Imaging of brain tumors with paramagnetic vesicles targeted to phosphatidylserine.

PURPOSE: To investigate paramagnetic saposin C and dioleylphosphatidylserine (SapC-DOPS) vesicles as a targeted contrast agent for imaging phosphatidylserine (PS) expressed by glioblastoma multiforme (GBM) tumors. MATERIALS AND METHODS: Gd-DTPA-BSA/SapC-DOPS vesicles were formulated, and the vesicle diameter and relaxivity were measured. Targeting of Gd-DTPA-BSA/SapC-DOPS vesicles to tumor cells in vitro and in vivo was compared with nontargeted paramagnetic vesicles (lacking SapC). Mice with GBM brain tumors were imaged at 3, 10, 20, and 24 h postinjection to measure the relaxation rate (R1) in the tumor and the normal brain. RESULTS: The mean diameter of vesicles was 175 nm, and the relaxivity at 7 Tesla was 3.32 (s*mM)(-1) relative to the gadolinium concentration. Gd-DTPA-BSA/SapC-DOPS vesicles targeted cultured cancer cells, leading to an increased R1 and gadolinium level in the cells. In vivo, Gd-DTPA-BSA/SapC-DOPS vesicles produced a 9% increase in the R1 of GBM brain tumors in mice 10 h postinjection, but only minimal changes (1.2% increase) in the normal brain. Nontargeted paramagnetic vesicles yielded minimal change in the tumor R1 at 10 h postinjection (1.3%). CONCLUSION: These experiments demonstrate that Gd-DTPA-BSA/SapC-DOPS vesicles can selectively target implanted brain tumors in vivo, providing noninvasive mapping of the cancer biomarker PS.

Whole genome sequencing of glioblastoma multiforme identifies multiple structural variations involved in EGFR activation.

Next generation sequencing has become a powerful tool in dissecting and identifying mutations and genomic structural variants that accompany tumourigenesis. Sequence analysis of glioblastoma multiforme (GBM) illustrates the ability to rapidly identify mutations that may affect phenotype. Approximately 50% of human GBMs overexpress epidermal growth factor receptor (EGFR) which renders the EGFR protein a compelling therapeutic target. In brain tumours, attempts to target EGFR as a cancer therapeutic, however, have achieved little or no benefit. The mechanisms that drive therapeutic resistance to EGFR inhibitors in brain tumours are not well defined, and drug resistance contributes to the deadly and aggressive nature of the disease. Whole genome sequencing of four primary GBMs revealed multiple pathways by which EGFR protein abundance becomes deregulated in these tumours and will guide the development of new strategies for treating EGFR overexpressing tumours. Each of the four tumours displayed a different mechanism leading to increased EGFR protein levels. One mechanism is mediated by gene amplification and tandem duplication of the kinase domain. A second involves an intragenic deletion that generates a constitutively active form of the protein. A third combines the loss of a gene which encodes a protein that regulates EGFR abundance as well as an miRNA that modulates EGFR expression. A fourth mechanism entails loss of an ubiquitin ligase docking site in the C-terminal part of the protein whose absence inhibits turnover of the receptor.

Detection of EGFRvIII mutant DNA in the peripheral blood of brain tumor patients.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens including surgical resection, radiation and chemotherapy. EGFRvIII is a truncated extracellular mutant of the EGF receptor (EGFR) found in about a third of GBMs. It confers enhanced tumorigenic behavior and is associated with chemo- and radio-resistance. GBM patients testing positive for EGFRvIII have a bleaker prognosis than those who do not. Targeting EGFRvIII positive tumors via vaccines or antibody-drug-conjugates represents a new challenging therapeutic avenue with potential great clinical benefits. In this study, we developed a strategy to detect EGFRvIII deletion in the circulating tumor DNA. The overall goal is to identify a simple and robust biomarker in the peripheral blood of patients diagnosed with GBM in order to follow their disease status while on treatment. Thirteen patients were included in this study, three of which were found to carry the EGFRvIII deletion. The circulating DNA status for EGFRvIII correlates with the analysis performed on the respective tumor samples, and its level seems to correlate with the extent of the tumor resection. This semi-quantitative blood biomarker may represent a strategy to (1) screen patients for an anti-EGFRvIII therapy and (2) monitor the patients' response to treatment.

Atypical meningiomas: is postoperative radiotherapy indicated?

OBJECT: The role of postoperative radiation therapy after surgery for atypical meningiomas remains controversial. In this retrospective cohort study, the authors examine the recurrence rates for atypical meningiomas after resection (with or without adjuvant radiotherapy) and identify which factors were associated with recurrence. METHODS: Of 90 patients with atypical meningiomas who underwent surgery between 1999 and 2009, 71 (79%) underwent gross-total resection (GTR) and 19 (21%) underwent subtotal resection (STR); 31 patients received adjuvant radiotherapy. All tumors were pathology-confirmed WHO Grade II atypical meningiomas. Univariate and multivariate analyses were performed to identify factors associated with recurrence-free survival. RESULTS: Among 90 patients, 17 developed tumor recurrence (81% recurrence-free survival at 5 years). In the overall group, adjuvant radiotherapy reduced the recurrence rate to 9% from 19% at 5 years (p = 0.048). After STR, adjuvant radiotherapy significantly reduced recurrence from 91% to 20% (p = 0.0016). However, after GTR, adjuvant radiotherapy did not significantly reduce the recurrence rate (16.7% without radiation therapy vs 11.8% with radiation therapy) (p = 1.00). Five factors independently predictive of tumor recurrence included mitotic index, sheeting, necrosis, nonuse of radiation therapy, and STR. Further recursive partitioning analysis showed significant increases in risk for patients older than 55 years with mitoses and sheeting. CONCLUSIONS: Adjuvant radiotherapy was effective at lowering recurrence rates in patients after STR but delivered no significant improvement in patients after GTR. Given that rates after GTR were similar with or without adjuvant radiotherapy, close observation without postoperative radiation therapy may be a viable option for these patients. Patients older than 55 years and those with mitoses noted during pathological examination had a significant risk of recurrence after GTR; for these patients, postoperative radiotherapy is recommended.

Results of phase I study of a multi-modality treatment for newly diagnosed glioblastoma multiforme using local implantation of concurrent BCNU wafers and permanent I-125 seeds followed by fractionated radiation and temozolomide chemotherapy.

Previously we demonstrated median survival of 69 weeks after combination therapy of permanent, low-activity I-125 seeds and BCNU wafers for recurrent glioblastoma multiforme (GBM). We designed this prospective phase I trial to assess efficacy of this combination treatment for newly diagnosed GBM. Patients with newly diagnosed GBMs deemed amenable to gross total resection were included. This dose-escalation study of I-125 seeds included three 6-patient cohorts, receiving increasing doses of 3000, 6000, and 9000 cGy, and a maximal number of BCNU wafers placed surgically. Postoperatively patients underwent standard fractionated radiation to 5,940 cGy followed by temozolomide chemotherapy. During enrollment of the first 6-patient cohort, the trial was stopped when 3 of 5 patients developed radiation toxicity. Five patients (median age 55 years, range 46-64 years) completed postoperative radiation; Karnofsky Performance Status ranged from 70 to 90. This lowest-dose cohort received I-125 seeds at 3,000 cGy and maximal BCNU wafer placement, and reached endpoint (median 26 weeks follow-up). Two patients developed local disease progression (median 34.4 weeks). The 3 patients who developed radiation toxicity, which was documented on follow-up MRI and confirmed by MRI spectroscopy (median 20 weeks), underwent treatment with steroids and bevacizumab. Our phase I study was closed during enrollment of the first 6-patient cohort because of the high incidence (60 %) of early radiation toxicity. We do not recommend the seed-wafer therapy for newly diagnosed GBM patients but rather reserve this as salvage therapy for select patients with recurrent GBM.

Management of newly diagnosed single brain metastasis with surgical resection and permanent I-125 seeds without upfront whole brain radiotherapy.

In this retrospective study, we evaluate the efficacy of surgical resection and I-125 seeds, without upfront whole brain radiotherapy (WBRT), for newly diagnosed single brain metastasis. About 40 women and 32 men underwent gross total resection and placement of permanent low-activity I-125 seeds at our institution (1997-2007). Primary systemic cancer sites varied. At follow-up (median 16 months), local control rate was 93%. Distant brain failures occurred in 23 (32%) patients: 5 patients within 3 months and 18 patients >3 months; brain failure underwent further treatment (i.e., radiosurgery in 13, WBRT in 5, surgical resection with I-125 seeds in 2). Four patients developed radiation necrosis. All 72 patients had stable or improved Karnofsky Performance Score at 1 month after surgery. Median actuarial survival rate was 14 months; 2-year survival rate was 27%. Permanent I-125 brachytherapy at initial operation without WBRT provided excellent local control. 67 patients (93%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

Regression of intracranial rosai-dorfman disease following corticosteroid therapy. Case report.

Rosai-Dorfman disease (RDD) is an idiopathic histioproliferative disorder usually presenting with massive, painless lymphadenopathy. Extranodal involvement has been reported including at least 50 cases affecting the central nervous system (CNS). The treatment of CNS RDD as reported in the literature has primarily involved a surgical technique. The authors report on the case of a 53-year-old man presenting with multiple skull base lesions mimicking meningiomas. The patient suffered visual deterioration and underwent a right orbitopterional craniotomy as well as optic nerve decompression. Histopathological analysis revealed histiocytic cells and emperipolesis consistent with RDD. Following surgery, corticosteroid agents were administered, leading to marked resolution of both the remaining surgically untreated lesions and the balance of the patient's symptoms. This report represents the first case of the resolution of intracranial RDD following corticosteroid therapy. Corticosteroid agents should be considered an effective option in the treatment of CNS RDD.

Metastatic disease from spinal chordoma: a 10-year experience.

OBJECT: Metastastic lesions have been reported in 5 to 40% of patients with spinal and sacrococcygeal chordoma, but few contemporary series of chordoma metastastic disease exist in the literature. Additionally, the outcome in patients with chordoma-induced metastastic neoplasms remains unclear. The authors performed a retrospective review of the neurosurgery database at the University of Texas M. D. Anderson Cancer Center in Houston to determine the incidence of metastatic disease in a contemporary series of spinal and sacrococcygeal chordoma as well as to determine the outcomes. METHODS: Thirty-seven patients underwent surgery for spinal and sacrococcygeal chordoma between June 1, 1993, and March 31, 2004. All records were reviewed, and appropriate statistical analyses were used to compare patient data for preoperative characteristics, treatments, and outcomes. The authors identified seven patients (19%) in whom metastatic disease developed; in three the disease had metastasized to the lungs only, in two to the lungs and liver, and in two to distant locations in the spine. There were no significant differences in age, sex, tumor location, or history of radiation treatments between patients with and those without metastases. In cases with local recurrent tumors, metastastic disease was more likely to develop than in those without recurrence (28 compared with 0%, respectively; p = 0.07). In two (12%) of 17 patients who underwent en bloc resection, metastatic disease developed, whereas it developed in five (25%) of 20 patients treated by curettage (p = 0.42). The median time from first surgery to the appearance of metastatic disease, as calculated using the Kaplan-Meier method, was 143.4 months (95% confidence interval [CI] 66.8-219.9). The median survival duration of patients with metastatic disease after the first surgery was 106 months (95% CI 55.7-155.7), and this did not differ significantly from that in patients in whom no metastases developed (p = 0.93). CONCLUSIONS: Spinal chordoma metastasized to other locations in 19% of the patients in this series. In patients with local disease recurrence, metastatic lesions are more likely to develop. Metastatic lesions were shown to be aggressive in some cases. Surgery and chemotherapy can play a role in controlling metastatic disease.

Flt-3 ligand: a potent dendritic cell stimulator and novel antitumor agent.

Dendritic cell (DC) vaccination has generated intense interest as a potential cancer therapy. However, the rate limiting step has been the generation of DCs. Flt-3 ligand (FL) is a growth factor that was first discovered by its ability to stimulate the proliferation of hematopoietic progenitor cells of both lymphoid and myeloid origin. The remarkable activity of FL to induce large numbers of dendritic cells both in vivo and in vitro soon captured the interest of numerous researchers. In this review, we examine the structure and function of the FL, its antitumor activity in animal models, and its potential as a novel cancer treatment.

Target definition for malignant gliomas: no difference in radiation treatment volumes between 1.5T and 3T magnetic resonance imaging.

PURPOSE: Currently, most high-grade glioma patients undergo a 1.5T brain magnetic resonance (MR) for radiation treatment planning. We hypothesized that 3T MR imaging (MRI) scanning is superior to 1.5T due to higher signal-to-noise ratio (SNR), and thus will result in more accurate quantification of tumor volumes. The purpose of this prospective study was to determine differences in radiation planning volumes for high-grade gliomas when scanned on 3T MR versus 1.5T MR. METHODS AND MATERIALS: In this prospective controlled trial, 23 patients with high-grade gliomas underwent brain MRI scanning in both 1.5T and 3T field strengths within a 24-hour period; no steroids or treatment changes were made in-between scans. After 3 investigators contoured the T2 fast low-angle inversion recovery (FLAIR) abnormality (gross tumor volumes or [GTV]) for all patients, clinical target volume (CTV) and planning treatment volumes (PTV) were defined. Calculations by an independent investigator included volumes, standard deviations, SNRs, and contrast-to-noise ratios (CNRs); statistical analysis was performed on raw data. RESULTS: Planning treatment volume ratios (3T:1.5T) for each investigator were 0.95 ± 0.12 (range, 0.64-1.10), 0.98 ± 0.10 (range, 0.64-1.16), and 0.99 ± 0.06 (range, 0.86-1.13). By paired 2-tailed t test, these volumes were not statistically different (P = .051), although there is a trend to 3T producing smaller volumes than 1.5T. Dice similarity coefficients were 0.90 ± 0.05, 0.90 ± 0.06, and 0.91 ± 0.05 for the investigators. CONCLUSIONS: Planning target volumes for high-grade gliomas were similar at 3T and 1.5T MR using our standard imaging protocols. However, in some patients, the 3T MR may reveal substantially smaller tumor volume due to inferior conspicuity of the lesion. These findings imply that while overall the radiation target volumes are comparable, there are differences in CNR and SNR that lead to differences in individual patients. The 1.5T may be better for gaining conspicuity of the tumor.

Management strategies after nondiagnostic results with frameless stereotactic needle biopsy: Retrospective review of 28 patients.

BACKGROUND: Although frameless stereotactic needle biopsy is an accepted procedure for the diagnosis of intracranial lesions, findings are nondiagnostic in 2-15% of patients and no recommendations yet exist to guide subsequent care. After reviewing the postoperative course after nondiagnostic biopsy of 28 patients, we developed a paradigm to guide management in the future. METHODS: In reviewing the medical records of 284 frameless stereotactic needle biopsies (January 2000 to December 2006), we identified a subset of 28 patients who underwent 29 (10.2%) biopsies that did not yield a definitive diagnosis based on permanent pathologic samples. Postoperative treatment plans and clinical courses were further examined in 21 patients; 7 without follow-up were excluded. RESULTS: Of the 21 patients, lesion location and characteristics guided the surgeon's decision to recommend further surgery or initiate empiric treatment. Soon after initial biopsy, five patients underwent a second procedure (biopsy or resection) that yielded diagnostic pathologic tissue. Of 16 patients who had empiric treatment, 7 (43.7%) subsequently had their treatment plan changed because of a lack of improvement and 5 underwent a second biopsy (4 diagnostic). Evolving clinical information precipitated treatment change in two patients. Of 10 patients who had a second surgery for better diagnostic information, the diagnostic yield was 90%. CONCLUSIONS: Considering the 90% diagnostic yield, we now recommend repeat surgery for most patients with nondiagnostic biopsies, especially for lesions considered potentially neoplastic or infectious. Empiric management, for lesions likely to be neurodegenerative, is an option but requires close follow-up examination.

Measuring surgical outcomes in neurosurgery: implementation, analysis, and auditing a prospective series of more than 5000 procedures.

OBJECT: Health care reform debate includes discussions regarding outcomes of surgical interventions. Yet quality of medical care, when judged as a health outcome, is difficult to define because of impediments affecting accuracy in data collection, analysis, and reporting. In this prospective study, the authors report the outcomes for neurosurgical treatment based on point-of-care interactions recorded in the electronic medical record (EMR). METHODS: The authors' neurosurgery practice collected outcome data for 19 physicians and ancillary personnel using the EMR. Data were analyzed for 5361 consecutive surgical cases, either elective or emergency procedures, performed during 2009 at multiple hospitals, offices, and an ambulatory spine surgery center. Main outcomes included complications, length of stay (LOS), and discharge disposition for all patients and for certain frequently performed procedures. Physicians, nurses, and other medical staff used validated scales to record the hospital LOS, complications, disposition at discharge, and return to work. RESULTS: Of the 5361 surgical procedures performed, two-thirds were spinal procedures and one-third were cranial procedures. Organization-wide compliance with reporting rates of major complications improved throughout the year, from 80.7% in the first quarter to 90.3% in the fourth quarter. Auditing showed that rates of unreported complications decreased from 11% in the first quarter to 4% in the fourth quarter. Complication data were available for 4593 procedures (85.7%); of these, no complications were reported in 4367 (95.1%). Discharge dispositions reported were home in 86.2%, rehabilitation center in 8.9%, and nursing home in 2.5%. Major complications included culture-proven infection in 0.61%, CSF leak in 0.89%, reoperation within the same hospitalization in 0.38%, and new neurological deficits in 0.77%. For the commonly performed procedures, the median hospital LOS was 3 days for craniotomy for aneurysm or intraaxial tumor and less than 1 day for angiogram, anterior cervical discectomy with fusion, or lumbar discectomy. CONCLUSIONS: With prospectively collected outcome data for more than 5000 surgeries, the authors achieved their primary end point of institution-wide compliance and data accuracy. Components of this process included staged implementation with physician pilot studies and oversight, nurse participation, point-of-service data capture, EMR form modification, data auditing, and confidential surgeon reports.

Isolated cerebellar mucormycosis, slowly progressive over 1 year in an immunocompetent patient.

BACKGROUND: Mucormycosis is a rare, aggressive fungal disease with high mortality, typically presenting as rhinosinusitis in immunocompromised patients. CASE DESCRIPTION: A 43-year-old man with a history of intravenous drug use, Hepatitis C, and no evidence of immunocompromise presented with worsening balance problems. He had received intravenous antibiotics 2.5 years earlier for local infection after injecting heroin into a neck vein. Imaging studies revealed a lesion, likely of neoplastic origin. At resection, purulent fluid sampled by neuropathology revealed right-angled, branching hyphae, suggesting mucormycosis. No further resection was performed, no other disease sites were found, and HIV findings were negative. Two weeks postoperatively, he developed renal failure; intravenous antifungal treatment and hemodialysis were discontinued. When kidney function recovered 2 weeks later, he declined additional treatment. CONCLUSION: In our immunocompetent patient, both the location of the infection in the posterior fossa and its slowly progressive characteristic were unique variations of this typically aggressive disease.

Adjuvant whole-brain radiation therapy after surgical resection of single brain metastases.

Adjuvant whole-brain radiation therapy (WBRT) after resection of single brain metastases remains controversial. Despite a phase III trial to the contrary, clinicians often withhold WBRT after resection of single brain metastases based on the argument that available evidence does not inform regarding treatment of all patients, such as those with radioresistant tumors. However, there is limited information about whether subpopulations benefit equally from WBRT after resection. Therefore, we undertook a retrospective study to determine the clinical, radiographic, and histologic features that influenced the effectiveness of adjuvant WBRT. We reviewed 358 patients with newly diagnosed, single brain metastases, who underwent resection, of which 142 (40%) received adjuvant WBRT and 216 (60%) did not. Median follow-up was 60.1 months. There were multiple tumor histologies, including 197 (55%) "radiosensitive" and 161 (45%) "radioresistant" tumors. Compared with observation, WBRT significantly reduced recurrence both locally (HR = 0.58; 95% CI 0.35-0.98, P = .04) and at distant brain sites (HR = 0.43, 95% CI 0.30-0.61, P < .001). Multivariate analyses demonstrated that withholding WBRT was an independent predictor of local and distant recurrence. For local recurrence, tumors with a maximum diameter of ≥3 cm that did not receive adjuvant WBRT had an increased risk of recurring locally (HR = 3.14, 95% CI 1.02-9.69, P = .05). For distant recurrence, patients whose primary disease was progressing and who did not receive WBRT had an increased risk of distant recurrence (HR = 2.16, 95% CI 1.01-4.66, P = .05). There was no effect of WBRT based on tumor type. Adjuvant WBRT significantly reduces local and distant recurrences in subsets of patients, particularly those with metastases >3 cm or with active systemic disease.

Comparing the risks of frameless stereotactic biopsy in eloquent and noneloquent regions of the brain: a retrospective review of 284 cases.

OBJECT: Frameless stereotactic biopsy has been shown in multiple studies to be a safe and effective tool for the diagnosis of brain lesions. However, no study has directly evaluated its safety in lesions located in eloquent regions in comparison with noneloquent locations. In this study, the authors determine whether an increased risk of neurological decline is associated with biopsy of lesions in eloquent regions of the brain. METHODS: Medical records, including imaging studies, were reviewed for 284 cases in which frameless stereotactic biopsy procedures were performed by 19 neurosurgeons at 7 institutions between January 2000 and December 2006. Lesion location was classified as eloquent or noneloquent in each patient. The incidence of neurological decline was calculated for each group. RESULTS: During the study period, 160 of the 284 biopsies predominately involved eloquent regions of the brain. In evaluation of the complication rate with respect to biopsy site, neurological decline occurred in 9 (5.6%) of 160 biopsies in eloquent brain areas and 10 (8.1%) of 124 biopsies in noneloquent regions; this difference was not statistically significant (p = 0.416). A higher number of needle passes was associated with the presence of a postoperative hemorrhage at the biopsy site, although not with a change in the result of neurological examination. CONCLUSIONS: Frameless stereotactic biopsy of lesions located in eloquent brain regions is as safe and effective as biopsy of lesions in noneloquent regions. Therefore, with careful planning, frameless stereotactic biopsy remains a valuable and safe tool for diagnosis of brain lesions, independent of lesion location.

Technologic advances in surgery for brain tumors: tools of the trade in the modern neurosurgical operating room.

Surgery is an essential part of the oncologic treatment of patients with brain tumors. Surgery is necessary for histologic diagnosis, and the cytoreduction of tumor mass has been shown to improve patient survival time and quality of life. Ultimately, the goal of any oncologic neurosurgery is to achieve maximal safe resection. Over the years, many technologic adjuncts have been developed to assist the surgeon in achieving this goal. In this article, we review the technologic advances of modern neurosurgery that are helping to reach this goal.

Results of contemporary surgical management of radiation necrosis using frameless stereotaxis and intraoperative magnetic resonance imaging.

OBJECTIVE: Radiation necrosis is a well-known complication of radiotherapy for malignant brain tumors. Although surgery was once considered the mainstay of treatment, no recent reports have evaluated the use of intraoperative magnetic resonance imaging (IOMRI) and frameless stereotaxis during surgical resection of radiation necrosis. In this retrospective review, we evaluate the effectiveness of surgical resection using frameless stereotaxis and IOMRI for the treatment of radiation necrosis. METHODS: From October 1999 through February 2002, 11 patients who had malignant brain tumors underwent surgery for radiation necrosis. The diagnosis of radiation necrosis was based primarily on MRI and clinical suspicion. Frameless stereotaxis was used in all patients and IOMRI was used in nine. All patients underwent at least one radiation treatment before surgery and nine patients had multiple treatments. Patient outcome was based on changes in steroid dose, Karnofsky Performance Score (KPS), and neurologic deficit. RESULTS: Optimal resection as confirmed by IOMRI was achieved in all patients by the use of frameless stereotaxis alone; no additional resection was performed in any patient. For nine patients taking steroids (mean preoperative dose 24 mg/day) before treatment of necrosis, all had a substantial reduction in steroid dosage (mean postoperative dose 8 mg/day) after surgical treatment. Postoperatively, KPS improved in four patients, remained stable in four, and worsened in three. Three complications that resulted from surgery included wound infection, asymptomatic carotid dissection, and pulmonary embolism; thus, overall morbidity including both surgical complications and neurologic deterioration was 54%. CONCLUSIONS: In this review, frameless stereotaxis was helpful in guiding the surgeon; however, IOMRI did not provide any additional benefit for the surgical treatment of radiation necrosis. Surgical treatment of radiation necrosis was associated with high risks of complication or neurologic deficit. Given the success of medical therapies, including hyperbaric oxygen, we believe that surgical treatment of radiation necrosis should be reserved for symptomatic patients in whom medical therapy has failed.