Radiosurgery for Intracranial Malignancies

Radiosurgery was historically designed as a technology to be used for the treatment of functional disorders, benign tumors, and vascular malformations. In the last 5 years, malignant lesions have become an increasingly common target for the radiosurgeon. In fact, by 1994 the most common disease treated with radiosurgery in the United States was metastatic disease. Published data suggest that radiosurgery offers excellent local control for intracranial metastatic lesions regardless of location or histology with the majority of patients demonstrating an improved quality of life. Recent information from the Joint Center for Radiation Therapy suggests that radiosurgery compares favorably with interstitial brachytherapy for both recurrent as well as in newly diagnosed patients with malignant gliomas in terms of improved survival and the need of surgery and steroid support for symptomatic radiation changes. Prospective studies (Phase I through III) are ongoing to determine the ultimate role of radiosurgery in the management of patients with newly diagnosed and recurrent malignant gliomas, recurrent pediatric brain tumors disease, and patients with single or multiple intracranial metastases.     

脑肿瘤合并脑血管畸形的高危因素分析

目的：探讨脑肿瘤合并脑血管畸形的危险因素。方法：回顾性分析2011年1月－2013年1月阳新县人民医院的109例脑肿瘤患者,对其中合并脑血管畸形的15例患者影响因素进行分析,并采用 Logostic 多因素进行影响因素分析。结果：高龄、高血压、糖尿病、心脏瓣膜病、高血脂、吸烟饮酒、颈动脉硬化、动脉瘤、硬脑膜动静脉瘘、肥胖、脑血流紊乱、家族遗传史是脑肿瘤合并脑血管畸形的独立危险因素（P 均＜0．05）。结论：脑肿瘤合并脑血管畸形危险因素和脑血管病相近。     

多层螺旋CT灌注成像诊断中老年脑胶质瘤

目的:探讨多层螺旋CT灌注成像对中老年脑胶质瘤的诊断作用,以期为临床中老年脑胶质瘤的诊疗提供借鉴。方法:以自2012年6月份以来入我院治疗的确诊为中老年脑胶质瘤的患者为研究对象,先后对患者行多层螺旋CT灌注成像扫描,获得并分析扫描图像中脑组织的多维多层螺旋灌注图像、CT血管成像,计算并分析多层螺旋CT灌注成像图像的病变实质部分和正常脑组织的达峰时间（TTP）、平均通过时间（MTT）、脑血流量（CBF）、脑血容量（CBV）参数、毛细血管表面通透性(ＰＳ)等灌注参数,通过灌注分析软件获得并分析时间-密度曲线(ＴＤＣ)。结果:共纳入患者43例患者,在所有病例中,多维多层螺旋灌注图像平均视觉评价分数明显高于单纯轴向灌注图(P=0.000),且对病变定位更为精确。CT血管造影（CT angiography,CTA）图中43 例患者中,有36例肿瘤发现供血大动脉,23 例肿瘤有引流静脉,29例大动脉受压,15例大动脉被肿瘤包裹,17例静脉窦受压。统计分析示,多层螺旋CT灌注成像图像的病变实质部分和正常脑组织的脑血流量（CBF）、毛细血管表面通透性(ＰＳ)、脑血容量（CBV）参数等灌注参数,两者之间差异具有统计学意义（P<0.05）。多层螺旋CT灌注成像图像的病变实质部分和正常脑组织的达峰时间（TTP）、平均通过时间（MTT）等灌注参数,两者之间差异无统计学意义（P>0.05）;低、高级别胶质瘤的病灶关键测试参数（critical test parameter,CTP）比较,ＣＢＦ、ＴＴＰ等灌注参数,两者之间差异具有统计学意义（P<0.05）。不同种类颅内肿瘤ＴＤＣ比较,高级别胶质瘤速升速降,低级别胶质瘤速升缓降型。结论:多层螺旋CT灌注成像图像不仅可以实现对邻近大血管颅内肿瘤的全面评价,有利于颅内肿瘤的术前整体评估和精确定位;且对颅内肿瘤的诊断及评价肿瘤与周围大血管的关系、对中老年脑胶质瘤的级别诊断也有一定的临床应用价值。     

Can permeability measurements add to blood volume measurements in differentiating tumefactive demyelinating lesions from high grade gliomas using perfusion CT?

Tumefactive demyelinating lesions (TDLs) can mimic a neoplasm on conventional imaging and may necessitate biopsy for diagnosis. The purpose of this study was to differentiate TDLs from high grade gliomas based on physiologic (permeability) and hemodynamic (blood volume) parameters using perfusion CT. Five patients who presented with tumefactive enhancing lesions on initial MRI that mimicked a neoplasm underwent perfusion CT. We compared the perfusion CT parameters of these patients with those of 24 patients with high grade gliomas. TDLs showed lower permeability surface area product (PS) (0.8 ± 0.2 vs 2.4 ± 1.4 ml/100 g/min, P-value 0.014) and lower cerebral blood volume (CBV) (1.0 ± 0.2 vs 2.8 ± 1.2 ml/100 g, P-value 0.006) as compared to high grade gliomas. TDLs show lower PS and CBV as compared to high grade gliomas, to which they can mimic on conventional MR imaging, due to lack of neoangiogenesis and vascular endothelial proliferation and hence perfusion CT can be used to differentiate the two entities.     

Gliomas following low-dose irradiation to the head report of three cases

Three patients developed cerebral gliomas decades after exposure to low-dose x-ray irradiation in childhood for the treatment of tinea capitis. One of the patients had a glioblastoma multiforme concomitant with multiple intracranial meningiomas, a condition highly correlated with previous irradiation. The other tumors were malignant cerebellar astrocytoma and a diffuse cerebral astrocytoma. We review the evidence suggesting that low-dose irradiation is involved in the pathogenesis of gliomas.     

Vascular abnormalities in surgical specimens obtained from the resected focus of intractable epilepsy

The histopathological features, particularly hypervascularity, were examined in specimens resected from 21 patients, 15 with intractable epilepsy accompanying cortical dysplasia or dysembryoplastic neuroepithelial tumor (DNT), and 6 with benign brain tumors, such as ganglioglioma and low-grade glioma. Hypervascularity was found in resected specimens from 15 of the 21 patients (71.4%) and in 10 of the 12 patients (83.3%) who had double pathology. Counting of numbers of vessels by CD31 immunohistochemistry revealed that hypervascularity was prominent, especially in cases of vascular malformation or cortical dysplasia. However, almost all cases were negative for vascular endothelial growth factor (VEGF) staining, except for some cases of benign brain tumors. Moreover, all cases showed low or no proliferative potential in MIB-1 immunohistochemistry. These results suggest that the etiology of hypervascularity in the dysplastic lesions is one of a variety of cerebral malformations, as is the case with abnormal maturation and differentiation in neuroglial elements.     

Pulmonary arteriovenous malformation: a rare anterior mediastinal mass

Pulmonary arteriovenous malformations are rare pulmonary vascular lesions which are associated with Osler Weber Rendu syndrome (hereditary haemorrhagic telangectasia). They act as right‐to‐left shunts and have cardiovascular and embolic complications. We present a patient with an apparent anterior mediastinal mass secondary to a pulmonary arteriovenous malformations which was successfully treated percutaneously.     

Special issues in the management of gliomas in children with neurofibromatosis 1

Neurofibromatosis 1 (NF1) is a common multisystem disorder that is frequently associated with neoplastic and non-neoplastic lesions within the central nervous system. Improvements in neuroimaging have led to increased detection of both types of lesions. Focal areas of increased T2 signal represent the most common abnormalities detected. The vast majority of such lesions are non-neoplastic and fluctuate in number and size during childhood. Optic pathway tumors are second in frequency and generally manifest an indolent natural history, although some lesions will increase in size over time and lead to progressive visual impairment. A smaller percentage of patients will develop gliomas within the cerebral and cerebellar hemispheres of brain-stem. This article will review areas of controversy in the evaluation and follow-up of patients with NF1 and will present our approach to these issues. We will also discuss therapeutic considerations in these patients that take into account the unique features of the underlying disorder.     

Cerebral Venous Malformations

Cerebral venous malformations (CVM) are increasingly being recognised with the widespread use of CT scanning. Five cases are presented which demonstrate typical angiographic features and CT findings. These lesions when located in the cerebral hemispheres are benign and have been distinguished from the better known arteriovenous malformations on the basis of their characteristic angiographic features. CT findings have been considered nonspecific but our early post contrast CT scans demonstrate characteristic features suggesting that in many cases the diagnosis of cerebral venous malformations may be made on the CT scan alone.     

Treatment guidelines of lymphatic malformations of the head and neck

Lymphatic malformations, traditionally called lymphangiomas, are diseases caused by development errors of the lymphatic system. About 90% of the cases occur within 2 years of age, except a few cases which occur in adulthood, and approximately 75% of the lesions are located in the head and neck region. The lesions can grow rapidly with infection, trauma or bleeding, resulting in disfigurement as well as severe impairment of respiration, swallow and speech. Although lymphatic malformations are benign lesions, they rarely resolve spontaneously, their infiltrating nature coupled with the difficulty in distinguishing involved vital structures of head and neck from adjacent normal tissues makes complete surgical resection even more difficult. The likelihood of postsurgical recurrence and complications is thus higher than other vascular lesions. Surgical resection, sclerotherapy and laser therapy are currently the main treatment modes of lymphatic malformations. Various treatment options have their advantages and disadvantages, the selection of treatment modalities should depend on the patient’s individual status and available technology and expertise. The treatment protocol should be individualized, comprehensive as well as sequential in order to obtain the best treatment outcome. Based on published literatures and clinical experiences, we devised the treatment guideline for management of head and neck lymphatic malformations. This protocol will be reviewed and updated periodically to include cutting edge knowledge to provide the best treatment options to benefit our patients.     

Comparison of transcranial Doppler ultrasound and computed tomography angiography in symptomatic middle cerebral artery stenosis

Transcranial Doppler ultrasound (TCD) and computed tomography angiography (CTA) of 10 patients with middle cerebral artery territory stroke were studied. To obtain data from patients with presumed in situ middle cerebral artery (MCA) stenosis, the study excluded patients with a known source of cardiac emboli, significant carotid stenosis and classical lacunar syndrome. As the gold standard for this study, CTA demonstrated MCA stenosis in all patients (100%), while abnormal TCDs suggesting MCA stenoses were found in only six patients (60%). The stenotic sites differed among patients with normal and abnormal TCDs. Patients with false negative TCDs were found to have more distal lesions (distal M1 or M2 segment) whereas patients with TCD abnormalities tend to have more proximal lesions as demonstrated by CTA. It is concluded that an abnormal TCD is highly suggestive of stenosis of MCA. A normal TCD, however, does not exclude such a lesion, especially in patients with distal M1 or M2 stenoses. Therefore, TCD may not be the best screening test for intracranial vascular stenotic lesion in MCA territory stroke.     

Expression of HMP/AN2, a melanoma associated antigen,in murine cerebral gliomas: potential for radioimmunotargeting

Human melanoma proteoglycan (HMP), a melanoma-associated antigen, is expressed in both human melanomas and gliomas. We used HMP-specific monoclonal antibody (mAb) VT68.2 to investigate whether murine GL261 cerebral gliomas express the HMP homologue AN2 and to determine whether AN2 could be targeted for selective delivery of radiation in vivo. HMP-specific mAb VT68.2 stained murine GL261 glioma cells grown in culture and intracerebrally in syngeneic C57BL/6 mice. Positron emission tomography with radiolabeled mAb VT68.2 showed high-contrast, positive images of gliomas against a negative background. At 96 h after injection, glioma uptake of radiolabeled mAb VT68.2 was 10× greater than that of the isotype control mAb and 20× greater than that detected in normal cerebral tissue. Our results show murine GL261 cerebral gliomas express AN2 and HMP-specific mAb VT68.2 accumulates selectively and specifically at high concentration and is retained within murine cerebral gliomas. Thus, HMP is a potential target for antibody-mediated selective delivery of radiation to cerebral gliomas in vivo.     

Correlation of F-18-fluoro-ethyl-tyrosin uptake with vascular and cell density in non-contrast-enhancing gliomas

Objective Even without contrast enhancement on MRI scans gliomas can show histological features of anaplasia. These tumors are heterogeneous regarding anaplastic and non-anaplastic areas. Increased amino acid uptake was shown to be associated with dismal prognosis in gliomas. We investigated histological correlates of tumor grading in biopsies obtained from regions with maximum amino acid uptake revealed by F-18-fluoro-ethyl-tyrosin positron emission tomography (FET-PET). Methods We included 22 patients with non-contrast enhancing lesions on MRI scans. PET was performed 10 min after FET injection, and the area of maximum FET uptake was chosen as the biopsy target. In 13 patients neuronavigated biopsies were obtained during tumor resection. Nine patients had a stereotactic biopsy. The ratio of maximum standardized uptake value (SUV) to background was calculated. Histological specimens were classified and graded according to world health organization (WHO) criteria. We investigated cell and vascular density, mitotic activity, proliferation index, microvascular proliferation, nuclear pleomorphism, necrosis and immunoreactivity of LAT1 (SLC7A5), an amino acid transporter with prognostic impact in gliomas. Results 12 of the 22 non-contrast enhancing gliomas corresponded to anaplastic astrocytomas WHO grade III. Vascular and cellular density was correlated highly to the SUV ratio (P = 0.0015 and P = 0.0021, respectively), but with no nuclear pleomorphism, mitotic activity, Mib-1 immunoreactivity, or microvascular proliferation. Thus, no correlation was found between FET uptake and tumor grade. Conclusion FET-PET correlates with vascular and cell density in non-contrast enhancing gliomas. Although tumor grade cannot be predicted, clinical use of FET PET as an indicator for neovascularization should be addressed in future studies. Florian Stockhammer and Michail Plotkin contributed equally to this work. Christian Woiciechowsky and Frank van Landeghem contributed equally to this work.     

Localized proton spectroscopy of inoperable brain gliomas. Response to radiation therapy

Within vivo 1H-MRS resonances of several metabolites were simultaneously measured in cerebral gliomas and adjacent normal brain. 15 patients with inoperable brain gliomas all histologically verified were monitored with 1H-MRS and MRI before and after radiotherapy. 11 patients were evaluable. 1H-MRS technique evolved from single volume measurements to one dimensional and two dimensional 1H spectroscopic imaging. In all patients N-acetyl-aspartate signals were decreased in tumour areas compared to the normal brain hemisphere. No recovery was seen after radiotherapy. Choline signals were increased in tumour margins of high grade gliomas and more diffusely in low grade gliomas. In 5 patients the choline resonance decreased after radiotherapy, accompanied by a shrinkage of tumour diameter on MRI. Lactate signals were present in high grade and unspecified astrocytomas and absent in most low grade gliomas. In 3 patients the lactate signal disappeared after radiotherapy. These observations indicate the feasibility of 1H-MRS in monitoring metabolic responses on radiotherapy of brain gliomas.     

Comparison of BOLD Cerebrovascular Reactivity Mapping and DSC MR Perfusion Imaging for Prediction of Neurovascular Uncoupling Potential in Brain Tumors

The coupling mechanism between neuronal firing and cerebrovascular dilatation can be significantly compromised in cerebral diseases, making it difficult to identify eloquent cortical areas near or within resectable lesions by using Blood Oxygen Level Dependent (BOLD) fMRI. Several metabolic and vascular factors have been considered to account for this lesion-induced neurovascular uncoupling (NVU), but no imaging gold standard exists currently for the detection of NVU. However, it is critical in clinical fMRI studies to evaluate the risk of NVU because the presence of NVU may result in false negative activation that may result in inadvertent resection of eloquent cortex, resulting in permanent postoperative neurologic deficits. Although NVU results from a disruption of one or more components of a complex cellular and chemical neurovascular coupling cascade (NCC) MR imaging is only able to evaluate the final step in this NCC involving the ultimate cerebrovascular response. Since anything that impairs cerebrovascular reactivity (CVR) will necessarily result in NVU, regardless of its effect more proximally along the NCC, we can consider mapping of CVR as a surrogate marker of NVU potential. We hypothesized that BOLD breath-hold (BH) CVR mapping can serve as a better marker of NVU potential than T2* Dynamic Susceptibility Contrast gadolinium perfusion MR imaging, because the latter is known to only reflect NVU risk associated with high grade gliomas by determining elevated relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) related to tumor angiogenesis. However, since low and intermediate grade gliomas are not associated with such tumoral hyperperfusion, BOLD BH CVR mapping may be able to detect such NVU potential even in lower grade gliomas without angiogenesis, which is the hallmark of glioblastomas. However, it is also known that glioblastomas are associated with variable NVU, since angiogenesis may not always result in NVU. Perfusion metrics obtained by T2* gadolinium perfusion MR imaging were compared to BOLD percentage signal change on BH CVR maps in a group of 19 patients with intracranial brain tumors of different nature and grade. Single pixel maximum rCBV and rCBF within holotumoral regions of interest (i.e., "ipsilesional" ROIs) were normalized to contralateral hemispheric homologous (i.e., "contralesional") normal tissue. Furthermore, percentage signal change on BH CVR maps within ipsilesional ROIs were normalized to the percentage signal change within contralesional homologous ROIs. Inverse linear correlation was found between normalized rCBF (r(flow)) or rCBV (r(vol)) and normalized CVR percentage signal change (r(CVR)) in grade IV lesions. In the grade III lesions a less steep inverse linear trend was seen that did not reach statistical significance, whereas no correlation at all was seen in the grade II group. Statistically significant difference was present for r(flow) and r(vol) between the grade II and IV groups and between the grade III and IV groups but not for r(CVR). The r(CVR) was significantly lower than 1 in every group. Our results demonstrate that while T2*MR perfusion maps and CVR maps are both adequate to map tumoral regions at risk of NVU in high grade gliomas, CVR maps can detect areas of decreased CVR also in low and intermediate grade gliomas where NVU may be caused by factors other than tumor neovascularity alone. Comparison of areas of abnormally decreased regional CVR with areas of absent BOLD task-based activation in expected eloquent cortical regions infiltrated by or adjacent to the tumors revealed overall 95% concordance, thus confirming the capability of BH CVR mapping to effectively demonstrate areas of NVU. ed by factors other than tumor neovascularity alone. Comparison of areas of abnormally decreased regional CVR with areas of absent BOLD task-based activation in expected eloquent cortical regions infiltrated by or adjacent to the tumors revealed overall 95% concordance, thus confirming the capability of BH CVR mapping to effectively demonstrate areas of NVU.     

Characterization of intracranial space-occupying lesions by 99mTc-Tetrofosmin SPECT

Differentiating neoplastic from non-neoplastic intracranial lesions is of paramount importance for patient management. Benign lesions can have many of the features of malignant brain tumors on both computed tomography (CT) and conventional magnetic resonance imaging (MRI). Herewith, we set out to investigate the role of ^99mTc-Tetrofosmin (^99mTc-TF) brain SPECT in the differentiation of neoplastic from non-neoplastic intracranial lesions. We prospectively studied, between September 2004 and September 2009, patients with intracranial lesions suspected of being tumors on CT/MRI that were operated on. All patients with suspected tumor on CT/MRI underwent ^99mTc-TF brain SPECT within a week before surgery and CT/MRI studies. Radiotracer accumulation in intracranial lesions was assessed visually and then a semiquantitative method of image analysis was applied, by calculating the lesion-to-normal (L/N) uptake ratio. We compared the L/N ratios between low-grade gliomas and high-grade gliomas, low and high-grade gliomas and intra-axial non-neoplastic lesions, low and high-grade gliomas and metastases, and typical versus anaplastic meningiomas Ninety patients suffered from neoplastic lesions and 16 harboured non-neoplastic pathologies. There was a significant difference between low-grade gliomas and high-grade gliomas (P = 0.0019). ROC analysis provided 2.8 as the optimum cutoff value thresholding discrimination between these two groups, with 91.3% sensitivity and 83.3% specificity. When comparing gliomas (low and high-grade) with intra axial non-neoplastic lesions the difference was statistically significant (P < 0.0001). There was no statistically significant difference between gliomas (low and high-grade) and metastases. Regarding meningiomas, there was a statistically significant difference between typical and anaplastic meningiomas (P = 0.0002). ROC analysis provided 9.6 as the optimum cutoff value thresholding discrimination between these two groups, with 96% sensitivity and 100% specificity. ^99mTc-TF brain SPECT may differentiate neoplastic from non-neoplastic intracranial pathologies and could prove useful for pre-surgical evaluation of intracranial lesions.     

Results of the treatment of children with recurrent gliomas with lomustine and vincristine

Gliomas comprise over 50% of all childhood brain tumors. Treatment of recurrent childhood gliomas has been disappointing and the effectiveness of therapy has been difficult to judge because of the variable natural history of the disease. Information gathered recently has suggested that treatment with [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea)] (CCNU) and vincristine (VCR) after radiotherapy is effective in prolonging survival in children with newly diagnosed anaplastic gliomas. The authors have used these same drugs--CCNU (100 mg/m2) and VCR (1.5 mg/m2 up to a maximum dose of 2 mg)--in 6-week cycles for a maximum of eight cycles in children with recurrent gliomas. To date, 15 patients have been treated; five patients had malignant gliomas and ten low-grade gliomas. Three children showed improvement, five had stable disease, and seven had progressive disease. Of the five patients with malignant gliomas, four progressed within two cycles of treatment and one had stable disease for 7 months on treatment and then relapsed. Seven of ten children with low-grade gliomas benefitted from treatment and six remain in continuous remission a median of 16 months after initiation of therapy. Three of these children are off all therapy 21, 30, and 30 months after treatment, respectively. Therapy was well tolerated and toxicity consisted primarily of reversible bone marrow suppression. The authors conclude that CCNU and VCR chemotherapy is effective in children with recurrent low-grade gliomas and can result in relatively long-term disease stabilization. In limited experience of the authors, it is not of benefit in children with recurrent anaplastic lesions.     

The morphologic effects of radiation administered therapeutically for intracranial gliomas: a postmortem study of 25 cases.

To investigate the pathologic consequences of therapeutic radiation, this morphologic study evaluated the brains of 25 patients with intracranial gliomas treated both with and without this form of therapy. Although beneficial effects such as the retardation of tumor growth were evident in these studies, among the seventeen patients who received from 5000--6000 rads for malignant gliomas, four developed "late delayed" radiation necrosis. The strong predilection of this tissue response for the white matter adjacent to the neoplasm suggests a local sensitivity which may have been engendered or enhanced by cerebral edema. A fifth case disclosed focal demyelination in the mid-brain suggesting "early delayed" radiation necrosis, and an additional case had distinctive foci of necrosis within the brain stem. Changes of diffuse cerebral edema were noted in many of the radiated brains. It is concluded that radiation therapy in commonly employed dosages for malignant gliomas carries a risk of injury to surrounding cerebral tissues.     

Outcomes in Patients Treated with Laser Interstitial Thermal Therapy for Primary Brain Cancer and Brain Metastases

Laser interstitial thermal therapy (LITT) is an emerging modality to treat benign and malignant brain lesions. LITT is a minimally invasive method to ablate tissue using laser-induced tissue heating and serves as both a diagnostic and therapeutic modality for progressive brain lesions. We completed a single-center retrospective analysis of all patients with progressive brain lesions treated with LITT since its introduction at our center in August of 2015. Twelve patients have been treated for a total of 13 procedures, of which 10 patients had brain metastases and 2 patients had primary malignant gliomas. Biopsies were obtained immediately prior to laser-induced tissue heating in 10 procedures (76.9%), of which seven biopsies showed treatment-related changes without viable tumor. After laser ablation, two of three patients previously on steroids were successfully weaned on first attempt. The results of this analysis indicate that LITT is a well-tolerated procedure enabling some patients to discontinue steroids that may be effective for diagnosing and treating radiation necrosis and tumor progression.     

The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin)

Malignant gliomas continue to be a significant sourceof mortality in young and middle aged adults.The introduction of new treatment strategies and multidisciplinaryapproaches has improved the outcome of patients withthese tumors only slightly. Because retinoic acid hasgrowth inhibitory activity against glioma and neuroblastoma cellsin cultures, we assessed the efficacy of all-trans-retinoicacid in the treatment of recurrent cerebral gliomas.Thirty-six patients with recurrent cerebral gliomas were enteredin the study and treated with 120 or150 mg/m²/day of all-trans-retinoic acid as a singleagent. The drug was given for 3 weeksfollowed with one week of rest. Two blocksof 4 weeks constituted one course of treatment.One (3%) of 34 evaluable patients had aminor response and 14 (41%) had stable disease.In the rest of the patients (56%), tumorscontinued to progress despite treatment. The median timeto progression of all evaluable patients was 8weeks, and for the responders was 17 weeks.The higher dose level (150 mg/m²) was associatedwith high incidence of headache, which responded todose reduction. The lower dose level was verywell tolerated, with mild, mainly dermatological toxicity.All-trans-retinoic acid as a single agent has nosignificant activity against recurrent cerebral gliomas.