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Latest Research on Brain Tumors
     
Curr Treat Options Oncol. 2008 Feb 7 [Epub ahead of print]
The Emerging Role of Anti-Angiogenic Therapy for Malignant Glioma.
Reardon DA, Desjardins A, Rich JN, Vredenburgh JJ.
Department of Surgery, Division of Neurosurgery, Duke University Medical Center, Box 3624, Durham, NC, 27710, USA, reard003@mc.duke.edu.

OPINION STATEMENT: Adults with glioblastoma multiforme (GBM), the most common primary brain tumor, have an unacceptably poor outcome with conventional cytotoxic therapies. Malignant gliomas are remarkably angiogenic, and vascular endothelial growth factor (VEGF) is the dominant pro-angiogenic factor. Recent clinical trials targeting VEGF signaling have achieved unprecedented rates of durable radiographic and clinical response, while also confirming adequate safety among recurrent malignant glioma patients. An array of additional clinical trials evaluating anti-angiogenic strategies are underway for both recurrent and newly diagnosed malignant glioma patients. Promising results of these approaches suggest that the treatment of GBM may represent an emerging paradigm of anti-angiogenic therapy.

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J Neurosurg. 2008 Feb;108(2):281-286.
State and trait anxiety and depression in patients with primary brain tumors before and after surgery: 1-year longitudinal study.
D'Angelo C, Mirijello A, Leggio L, Ferrulli A, Carotenuto V, Icolaro N, Miceli A, D'Angelo V, Gasbarrini G, Addolorato G.
1 Institute of Internal Medicine, Catholic University of Rome;, 2 Department of Neurosurgery, IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo; and, 3 Department of Cardiac Surgery, St. Andrea Hospital, University of Rome “La Sapienza,” Rome, Italy.

Object The aim in this study was to assess the state and trait types of anxiety as well as current depression before and after surgery in patients affected by brain tumors. The relationships between these affective disorders and the patient's sex, tumor histology, and laterality of the tumor were also evaluated. Methods A total of 72 patients affected by a primary brain tumor were enrolled in the study. Histological grades were assigned according to the World Health Organization classification. State and trait anxiety were assessed using the State and Trait Anxiety Inventory; current depression was assessed using the Zung Self-Rating Depression Scale. Cognitive impairment was assessed using the 10-item Short Portable Mental Status Questionnaire. Psychometric evaluation was assessed before surgery and at 1, 3, 6, and 12 months after surgery. Results Before brain surgery, 62.5% of patients showed state anxiety, 50% of patients showed trait anxiety, and 9.7% of patients showed current depression. During the follow-up period there was no significant variation in the percentage of patients with state anxiety (p = 0.416) and trait anxiety (p = 0.7), whereas a significant increase in the percentage of those with current depression was found (p < 0.0001), in particular at 1 month (p = 0.002) and 3 months (p = 0.039) after surgical treatment. The tumor's laterality and histology showed no correlation with psychometric variables, whereas a relationship between the presence of trait anxiety at the enrollment and current depression after surgery (p < 0.0001) was found. Conclusions Patients affected by brain tumors frequently experience affective disorders. After brain surgery, a depressive state can develop. The psychometric assessment could be useful in these patients for quick recognition of psychological disorders.

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Arch Pathol Lab Med. 2008 Jan;132(1):77-80.
Pediatric pituitary adenomas.
Webb C, Prayson RA.
Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA.

CONTEXT: Pituitary adenomas are relatively rare occurrences in the pediatric population, and there are few studies documenting the profile of these tumors in this age group. OBJECTIVE: To study the clinical and pathologic features of pediatric pituitary adenomas in conjunction with a review of the available literature. DESIGN: A retrospective clinicopathologic review of 20 pediatric patients (younger than 20 years of age) with pituitary adenomas resected during a 24.5-year period (1981-2005). RESULTS: A total of 20 patients, including 12 females and 8 males, comprise the study group. Mean age at onset of symptoms was 14.0 years (range, 5-18 years). Four patients had onset of symptoms before the age of 12 years. The majority of patients presented with headaches (n = 12), visual disturbances (n = 12) or, in females, menstrual dysfunction (n = 9/12). Tumor size based on radiographic data was known for 19 tumors; 12 adenomas were greater than 1 cm in greatest dimension, and 7 were less than 1 cm. On follow-up, 2 patients with total gross tumor resections had recurrent adenomas; time to recurrence was 5 months and 17 months, respectively. Nine adenomas stained solely for prolactin, 5 for adrenocorticotropic hormone, and 3 for growth hormone. Two stained for growth hormone and prolactin. One did not stain with hormone antibodies. CONCLUSIONS: Most pediatric pituitary adenomas present after the onset of puberty and present with frequent headaches, changes in visual acuity and, in females, menstrual dysfunction. Most (19/20) were secretory, with prolactinomas being the most common type.

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N Engl J Med. 2008 Jan 3;358(1):18-27. Comment in: N Engl J Med. 2008 Jan 3;358(1):6-7.
Functional outcome after language mapping for glioma resection.
Sanai N, Mirzadeh Z, Berger MS.
Department of Neurological Surgery and the Brain Tumor Research Center, University of California at San Francisco, San Francisco, CA 94143-0112, USA. sanain@neurosurg.ucsf.edu

BACKGROUND: Language sites in the cortex of the brain vary among patients. Language mapping while the patient is awake is an intraoperative technique designed to minimize language deficits associated with brain-tumor resection. METHODS: To study language function after brain-tumor resection with language mapping, we examined 250 consecutive patients with gliomas. Positive language sites (i.e., language regions in the cortex of the brain, 1 cm by 1 cm, which were temporarily inactivated by means of a bipolar electrode) were identified and categorized into cortical language maps. The tumors were resected up to 1 cm from the cortical areas where intraoperative stimulation produced a disturbance in language. Our resection strategy did not require identification of the stimulation-induced language sites within the field of exposure. RESULTS: A total of 145 of the 250 patients (58.0%) had at least one site with an intraoperative stimulation-induced speech arrest, 82 patients had anomia, and 23 patients had alexia. Overall, 3094 of 3281 cortical sites (94.3%) were not associated with stimulation-induced language deficits. A total of 159 patients (63.6%) had intact speech preoperatively. One week after surgery, baseline language function remained in 194 patients (77.6%), it worsened in 21 patients (8.4%), and 35 patients (14.0%) had new speech deficits. However, 6 months after surgery, only 4 of 243 surviving patients (1.6%) had a persistent language deficit. Cortical maps generated with intraoperative language data also showed surprising variability in language localization within the dominant hemisphere. CONCLUSIONS: Craniotomies tailored to limit cortical exposure, even without localization of positive language sites, permit most gliomas to be aggressively resected without language deficits. The composite language maps generated in our study suggest that our current models of human language organization insufficiently account for observed language fu
nction. Copyright 2008 Massachusetts Medical Society.

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Expert Rev Anticancer Ther. 2008 Jan;8(1):125-32.
Palliative treatment of poor prognosis patients with malignant gliomas.
Hadziahmetovic M, Lo SS, Clarke JW, Farace E, Cavaliere R.
The Ohio State University College of Medicine, Ohio State University Medical Center, 300 West 10th Avenue, Ste 083A, Columbus, OH 43210, USA. mersiha.hadziahmetovic@osumc.edu

High-grade gliomas are the most commonly diagnosed malignant brain tumor in adults. Prognosis can be estimated by examining risk factors, including histology, age and performance status. Postoperative radiation therapy is associated with improved survival and standard treatment includes external beam radiotherapy to a dose of 60 Gy in 30-33 fractions. Patients with poor prognostic features have a more limited benefit from radiotherapy. This article reviews the current state of knowledge on risk stratification and analyzes strategies that can be employed to better individualize treatment for poor-prognosis patients.

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Expert Rev Neurother. 2008 Jan;8(1):121-32.
Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy in pediatric brain tumors.
Lo SS, Fakiris AJ, Abdulrahman R, Henderson MA, Chang EL, Suh JH, Timmerman RD.
Department of Radiation Medicine, Arthur G James Cancer Hospital, Ohio State University Medical Center, 300 West 10th Avenue, Ste 088A, Columbus, OH 43210, USA. simon.lo@osumc.edu

Brain tumors are the most common solid tumor in childhood. Surgery and/or fractionated radiotherapy are conventional treatment modalities. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) are advanced radiation therapy techniques that have been frequently used in adults with brain tumors but they are less frequently used in pediatric patients. SRS and FSRT can potentially add to the armamentarium against brain tumors in children. This article will review the role of SRS and FSRT in the management of pediatric brain tumors.

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Curr Pharm Des. 2007;13(35):3545-58.
Antiangiogenic therapy in malignant glioma: promise and challenge.
Sathornsumetee S, Rich JN.
The Preston Robert Tisch Brain Tumor Center, Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are cu
rrently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.

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J Clin Oncol. 2007 Dec 20;25(36):5723-30.
Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial.
Taphoorn MJ, van den Bent MJ, Mauer ME, Coens C, Delattre JY, Brandes AA, Sillevis Smitt PA, Bernsen HJ, Frénay M, Tijssen CC, Lacombe D, Allgeier A, Bottomley A; European Organisation for Research and Treatment of Cancer.
Department of Neurology, Medical Center Haaglanden/Westeinde Ziekenhuis, the Hague, The Netherlands. m.taphoorn@mchaaglanden.nl

PURPOSE: Little is known about the health-related quality of life (HRQOL) of patients treated for anaplastic oligodendrogliomas. The impact of combined procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy after radiotherapy (RT) compared with RT alone on HRQOL in the randomized European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial was studied. PATIENTS AND METHODS: Adult patients with anaplastic oligodendrogliomas received RT alone or RT plus PCV chemotherapy. HRQOL was assessed with the EORTC Quality of Life Questionnaire C30 and Brain Cancer Module. Seven prespecified HRQOL end points were selected. We hypothesized that chemotherapy would impair HRQOL during treatment but that there would be a similar HRQOL between treatment arms once off treatment. Assessments were performed at randomization, at the end of RT, and then every 3 to 6 months until progression. RESULTS: A total of 368 patients were randomly assigned to one of the two arms; overall, 58% were male, and the median age was 49 years. Compliance with HRQOL was 78% at baseline and dropped to 55% to 72% up to 2.5 years post-RT. Baseline scores demonstrated considerable impairments in HRQOL for both treatment groups. The longitudinal analysis showed a significant increase in nausea/vomiting in the RT plus PCV chemotherapy arm during and shortly after chemotherapy. Because of a difference in baseline scores for fatigue and physical functioning, the differences between treatment arms during PCV did not reach significance. The nonselected scales of appetite loss and drowsiness demonstrated significant differences between treatment arms during chemotherapy in favor of the RT arm. The long-term results showed no difference between arms. CONCLUSION: The major impact of PCV on HRQOL is on nausea/vomiting, loss of appetite, and drowsiness during and shortly after treatment. There are no long-term effects of PCV chemotherapy.

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J Clin Oncol. 2007 Dec 20;25(36):5731-7.
Prognostic value of health-related quality-of-life data in predicting survival in patients with anaplastic oligodendrogliomas, from a phase III EORTC brain cancer group study.
Mauer ME, Taphoorn MJ, Bottomley A, Coens C, Efficace F, Sanson M, Brandes AA, van der Rijt CC, Bernsen HJ, Frénay M, Tijssen CC, Lacombe D, van den Bent MJ; EORTC Brain Cancer Group.
European Organisation for Research and Treatment of Cancer Data Center, Quality of Life Unit, Ave Mounier 83/11, Brussels, Belgium 1200. murielle.mauer@eortc.be

PURPOSE: This is one of a few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in patients with brain cancer. PATIENTS AND METHODS: Baseline HRQOL scores (from the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire C30 and the EORTC Brain Cancer Module) were examined in 247 patients with anaplastic oligodendrogliomas to determine the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap resampling procedure and the computation of C indexes and R2 coefficients were used to explore the stability of the models as well as better assess the potential benefit of using HRQOL to predict survival in clinical practice and research. RESULTS: Classical analysis controlled for major clinical prognostic factors selected emotional functioning (P = .0016), communication deficit (P = .0261), future uncertainty (P = .0481), and weakness of legs (P = .0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings and no single model was found to be preferable over all others. C indexes, which estimate the probability of a model to correctly predict which patient among a randomly chosen pair of patients will survive longer, and R2 coefficients, which measure the proportion of variability explained by the model, did not exhibit major improvement when adding selected or all HRQOL scores to clinical factors. CONCLUSION: While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor for patients with cancer.

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Expert Rev Anticancer Ther. 2007 Dec;7(12 Suppl):S29-36.
Emerging therapies for malignant glioma.
Lukas RV, Boire A, Nicholas MK.
University of Chicago, Department of Neurology, MC 2030, 5841 S. Maryland Avenue, Chicago, IL 60637, USA. rlukas@neurology.bsd.uchicago.edu

The current standard of care for malignant gliomas consists of surgery, radiotherapy and conventional (DNA-damaging) chemotherapies. These treatments are relatively nonspecific and may be applied to all glioma subtypes. Developments in cancer medicine, however, now offer the opportunity to direct therapies to specific molecular pathways involved in tumorigenesis. This offers the potential to tailor treatments to tumor subtypes--perhaps with greater efficacy and less toxicity. Many of the so-called targeted therapies are under investigation in the treatment of malignant glioma. In this review, we will focus on the use of agents that affect signal transduction. In particular, we will review the potential role for inhibitors of: tyrosine kinases, targets of rapamycin, farnesyl transferase and histone deacetylase. Inhibitors of angiogenesis will also be discussed. Some 'targeted' therapies are less specific than others, working on more than one pathway or receptor, thus complex i
nteractions are possible.

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Expert Rev Anticancer Ther. 2007 Dec;7(12 Suppl):S69-77.
Radiotherapy for pediatric brain tumors: when and how.
Knab B, Connell PP.
Wentworth-Douglas Hospital, 789 Central Ave., Dover, NH 03820, USA. brknab@gmail.com

Radiotherapy plays a central role in the treatment of pediatric brain tumors. Historically, surgical resection alone was the mainstay of treatment for pediatric CNS malignancies. During the past 75 years, radiotherapy has been incorporated into the upfront treatment of many pediatric brain tumors either as adjuvant therapy for resected tumors, definitive treatment for unresectable malignancies or as prophylactic therapy for occult microscopic disease. Many CNS malignancies, which were once universally fatal are now curable with multimodality approaches that integrate surgery, chemotherapy and radiotherapy. Unfortunately, the long-term CNS side effects of radiotherapy remain a major obstacle for survivors of childhood tumors. In this article we will discuss these issues in detail and summarize the ongoing efforts to reduce the risks of these toxicities.

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Curr Opin Pediatr. 2007 Dec;19(6):670-4.
Update on new treatments and developments in childhood brain tumors.
Partap S, Fisher PG.
aDepartments of Neurology, USA bPediatrics, USA cNeurosurgery, USA dHuman Biology, Stanford University, Stanford, California, USA.

PURPOSE OF REVIEW: Childhood primary central nervous system tumors remain a therapeutic conundrum. As the second most common pediatric cancer, brain tumors lead to significantly worse survival and long-term effects compared with those seen with hematologic malignancies and other solid tumors. This review discusses current management strategies in three pediatric brain tumors, the long-term effects of therapy, as well as novel laboratory findings that may alter future treatment strategies. RECENT FINDINGS: The current literature focuses on tactics to predict those at risk of treatment failure and long-term effects. By analyzing tumors at a molecular genetics level rather than traditional histology, new data have begun to emerge on methods to begin to consider targeted therapies, tailored to the individual child. Furthermore, as survivorship has improved with current radiation and chemotherapy regimens, long-term effects have been identified and merit clinical attention. SUMMARY: Even though long-term survival for children with a brain tumor approaches 70%, the need for improved treatment regimens is striking. Secondary malignancies, neurocognitive deficits and treatment failure continue to afflict these children and young adults. The current review will inform clinicians of the challenges faced by basic scientists and clinicians when treating brain tumors, and point to future research directions.

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Clin Cancer Res. 2007 Nov 15;13(22):6712-8.
Phase I trial of single-dose temozolomide and continuous administration of o6-benzylguanine in children with brain tumors: a pediatric brain tumor consortium report.
Broniscer A, Gururangan S, Macdonald TJ, Goldman S, Packer RJ, Stewart CF, Wallace D, Danks MK, Friedman HS, Poussaint TY, Kun LE, Boyett JM, Gajjar A; for the Pediatric Brain Tumor Consortium.
Authors' Affiliations: Departments of Oncology, Pharmaceutical Sciences, Biostatistics, Molecular Pharmacology, and Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennesee.

PURPOSE: To estimate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of temozolomide combined with O(6)-benzylguanine in patients </=21 years with recurrent brain tumors. EXPERIMENTAL DESIGN: Treatment strata consisted of patients who had previously received no or local radiotherapy (Str1) and patients who had undergone craniospinal radiotherapy or myeloablative chemotherapy (Str2). One-hour i.v. administration of O(6)-benzylguanine at 120 mg/m(2) was followed by 48-h continuous infusion at 30 mg/m(2)/day. Single-dose temozolomide at five dosage levels (267, 355, 472, 628, and 835 mg/m(2)) was given at least 6 h after completion of O(6)-benzylguanine bolus. Treatment was repeated after recovery from toxicities at least 4 weeks apart for a maximum of 12 courses. Dose escalation followed the modified continual reassessment method. Pharmacokinetic analyses of temozolomide and 5-triazeno imidazole carboxamide (MTIC) were done in 28 patients. RESULTS: A total of 44 and 26 eligible patients were enrolled on Str1 and Str2, respectively. Median age at study entry in each stratum was 8.6 and 11.3 years, respectively. Predominant diagnoses were high-grade/brainstem glioma in Str1 and medulloblastoma in Str2. Whereas the estimated MTDs of temozolomide for Str1 and Str2 were 562 and 407 mg/m(2), respectively, the doses recommended for phase II investigations are 472 and 355 mg/m(2), respectively. DLTs were predominantly neutropenia and thrombocytopenia. Three patients with gliomas experienced centrally confirmed partial responses to therapy. Four patients completed all planned therapy. Temozolomide and MTIC exposures were statistically associated with temozolomide dosage. CONCLUSIONS: The current schedule of temozolomide and O(6)-benzylguanine is safe and showed modest activity against recurrent brain tumors in children.

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Neurol Clin. 2007 Nov;25(4):975-1003.
Advances in brain tumor surgery.
Asthagiri AR, Pouratian N, Sherman J, Ahmed G, Shaffrey ME.
National Institutes of Health/NINDS, Bethesda, MD, USA.

Advances in the fields of molecular and translational research, oncology, and surgery have emboldened the medical community to believe that intrinsic brain tumors may be treatable. Intraoperative imaging and brain mapping allow operations adjacent to eloquent cortex and more radical resection of tumors with increased confidence and safety. Despite these advances, the infiltrating edge of a neoplasm and distant microscopic satellite lesions will never be amendable to a surgical cure. Indeed, it is continued research into the delivery of an efficacious chemobiologic agent that will eventually allows us to manage this primary cause of treatment failure.

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Eur J Surg Oncol. 2007 Oct 22; [Epub ahead of print]
The use of high-frequency electromagnetics in brain tumour surgery.
Gharabaghi A, Safavi-Abbasi S, Krischek B, Feigl GC, Lüdemann W, Mirzayan MJ, Samii M, Tatagiba M, Heckl S.
Department of Neurosurgery, Eberhard Karls University, Tübingen, Germany; International Neuroscience Institute, Hannover, Germany.

OBJECTIVE: The first commercially available high-frequency electromagnetic field (EMF) system promises additional functionality for neurosurgical procedures. In a prospective study, we evaluated the optimal use as well as the limitations of this system designed for vaporizing tissue and for coagulation in brain tumour surgery. METHODS: For the microsurgical treatment of 63 consecutive patients with various intracranial tumours, the EMF system was used in addition to the standard neurosurgical instrumentarium. The system was assessed with respect to its compatibility with the operating room environment. Furthermore, attention was given to the particular techniques required to use the system most effectively. The efficiency of the investigated tool was monitored throughout the study. RESULTS: The EMF system functioned properly in all procedures and did not cause any complications. Specific handling techniques and electrode tip configurations could be defined for optimal use of high-frequency electromagnetics for vaporization and coagulation in different intraoperative settings. Thereby, the efficiency of the device could be increased throughout the study while ineffective use decreased from 7 to 2 cases. Although this tool is designed ergonomically and offers high tactile control, it cannot be used submerged in cerebrospinal fluid or under continuous irrigation, which makes it necessary to use it in tandem with suction devices to obtain a clear view on the surgical field. CONCLUSION: Maneuvering with the EMF system was substantially different to both monopolar and bipolar systems, clearly necessitating a learning curve for the surgeon. This device was found to be a valuable complementary tool to standard electrosurgical instruments when applied effectively and with elaborated techniques.

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J Clin Oncol. 2007 Oct 20;25(30):4722-9. Comment in: J Clin Oncol. 2007 Oct 20;25(30):4705-6.
Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.
Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS.
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA. vrede001@mc.duke.edu

PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. PATIENTS AND METHODS: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. RESULTS: The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

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J Neurosurg. 2007 Oct;107(4 Suppl):286-91.
Pediatric infratentorial gangliogliomas: a retrospective series.
Baussard B, Di Rocco F, Garnett MR, Boddaert N, Lellouch-Tubiana A, Grill J, Puget S, Roujeau T, Zerah M, Sainte-Rose C.
Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, Paris, France.

OBJECT: The aim of this study was to retrospectively review the clinical presentation, the roles of surgery and adjuvant therapy, and the treatment-related morbidity in children with a ganglioglioma in the posterior fossa and to try and determine the prognostic factors. METHODS: Between 1991 and 2006, 10 children were treated for a posterior fossa ganglioglioma at the authors' institution. The mean age of the children, the duration of symptoms prior to diagnosis, and the follow-up were 8.2, 2.4, and 3.9 years, respectively. Nine of the children presented with symptoms of raised intracranial pressure. Preoperative imaging showed enhancement in all patients; in eight it was in a patchy distribution. The operations consisted of radical resection (> 75%) in seven children, biopsy in two, and a total macroscopic excision in one. RESULTS: The surgical procedure did not cause deterioration in the neurological condition in any of the children. There was no recurrence in the child who underwent total macroscopic excision of the tumor, and there has been no tumor progression in three children, two of whom have had no evidence of enhancement of the postoperative residual tumor. The tumor has progressed in six children, requiring further surgery in three, chemotherapy in four, and radiotherapy and second-line chemotherapy in one child to control the tumor. CONCLUSIONS: The imaging of gangliogliomas in the posterior fossa showed patchy enhancement. The patients in whom it was possible to achieve a radical resection, aimed at removing at least the enhancing portion of the tumor, have not required further treatment. A second excision, for progressive tumors, is an effective adjuvant therapy.

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Curr Oncol. 2007 Oct;14(5):189-94.
Gliadel wafers in the treatment of malignant glioma: a systematic review.
Perry J, Chambers A, Spithoff K, Laperriere N.
Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario.

QUESTION: What is the safety and efficacy of interstitial chemotherapy with carmustine-loaded polymers (Gliadel wafers: MGI Pharma, Bloomington, MN, U.S.A.) in the treatment of newly diagnosed or recurrent malignant glioma (that is, glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligoastrocytoma, and anaplastic oligodendroglioma)? PERSPECTIVES: Malignant glioma is the most common type of primary brain tumour in adults. In general, efficacy of systemic therapy in this patient population has been disappointing, and novel treatment approaches are needed. Because several randomized controlled trials (rcts) investigating the safety and efficacy of Gliadel are available, the Neuro-oncology Disease Site Group of Cancer Care Ontario's Program in Evidence-Based Care decided that a systematic review of the evidence was necessary. OUTCOMES: The outcomes of interest for this review were overall survival, adverse events, and quality of life. METHODOLOGY: Systematic searches of the medline, embase, and Cochrane Library databases were conducted for relevant evidence. Fully-published reports of rcts comparing treatment with Gliadel wafers to placebo or alternative treatment were selected for inclusion. Prospective cohort studies were also included. RESULTS: Two rcts that compared Gliadel to placebo in patients with newly diagnosed malignant glioma were obtained. Both rcts reported a significant survival benefit for patients who received Gliadel as compared with patients in the control group. One rct and one prospective cohort study were obtained that examined the role of Gliadel in patients with recurrent malignant glioma. The rct demonstrated a significant survival benefit for Gliadel only after adjustment for prognostic factors, and the prospective cohort study reported no survival benefit for Gliadel as compared with a historical control group. All three rcts reported similar rates of adverse events in the treatment and control groups. The most frequently reported adverse events were convulsions, confusion, brain edema, infection, hemiparesis, aphasia, and visual field defects. CONCLUSIONS: Gliadel is an option for selected patients with newly diagnosed malignant glioma where a near gross total resection is possible. No evidence is available comparing Gliadel with systemic therapy, and a decision to combine Gliadel with systemic therapy should be made for patients individually. The patient population that would benefit from Gliadel (age, histology, and performance status) is unclear; further investigation is needed. Gliadel is also an option for patients with surgically resectable recurrent malignant glioma.

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Mayo Clin Proc. 2007 Oct;82(10):1271-86.
Central nervous system tumors.
Buckner JC, Brown PD, O'Neill BP, Meyer FB, Wetmore CJ, Uhm JH.
Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Central nervous system tumors are relatively common in the United States, with more than 40,000 cases annually. Although more than half of these tumors are benign, they can cause substantial morbidity. Malignant primary brain tumors are the leading cause of death from solid tumors in children and the third leading cause of death from cancer in adolescents and adults aged 15 to 34 years. Common presenting symptoms include headache, seizures, and altered mental status. Whereas magnetic resonance imaging helps define the anatomic extent of tumor, biopsy is often required to confirm the diagnosis. Treatment depends on the histologic diagnosis. Benign tumors are usually curable with surgical resection or radiation therapy including stereotactic radiation; however, most patients with malignant brain tumors benefit from chemotherapy either at the time of initial diagnosis or at tumor recurrence. Metastases to the brain remain a frequent and morbid complication of solid tumors but are frequently controlled with surgery or radiation therapy. Unfortunately, the mortality rate from malignant brain tumors remains high, despite initial disease control. This article provides an overview of current diagnostic and treatment approaches for patients with primary and metastatic brain tumors.

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J Exp Clin Cancer Res. 2007 Sep;26(3):297-300.
Home rehabilitation for brain tumor patients.
Pace A, Parisi C, Di Lelio M, Zizzari A, Petreri G, Giovannelli M, Pompili A.
Palliative Home-Care Unit for Brain Tumor Patients, Regina Elena National Cancer Institute, Rome, Italy. pace@ifo.it

To determine whether a program of post-discharge rehabilitation at home for patients operated for brain tumor was associated with functional gain and improvement in Quality of Life (QoL). One hundred and twenty-one patients affected by malignant brain tumor were enrolled in a program of post-discharge home care including neurorehabilitation. Functional outcome was evaluated with Barthel Index (BI) and Karnofsky Performance Status (KPS) measured before and after rehabilitation. The impact of rehabilitation on quality of life was evaluated with a quality of life questionnaire (EORTC QLQ-C30-BM 20). Results: Barthel Index improved in 47 (39%) patients, was stable in 20 (16%) and worsened in 54 (44%). Only 54 patients completed the QoL questionnaire before and after treatment. After three months of rehabilitation, 72% of patients were found to have an improvement in at least one domain score compared with their baseline QoL scores. Rehabilitation at home in brain tumor patients was associated with significant functional gain measured both with BI and KPS. The benefit of rehabilitation may influence patient's perception of quality of life.

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Neurology. 2007 Sep 25;69(13):1366-73.
Outcome in adult low-grade glioma: the impact of prognostic factors and treatment.
Schiff D, Brown PD, Giannini C.
Neuro-Oncology Center, University of Virginia Health Sciences Center, Box 800432, Charlottesville, VA 22908-0432, USA. ds4jd@virginia.edu

Low-grade gliomas (LGGs) represent a vexing clinical problem. Some patients present with readily controllable seizures and will enjoy years of freedom from tumor progression without intervention, whereas others progress rapidly with eventual neurologic decompensation and death. Both radiation and chemotherapy are helpful to many patients, but the optimal timing and sequencing of these therapies remain unknown. Recent studies have informed our understanding of clinical, histologic, and molecular prognostic factors and help provide guidance as to which patients require early intervention and when observation is feasible or warranted. We review contemporary knowledge regarding prognostic factors, our current evidence-based understanding of the roles and timing of radiation and chemotherapy, and ongoing clinical trials that will further elucidate management of LGGs.

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J Clin Oncol. 2007 Jul 20;25(21):3137-43.
Phase I and pharmacokinetic study of the oral farnesyltransferase inhibitor lonafarnib administered twice daily to pediatric patients with advanced central nervous system tumors using a modified continuous reassessment method: a pediatric brain tumor consortium study.
Kieran MW, Packer RJ, Onar A, Blaney SM, Phillips P, Pollack IF, Geyer JR, Gururangan S, Banerjee A, Goldman S, Turner CD, Belasco JB, Broniscer A, Zhu Y, Frank E, Kirschmeier P, Statkevich P, Yver A, Boyett JM, Kun LE.
Dana-Farber Cancer Institute, Pediatric Neuro-Oncology, 44 Binney St, Room SW331, Boston, MA 02115; e-mail: mark_Kieran@dfci.Harvard.edu.

PURPOSE A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. PATIENTS AND METHODS Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m(2)/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Results Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m(2)/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m(2)/dose levels resulted in a recommended phase II dose of 115 mg/m(2)/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. CONCLUSION Although the estimated MTD by the CRM model was 98.5 mg/m(2)/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m(2)/dose administered twice daily by mouth with concurrent loperamide.

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J Neurosurg. 2007 Jun;106(6):1028-33.
Safety and efficacy of the porcine small intestinal submucosa dural substitute: results of a prospective multicenter study and literature review.
Bejjani GK, Zabramski J; Durasis Study Group.
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. bejjanigk@msx.upmc.edu

OBJECT. Dural substitutes are often needed after neurosurgical procedures to expand or replace dura mater resected during surgery. A new dural repair material derived from porcine small intestinal submucosa (SIS) was evaluated in a prospective multicenter clinical study. METHODS. Between 2000 and 2003, 59 patients at five different institutions underwent dural reconstruction with the SIS dural substitute, with a minimum follow up of 6 months. The primary goals of the study were to assess the efficacy and safety of the SIS dural substitute according to the rate of cerebrospinal fluid (CSF) leakage, infection, and meningitis. Chiari malformation Type I decompression (32 patients) and tumor resection (18 patients) were the most common procedures performed, with 81% of SIS grafts implanted in the posterior fossa or spine. There was one case of a CSF leak (1.7%), two cases of wound infection (3.4%), and no cases of bacterial meningitis (0%) in the 58 patients available for follow up. In both cases of wound infection, the SIS graft acted as a barrier to infection and was not removed. Intraoperatively, a watertight seal was achieved in all 59 cases. On follow-up imaging available in 27 patients there was no evidence of any adverse reaction to the graft or of cerebral inflammation. CONCLUSIONS: The SIS dural substitute demonstrated substantial efficacy in these patients after a mean follow up of 7.3 +/- 2.2 months. Rates of infection, CSF leakage, and meningitis were comparable to those reported for other dural substitute materials. A lack of adverse reactions to the graft, favorable safety profile, and clinical efficacy all point to the utility of this material as an alternative for dural repair.

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Am J Clin Oncol. 2007 Jun;30(3):310-4.
Stereotactic radiosurgical treatment of cerebral metastases arising from breast cancer.
Akyurek S, Chang EL, Mahajan A, Hassenbusch SJ, Allen PK, Mathews LA, Shiu AS, Maor MH, Woo SY.
Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

OBJECTIVE: This study was undertaken to evaluate the outcome of patients undergoing stereotactic radiosurgery (SRS) as primary or salvage treatment of brain metastases arising from breast cancer. MATERIALS AND METHODS: Between July 2000 and September 2005, the medical records of 49 breast cancer patients who underwent SRS for 84 brain metastases were reviewed retrospectively. Thirty-four patients received SRS as primary brain metastasis treatment and 15 patients received SRS as salvage treatment of brain metastasis recurrence following prior whole-brain radiation therapy. The Kaplan-Meier method, univariate comparisons with log-rank test, and multivariate analysis were performed. RESULTS: Median follow-up was 12 months (range, 5-50 months) and median survival was 19 months for all patients. The 1- and 2-year overall survival (OS) rates were 60%, 56%, and 55%, 23% for initial SRS alone and SRS salvage groups, respectively (P = 0.99). A multivariate analysis showed that a high KPS score (KPS > or =90 vs. <90; P = 0.02), a higher SIR value (SIR > or =6 vs. <6; P = 0.001), postmenopausal status (P = 0.003), and positive estrogen receptor status (P = 0.04) were predictive of better survival. The 1- and 2-year local control rates were 79%, 49%, and 77%, 46% for SRS alone and SRS salvage group, respectively. CONCLUSION: SRS can be used as primary treatment of brain metastases or salvage of recurrences after whole-brain radiation therapy to achieve good local control on the order of close to 80% at 1 year. The median survival of brain metastasis patients with breast cancer of 19 months appears favorable compared with the general brain metastasis population.

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J Neurosurg. 2007 May;106(5 Suppl):354-62.
Thalamic tumors in children: a reappraisal.
Puget S, Crimmins DW, Garnett MR, Grill J, Oliveira R, Boddaert N, Wray A, Lelouch-Tubiana A, Roujeau T, Di Rocco F, Zerah M, Sainte-Rose C.
Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, Paris, France.

OBJECT: Two to five percent of pediatric brain tumors are located in the thalamus. The optimal management for these tumors remains unclear. The aim of this study was to determine whether clinical and neuroimaging features could guide treatment, and to what extent these features, together with histological diagnosis and treatment modalities, influenced survival. METHODS: The records of 69 children who presented with a thalamic tumor between 1989 and 2003 were retrospectively reviewed. Three groups of tumors were analyzed separately: 1) unilateral thalamic tumors (54 lesions); 2) thalamopeduncular tumors (six); and 3) bilateral thalamic tumors (nine). In the patients in whom a unilateral thalamic tumor was diagnosed, 33 had an astrocytic tumor. Of the 54 patients, 32 had a low-grade and 22 had a high-grade tumor. The survival rate was significantly better for patients with the following characteristics: symptom duration longer than 2 months (p < 0.001), lesions with low-grade histological features (p = 0.003), and tumor excision greater than 90% at surgery (p = 0.04). The perioperative morbidity and mortality rates were 37 and 4%, respectively. Fifty-four percent of the patients in this group had a long-term and independent survival. The thalamopeduncular tumors were mostly pilocytic astrocytomas, which had a good prognosis following surgery. The bilateral thalamic tumors in this series were mainly low-grade astrocytic lesions, and more than half of the children attained long-term survival (mean follow-up duration 4.5 years). CONCLUSIONS: The majority of tumors arising in the thalamus are astrocytic, of which less than half are high-grade lesions. Histological evaluations should be performed in all patients in whom resection is being considered for discrete lesions. Long-term survival is possible in patients with these tumors.

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J Neurosurg. 2007 May;106(5):833-8.
Radiosurgery of growth hormone-producing pituitary adenomas: factors associated with biochemical remission.
Pollock BE, Jacob JT, Brown PD, Nippoldt TB.
Department of Neurological Surgery, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. pollock.bruce@mayo.edu

OBJECT: The authors reviewed outcomes after stereotactic radiosurgery for patients with acromegaly and analyzed factors associated with biochemical remission. METHODS: Retrospective analysis was performed for 46 consecutive cases of growth hormone (GH)-producing pituitary adenomas treated by radiosurgery between 1991 and 2004. Biochemical remission was defined as a fasting GH less than 2 ng/ml and a normal age- and sex-adjusted insulin-like growth factor-I (IGF-I) level while patients were not receiving any pituitary suppressive medications. The median follow up after radiosurgery was 63 months (range 22-168 months). Twenty-three patients (50%) had biochemical remission documented at a median of 36 months (range 6-63 months) after one radiosurgical procedure. The actuarial rates of biochemical remission at 2 and 5 years after radiosurgery were 11 and 60%, respectively. Multivariate analysis showed that IGF-I levels less than 2.25 times the upper limit of normal (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.2-6.9, p = 0.02) and the absence of pituitary suppressive medications at the time of radiosurgery (HR 4.2, 95% CI 1.4-13.2, p = 0.01) correlated with biochemical remission. The incidence of new anterior pituitary deficits was 10% at 2 years and 33% at 5 years. CONCLUSIONS: Discontinuation of pituitary suppressive medications at least 1 month before radiosurgery significantly improved endocrine outcomes for patients with acromegaly. Patients with GH-producing pituitary adenomas should not undergo further radiation therapy or surgery for at least 5 years after radiosurgery because GH and IGF-I levels continue to normalize over that interval.

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J Appl Clin Med Phys. 2007 Apr 19;8(2):47-60.
Intensity modulated radiation therapy versus three-dimensional conformal radiation therapy for the treatment of high grade glioma: a dosimetric comparison.
MacDonald SM, Ahmad S, Kachris S, Vogds BJ, DeRouen M, Gittleman AE, DeWyngaert K, Vlachaki MT.
Massachusetts General Hospital, Boston, Massachusetts, USA.

The present study compared the dosimetry of intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3D-CRT) techniques in patients treated for high-grade glioma. A total of 20 patients underwent computed tomography treatment planning in conjunction with magnetic resonance imaging fusion. Prescription dose and normal-tissue constraints were identical for the 3D-CRT and IMRT plans. The prescribed dose was 59.4 Gy delivered at 1.8 Gy per fraction using 4-10 MV photons. Normal-tissue dose constraints were 50-54 Gy for the optic chiasm and nerves, and 55-60 Gy for the brainstem. The IMRT plan yielded superior target coverage as compared with the 3D-CRT plan. Specifically, minimum and mean planning target volume cone down doses were 54.52 Gy and 61.74 Gy for IMRT and 50.56 Gy and 60.06 Gy for 3D-CRT (p < or = 0.01). The IMRT plan reduced the percent volume of brainstem receiving a dose greater than 45 Gy by 31% (p = 0.004) and the percent volume of brain receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by 10% (p = 0.059), 14% (p = 0.015), and 40% (p < or = 0.0001) respectively. With IMRT, the percent volume of optic chiasm receiving more than 45 Gy was also reduced by 30.40% (p = 0.047). As compared with 3D-CRT, IMRT significantly increased the tumor control probability (p < or = 0.005) and lowered the normal-tissue complication probability for brain and brainstem (p < 0.033). Intensity-modulated radiation therapy improved target coverage and reduced radiation dose to the brain, brainstem, and optic chiasm. With the availability of new cancer imaging tools and more effective systemic agents, IMRT may be used to intensify tumor doses while minimizing toxicity, therefore potentially improving outcomes in patients with high-grade glioma.

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Neurosurg Focus. 2007 Mar 15;22(3):E2.
Surgical management of brain metastases.
Ranasinghe MG, Sheehan JM.
Department of Neurosurgery, Pennsylvania State University, Hershey, Pennsylvania 17033, USA.

Metastatic brain tumors continue to increase in incidence as patients with cancer live longer. The options for management continue to evolve as well, with advances in radiation-based treatment, chemotherapy, and surgery. Although metastatic brain tumors are frequently treated without surgical intervention, there continues to be a significant role for surgery in caring for patients with these lesions. Study data have proven that surgery has a positive effect on survival and quality of life in properly selected patients. Those with a suitable age, functional status, systemic disease control, and several metastases may be suitable for surgical treatment. Advances in preoperative imaging and planning as well as intraoperative surgical adjuncts have lowered the morbidity associated with resection. With proper patient selection and operative and postoperative management, resection continues to play a significant and evolving role in the care of patients with metastatic brain tumor.

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J Clin Oncol. 2007 Mar 1;25(7):837-44.
Direct Intracerebral Delivery of Cintredekin Besudotox (IL13-PE38QQR) in Recurrent Malignant Glioma: A Report by the Cintredekin Besudotox Intraparenchymal Study Group.
Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM, Sampson JH, Ram Z, Gutin PH, Gibbons RD, Aldape KD, Croteau DJ, Sherman JW, Puri RK.
Department of Neurological Surgery, University of California San Francisco, 400 Parnassus Ave, A808, San Francisco, CA, 94143-0350; e-mail: KunwarS@neurosurg.ucsf.edu.

PURPOSE Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG). PATIENTS AND METHODS Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion. Results A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 mug/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years. CONCLUSION CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.

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Neuro-oncol. 2007 Feb 9; [Epub ahead of print]
Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium report.
Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW, Phillips P, Kun LE, Friedman H, Packer R, Banerjee A, Geyer JR, Goldman S, Poussaint TY, Krasin MJ, Wang Y, Hayes M, Murgo A, Weiner S, Boyett JM.
Children's Hospital of Pittsburgh Pittsburgh, PA 15213.

This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.

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J Clin Oncol. 2007 Feb 1;25(4):399-404.
Phase I trial of polifeprosan 20 with carmustine implant plus continuous infusion of intravenous O6-benzylguanine in adults with recurrent malignant glioma: new approaches to brain tumor therapy CNS consortium trial.
Weingart J, Grossman SA, Carson KA, Fisher JD, Delaney SM, Rosenblum ML, Olivi A, Judy K, Tatter SB, Dolan ME.
New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, MD, USA.

PURPOSE: This phase I trial was designed to (1) establish the dose of O6-benzylguanine (O6-BG) administered intravenously as a continuous infusion that suppresses O6-alkylguanine-DNA alkyltransferase (AGT) levels in brain tumors, (2) evaluate the safety of extending continuous-infusion O6-BG at the optimal dose with intracranially implanted carmustine wafers, and (3) measure the pharmacokinetics of O6-BG and its metabolite. PATIENTS AND METHODS: The first patient cohort (group A) received 120 mg/m2 of O6-BG over 1 hour followed by a continuous infusion for 2 days at escalating doses presurgery. Tumor samples were evaluated for AGT levels. The continuous-infusion dose that resulted in undetectable AGT levels in 11 or more of 14 patients was used in the second patient cohort. Group B received the optimal dose of O6-BG for 2, 4, 7, or 14 days after surgical implantation of the carmustine wafers. The study end point was dose-limiting toxicity (DLT). RESULTS: Thirty-eight patients were accrued. In group A, 12 of 13 patients had AGT activity levels of less than 10 fmol/mg protein with a continuous-infusion O6-BG dose of 30 mg/m2/d. Group B patients were enrolled onto 2-, 4-, 7-, and 14-day continuous-infusion cohorts. One DLT of grade 3 elevation in ALT was seen. Other non-DLTs included ataxia and headache. For up to 14 days, steady-state levels of O6-BG were 0.1 to 0.4 micromol/L, and levels for O6-benzyl-8-oxoguanine were 0.7 to 1.3 micromol/L. CONCLUSION: Systemically administered O6-BG can be coadministered with intracranially implanted carmustine wafers, without added toxicity. Future trials are required to determine if the inhibition of tumor AGT levels results in increased efficacy.

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Expert Opin Biol Ther. 2007 Feb;7(2):197-208.
The status of gene therapy for brain tumors.
Fulci G, Chiocca EA.
Brain Tumor Research Center, Simches Research Building CRPZN-3800, Neurosurgery Service, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. gfulci@partners.org

The advent of gene therapy in the early 1990's raised expectations for brain tumor therapies; however, whereas clinical trials in patients with malignant gliomas provided evidence of safety, therapeutic benefit was not convincing. These early forays resembled the historical introductions of other therapies that seemed promising, only to fail in human trials. Nevertheless, re-study in the laboratory and retesting in iterative laboratory-clinic processes enabled therapies with strong biological rationales to ultimately show evidence of success in humans and become accepted. Examples, such as organ transplantation, monoclonal antibody therapy and antiangiogenic therapy, provide solace that a strategy's initial lack of success in humans provides an opportunity for its further refinement in the laboratory and development of solutions that will translate into patient success stories. The authors herein summarize results from clinical trials of gene therapy for malignant gliomas, and discuss the influence of these results on present thought in preclinical research.

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J Neurosurg. 2007 Jan;106(1):8-17. Comment in: J Neurosurg. 2007 Jan;106(1):6-7.
Gamma knife surgery for focal brainstem gliomas.
Yen CP, Sheehan J, Steiner M, Patterson G, Steiner L.
Lars Leksell Center for Gamma Surgery, Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22908, USA.

OBJECT: Focal tumors, a distinct subgroup of which is composed of brainstem gliomas, may have an indolent clinical course. In the past, their management involved monitoring of open-ended imaging studies and shunt placement if cerebrospinal fluid diversion was required. Nonetheless, their treatment remains a significant challenge for neurosurgeons. Gamma Knife surgery (GKS) has recently been tried as an alternative to surgical extirpation. In the present study the authors assess clinical and imaging results in 20 patients who harbored focal brainstem gliomas treated with GKS between 1990 and 2001. METHODS: There were 10 male and 10 female patients with a mean age of 19.1 years. Sixteen tumors were located in the midbrain, three in the pons, and one in the medulla oblongata. The mean tumor volume at the time of GKS was 2.5 cm3. In 10 cases a tumor specimen was obtained either by open surgery or stereotactic biopsy, securing the diagnosis of pilocytic astrocytoma in five patients and nonpilocytic astrocytoma in five others. In the remaining 10 cases, the diagnosis was based on clinical and neuroimaging findings. The prescription Gamma Knife dose varied between 10 and 18 Gy, except in three patients who were receiving a boost to a site in which external-beam radiation was previously delivered. An average of four isocenters were utilized per GKS. Patients were followed up for a mean of 78.0 months. The tumors disappeared in four patients and shrank in 12 patients. Of these patients, one experienced transitory extrapyramidal symptoms and fluctuating impairment of consciousness (from somnolence to coma) for 6 months. Another patient whose tumor disappeared 3 years following GKS died of stroke 8 years postoperatively. The rest of the patients either remained stable or improved clinically. Tumor progression occurred in four patients; of these four, one patient developed hydrocephalus requiring a ventriculoperitoneal shunt, two showed neurological deterioration, and one 4-year-old boy died of tumor progression. CONCLUSIONS: Gamma Knife surgery may be an effective primary treatment or adjunct to open surgery for focal brainstem gliomas.

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Expert Opin Biol Ther. 2006 Dec;6(12):1255-62.
Immunomodulatory neural stem cells for brain tumour therapy.
Yu JJ, Sun X, Yuan X, Lee JW, Snyder EY, Yu JS.
Cedars Sinai Medical Center, Department of Neurosurgery, Los Angeles, CA, USA. yuj@cshs.org

Advances in the understanding of stem cells have enabled the development of novel therapies for brain tumours. Neural stem cells (NSCs) possess the ability to migrate throughout the CNS. By exploiting the tropism of NSCs to various neural pathologies (e.g., glioma, degeneration, stroke and so on) and the delivery of various immunomodulatory cytokines, new treatments for brain tumours have been investigated. These new strategies offer significantly more specificity than existing treatment regimens, such as surgery, radiation and chemotherapy. As methods in isolating and culturing NSCs are better understood, clinical applications of this therapeutic strategy may inevitably emerge. Here, the preclinical advances and the results supporting the effectiveness of stem cell therapies are reviewed. In addition, the obstacles to clinical development and methods to circumvent these caveats are discussed.

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Neurology. 2006 Dec 26;67(12 Suppl 4):S10-3.
Optimizing therapy of seizures in patients with brain tumors.
Vecht CJ, van Breemen M.
Department of Neurology, Medical Center The Hague, POB 432, 2501 CK The Hague, The Netherlands. c.vecht@mchaaglanden.nl.

The mechanism of epilepsy in brain tumor patients is probably multifactorial, and its incidence depends on tumor type and location. Refractory epilepsy is common in patients with structural brain lesions, and a role for multidrug-resistance proteins has been suggested. The medical treatment of epilepsy in brain tumor patients has mainly been studied retrospectively, and the optimal management of seizures with antiepileptic drugs (AEDs) is unclear. Enzyme-inducing anticonvulsants are generally not recommended because they can lead to insufficient serum levels of concomitantly administered chemotherapeutic drugs. Although valproic acid is an enzyme inhibitor and may therefore lead to toxic levels of simultaneously administered chemotherapeutic agents, this does not appear to be a major problem in patients with brain tumors. Preliminary observations of add-on treatment with the AEDs levetiracetam or gabapentin suggest that these non-enzyme-inducing AEDs can be useful for control of seizures in patients with brain tumors. Conversely, prophylactic use of AEDs in brain tumor patients is generally not recommended.

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Anticancer Res. 2006 Nov-Dec;26(6C):4959-64.
Concomitant radiochemotherapy with temozolomide in non-selected patients with newly diagnosed high-grade gliomas.
Eberlein KH, Nagel B, Franz K, Imhoff D, Seifert V, Boettcher HD, Mose S.
Department of Radiotherapy and Oncology, Johann Wolfgang Goethe-Universitat Frankfurt/Main, Frankfurt, Germany.

BACKGROUND: Malignant gliomas still present a medical challenge, despite decades of continuous extensive research with optimization of surgical techniques, radiotherapy and systemic treatments. PATIENTS AND METHODS: From 1999 to 2004, 104 patients with WHO grade III and IVgliomas underwent surgery and received concomitant radiotherapy combined with concomitant oral temozolomide. Patients with progressive disease received sequential 5-day cycles of temozolomide at 28-day intervals. RESULTS: The median overall survival was 19.7 and 15.0 months for patients with WHO grade III versus IV gliomas, respectively. Patient compliance was good and toxicity moderate. The overall survival was as long as 18.0 months in a subgroup of subjects with glioblastoma, performance status >60% and complete radiochemotherapy. CONCLUSION: Although our patients had more negative characteristics (age, performance, biopsy only), the results confirmed those from recently published optimistic phase III trial data and indeed surpassed them in some cases.

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Anticancer Res. 2006 Nov-Dec;26(6C):4675-86.
Post-operative combined radiation and chemotherapy with temozolomide and irinotecan in patients with high-grade astrocytic tumors. A phase II study with biomarker evaluation.
Fountzilas G, Karkavelas G, Kalogera-Fountzila A, Karina M, Ignatiadis M, Koukoulis G, Plataniotis G, Misailidou D, Bobos M, Pectasides D, Razis E, Karavelis A, Selviaridis P.
Department of Medical Oncology, Aristotle University of Thessaloniki, Thessaloniki, Greece. fountzil@med.auth.gr

BACKGROUND: Clinical studies have shown that temozolomide (TMZ) and irinotecan demonstrate activity in high grade astrocytic tumors (HGAT). However, the optimal schedule of administration is unknown. PATIENTS AND METHODS: In the present study, a total of 45 HGAT patients, 38 with glioblastoma multiforme (GBM) and 7 with anaplastic astrocytoma (AA), were treated with TMZ, 150 mg/m(2) on days 1-5, followed by irinotecan, 150 mg/m(2) on days 6 and 17, every 4 weeks for 6 cycles or until the occurrence of unacceptable toxicity or disease progression. Radiation therapy (60 Gy) was initiated on the first day of treatment. RESULTS: Twenty-two patients completed six cycles of treatment. Most frequently recorded side-effects included neutropenia (37%), nausea/vomiting (66%), diarrhea (31%) and infection (44%). Five episodes of vaso-occlusive disease, all of them fatal, were observed. After a median follow-up of 49.8 months, median progression-free survival for patients with GBM was 7.7 months, while median overall survival was 12.8 months. There were six long-term survivors, three of them with GBM. Two out of the five biomarkers studied, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor-C (VEGF-C), were found to be overexpressed in 74% of the tumors, however they had no predictive value for progression-free or overall survival. CONCLUSION: The combination of TMZ and irinotecan, as administered in this study, was accompanied by high rates of toxicity, especially myelotoxicity and infection. Further development of this regimen in the treatment of HGAT is not recommended.
 

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