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Mark K. Lyons, Gilbert R. Gonzales, Steven E. Schild and Kent D. Nelson

The authors report the long-term result of treatment of a presumed pituitary adenoma with external-beam radiation therapy, which appears to be the development of a radiation-induced meningioma. Of the post radiation neoplasms that have been reported, meningiomas constitute a large proportion of these lesions.

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Herbert H. Engelhard

Complete surgical removal, including resection of involved bone and dura, is curative of intracranial meningiomas in approximately 90% of cases. However, complete removal may entail unwarranted risk if the tumor involves or is adjacent to critical vascular or neural structures. In addition, it is possible for fragments of tumor to “evade” resection, even with the use of meticulous microsurgical technique. Because of this, clinicians may be faced with the decision of whether to offer or recommend radiation therapy or radiosurgery to a patient with a residual or recurrent meningioma. For many years, it has been recommended that external-beam radiation therapy be considered in the treatment of incompletely resected or malignant meningiomas. More recently, the role of radiosurgery as adjuvant or even primary therapy for meningiomas has attracted considerable attention. This article presents a review of the literature on postoperative radiotherapy of intracranial meningiomas.

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Bridget J. McCarthy, Faith Davis, Sally Freels, Tanya S. Surawicz, Denise Damek, James Grutsch, Herman R. Menck and Edward R. Laws Jr.

Factors affecting the survival rate in patients with meningiomas were explored using the National Cancer Database (NCDB), which includes tumors from approximately 1000 hospitals participating in the American College of Surgeons tumor registry program. Analysis included over 9000 cases diagnosed from 1985 to 1988 and 1990 to 1992. Survival estimates were computed and prognostic factors were identified using a proportional hazards model. The overall 5-year survival rate was 69% and it declined with age. This rate was 81% in patients aged 21 to 64 and 56% for patients 65 years of age or older. When patients were grouped by the histological type of their tumors, those with benign tumors had an overall 5-year survival rate of 70%, whereas the overall 5-year survival rates in patients with atypical and malignant meningiomas were 75% and 55%, respectively. Prognostic factors for benign tumors included age at diagnosis, tumor size, whether treated surgically, hospital type, and radiation therapy; for malignant tumors, age at diagnosis, whether treated surgically, and radiation therapy were statistically significant. The 5-year rate for recurrence of symptoms (regardless of the method of treatment) was 18.2% for those with benign tumors and 27.5% for those with malignant tumors. In patients whose benign tumor had been completely removed, the 5-year rate of tumor recurrence was 20.5%. Although not population-based, the NCDB has the potential for providing pertinent information regarding patient characteristics and methods of treatment for benign, as well as malignant, brain tumors.

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Uwe M. H. Schrell, Uwe Koch, Rolf Marschalek, Thomas Schrauzer, Marc Anders, Eric Adams and Rudolf Fahlbusch

It has been demonstrated that growth of cerebral meningiomas found in humans is controlled by a variety of factors, including growth factors, aminergic agents, neuropeptides, and steroids. The authors investigated the presence and function of the cytokines leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and oncostatin M (OSM) on meningioma cell proliferation.

Active transcription of LIF, IL-6, OSM, their related receptors (LIF-R, IL-6-R, gp130), and the consecutive signal-transducing molecules (STAT 1, STAT 3, and STAT 5a) were analyzed in reverse transcriptase-polymerase chain reaction experiments.

The presence of endogenous LIF, IL-6, and OSM proteins was demonstrated in the supernatant of cultured meningioma cells using enzyme-linked immunosorbent assay and Western blot experiments, thus indicating an autocrine signaling pathway for all three cytokines.

The biological function of all three cytokines was evaluated by studying their effects on meningioma cell growth. Recombinant LIF and IL-6 showed no significant growth modulating effects; however, recombinant OSM decreased meningioma cell growth by 66%. The antiproliferative potency of OSM was demonstrated by cell count experiments, [3H]thymidine incorporation assay, and cell cycle analysis. These in vitro data support the concept that growth of meningioma cells may be modulated by cytokines and also indicates that recombinant OSM may be one of the future candidates for use in the adjuvant treatment of inoperable and recurrent meningiomas.

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Thomas Chr. Vukovich, Adelheid Gabriel, Bruno Schaefer, Mario Veitl, Christian Matula and Christian K. Spiss

Patients undergoing brain tumor surgery are at high risk for the occurrence of a thromboembolic event. To identify a laboratory marker suitable for risk estimation the authors studied the perioperative time pattern of routine coagulation parameters and the specific hemostasis activation marker D-dimer in 28 consecutive patients at high risk (11 patients with glioma and eight patients with menigioma) and low risk (9 patients with metastases) for thromboembolism, as previously reported. As is typical during major surgery, most of the routine parameters declined, probably because of hemodilution, and recovered postoperatively to values higher than baseline, probably because of an acute-phase reaction. On Days 2 and 7 after surgery no difference in the routine parameters was recorded between patients at high (meningioma and glioma) and low risk (metastases). The level of D-dimer was elevated at baseline in patients with metastases, indicating a hemostatic hyperactivity that is usual in cancer patients. During surgery a marked increase in D-dimer levels occurred in patients with meningioma and glioma (pre- and postoperative median 90/2000 and 100/1020 ng/ml, respectively), but the increase was less pronounced in patients with metastases (320/660 ng/ml). Postoperatively, D-dimer declined in patients with metastases to lower levels than preoperatively (Day 7, 270 ng/ml); in patients with meningioma or glioma, however, D-dimer levels remained elevated until Day 7 (450 and 200 ng/ml). These results indicate that levels of D-dimer correlate with the reported high risk for thromboembolism in patients with meningioma and glioma, and D-dimer should be evaluated for its use in estimating individual risk and the efficiency of its use in the control of prophylactic treatment.

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Uwe M. H. Schrell, Michael G. Rittig, Marc Anders, Franklin Kiesewetter, Rolf Marschalek, Uwe H. Koch and Rudolf Fahlbusch

Meningiomas, which invade intracranial bone structures and the adjacent connective tissue, are frequently unresectable because of their aggressive and recalcitrant growth behavior. They have a high recurrence rate, and in approximately 10% of these tumors there is an increased risk of malignancy. Significant morbidity and mortality rates associated with recurrent meningiomas demand nonsurgical approaches. To date, adjuvant hormonal treatment has not proven beneficial. The anticancer drug hydroxyurea was therefore tested for its potential use in the treatment of meningiomas.

Early-passaged cell cultures were established from 20 different meningiomas. The addition of 5 X 10−4 and 10−3 M hydroxyurea over a period of 5 to 9 days resulted in a remarkable decrease in cell proliferation and even blocked tumor cell growth when compared with untreated cells. A significant arrest of meningioma cell growth in the S phase of the cell cycle was revealed on DNA flow cytometry.

Electron micrographs of hydroxyurea-treated tumor cells showed ultrastructural features consistent with apoptosis, and light microscopy demonstrated DNA fragmentation by in situ DNA strand break labeling. Short-term treatment of meningioma cell cultures with hydroxyurea for 24 to 48 hours resulted in discrete oligonucleosomal fragments (DNA ladder), another characteristic sign of apoptosis. In addition to the in vitro studies, tissue from five different meningiomas was transplanted into nude mice followed by treatment with 0.5 mg/g body weight hydroxyurea over 15 days. In situ DNA strand break labeling demonstrated DNA fragmentation in distinct regions with different tumor cell densities in all hydroxyurea-treated meningioma transplants.

These data provide evidence that hydroxyurea is a powerful inhibitor of meningioma cell growth, most likely by causing apoptosis in the tumor cells. Thus, hydroxyurea may be a suitable chemotherapeutic agent for the long-term treatment of unresectable or semi- to malignant meningiomas, or for preventing recurrent growth of meningiomas after resection.

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Uwe M. H. Schrell, Michael G. Rittig, Marc Anders, Uwe H. Koch, Rolf Marschalek, Franklin Kiesewetter and Rudolf Fahlbusch

In this paper the authors present the first evidence that meningiomas respond to treatment with hydroxyurea. Hydroxyurea was administered as an adjunct chemotherapeutic treatment in patients with recurrent and unresectable meningiomas. Hydroxyurea was used because experimental data demonstrated that it inhibits growth of cultured human meningioma cells and meningioma transplants in nude mice by inducing apoptosis. The authors therefore treated four selected patients with hydroxyurea. All patients had undergone multiple gross resections and all except one received radiotherapy. Three patients with recurrent Grade I meningiomas assessed according to World Health Organization (WHO) guidelines received hydroxyurea because of an increased tumor growth rate, documented by magnetic resonance (MR) imaging, within a 6- or 12-month interval. A fourth patient with a malignant meningioma (WHO Grade III) began a course of treatment with hydroxyurea immediately after his sixth palliative operation without waiting for another relapse to be demonstrated on MR imaging. Because of their location and invasive growth behavior none of the meningiomas could have been removed completely by surgical intervention.

All patients received hydroxyurea at a dosage level of 1000 to 1500 mg/day (approximately 20 mg/kg/day). In a man with a large sphenoid wing meningioma invading the right cavernous sinus and the temporal base, the intracranial tumor mass was reduced by 60% during 6 months of treatment. A woman with a large ball-shaped meningioma of the right sphenoid wing invading the cavernous sinus exhibited a 74% decrease of the initial tumor volume in 10 months of treatment with oral hydroxyurea. Serial MR images obtained monthly revealed that the process of size reduction was continuous and proportionate. The shrinkage of the tumor was accompanied by a complete remission of symptomatic trigeminal neuralgia after 2 months and by improved abducent paresis after 5 months. The third patient had a slowly growing meningioma that exhibited a 15% reduction in mass when reassessed after 5 months of hydroxyurea treatment. The fourth patient with the malignant meningioma in the left cerebellopontine angle has had no recurrence for 24 months. Long-term treatment with hydroxyurea may result in full remission of tumors in meningioma patients.

The preliminary data indicate that hydroxyurea provides true medical treatment in patients with unresectable and recurrent meningiomas, replacing palliative surgery and radiotherapy in the management of this disease.

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Michael Bitzer, Lars Wöckel, Andreas R. Luft, Ajay K. Wakhloo, Dirk Petersen, Holger Opitz, Theo Sievert, Ulrike Ernemann and Karsten Voigt

The authors studied the pial and dural blood supplies in 74 intracranial meningiomas and quantified their associated peritumoral brain edema (PTBE). The extent and localization of pial blush in relation to the total tumor volume were determined angiographically. The amount of edema and tumor size were calculated using computerized tomography. The edema-tumor volume ratio was defined as Edema Index (EI). There were 49 meningiomas with PTBE; of those tumors, 46 were supplied by pial vessels, and three were supplied exclusively by dural vessels. Tumors without PTBE showed no pial blush. The mean EI in meningiomas with pial blush was significantly larger (EI = 3.0) than in meningiomas without pial supply (EI = 1.1; p < 0.0001). Meningiomas in which 10% of the whole tumor volume was supplied by pial vessels had only a small mean EI of 2.2, whereas tumors with pial blood supply greater than or equal to 20% had a mean EI of 3.3 (p < 0.026). In 69.9% of cases with pial blood supply, major portions of the edema were located adjacent to the tumor region supplied by pial vessels. Edema index differences among tumors of different subgroups, as defined by size or histology, were significantly related to the pial supply in each subset. Thus, pial blood supply may be causative for the development of PTBE in meningiomas.

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Lucio Palma, Paolo Celli, Carmine Franco, Luigi Cervoni and Giampaolo Cantore

To contribute to a better understanding of the prognostic differences between atypical and malignant meningiomas as defined by the World Health Organization (WHO) and the influence of the grade of initial surgical excision on postoperative course, 42 cases of atypical and 29 of malignant meningioma were studied, along with long-term follow up. The two groups were compared with respect to long-term survival, recurrence-free survival, and median time to recurrence. The prognostic significance of the Simpson grade of surgical resection and tumor location was also considered. Survival at 5 and 10 years was recorded in 95% and 79%, respectively, of patients with atypical meningioma and in 64.3% and 34.5% of patients with malignant meningioma (p = 0.001). Recurrence-free survival and median time to recurrence were also significantly longer in patients with atypical than in those with malignant meningiomas: 11.9 versus 2 years (p = 0.001) and 5 versus 2 years (p < 0.0041), respectively. Six (26%) of the 23 recurring atypical meningiomas became malignant. Simpson Grade I resection and location in the cerebral convexity, which were closely related, were found to be associated with a significantly better clinical course in the entire series (p ¾ 0.0016). Patients with atypical meningiomas fared better than those with malignant meningiomas after incomplete surgical excision (Simpson Grades II-III), but the difference was not statistically significant. Multivariate analysis using the Cox model indicated that radical extirpation (Simpson Grade I vs. II-III) and histological findings (atypical meningioma vs. malignant meningioma) were significantly related to prolonged survival (p < 0.0003 and p < 0.0388, respectively). In conclusion, the current study shows that for most patients with atypical meningioma the prognosis was less severe than for those with malignant meningioma, but the risk of a downhill course resulting from malignancy after incomplete resection and recurrence was not negligible (26%). In addition, the WHO classification was found to be inadequate for a minority of the atypical meningioma cases, which currently have the same unfavorable course as cases of malignant meningioma. The results also indicate that objective Simpson Grade I extirpation of convexity meningiomas can be successful despite histological findings of malignancy.

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Rudolf Fahlbusch