Brainstem Glioma Research Articles

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

A Case of Sustained Objective Response of Recurrent/Progressive Diffuse Intrinsic Pontine Glioma with Phenylbutyrate and Targeted Agents

Diffuse intrinsic pontine glioma (DIPG) is the most common type of brainstem glioma and one of the most deadly brain tumors. DIPG in young adult patients is a rare disease for which treatment options are limited. Radiation therapy remains the standard-of-care for newly-diagnosed DIPG, but no established therapies for recurrent disease are available. This paper describes the results of treatment of a young adult patient diagnosed with DIPG that progressed after radiation therapy. Therapy included sodium phenylbutyrate (PB) in combination with the targeted agents: pazopanib, everolimus, erlotinib, and bevacizumab. The patient achieved a rapid partial response, which persisted over a year and five months. The patient opted to discontinue the therapy and thereafter elected chemotherapy, which resulted in a subsequent rapid progression and death within one month. The targeted treatment was associated with minor toxicity that included a Grade 2 skin rash and Grade 1 elevation of transaminases. In conclusion, a combination of PB and currently available targeted drugs may offer extended survival in patients with recurrent DIPG.

Temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: a broken promise?

Background:The purpose of this study was to assess the efficacy and toxicity of radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG).Methods:Patients younger than 18 years with newly diagnosed DIPG were enrolled. Children were treated with focal RT along with concurrent daily TMZ. Four weeks after completing the initial RT–TMZ schedule, adjuvant TMZ was given every 28 days up to 12 cycles or progression disease.Results:Fifteen children with a median age of 9 years were enrolled. Fourteenth out of the 15 patients completed the chemoradiotherapy. The toxicity associated with TMZ was primarily haematopoietic. At a median follow-up of 15 months 13 children had died and 2 children were alive with progressive disease. No patient experienced complete response (CR). The median time to progression was 7·15 months.Conclusion:Chemoradiotherapy with TMZ followed by adjuvant TMZ did not improve the poor prognosis associated with DIPG in children.

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.

Inhibition of C-terminal truncated PPM1D enhances the effect of doxorubicin on cell viability in human colorectal carcinoma cell line

PPM1D is a p53-inducible Ser/Thr phosphatase. One of the main functions of PPM1D in normal cells is to act as a negative regulator of the p53 tumor suppressor by dephosphorylating p53 and several kinases. PPM1D is considered an oncoprotein owing to both its functions and the fact that gene amplification and overexpression of PPM1D are reported in several tumors. Recently, PPM1D mutations resulting in C-terminal truncated alterations were found in brainstem gliomas and colorectal cancers, and these mutations enhanced the activity of PPM1D. Therefore, C-terminal truncated PPM1D should be also considered as a potential candidate target of anticancer drugs. Here we showed that combination treatment with PPM1D-specific inhibitor SPI-001 and doxorubicin suppressed cell viability of HCT-116 cells overexpressing C-terminal truncated PPM1D through p53 activation compared with doxorubicin alone. Our results suggest that combination treatment with PPM1D inhibitor and doxorubicin may be a potential anti-cancer treatment in PPM1D-mutated cancer cells.

PM-12 * Pax3 EXPRESSION ENHANCES PDGF-B-INDUCED BRAINSTEM GLIOMAGENESIS AND CHARACTERIZES A SUBSET OF BRAINSTEM GLIOMA

High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.

AT-15 * A PHASE II STUDY OF ANTINEOPLASTONS A10 AND AS2-1 IN PATIENTS WITH BRAINSTEM GLIOMAS FINAL REPORT (PROTOCOL BT-11)

PURPOSE: To evaluate the efficacy and safety of antineoplastons A10 and AS2-1 (ANP) in patients with brainstem glioma (BSG). METHODS: In the intent to treat (ITT) population forty patients (median age 11.2 years) were enrolled, and all were included in safety analysis, but only 39 patients were evaluated for efficacy. ANP was administered intravenously daily. Efficacy analyses were conducted in all BSG patients and in two subgroups: recurrent pediatric diffuse intrinsic pontine glioma (RPDIPG) and non-DIPG (NDIPG). RESULTS: In BSG, complete responses (CR) were observed in 13% of patients, partial responses (PR) 10%, and stable disease (SD) 20.5%. Overall survival (OS) at 1, 2, 5, 10 and 15 years was 38.5%, 28%, 23%, 20%, and 17% correspondingly. Six patients are presently alive 7.6 years to over 18 years. In the RPDIPG group, CR was 6%, PR 23.5%, and SD 17.5%. One year OS was 29%, 2 years 12%, and 5, 10 and 15 years 6%. In the NDIPG group, there were 36% CR and 27% SD. OS at 1, 2, 5, 10, and 15 years was 82%, 73%, 73%, 62%, and 50% correspondingly. Grade 3 and higher sodium and potassium abnormalities occurred in 15%, fatigue and somnolence in 12.5%, skin allergy and urinary incontinence occurred in 2.5% (all toxicities in ITT). No chronic adverse events occurred. Responding patients experienced improved quality of life. CONCLUSION: The results suggest that ANP shows efficacy and acceptable tolerability profile in patients with BSG, RPDIPG, and NDIPG.

ED-06 * BRAINSTEM GLIOMAS IN ADULTS: DO ADULT DIFFUSE INTRINSIC PONTINE GLIOMAS EXIST?

BACKGROUND: The majority of brainstem tumors in children are diffuse intrinsic pontine gliomas (DIPG), and are diagnosed in middle childhood. Recent data suggests DIPG is a disease of development. Relatively little information is available for adult brainstem gliomas (BSG). We reviewed clinical and radiographic information from adults with BSG referred to our institution. METHODS: Patients were enrolled on IRB-approved protocols. Clinical data was obtained from patient charts and electronic records. Radiographic data was reviewed on a Picture Archiving and Communications System (PACS) and assessed for primary tumor location, enhancement, intensity on T1, invasion of surrounding anatomical structures, and presence of CNS disease outside of the brainstem. RESULTS: 18 patients diagnosed with BSG were identified; diagnostic MRI was available for review on 15. M:F was 16:2; median age 29.5 (range 16-71) years at diagnosis. Presenting symptoms included long tract signs (61%), diplopia (50%), other visual changes (22%), imbalance (44%), headache (33%) and nausea/vomiting (33%). Primary tumor location varied: 27% were located in the pons only, 33% in pons with extension to medulla, 13% in pons with extension to midbrain, and 20% in pons with extension to midbrain and medulla. 80% showed contrast enhancement, with the majority (58%) of these enhanced diffusely. Other radiographic findings included encasement of the basilar artery (20%) and evidence of CNS disease outside of the brainstem (20%) at diagnosis (cerebellum and parietal lobe). The majority (88%) received radiation treatment; 56% received concurrent chemotherapy and 44% received adjuvant chemotherapy. Median time to first progression (defined radiographically and clinically) was 22 months (range 3-192 months). CONCLUSIONS: Although adults with brainstem tumors involving the pons have similar presentation as children with DIPG, imaging findings and clinical outcome differ significantly. Investigation into the biology of the adult lesions, including H3.3 mutations, may help define these as more distinct entities.

NI-44 * LIPOSOMAL NANOPARTICLES FOR TARGETING AND IMAGING OF PEDIATRIC BRAIN TUMORS

BACKGROUND: This study reports the targeting and real-time optical imaging of brainstem tumors using liposomal nanocarriers. Patients with infiltrating brainstem gliomas (BSG) known as diffuse intrinsic pontine gliomas (DIPGs) have one of the poorest survival rates. Blood brain barrier (BBB) is the main obstacle in the delivery of drugs and contrast agents to DIPGs. OBJECTIVE: Here, we demonstrate the specific delivery of liposomal nanoparticles containing Evans blue (nano-EB) to tumor in a murine model of BSG. METHODS/DESIGN: Mice with brainstem tumors were tail vein injected with nano-EB and in vivo tumor enhancement was monitored by optical fluorescence imaging. RESULTS/DISCUSSION: Necropsy analysis conducted 24 hr post injection showed site-specific delivery of nano-EB to the tumor but not adjacent normal tissue. Immunohistochemical assays confirmed high grade tumor at the site of nano-EB accumulation. These findings demonstrate the feasibility of nano-EB for drug delivery and real-time, sensitive optical imaging of BSGs in vivo. The study shows the specific accumulation of liposomal nano-EB nanocarriers in brainstem tumors in our murine model of brainstem glioma. Liposomes are an ideal drug delivery vehicle able to cross the BBB . Specific accumulation of nano-EB in tumor cells is explained by the enhanced permeability and retention (EPR) property of cancer cells which is believed to be due to the abnormal neovasculature with poorly-aligned defective endothelial cells and structure. This pilot study shows the efficacy of liposomes for targeted delivery and possibility of using nano-EB for in vivo imaging of tumors in a murine model of brain tumors.

RT-32 * CLINICAL PROFILE AND OUTCOMES IN BRAINSTEM GLIOMA. AN INSTITUTIONAL EXPERIENCE

BACKGROUND AND PURPOSE: The aim of our retrospective study was to analyze the clinical outcomes of brain stem glioma treated with radiation therapy (RT) in our institution. MATERIAL AND METHODS: Records of 48 patients with brainstem glioma treated between January 2007 and January 2013 were reviewed. Demographic variables, clinical variables, radiological findings and treatment details with respect to age, sex, location of tumor ( pontine Vs non pontine ), signs and symptoms, RT dose, follow up period and outcomes were recorded. Patients were subdivided into two groups based on their age, age = 15 yrs (group II). RESULTS: The median age at diagnosis was 10 years (range 4-50). Male to female ratio was 11:10. Of the 48 cases analyzed, 27 patients (56%) were in group I and 21 (44%) were in group II. At initial presentation 62% had features of raised intracranial tension, 71% had cranial nerve defects and 57% had cerebellar signs. Radiologically, 90.5% had involvement of pons. 10 (21%) patients received RT dose >60 Gy and 38 (79 %) patients received RT dose of 54-60 Gy. Median overall survival was 7months (range 3 - 44 months). The median age at diagnosis for group I and II was 6.5 and 32 years respectively. At initial presentation, 67% in group I and 56% patients in group II had features of raised intracranial tension, 67% in group I and 78% in group II had cranial nerve defects, 83% patients group I and 100% group II had involvement of pons. Median overall survival in group I and group II was 4 months and 10 months respectively (p = 0.042). CONCLUSIONS: Brain stem glioma in pediatric age group is associated with worse outcomes than in adults.

PT-02 * LONG-TERM SURVIVAL (>20 YEARS) OF A CHILD WITH BRAINSTEM GLIOMA TREATED WITH ANTINEOPLASTONS A10 AND AS2-1: A CASE REPORT

Tectal glioma is a subtype of midbrain brainstem glioma which occupies the tectum or quadrigeminal plates. The patient generally presents with symptoms related to increased intracranial pressure and requires treatment for hydrocephalus. No effective pharmacological treatments have yet been introduced. This report discusses a case of a 12-year-old male diagnosed with tectal glioma that had the onset of symptoms in November 1993. Initial treatment consisted of the placement of a ventriculoperitoneal shunt. After six years of stabilization of the disease, there had been an increase in the tumor size with signs of malignant transformation. In August 2001, he started treatment with Antineoplaston (ANP) A10 and AS2-1 infusions and continued for 20 months according to Phase II Protocol BT-09. The dosage of A10 was maintained between 12.5 and 14.7 g/kg/d and AS2-1 from 0.3 and 0.4 g/kg/d. He obtained a complete response and was switched to a maintenance study with A10 and AS2-1 capsules (0.26 g/kg/d of each), according to Protocol BT-34. All treatments were discontinued in December 2003. His condition continued to improve during the treatment with ANP and currently, 20 years from his diagnosis and over 12 years from treatment start, he is symptom free and leads a normal, productive life. This report indicates that it is possible to obtain long-term survival of a child with aggressive brainstem glioma with currently available investigational treatment.

AT-26 * CLINICAL MANAGEMENT AND OUTCOME OF HISTOLOGICALLY VERIFIED ADULT BRAINSTEM GLIOMAS IN SWITZERLAND: A RETROSPECTIVE ANALYSIS OF 21 PATIENTS

BACKGROUND: Because of low incidence, mixed study populations and paucity of clinical and histological data, the management of adult brainstem gliomas remains non-standardized. We here describe characteristics, treatment and outcome of patients with exclusively histologically confirmed adult brainstem gliomas. METHODS: A retrospective chart review of adults (> age 18 years) was conducted. Brainstem glioma was defined as a glial tumor located in the midbrain, pons or medulla. Characteristics, management and outcome were analyzed. RESULTS: 21 patients (17 males; median age 41 years) were diagnosed between 2004 and 2012 by biopsy (n = 15), partial (n = 4) or complete resection (n = 2). Diagnoses were glioblastoma (WHO grade IV, n = 6), anaplastic astrocytoma (WHO grade III, n = 7), diffuse astrocytoma (WHO grade II, n = 6) and pilocytic astrocytoma (WHO grade I, n = 2). Diffuse gliomas were mainly located in the pons and frequently showed MRI contrast enhancement. Endophytic growth was common (16 versus 5). Postoperative therapy in low-grade (WHO grade I/II) and high-grade gliomas (WHO grade III/IV) consisted of radiotherapy alone (3 in each group), radiochemotherapy (2 versus 6), chemotherapy alone (0 versus 2) or no postoperative therapy (3 versus 1). Median PFS (24.1 versus 5.8 months; log-rank, p = 0.009) and mOS (30.5 versus 11.5 months; log-rank, p = 0.028) was significantly better in WHO grade II than in WHO grade III/IV tumors. Second-line therapy considerably varied. CONCLUSIONS: Histologically verification of adult brainstem glioma is feasible and has an impact on postoperative treatment. Low-grade gliomas can simple be followed or treated with radiotherapy alone. Radiochemotherapy with temozolomide can safely be prescribed for high-grade gliomas without additional CNS toxicities.

ET-64 * PRE-CLINICAL ASSESSMENT OF DISSOCIATIVE STEROIDS AS DEXAMETHASONE SUBSTITUTE FOR TREATMENT IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

BACKGROUND: Although corticosteroids are widely used to treat cancer, cerebral edema, and other inflammatory disorders, their exact mechanism of action is poorly understood and less toxic alternatives are needed. The purpose of this study was to use a genetically engineered DIPG murine model to conduct pre-clinical testing of a new orally-administered steroid derivative, VBP15, which promises to reduce side effects through dissociating GRE-mediated transcription and NFkB-mediated modulatory actions. METHODS: First, to compare VPB15 to dexamethasone in reducing pro-inflammatory signals in vitro, BSG D10 murine and Control D10 cells were expanded in culture for 24 hours, serum starved and treated at 12 hours with dexamethasone, VBP15 or DMSO (control) and no drug in complete media for two hours. Using extracted RNA from the cells, NanoString evaluated specific inflammatory pathways. Second, in vivo efficacy of VBP15 was assessed. CSPG4+/+ neurospheres were into the brainstem of 18 mice at P2, 7 were treated with oral dexamethasone, 7 with VBP15 and 4 with cherry syrup (control) for up to 45 days. RESULTS: (In Vitro) Compared to DMSO, both dexamethasone and VBP15 given 12 hours into serum starvation decreased cytokine expression of IL10, IL6 and Tnf, which are cytokines in the NfKB pathway. (In Vivo) Post-mortem H&E staining revealed that 17 of 18 mice had developed tumor. Kaplan-Meir survival curves indicated a survival advantage for mice treated with VBP15 compared to dexamethasone or control. CONCLUSIONS: VPB15 has similar or better efficacy vs. dexamethasone (DEX) in reducing pro-inflammatory signals in brainstem glioma cells in vitro, and VBP15-treated DIPG mice show better survival compared to dexamethasone in vivo. These pilot results warrant more extensive pre-clinical testing and possibly development of a clinical trial.

RT-08 * PROTON THERAPY (PT) LARGE-VOLUME RE-IRRADIATION FOR RECURRENT GLIOMA: OVERALL SURVIVAL (OS) AND TOXICITY OUTCOMES

BACKGROUND: The therapeutic benefit of targeting T2/FLAIR in addition to contrast-enhancing (CE) tumor during re-irradiation for recurrent glioma can be attenuated by augmented toxicity. Given its steep dose fall-off and narrow penumbrae, PT minimizes volume of brain parenchyma outside target volume, potentially permitting a less toxic delivery of large-volume re-irradiation. METHODS: From 2/2011 to 12/2013, 19 consecutive adult patients with recurrent glioma treated with PT re-irradiation at a single institution were retrospectively analyzed. Planning target volume (PTV) included T2/FLAIR and CE abnormalities. Covariates assessed were age, gender, KPS at time of PT, number of salvage treatments, grade at initial diagnosis, interval between prior radiotherapy and PT, PT dose, PT PTV, bevacizumab failure, concurrent use of temozolomide and/or bevacizumab, and post-PT radiation necrosis. OS time from PT start was estimated with Kaplan-Meier analysis; comparisons used log-rank statistic. Multivariate analysis used the Cox proportional hazards model. RESULTS: Median age was 42 and median KPS was 90. Median salvage treatments was 2 (range 1-9). Median interval between prior radiotherapy and PT was 36.1 months (mos) (range 6.9-162.9). 12 patients (63%) were bevacizumab-refractory. Median PT dose was 50.4 CGE and median PTV was 224.2 cc. 5 patients (26%) remain alive. Median OS was 9.4 mos overall, 6.6 mos amongst bevacizumab-refractory patients, and 12.3 mos amongst bevacizumab-naive patients. Prior bevacizumab failure (hazard ratio (HR) 3.79; P = 0.047), shorter interval since prior radiotherapy (HR 1.04; P = 0.02), and Grade 4 disease (HR 4.17; P = 0.03) were prognostic of inferior OS. One patient had grade 3 radiation necrosis in the setting of PT re-irradiation for progressive brainstem glioma. One patient had grade 2 radiation necrosis, and another had grade 2 stroke. No other grade ≥3 toxicities were observed. CONCLUSION: Large-volume PT re-irradiation for recurrent glioma is safe and associated with promising OS outcomes, particularly in the setting of bevacizumab-refractory tumors.

Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.

High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0134-6) contains supplementary material, which is available to authorized users.

Commentary on: "The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma." By Burzynski et al.

A potential effective therapy for diffuse intrinsic pontine glioma (DIPG) is far to be developed. There are no "shortcuts" to reach this goal. Only a rigid, scientific, and ethically correct approach can help develop effective therapeutic approaches for such a devastating brain tumor. There are no alternative ways. The children affected by DIPG deserve to become the focus of serious collaborative researches. For these children, there are many "lacks" which should be promptly corrected such as the lack of knowledge, the lack of basic and clinical scientists' passion to the problem of finding "the solution" for DIPG, the lack of rigid methods to run research in this frustrating field, the lack of research proposals, and the lack of serious, despite not magic, protocols to offer them.

Erratum to: Temozolomide after radiotherapy in recurrent ‘‘low grade’’ diffuse brainstem glioma in adults

Erratum to: Temozolomide after radiotherapy in recurrent ‘‘low grade’’ diffuse brainstem glioma in adults

Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of CNS oncology

Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of CNS oncology

Commentary on: "Hydrocephalus Following Bilateral Dumbbell-Shaped C2 Spinal Neurofibromas Resection and Postoperative Cervical Pseudomeningocele in a Patient with Neurofibromatosis Type 1: A Case Report".

In this report, Nicola and colleagues report the occurrence of hydrocephalus 1 month after resection of dumbbell C2 neurofibromas. Prior to surgical intervention, the patient had a mild progressive quadriparesis, which improved after tumor resection. At 1 month postoperatively, the patient had a pseudomeningocele and enlarging ventricles consistent with the symptomatic hydrocephalus. Hydrocephalus can occur in patients with neurofibromatosistype1 but is usuallyassociatedwith opticpathwaygliomas, thalamic and hypothalamic tumors, intrinsic brainstem gliomas, or aqueductal stenosis. 1 Furthermore, hydrocephalus is a well-described entity with spinal cord tumors, and it is estimated that 1% of patients with spinal cord tumors present have hydrocephalus at presentation. 2 Most commonly, hydrocephalus is associated with intrinsic spinal cord tumors (75%), though it can happen with extramedullary tumors. Several mechanisms have been implicated, including increased protein from tumor or hemorrhage, obstruction of cerebrospinal fluid(CSF) pathways, or even neoplastic seeding. However,if it is identified before surgery, it is important to resect the spinal cord tumor before inserting a shunt to avoid shunt-related neurological deterioration. The authors of this report suggest that there was no hydrocephalus on presentation, though it is uncertain if this was evaluated radiologically. The most likely etiology for the hydrocephalus is a postoperative pseudomeningocele or CSF fistula with compression of the foramina of Magendie and Luschka, preventing normal CSF flow. In large series of posterior fossa decompressions for etiologies such as Chiari malformations or tumors, CSF leaks and pseudomeningoceles can form at rates of 6 to 10% with delayed hydrocephalus presenting in 3 to 5% ofpatients. 3,4 Inchildrenwith posterior fossatumors, the rate of postoperative hydrocephalus is very high, with 30% needing additional intervention after the original operation. 5 The presence of a postoperative pseudomeningocele in these patients is a harbinger of hydrocephalus as it was in the current case. Hydrocephalus can also occur after closed head injury with estimatesof posttraumatic hydrocephalus as high as 30% in patients with severe closed head injury. If the patient has concomitant injury to the upper cervical spine that requires intervention, a pseudomeningocele may form at the site of cervical injury with cranial imaging revealing ventricular enlargement. 6,7 The mechanism of posttraumatic hydrocephalus formation is not dissimilar to the presumed mechanism in the current case with obstruction of CSF outflow from the cranium or decreased resorption of CSF duetobloodandproteinblocking thearachnoidgranulations. In any event, the authors astutely recognized that this patient’s pseudomeningocele was a sign of hydrocephalus and treated the hydrocephalus before further morbidity or even death ensued.

O8.04 * TEMOZOLOMIDE AFTER RADIOTHERAPY IN RECURRENT "LOW-GRADE" DIFFUSE BRAINSTEM GLIOMA IN ADULTS

Diffuse brainstem glioma is a rare disease in adults. Radiotherapy (RT) is usually considered to be the standard treatment. However, the role of chemotherapy in treating relapses after RT is unclear, and this study aimed to assess the use of temozolomide (TMZ) in this situation. We conducted a retrospective analysis of patients from our database with “low grade” adult diffuse infiltrating brainstem glioma who received TMZ at relapse after failing RT. The patients were diagnosed by histology or MRI criteria compatible with a low-grade glioma. The tumors were localized in the pons, medulla oblongata or midbrain, excluding supratentorial or infratentorial tumors that had infiltrated the brainstem secondarily. The patients’ clinical and radiological responses were assessed, and their progression free survival (PFS) and overall survival (OS) time were estimated. Fifteen adult patients (median age 34 years) fulfilled the inclusion criteria. Histological analysis was available in 5 cases and showed grade II oligodendroglioma (2 cases), grade II oligoastrocytoma (2 cases), and grade II astrocytoma (1 case). Ten patients were selected by MRI criteria only. All patients received RT as initial treatment and had a median PFS of 34.2 months (95 % CI 24.1–44.2). The median KPS at the time of relapse was 80. TMZ was administered orally at 150–200 mg/m2 for 5 days, every 28 days. Clinical improvement after TMZ was observed in 9 cases (60 %), whereas radiological assessment detected responses in 6/15 cases, including 4 partial and 2 minor responses. The estimated median PFS after TMZ was 9.5 months (95 % CI 7.9–11), and the median OS was 14.4 months (95 % CI 10.5–18.2). Grade 3 thrombopenia was observed in 26 % of cases. TMZ could be useful after RT failure in adult patients with recurrent diffuse “low grade” brainstem glioma.