Guidelines in the management of CNS tumors.

INTRODUCTION: Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS). METHODS: The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice. CONCLUSION: This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low grade gliomas, vestibular schwannomas, and metastatic brain tumors.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults.

QUESTION: What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect. QUESTION: Is there benefit to adjuvant temozolomide treatment in elderly patients (> 65 years old?). TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM. QUESTION: What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol. QUESTION: What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy.

Combination of systemic chemotherapy with local stem cell delivered S-TRAIL in resected brain tumors.

Despite advances in standard therapies, the survival of glioblastoma multiforme (GBM) patients has not improved. Limitations to successful translation of new therapies include poor delivery of systemic therapies and use of simplified preclinical models which fail to reflect the clinical complexity of GBMs. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis specifically in tumor cells and we have tested its efficacy by on-site delivery via engineered stem cells (SC) in mouse models of GBM that mimic the clinical scenario of tumor aggressiveness and resection. However, about half of tumor lines are resistant to TRAIL and overcoming TRAIL-resistance in GBM by combining therapeutic agents that are currently in clinical trials with SC-TRAIL and understanding the molecular dynamics of these combination therapies are critical to the broad use of TRAIL as a therapeutic agent in clinics. In this study, we screened clinically relevant chemotherapeutic agents for their ability to sensitize resistant GBM cell lines to TRAIL induced apoptosis. We show that low dose cisplatin increases surface receptor expression of death receptor 4/5 post G2 cycle arrest and sensitizes GBM cells to TRAIL induced apoptosis. In vivo, using an intracranial resection model of resistant primary human-derived GBM and real-time optical imaging, we show that a low dose of cisplatin in combination with synthetic extracellular matrix encapsulated SC-TRAIL significantly decreases tumor regrowth and increases survival in mice bearing GBM. This study has the potential to help expedite effective translation of local stem cell-based delivery of TRAIL into the clinical setting to target a broad spectrum of GBMs.

Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide.

Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II-IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings.

Management of patients with recurrence of diffuse low grade glioma: A systematic review and evidence-based clinical practice guideline.

TARGET POPULATION: These recommendations apply to adult patients with recurrent low-grade glioma (LGG) with initial pathologic diagnosis of a WHO grade II infiltrative glioma (oligodendroglioma, astrocytoma, or oligo-astrocytoma). QUESTION: Do pathologic and molecular characteristics predict outcome/malignant transformation at recurrence? RECOMMENDATIONS: IDH STATUS AND RECURRENCE: (Level III) IDH mutation status should be determined as LGGs with IDH mutations have a shortened time to recurrence. It is unclear whether knowledge of IDH mutation status provides benefit in predicting time to progression or overall survival. TP53 STATUS AND RECURRENCE: (Level III) TP53 mutations occur early in LGG pathogenesis, remain stable, and are not recommended as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. MGMT STATUS AND RECURRENCE: (Level III) Assessment of MGMT status is recommended as an adjunct to assessing prognosis as LGGs with MGMT promoter methylation are associated with shorter PFS (in the absence of TMZ) and longer post-recurrence survival (in the presence of TMZ), ultimately producing similar overall survival to LGGs without MGMT methylation. The available retrospective reports are conflicting and comparisons between reports are limited CDK2NA STATUS AND RECURRENCE: (Level III) Assessment of CDK2NA status is recommended when possible as the loss of expression of the CDK2NA via either methylation or loss of chromosome 9p is associated with malignant progression of LGGs. PROLIFERATIVE INDEX AND RECURRENCE: (Level III) It is recommended that proliferative indices (MIB-1 or BUdR) be measured in LGGs as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival. 1P/19Q STATUS AND RECURRENCE: There is insufficient evidence to make any recommendations. QUESTION: What role does chemotherapy have in LGG recurrence? RECOMMENDATIONS: TEMOZOLOMIDE AND RECURRENCE: (Level III) Temozolomide is recommended in the therapy of recurrent LGG as it may improve clinical symptoms. Oligodendrogliomas and tumors with 1p/19q co-deletion may derive the most benefit. PCV AND RECURRENCE: (Level III) PCV is recommended in the therapy of LGG at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. CARBOPLATIN AND RECURRENCE : (Level III) Carboplatin is not recommended as there is no significant benefit from carboplatin as single agent therapy for recurrent LGGs. OTHER TREATMENTS (NITROSUREAS, HYDROXYUREA/IMANITIB, IRINOTECAN, PACLITAXEL) AND RECURRENCE: There is insufficient evidence to make any recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess these chemotherapeutic agents. QUESTION: What role does radiation have in LGG recurrence? RECOMMENDATIONS: RADIATION AT RECURRENCE WITH NO PREVIOUS IRRADIATION: (Level III) Radiation is recommended at recurrence if there was no previous radiation treatment. RE-IRRADIATION AT RECURRENCE: (Level III) It is recommended that re-irradiation be considered in the setting of LGG recurrence as it may provide benefit in disease control. SURGERY AT RECURRENCE: There is insufficient evidence to make any specific recommendations. It is recommended that individuals with recurrent LGGs be enrolled in a properly designed clinical trial to assess the role of surgery at recurrence.

Cushing's Disease Associated With Partially Empty Sella Turcica Syndrome: A Case Report.

The association between empty sella turcica (EST) syndrome and Cushing's disease has been rarely reported. It is plausible to hypothesize that EST syndrome in association with Cushing's disease can be attributed to intracranial hypertension. In this case report, we present a 47-year-old male patient who presented with weight loss, fatigue, easy bruising, acanthosis nigricans, and skin creases hyperpigmentation. Investigations revealed hypokalemia and confirmed the diagnosis of Cushing's disease. Magnetic resonance imaging (MRI) brain showed a partial EST syndrome and a new pituitary nodule as compared with previous brain imaging. Transsphenoidal surgery was pursued and was complicated by cerebrospinal fluid leakage. This case reflects the rare association of EST syndrome and Cushing's disease, suggesting the increased risk of postoperative complications in this setting and the diagnostic challenge that EST syndrome imposes. We review the literature for a possible mechanism of this association.

Single-cell analysis reveals diversity of tumor-associated macrophages and their interactions with T lymphocytes in glioblastoma.

Glioblastoma (GBM) is an aggressive primary CNS malignancy and clinical outcomes have remained stagnant despite introduction of new treatments. Understanding the tumor microenvironment (TME) in which tumor associated macrophages (TAMs) interact with T cells has been of great interest. Although previous studies examining TAMs in GBM have shown that certain TAMs are associated with specific clinical and/or pathologic features, these studies used an outdated M1/M2 paradigm of macrophage polarization and failed to include the continuum of TAM states in GBM. Perhaps most significantly, the interactions of TAMs with T cells have yet to be fully explored. Our study uses single-cell RNA sequencing data from adult IDH-wildtype GBM, with the primary aim of deciphering the cellular interactions of the 7 TAM subtypes with T cells in the GBM TME. Furthermore, the interactions discovered herein are compared to IDH-mutant astrocytoma, allowing for focus on the cellular ecosystem unique to GBM. The resulting ligand-receptor interactions, signaling sources, and global communication patterns discovered provide a framework for future studies to explore methods of leveraging the immune system for treating GBM.

Infection following operations on the central nervous system: deconstructing the myth of the sterile field.

Neurosurgical patients are at a high risk for infectious sequelae following operations. For neurosurgery in particular, the risk of surgical site infection has a unique implication given the proximity of the CSF and the CNS. Patient factors contribute to some degree; for example, cancer and trauma are often associated with impaired nutritional status, known risk factors for infection. Additionally, care-based factors for infection must also be considered, such as the length of surgery, the administration of steroids, and tissue devascularization (such as a craniotomy bone flap). When postoperative infection does occur, attention is commonly focused on potential lapses in surgical "sterility." Evidence suggests that the surgical field is not free of microorganisms. The authors propose a paradigm shift in the nomenclature of the surgical field from "sterile" to "clean." Continued efforts aimed at optimizing immune capacity and host defenses to combat potential infection are warranted.

Cerebrospinal fluid fistula prevention and treatment following frontal sinus fractures: a review of initial management and outcomes.

Frontal sinus fractures are heterogeneous, and management of these fractures is often modified based on injury pattern and institutional experience. The optimal initial treatment of frontal sinus fractures is controversial. Treatment strategies are aimed at correcting cosmetic deformity, as well as at preventing delayed complications, including CSF fistulas, mucocele formation, and infection. Existing treatment options include observation, reconstruction, obliteration, cranialization, or a combination thereof. Modalities for treatment encompass both open surgical approaches and endoscopic techniques. In the absence of Class I data, the authors review the existing literature related to treatment strategies of frontal sinus fractures, particularly as they relate to CSF fistulas, to provide recommendations based on the best available evidence.

Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline.

PURPOSE: American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: "Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline"2 was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS: The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline, published May 6, 2022, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorses "Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline."2. RECOMMENDATIONS: Within the guideline, stereotactic radiosurgery (SRS) is recommended for patients with Eastern Cooperative Oncology Group performance status of 0-2 and up to four intact brain metastases, and conditionally recommended for patients with up to 10 intact brain metastases. The guideline provides detailed dosing and fractionation recommendations on the basis of the size of the metastases. For patients with resected brain metastases, radiation therapy (SRS or whole-brain radiation therapy [WBRT]) is recommended to improve intracranial disease control; if there are limited additional brain metastases, SRS is recommended over WBRT. For patients with favorable prognosis and brain metastases ineligible for surgery and/or SRS, WBRT is recommended with hippocampal avoidance where possible and the addition of memantine is recommended. For patients with brain metastases, limiting the single-fraction V12Gy to brain tissue to ≤ 10 cm3 is conditionally recommended.Additional information is available at www.asco.org/neurooncology-guidelines.

Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline.

PURPOSE: To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. METHODS: ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS: Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. RECOMMENDATIONS: Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.

Determination of geographic variance in stroke prevalence using Internet search engine analytics.

OBJECT: Previous methods to determine stroke prevalence, such as nationwide surveys, are labor-intensive endeavors. Recent advances in search engine query analytics have led to a new metric for disease surveillance to evaluate symptomatic phenomenon, such as influenza. The authors hypothesized that the use of search engine query data can determine the prevalence of stroke. METHODS: The Google Insights for Search database was accessed to analyze anonymized search engine query data. The authors' search strategy utilized common search queries used when attempting either to identify the signs and symptoms of a stroke or to perform stroke education. The search logic was as follows: (stroke signs + stroke symptoms + mini stroke--heat) from January 1, 2005, to December 31, 2010. The relative number of searches performed (the interest level) for this search logic was established for all 50 states and the District of Columbia. A Pearson product-moment correlation coefficient was calculated from the statespecific stroke prevalence data previously reported. RESULTS: Web search engine interest level was available for all 50 states and the District of Columbia over the time period for January 1, 2005-December 31, 2010. The interest level was highest in Alabama and Tennessee (100 and 96, respectively) and lowest in California and Virginia (58 and 53, respectively). The Pearson correlation coefficient (r) was calculated to be 0.47 (p = 0.0005, 2-tailed). CONCLUSIONS: Search engine query data analysis allows for the determination of relative stroke prevalence. Further investigation will reveal the reliability of this metric to determine temporal pattern analysis and prevalence in this and other symptomatic diseases.

Pre-clinical tumor models of primary brain tumors: Challenges and opportunities.

Primary brain tumors are a heterogeneous group of malignancies that originate in cells of the central nervous system. A variety of models tractable for preclinical studies have been developed to recapitulate human brain tumors, allowing us to understand the underlying pathobiology and explore potential treatments. However, many promising therapeutic strategies identified using preclinical models have shown limited efficacy or failed at the clinical trial stage. The inability to develop therapeutic strategies that significantly improve survival rates in patients highlight the compelling need to revisit the design of currently available animal models and explore the use of new models that allow us to bridge the gap between promising preclinical findings and clinical translation. In this review, we discuss current strategies used to model glioblastoma, the most malignant brain tumor in adults and highlight the shortcomings of specific models that must be circumvented for the development of innovative therapeutic strategies.

Prospective prediction of clinical drug response in high-grade gliomas using an ex vivo 3D cell culture assay.

BACKGROUND: Clinical outcomes in high-grade glioma (HGG) have remained relatively unchanged over the last 3 decades with only modest increases in overall survival. Despite the validation of biomarkers to classify treatment response, most newly diagnosed (ND) patients receive the same treatment regimen. This study aimed to determine whether a prospective functional assay that provides a direct, live tumor cell-based drug response prediction specific for each patient could accurately predict clinical drug response prior to treatment. METHODS: A modified 3D cell culture assay was validated to establish baseline parameters including drug concentrations, timing, and reproducibility. Live tumor tissue from HGG patients were tested in the assay to establish response parameters. Clinical correlation was determined between prospective ex vivo response and clinical response in ND HGG patients enrolled in 3D-PREDICT (ClinicalTrials.gov Identifier: NCT03561207). Clinical case studies were examined for relapsed HGG patients enrolled on 3D-PREDICT, prospectively assayed for ex vivo drug response, and monitored for follow-up. RESULTS: Absent biomarker stratification, the test accurately predicted clinical response/nonresponse to temozolomide in 17/20 (85%, P = .007) ND patients within 7 days of their surgery, prior to treatment initiation. Test-predicted responders had a median overall survival post-surgery of 11.6 months compared to 5.9 months for test-predicted nonresponders (P = .0376). Case studies provided examples of the clinical utility of the assay predictions and their impact upon treatment decisions resulting in positive clinical outcomes. CONCLUSION: This study both validates the developed assay analytically and clinically and provides case studies of its implementation in clinical practice.

Stereotactic Radiation as Salvage Therapy for Recurrent Rathke Cleft Cysts.

BACKGROUND: Rathke cleft cysts (RCCs) are sellar-based cystic lesions that are often found incidentally but occasionally become symptomatic with significant visual and/or endocrine deficits. The standard of treatment is surgery, but rare cases of multiply recurrent RCCs can be refractory to surgical drainage, leading to significant morbidity. OBJECTIVE: To demonstrate the safety and feasibility of fractionated stereotactic radiotherapy (SRT) as salvage therapy in multiply recurrent RCCs refractory to surgical drainage. METHODS: An IRB-approved retrospective review at a single institution was conducted to identify and describe patients with multiply recurrent RCCs refractory to surgical drainage who underwent SRT. RESULTS: From 1994 to 2015, 6 patients (5 female) who underwent SRT for recurrent RCCs were identified. A total of 4 presented with visual deficits, and 2 presented with endocrine dysfunction and severe headaches prior to their initial drainage. All patients had initial postoperative improvement but then developed multiple, symptomatic recurrences. Median number of surgical drainage procedures prior to radiotherapy was 3. A total of 3 patients underwent LINAC-based SRT, and 3 had proton-based SRT. Treatment doses were 45 Gy over 25 fractions (n = 5) and 50.4 Gy over 28 fractions (n = 1). Median follow-up after radiation therapy was 69 mo (range 24-154 mo). In the follow-up period, stabilization of the RCC was achieved, although 2 patients required additional drainage procedures. Only 1 patient developed new hypothyroidism and hypoadrenalism after SRT. CONCLUSION: In rare cases of multiply recurrent RCCs refractory to repeat surgical drainage, stereotactic fractionated radiation therapy is a safe and effective salvage therapy.

CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas.

PURPOSE: The chemokine receptor CXCR4 is expressed in many different cancers. In malignant brain tumors, CXCR4 signaling has been implicated in tumor growth, survival, and migration, and pharmacologic inhibition of CXCR4 results in decreased tumor growth in preclinical models. To understand how CXCR4 inhibitors may be incorporated into clinical therapy, we examined determinants of responsiveness to CXCR4 inhibition. Because optimal use of CXCR4 inhibition will likely be a part of multimodality therapy, we also investigated the efficacy of CXCR4 inhibition combined with conventional cytotoxic chemotherapy. EXPERIMENTAL DESIGN: CXCR4 protein levels and responsiveness to the CXCR4 inhibitor AMD3100 were determined in a panel of glioblastoma multiforme cell lines. The effects of AMD3100, alone or in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), on cell growth were determined for several of these cell lines in vitro. We used an orthotopic model of glioblastoma multiforme to evaluate the antitumor efficacy of AMD3100 combined with BCNU in vivo. RESULTS: The level of CXCR4 protein expression in glioblastoma multiforme cells predicts the dose at which there is a response to AMD3100; cells that express higher levels of CXCR4 protein require higher doses for equivalent response. In all cell lines tested, treatment of glioblastoma multiforme cells with BCNU followed by AMD3100 results in synergistic antitumor efficacy in vitro. This synergy can also be seen in an orthotopic glioblastoma multiforme model. Treatment with subtherapeutic doses of BCNU in combination with AMD3100 results in tumor regression in vivo, and this reflects both increased apoptosis and decreased proliferation following combination therapy. CONCLUSION: These studies support testing CXCR4 inhibitors in patients with glioblastoma multiforme and establish that inhibition of CXCR4 synergizes with conventional cytotoxic therapies in a clinically relevant combinatorial strategy.

Acute lymphocytic leukemia presenting as a single brain mass.

Hematologic malignancies most commonly spread to the central nervous system via leptomeningeal infiltration. We present a unique case of a woman who presented with a right parietal mass as the initial manifestation of B cell acute lymphocytic leukemia. Because the diagnosis was unclear at the time of presentation she underwent surgical debulking of the mass prior to treatment with chemotherapy. Unfortunately, she relapsed several months after treatment and ultimately entered hospice care. We review the literature surrounding management considerations in patients with intracranial leukemic involvement.

Intracranial dural based chondroma.

Intracranial chondromas are benign, slow-growing, cartilaginous tumors, which comprise only about 0.2% of all intracranial tumors. The majority of these lesions occur at the base of the skull, where they are thought to arise from residual embryonic chondrogenic cells along the basal synchondrosis. Very rarely, they may also originate from the convexity dura, falx cerebri, or the brain parenchyma. We present a patient with a dural based chondroma to highlight the technical considerations of surgical resection. The recent literature on intracranial chondromas regarding incidence, pathophysiologic origin, clinical symptoms, imaging, histopathology and prognosis is reviewed.

PET imaging of glioblastoma multiforme EGFR expression for therapeutic decision guidance.

After initial therapy and total resection of glioblastoma multiforme (GBM), 80-90% of recurrences occur at the surgical margins. Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease. A tumor-specific imaging agent for GBM may improve detection of small residual disease in the post-operative period, and improve ability to distinguish tumor recurrence from its imaging mimics that can delay diagnosis. To this end, we developed an EGFR-targeted PET probe and assessed its ability to image EGFR WT (U87) and EGFRvIII (Gli36vIII) expressing GBMs in both murine intra-cranial xenografts and in a surgical-resection model. The developed imaging probe, (64)Cu-DOTAcetuximab-F(ab´)2, binds with a Kd of 11.2 nM to EGFR expressing GBM. (64)Cu-DOTA-cetuximab-F(ab´)2 specifically localized to intra-cranial tumor with a significant difference in SUVmean between tumor and contralateral brain for both Gli36vIII and U87 tumors (P<0.01 for both comparisons), with mean TBR of 22.5±0.7 for Gli36vIII tumors and 28.9±2.1 for U87 tumors (TBR±SEM). Tracer uptake by tumor was significantly inhibited by pre-injection with cetuximab (P<0.01 for both), with SUVmean reduced by 68% and 58% for Gli36vIII and U87 tumors, respectively. Surgical resection model PET-CT imaging demonstrates residual tumor and low nonspecific uptake in the resection site. We conclude that (64)Cu-DOTA-cetuximab-F(ab´)2 binds specifically to intracranial EGFR WT and EGFRvIII expressing GBM, demonstrates excellent TBR, and specifically images small residual tumor in a surgical model, suggesting future clinical utility in identifying true tumor recurrence.