumors in seven patients as WHO III. The median surface dose was 14 Gy (range: 10-15 Gy) with a median tumor volume of 4.8 ml (range: 0.51-51.4 ml). Clinical condition improved in four patients, remained unchanged in nine and deteriorated in one. Tumor shrinkage was seen in eight of 28 meningiomas and a stable disease in 12. Eight of 28 meningiomas showed local tumor progression. The overall tumor control rate (TCR) was 84%, 70%, 70% after 3, 5, 10 years. According to grading the corresponding TCR after 3, 5, 10 years was 91%, 81%, 81% for grade II and 77%, 60%, 60% for grade III meningiomas. Overall progression-free survival (PFS) was 74%, 67%, 58% after 3, 5, 10 years. According to grading the PFS after 3, 5, 10 years was 88%, 75%, 75% for grade II meningiomas and 57%, 57%, 43% for grade III meningiomas. Our results show the efficacy and safety of LINAC radiosurgery for incompletely resected or recurrent malignant meningiomas with a relatively high local tumor control and low morbidity.

A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas

The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.

Boron neutron capture therapy for recurrent malignant meningioma

Malignant meningioma is a rare brain tumor with a high risk of recurrence. If this tumor recurs after complete resection and adjuvant radiotherapy, there is no optimal treatment to control it. The authors report the first case of recurrent malignant meningioma treated using boron neutron capture therapy (BNCT). This 25-year-old pregnant woman presented with a large frontal tumor. After her baby was born, she underwent gross-total resection of the tumor. A second resection and three Gamma Knife surgeries could not control progression of the enhancing mass; therefore, the authors applied BNCT based on their experience with it in the treatment of malignant gliomas. The minimum tumor dose and maximum brain tissue dose were estimated as 39.7 Gy-Eq and less than 9.0 Gy-Eq, respectively. Before BNCT the patient was mobile by wheelchair only, whereas 1 week after therapy she was able to walk. Twenty-two weeks later she underwent a second BNCT for tumor regrowth on the contralateral side, and the lesion was subsequently reduced. The tumor volume was markedly decreased from 65.6 cm3 at the time of the first BNCT to 31.8 cm3 at 26 weeks thereafter. The treatment of recurrent malignant meningioma is difficult and has been discouraging thus far. Data in the present case indicate that BNCT may be a promising treatment option for this challenging tumor.

Edema following Gamma-Knife® radiosurgery for intracranial meningiomas

Purpose/Objective: Stereotactic radiosurgery is a primary or adjuvant treatment option for patients with unresected, incompletely resected, and recurrent benign, atypical and malignant intracranial meningiomas. Based on previously reported series, local control rates for meningiomas treated with Gamma-Knife® stereotactic radiosurgery (GKSRS) are approximately 90%. However, one potentially serious complication of GKSRS is symptomatic cerebral edema requiring steroid treatment or open surgery. The purpose of this study was to determine the predictive factors for developing cerebral edema after GKSRS in patients with intracranial meningioma. Materials/Methods: Clinical and radiographic data were collected on 19 patients with 23 intracranial meningiomas (21 benign, 2 atypical/malignant) treated with GKSRS at Wake Forest University Baptist Medical Center between September 1999 and December 2000 (16 women, 3 men; age range 28-87 years; mean age, 65.5 years). The most common tumor locations were parasagittal (39%) and posterior fossa (22%). The median tumor volume was 4 cc (range 0.4 to 18.5 cc). 6 tumors had image-based peritumoral edema before GKSRS while 17 tumors had no edema. A median dose of 14 Gy (range 9-18 Gy) was delivered to the tumor margin (50% isodose line). Median follow up time was 1.4 years. Kaplan-Meier methodology was used to estimate actuarial incidence. Proportional hazard regressions with likelihood ratio tests were used to assess predictors for the development of edema or worsening edema after GKSRS. Results: After GKSRS, 39% (9/23) of tumors developed new or worsening image-based cerebral edema. The actuarial incidence of edema was 22% at 6 months, 39% at 12 months, and 59% at 18 months. 7 of 9 tumors (78%) developed symptomatic edema requiring steroid therapy after GKSRS. One patient refused steroid treatment and died of edema-associated complications. The actuarial incidence of edema causing symptoms and requiring steroid therapy was 26% at 6 and 12 months and 41% at 18 and 24 months. Predictive factors for the development of edema or worsening edema after GKSRS were parasagittal location (p = 0.006), tumor volume (p = 0.005) and the presence of image-based pretreatment edema (p = 0.06). Of the tumors with edema or worsening edema after GKSRS, 78% were parasagittal and 78% were large (> 4cc). Of the 17 tumors without pre-existing edema, 24% (4/17) developed new edema, whereas 83% (5/6) of tumors with pre-existing edema developed worsening edema after GKSRS. At last follow-up, 91% of 23 tumors were locally controlled. Of the 2 tumors which progressed, one was benign and the other malignant. Conclusions: In our experience, 39% of meningiomas treated with GKSRS developed new or worsening image-based cerebral edema. The incidence of new or worsening edema with parasagittal tumors, tumors > 4 cc in volume, and tumors associated with pre-GKSRS peritumoral edema was 78%, 78%, and 83%, respectively, including one edema-associated death. Select patients with large, parasagittal meningiomas demonstrating peritumoral edema should be considered for other treatment options such as open surgery or conventionally fractionated 3D conformal RT.

Radiosurgery for malignant meningioma: results in 22 patients

Object. The initial treatment of malignant meningiomas in the past has included surgical removal followed by fractionated external-beam radiotherapy. Radiosurgery has been added to the options for treatment of primary or recurrent tumors over the last 10 years. The authors report their results of using gamma knife radiosurgery (GKS) to treat 22 patients over an 8-year period. Methods. Twenty-two patients who underwent GKS for malignant meningioma between December 1991 and May 1999 were evaluated. Three patients were treated with GKS as a boost to radiotherapy and 19 for recurrence following radiotherapy. Outcome factors including patient survival, freedom from progression, and complications were analyzed. In addition, in the recurrent group, variables such as patient age, sex, tumor location, target volume, margin dose, and maximum dose were also analyzed. Univariate and multivariate analyses were performed. Overall 5-year survival and progression-free survival estimates were 40% and 26%, respectively. Age (p ≤ 0.003) and tumor volume (p ≤ 0.05) were significant predictors of time to progression and survival in both univariate and multivariate analyses. Five patients (23%) developed radiation necrosis. Significant relationships between complications and treatment variables or patient characteristics could not be established. Conclusions. Tumor control following GKS is greater in patients with smaller-sized tumors (&lt; 8 cm3) and in younger patients. Gamma knife radiosurgery can be performed to treat malignant meningioma with acceptable toxicity. The efficacy of GKS relative to other therapies for recurrent malignant meningioma as well as the value of GKS as a boost to radiotherapy will require further evaluation.

Four-extremity deep venous thrombosis on a brain injury rehabilitation unit: case report

Lower extremity deep venous thrombosis (LE DVT) is a fairly common condition among brain injury rehabilitation patients, occurring in up to 20% of all admissions. Upper extremity deep venous thrombosis (UE DVT) is less common. However, its incidence is expected to increase due to the increasing usage of central venous catheterization (CVC). This paper reviews the course of treatment of a patient with recurrent malignant meningioma who was found to have fourextremity deep venous thrombosis on a baseline screening duplex Doppler ultrasonography at admission to an inpatient brain injury rehabilitation unit. The need for tumor embolization followed by surgical resection was felt to preclude chemical prophylaxis for DVT despite the significant risk factors of; age > 60, immobility, quadriplegia, surgery with anesthesia > 30 minutes, and diagnosis of cancer. Aggressive anticoagulation with close clinical monitoring allowed for successful participation in a full rehabilitation with only a brief delay. The appropriate treatment of this patient is discussed in light of the latest research findings. Recommendations for future treatment protocols and research are made.

脳葉切除による悪性脳腫よう全摘出における超音波診断の応用

The outcome of treatment for malignant brain tumors is still disappointing. For this reason, total removal of the tumor is required to obtain a better outcome. It is acknowledged that en bloc total removal of a tumor by lobectomy results in a better outcome than subtotal or partial removal. For extensive removal of a tumor, recognition of the location, infiltration, and cleavage of the tumor is very important. We tried to carry out intraoperative ultrasonography in order to obtain data about brain tumors. We examined three cases of glioblastoma in the frontal region, two in the temporal region, and one in the occipital region, and a case of recurrent malignant meningioma in the temporal region.Extra- and intradural intraoperative ultrasonography was carried out, and silastic or plastic tubes were implanted around the tumor under ultrasonographic guidance. Thus en bloc total removal of the tumor was carried out successfuly without any neurological deficit. The application of intraoperative ultrasonography for malignant brain tumors is very useful, and should help to improve postoperative outcome.

The Treatment of Recurrent Unresectable and Malignant Meningiomas with Interferon Alpha-2B

The Treatment of Recurrent Unresectable and Malignant Meningiomas with Interferon Alpha-2B