Dual-Use Intraoperative MRI in Glioblastoma Surgery: Results of Resection, Histopathologic Assessment, and Surgical Site Infections.

BACKGROUND: To achieve maximal resection in glioblastoma (GBM) surgery, intraoperative imaging is important. An intraoperative magnetic resonance imaging (iMRI) suite used for both diagnostic and intraoperative imaging is considered being a reasonable concept for modern hospital management. It is still discussed if the dual use increases the risk of surgical site infections (SSI). This article assesses the rate of gross total resection (GTR), extent of resection (EOR), and histopathology after iMRI-guided resections in patients with GBM. The rate of surgical site infections (SSIs) is evaluated. METHODS: In all, 79 patients with GBM were operated on with iMRI. Additional resection was performed if iMRI depicted contrast enhancing tissue suggestive of residual tumor. GTR and EOR were determined by segmentation and volumetric analysis of the MR images. SSIs and the role of intravenous only or intravenous plus intrathecal antibiotics were evaluated. Statistical analysis was performed to detect the sensitivity, specificity, positive predictive value, and negative predictive value of iMRI-guided extended resections. Pearson's two-tailed chi-square test was performed to evaluate the rates of GTR and variables associated with SSI. RESULTS: GTR was achieved in 59 patients (74.68%). Rate of GTR was 35.44% before iMRI and additional resections (p < 0.0001). Mean EOR was 96.27%. Positive predictive value for tumor cells in the additionally resected tissue was 88.6%, negative predictive value was 100%, sensitivity was 100%, and specificity was 70. 6%. Rate of SSIs was 5.06% (n = 4). Two superficial SSIs, one subdural empyema and one cerebritis, were seen. SSI rates with parenteral only and additional intrathecal antibiotics were 0% and 8%, respectively (p = 0.133). CONCLUSION: Increase of extent of tumor resection using iMRI is evident. SSI rate is within the normal range of neurosurgical procedures. A dual-use iMRI suite is a safe concept.

Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature.

In malignant gliomas, the integrin adhesion receptors seem to play a key role for invasive growth and angiogenesis. However, there is still a controversy about the expression and the distribution of alpha(v)beta(3) integrin caused by malignancy. The aim of our study was to assess the extent and pattern of alpha(v)beta(3) integrin expression within primary glioblastomas (GBMs) compared with low-grade gliomas (LGGs). Tumor samples were immunostained for the detection of alpha(v)beta(3) integrin and quantified by an imaging software. The expression of alpha(v)beta(3) was found to be significantly higher in GBMs than in LGGs, whereby focal strong reactivity was restricted to GBMs only. Subsequent analysis revealed that not only endothelial cells but also, to a large extent, glial tumor cells contribute to the overall amount of alpha(v)beta(3) integrin in the tumors. To further analyze the integrin subunits, Western blots from histologic sections were performed, which demonstrated a significant difference in the expression of the beta(3) integrin subunit between GBMs and LGGs. The presented data lead to new insights in the pattern of alpha(v)beta(3) integrin in gliomas and are of relevance for the inhibition of alpha(v)beta(3) integrin with specific RGD peptides and interfering drugs to reduce angiogenesis and tumor growth.

Congestion of epidural venous plexus secondary to vertebral artery occlusion mimicking a herniated cervical disc.

Vascular abnormalities or dissection of the vertebral artery are rare causes for cervical monoradiculopathy. We present the case of a 44-year-old female patient with a short history of radiculopathy of the right C5 root with radicular pain and a severe motor deficit. CT-imaging showed a hyperdense structure at the C4/C5 level suggesting a herniated disc. Because of the neurological deficit the patient was operated by a dorsal approach. Intraoperatively no herniated disc but only a congested epidural venous plexus was found. Postoperative MRI and angiography showed occlusion of the vertebral artery from C3 to C6 level probably due to dissection. The present case shows that a CT-study suggestive for a herniated disc can be misleading. Enlargement of the vertebral artery secondary to dissection or occlusion may lead to compression of the venous plexus which resembles disc material on CT-scan.

Accuracy of High-Field Intraoperative MRI in the Detectability of Residual Tumor in Glioma Grade IV Resections.

Objective To assess the sensitivity/specificity of tumor detection by T1 contrast enhancement in intraoperative MRI (ioMRI) in comparison to histopathological assessment as the gold standard in patients receiving surgical resection of grade IV glioblastoma. Materials and Methods 68 patients with a primary or a recurrent glioblastoma scheduled for surgery including fluorescence guidance and neuronavigation were included (mean age: 59 years, 26 female, 42 male patients). The ioMRI after the first resection included transverse FLAIR, DWI, T2-FFE and T1 - 3 d FFE +/- GD-DPTA. The second resection was performed whenever residual contrast-enhancing tissue was detected on ioMRI. Resected tissue samples were histopathologically evaluated (gold standard). Additionally, we evaluated the early postoperative MRI scan acquired within 48 h post-OP for remaining enhancing tissue and compared them with the ioMRI scan. Results In 43 patients ioMRI indicated residual tumorous tissue, which could be confirmed in the histological specimens of the second resection. In 16 (4 with recurrent, 12 with primary glioblastoma) cases, ioMRI revealed truly negative results without residual tumor and follow-up MRI confirmed complete resection. In 7 cases (3 with recurrent, 4 with primary glioblastoma) ioMRI revealed a suspicious result without tumorous tissue in the histopathological workup. In 2 (1 for each group) patients, residual tumorous tissue was detected in spite of negative ioMRI. IoMRI had a sensitivity of 95 % (94 % recurrent and 96 % for primary glioblastoma) and a specificity of 69.5 % (57 % and 75 %, respectively). The positive predictive value was 86 % (84 % for recurrent and 87 % for primary glioblastoma), and the negative predictive value was 88 % (80 % and 92 %, respectively). Conclusion ioMRI is effective for detecting remaining tumorous tissue after glioma resection. However, scars and leakage of contrast agent can be misleading and limit specificity. Key points · Intraoperative MRI (ioMRI) presents with a high sensitivity for residual contrast-enhancing tumorous tissue during glioma resection.. · Contrast leakage due to bleeding and scars with reactive contrast enhancement can cause possible misleading artifacts in ioMRI, leading to a limited specificity of ioMRI.. · Bleeding control in glioma resection is crucial for successful usage of ioMRO for glioma resection.. Citation Format · Heßelmann V, Mager A, Goetz C et al. Accuracy of High-Field Intraoperative MRI in the Detectability of Residual Tumor in Glioma Grade IV Resections. Fortschr Röntgenstr 2017; 189: 519 - 526.

Long-term outcome of patients with WHO Grade III and IV gliomas treated by fractionated intracavitary radioimmunotherapy.

OBJECT: The aim in this study was to present long-term results regarding overall survival (OS), adverse effects, and toxicity following fractionated intracavitary radioimmunotherapy (RIT) with iodine-131- or yttrium-90-labeled anti-tenascin monoclonal antibody ((131)I-mAB or (90)Y-mAB) for the treatment of patients with malignant glioma. METHODS: In 55 patients (15 patients with WHO Grade III anaplastic astrocytoma [AA] and 40 patients with WHO Grade IV glioblastoma multiforme [GBM]) following tumor resection and conventional radiotherapy, radioimmunoconjugate was introduced into the postoperative resection cavity. Patients received 5 cycles of (90)Y-mAB (Group A, average dose 18 mCi/cycle), 5 cycles of (131)I-mAB (Group B, average dose 30 mCi/cycle), or 3 cycles of (131)I-mAB (Group C, 50, 40, and 30 mCi). RESULTS: Median OS of patients with AA was 77.2 months (95% CI 30.8 to > 120). Five AA patients (33%) are currently alive, with a median observation time of 162.2 months. Median OS of all 40 patients with GBM was 18.9 months (95% CI 15.8-25.3), and median OS was 25.3 months (95% CI18-30) forthose patients treated with the (131)I-mAB. Three GBM patients are currently alive. One-, 2-, and 3-year survival probabilities were 100%, 93.3%, and 66.7%, respectively, for AA patients and 82.5%, 42.5%, and 15.9%, respectively, for GBM patients. Restratification of GBM patients by recursive partitioning analysis (RPA) Classes III, IV, and V produced median OSs of 31.1, 18.9, and 14.5 months, respectively (p = 0.004), which was higher than expected. Multivariate analysis confirmed the role of RPA class, age, and treatment in predicting survival. No Grade 3 or 4 hematological, nephrologic, or hepatic toxic effects were observed; 4 patients developed Grade 3 neurological deficits. Radiological signs of radionecrosis were observed in 6 patients, who were all responding well to steroids. CONCLUSIONS: Median OS of GBM and AA patients treated with (131)I-mABs reached 25.3 and 77.2 months, respectively, thus markedly exceeding that of historical controls. Adverse events remained well controllable with the fractionated dosage regimen.

5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging.

BACKGROUND: 5-Aminolevulinic acid is used for fluorescence-guided resections. During resection, different macroscopic fluorescence qualities ("strong," "weak") can be distinguished that help guide resections. OBJECTIVE: This prospective study was designed to assess the reliability of visible fluorescence qualities by spectrometry, pathology, and imaging. METHODS: Thirty-three patients with malignant gliomas received 5-aminolevulinic acid (20 mg/kg). After debulking surgery, standardized biopsies were obtained from tissues with "weak" and "strong" fluorescence and from nonfluorescing near and distant brain for blinded assessment of cell density and tissue type (necrosis, solid or infiltrating tumor, normal tissue). The positive predictive value was calculated. Unresected fluorescing tissue was navigated for blinded correlation to postoperative magnetic resonance imaging (MRI). Receiver operating characteristic curves were generated for assessing the classification efficiency of spectrometry. RESULTS: "Strong" fluorescence corresponded to greater spectrometric fluorescence, solidly proliferating tumor, and high cell densities, whereas "weak" fluorescence corresponded to lower spectrometric fluorescence, infiltrating tumor, and medium cell densities. The positive predictive value was 100% in strongly fluorescing tissue and 95% in weakly fluorescing tissue. Spectrometric fluorescence was detected in marginal tissue without macroscopic fluorescence. Depending on the threshold, spectrometry displayed greater sensitivity but lower specificity (accuracy 88.4%). Residual MRI enhancement in the tumor bed was detected in 15 of 23 (65%) patients with residual fluorescence, but in none of the patients without residual fluorescence. CONCLUSION: Macroscopic fluorescence qualities predict solid and infiltrating tumor, providing useful information during resection. Fluorescence appears superior to contrast enhancement on MRI for indicating residual tumor. Spectrometry, on the other hand, is more sensitive but less specific, depending on threshold definition. ABBREVIATIONS: 5-ALA, 5-aminolevulinic acidCI, confidence intervalgamma-GT, gamma-glutamyl transpeptidaseGBM, glioblastoma multiformeNPV, negative predictive valuePPIX, protoporphyrin IXPPV, positive predictive valueSD, standard deviationWHO, World Health Organization.

Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article.

OBJECT: Accumulating data suggest more aggressive surgery in patients with malignant glioma to improve outcome. However, extended surgery may increase morbidity. The randomized Phase III 5-aminolevulinic acid (ALA) study investigated 5-ALA-induced fluorescence as a tool for improving resections. An interim analysis demonstrated more frequent complete resections with longer progression-free survival (PFS). However, marginal differences were found regarding neurological deterioration and the frequency of additional therapies. Presently, the authors focus on the latter aspects in the final study population, and attempt to determine how safety might be affected by cytoreductive surgery. METHODS: Patients with malignant gliomas were randomized for fluorescence-guided (ALA group) or conventional white light (WL) (WL group) microsurgery. The final intent-to-treat population consisted of 176 patients in the ALA and 173 in the WL group. Primary efficacy variables were contrast-enhancing tumor on early MR imaging and 6-month PFS. Among secondary outcome measures, the National Institutes of Health Stroke Scale (NIH-SS) score and the Karnofsky Performance Scale (KPS) score were used for assessing neurological function. RESULTS: More frequent complete resections and improved PFS were confirmed, with higher median residual tumor volumes in the WL group (0.5 vs 0 cm(3), p = 0.001). Patients in the ALA group had more frequent deterioration on the NIH-SS at 48 hours. Patients at risk were those with deficits unresponsive to steroids. No differences were found in the KPS score. Regarding outcome, a combined end point of risks and neurological deficits was attempted, which demonstrated results in patients in the ALA group to be superior to those in participants in the WL group. Interestingly, the cumulative incidence of repeat surgery was significantly reduced in ALA patients. When stratified by completeness of resection, patients with incomplete resections were quicker to deteriorate neurologically (p = 0.0036). CONCLUSIONS: Extended resections performed using a tool such as 5-ALA-derived tumor fluorescence, carries the risk of temporary impairment of neurological function. However, risks are higher in patients with deficits unresponsive to steroids.

Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography.

Inhibitors targeting the integrin alpha(v)beta(3) are promising new agents currently tested in clinical trials for supplemental therapy of glioblastoma multiforme (GBM). The aim of our study was to evaluate (18)F-labeled glycosylated Arg-Gly-Asp peptide ([(18)F]Galacto-RGD) PET for noninvasive imaging of alpha(v)beta(3) expression in patients with GBM, suggesting eligibility for this kind of additional treatment. Patients with suspected or recurrent GBM were examined with [(18)F]Galacto-RGD PET. Standardized uptake values (SUVs) of tumor hotspots, galea, and blood pool were derived by region-of-interest analysis. [(18)F]Galacto-RGD PET images were fused with cranial MR images for image-guided surgery. Tumor samples taken from areas with intense tracer accumulation in the [(18)F]Galacto-RGD PET images and were analyzed histologically and immunohistochemically for alpha(v)beta(3) integrin expression. While normal brain tissue did not show significant tracer accumulation (mean SUV, 0.09 +/- 0.04), GBMs demonstrated significant but heterogeneous tracer uptake, with a maximum in the highly proliferating and infiltrating areas of tumors (mean SUV, 1.6 +/- 0.5). Immunohistochemical staining was prominent in tumor microvessels as well as glial tumor cells. In areas of highly proliferating glial tumor cells, tracer uptake (SUVs) in the [(18)F]Galacto-RGD PET images correlated with immunohistochemical alpha(v)beta(3) integrin expression of corresponding tumor samples. These data suggest that [(18)F] Galacto-RGD PET successfully identifies alpha(v)beta(3) expression in patients with GBM and might be a promising tool for planning and monitoring individualized cancer therapies targeting this integrin.

Positron emission tomography with O-(2-[18F]fluoroethyl)-l-tyrosine versus magnetic resonance imaging in the diagnosis of recurrent gliomas.

OBJECTIVE: New treatment modalities are available for patients with glioma, which may lead to unspecific changes in posttherapeutic magnetic resonance imaging (MRI) findings. Differentiation between tumor- and therapy-associated contrast enhancement on MRI scans after treatment may be difficult. The aim of this study was to analyze the diagnostic value of O-(2-[F]fluoroethyl)-l-tyrosine (FET)-positron emission tomography (PET) and MRI in the detection of tumor recurrence in patients with glioma after radiotherapy, radiosurgery, or multimodal treatment. METHODS: The study included 36 patients with gliomas and neuroradiological diagnosis of tumor recurrence and 9 patients who had undergone radioimmunotherapy. Patients were consecutively treated between September 2001 and May 2003. A contemporary FET-PET investigation was performed in all patients. A tissue diagnosis was made for comparative analysis in all patients with progressive neuroradiological or clinical findings (32 of 45 patients). In patients with transient neuroradiological or clinical deterioration (13 of 45 patients), clinical follow-up was used to support or contradict the imaging-based diagnosis. RESULTS: Tumor recurrence was documented in 31 of 45 patients, and 14 of 45 patients were tumor free. FET-PET and MRI revealed a correct diagnosis in 44 and 36 patients, respectively. The difference was statistically significant (P < 0.01). Concordant findings after MRI and FET-PET were documented in 37 patients and discordant findings in 8 patients. The difference was statistically significant (P < 0.01). Specificity of FET-PET was 92.9%, and sensitivity was 100% (in patients suspected of having recurrent tumor as revealed by MRI). Sensitivity of MRI was 93.5%, and specificity was 50% (P < 0.05). CONCLUSION: For patients with gliomas undergoing multimodal treatment or various forms of irradiation, conventional follow-up with MRI is insufficient to distinguish between benign side effects of therapy and tumor recurrence. FET-PET is a powerful tool to improve the differential diagnosis in these patients.

Distribution of labelled anti-tenascin antibodies and fragments after injection into intact or partly resected C6-gliomas in rats.

INTRODUCTION: For treatment of malignant glioma, radioimmunotherapy has become a valuable alternative for more than 2 decades. Surprisingly, very little is known about the distribution of intralesionally administered labelled antibodies or fragments. We investigated the migration of labelled antibodies and antibody fragments injected into intact and partly resected C6-glioma in rats at different times after injection. MATERIALS AND METHODS: Nine days after induction of a C6-glioma, 5 microl of 125I-labelled murine anti-tenascin antibodies (n = 31) or 125I-labelled fragments of anti-tenascin antibodies (n = 32) was injected slowly into the tumour (group I). In group II the tumour was subtotally resected 9 days after induction of the C6-glioma, and 24 h later the labelled antibodies (n = 30) or fragments (n = 12) were injected into the resection cavity. At 6, 24 or 48 h after the injection, animals were sacrificed, and brains removed. Distribution of labelled antibodies and fragments was determined by superimposing autoradiographs onto frozen sections and HE-stained neighbouring sections using a digital image analysing system. RESULTS: After injection into intact C6-glioma, labelled antibodies covered a maximum distance of 3.2 +/- 1.0, 4.1 +/- 1.9 and 4.8 +/- 0.9 mm after 6, 24 and 48 h, respectively; while labelled fragments were found at a distance of 6.7 mm (+/-1.1) after 24 h and 5.8 mm (+/-0.9) after 48 h (significant in univariate analysis). Following partial tumour resection, the respective distances at 24 h were 3 +/- 0.4 mm for anti-tenascin antibodies and 3.4 +/- 0.3 mm for Fab fragments. CONCLUSION: After injection into C6-glioma, labelled fragments are able to cover a greater distance than labelled antibodies. Injection of antibodies and fragments 1 day after tumour resection results in reduced velocity of both antibodies and fragments.

Mixed malignant germ cell tumour of the lateral ventricle in an 8-month-old girl: case report and review of the literature.

CASE REPORT: We report a huge intracerebral malignant germ cell tumour (GCT) which appeared in the lateral ventricles of an 8-month-old girl. Due to extensive tumour vascularisation only partial resection was achieved. Histology revealed an embryonal carcinoma mixed with a teratoma. The MIB-1 staining index was >20%. Chemotherapy induced a marked regression of the tumour. After chemotherapy complete resection of the tumour remnant was easily achieved. Histology showed only mesenchymal differentiated tumour tissue and the embryonal carcinoma could no longer be detected. More than 2 years after the second operation and 31 months after diagnosis the child remains tumour-free. CONCLUSION: The majority of cranial mixed malignant GCTs affects patients older than 4 years of age. To our knowledge this is the youngest patient in whom an intracranial malignant GCT containing an embryonal carcinoma has been diagnosed and successfully treated.

Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries.

Medulloblastoma is an embryonal childhood malignancy with poor prognosis. By screening 4 medulloblastoma cDNA expression libraries (SEREX) with autologous sera, 15 different antigens were identified. These antigens were encoded by 3 novel genes, genes of unknown function (KIAA0445, KIAA1853, KIAA0665, FLJ13942, HSPC213), a proto-oncogene (rab18), candidate tumor suppressor genes (BAP1, PRDM13) and genes encoding a motor protein (kinesin-2), a histone (H2A1.2), the ankyrin residue-rich nasopharyngeal cancer susceptibility protein (NZ16) and the transcription factor TZP, which is homologous to the tumor-associated antigens HCA58 and GLEA2. In a consecutive analysis of serum antibody titers and tumor load, a more than 10-fold increase in serum antibodies against PRDM13 preceded the clinical diagnosis of recurrent tumor growth in a patient with aggressive large cell medulloblastoma. When sera of pediatric patients with cancer (n = 40) and healthy controls (n = 40) were tested for humoral responses against the SEREX-defined antigens, 5 antigens were exclusively recognized by sera from cancer patients. These antigens included a novel rab18 gene product translated from mRNA sequences formerly described as 3' untranslated region. Humoral responses against 2 of the remaining 10 antigens were found preferentially in cancer patients. Antibodies against these antigens were detected in 8/40 and 12/40 cancer patients, respectively, but in only 1 healthy control. The 2 antigens were characterized by a tumor-specific deletion and a tumor-specific mutation, respectively. These findings indicate that the humoral immune response against medulloblastoma is directed against diverse antigens that may be useful as diagnostic markers or targets for immunotherapy.