Intraoperative MRI in Brain Tumor Surgeries

Intraoperative MRI (ioMRI) has evolved since it used in 1991. ioMRI has been effective tool not only in glioma surgeries but also in other neurosurgical procedures. It provides real time information with high quality resolution and it is not affected by brain shift. ioMRI images can be uploaded in the navigation which helps in further resection of residual tumors. ioMRI can be used for confirmation of complete excision of tumor or location of microelectrode catheter tip DBS/sterotatic biopsy. It provides valuable information like location and amount of residue which guides surgeon for further resection safely as possible. ioMRI requires specialized operation theater with MRI compatible instruments which makes this setup expensive and it is available in only few centers across the globe

PBEF1/NAmPRTase/Visfatin: a potential malignant astrocytoma/glioblastoma serum marker with prognostic value

Malignant astrocytomas comprise anaplastic astrocytoma (AA; grade III) and Glioblastoma (GBM; grade IV). GBM is the most malignant with a median survival of 10-12 months in patients. Using cDNA microarray based expression profiling of different grades of astrocytomas, we identified several fold increased levels of PBEF1 transcripts in GBM samples. Pre-B-cell colony enhancing factor 1 gene (PBEF1) encodes Nicotinamide phosphoribosyltransferase (NAmPRTase), which catalyses the rate limiting step in the salvage pathway of NAD metabolism in mammalian cells. Further validation using real time RT-qPCR on an independent set of tumor samples (n=91) and normal brain samples (n=9), GBM specific higher expression of PBEF1 was confirmed. Immunohistochemical staining for PBEF1 on a subset of the above samples largely reinforced our finding. We carried out ELISA analysis on serum samples of astrocytoma patients to determine whether this protein levels would correlate with the presence of tumor and tumor grade. PBEF1 serum levels were substantially elevated in many of the AA and GBM patients. Statistical analysis of these data indicates that in patients with astrocytoma, serum PBEF1 levels correlate with tumor grade and is highest in GBM. Immunohistochemical analysis of an independent set of 51 retrospective GBM cases with known survival data revealed that PBEF1 expression in the tumor tissue along with its co-expression with p53 was associated with poor survival. Thus, we have identified PBEF1 as a potential malignant astrocytoma serum marker and prognostic indicator among GBMs

Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis

Background: The aim of this study is to identify serum biomarkers with classification and prognosis utility for astrocytoma, in particular glioblastoma (GBM). Methods: Our previous glioma microarray database was mined to identify genes that encode secreted or membrane-localized proteins. Subsequent analysis was done using significant analysis of microarrays, followed by reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical validation in tumor tissues, ELISA and Western blot validation in sera, and correlation with survival of GBM patients. Results: Significant analysis of microarrays identified 31 upregulated and 3 downregulated genes specifically in GBMs. RT-qPCR validation on an independent set of samples confirmed the GBM-specific differential expression of several genes, including three upregulated (CALU, CXCL9, and TIMP1) and two downregulated (GPX3 and TIMP3) novel genes. With respect to osteopontin (OPN), we show the GBM-specific upregulation by RT-qPCR and immunohistochemical staining of tumor tissues. Elevated serum OPN levels in GBM patients were also shown by ELISA and Western blot. GBM patients with high serum OPN levels had poorer survival than those with low serum OPN levels (median survival 9 versus 22 months respectively; P = 0.0001). Further, we also show high serum TIMP1 levels in GBM patients compared with grade II/III patients by ELISA and downregulation of serum GPX3 and TIMP3 proteins in GBMs compared with normal control by Western blot analysis. Conclusions: Several novel potential serum biomarkers of GBM are identified and validated. High serum OPN level is found as a poor prognostic indicator in GBMs. Impact: Identified serum biomarkers may have potential utility in astrocytoma classification and GBM prognosis

Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis

Purpose: Current methods of classification of astrocytoma based on histopathologic methods are often subjective and less accurate. Although patients with glioblastoma have grave prognosis, significant variability in patient outcome is observed. Therefore, the aim of this study was to identify glioblastoma diagnostic and prognostic markers through microarray analysis. Experimental Design: We carried out transcriptome analysis of 25 diffusely infiltrating astrocytoma samples [WHO grade II - diffuse astrocytoma, grade III - anaplastic astrocytoma, and grade IV - glioblastoma (GBM)] using cDNA microarrays containing 18,981 genes. Several of the markers identified were also validated by real-time reverse transcription quantitative PCR and immunohistochemical analysis on an independent set of tumor samples (n = 100). Survival analysis was carried out for two markers on another independent set of retrospective cases (n = 51). Results: We identified several differentially regulated grade-specific genes. Independent validation by real-time reverse transcription quantitative PCR analysis found growth arrest and DNA-damage-inducible α (GADD45α) and follistatin-like 1 (FSTL1) to be up-regulated in most GBMs (both primary and secondary), whereas superoxide dismutase 2 and adipocyte enhancer binding protein 1 were up-regulated in the majority of primary GBM. Further, identification of the grade-specific expression of GADD45α and FSTL1 by immunohistochemical staining reinforced our findings. Analysis of retrospective GBM cases with known survival data revealed that cytoplasmic overexpression of GADD45α conferred better survival while the coexpression of FSTL1 with p53 was associated with poor survival. Conclusions: Our study reveals that GADD45α and FSTLI are GBM-specific whereas superoxide dismutase 2 and adipocyte enhancer binding protein 1 are primary GBM-specific diagnostic markers. Whereas GADD45α overexpression confers a favorable prognosis, FSTL1 overexpression is a hallmark of poor prognosis in GBM patients

Mixed acid-base disorder secondary to topiramate use in traumatic brain injury

We report a case of a man with traumatic brain injury. He was started on to prophylactic topiramate which led to a mixed acid-base disorder. He had severe metabolic acidosis secondary to renal tubular acidification defect and respiratory alkalosis secondary to hyperventilation. Withdrawal of the offending drug led to the prompt resolution of the acid-base disturbance

Malignant and benign ganglioglioma: A pathological and molecular study1

Gangliogliomas are generally benign tumors, composed of transformed neuronal and glial elements, with rare malignant progression of the glial component. The current study of a rare case of a woman harboring a ganglioglioma with areas of malignant transformation addresses two fundamental questions: (1) Are the ganglioglioma and its malignant component clonal in origin? (2) What are the genetic alterations associated with the initiation and subsequent malignant progression of ganglioglioma? By using the human androgen receptor gene (HUMARA) assay, we found the ganglioglioma and the malignant component to be clonal in origin, suggestive of initial transformation of a single neuroglial precursor cell with subsequent malignant progression. Conventional and array comparative genomic hybridization (approximately 2.5-Mb resolution) analyses found chromosomal losses to be predominant in the benign areas of the ganglioglioma, with gains more prevalent in the malignant component. Regions of chromosomal loss, postulated to harbor genes involved in the initiation of ganglioglioma, included 1p35-36, 2p16-15, 3q13.1-13.3, 3q24-25.3, 6p21.3-21.2, 6q24-25.2, 9p12, Xp11.3-11.22, and Xq22.1-22.3. Direct analysis demonstrated loss of p19 expression and p53 mutation in the malignant areas, highly suggestive of these alterations being involved in the malignant progression of the ganglioglioma. Additional chromosomal alterations specific to the malignancy involved gains on 1p35-34.2, 2q24.1-32.3, 3q13.1-13.3, 6q13-16.2, 7q11.2-31.3, 8q21.1-23, 11q12-31, and 12q13.2-21.3. This molecular-pathological study has provided insight into the pathogenesis of gangliogliomas and associated rare malignant progression. Deciphering the specific genes residing in these chromosomal regions may further our understanding of not only these rare tumors but also the more common gliomas

Glioblastoma multiforme after stereotactic radiotherapy for acoustic neuroma: Case report and review of the literature

Indications for the use of radiotherapy in the management of a variety of benign intracranial neoplastic and nonneoplastic pathologies are increasing. Although the short-term risks are minimal, the long-term risks of radiation-induced de novo secondary neoplasms or malignant progression of the primary benign tumor need to be considered. There are currently 19 reported cases of tumors linked with stereotactic radiotherapy/radiosurgery, to which we add our second institutional experience of a patient who succumbed to a glioblastoma multiforme (GBM) after stereotactic radiotherapy for an acoustic neuroma (AN). Review of these 20 cases revealed 10 de novo secondary tumors, of which eight were malignant, with six being malignant gliomas. The majority of the cases (14 of 20) involved AN, with most being in patients with neurofibromatosis-2 (NF2; 8 of 14), reflecting the large numbers and long-term use of radiotherapy for AN. Accelerated growth of the primary benign AN, some 2 to 6 years after focused radiotherapy, was found in six of eight NF2 patients, with pathological verification of a malignant nerve sheath tumor documented in most. The exact carcinogenic risk after radiotherapy is unknown but likely extremely low. However, the risk is not zero and requires discussion with the patient, with specific consideration in young patients and those with a cancer predisposition

Adjunctive Benefit of High-Field 3 Tesla MRI Guidance in Endoscopic Transsphenoidal Resection of Pituitary Adenoma

Introduction Pituitary adenomas (PAs) although benign, are difficult to resect intracranial tumors and their residues are associated with morbidity and reduced quality of life. Thus, gross total resection (GTR) is the goal for all PAs. Role of various modalities for better intraoperative visualization and thus improve resection of adenoma have been tested and each have their pros and cons. The aim of this paper is to analyze adjunctive benefit of high-field 3 Tesla intraoperative magnetic resonance imaging (iMRI) in PAs resection by endoscopic transnasal transsphenoidal surgery (eTSS). Materials and Methods A total of 50 patients who underwent iMRI-guided eTSS were included. MRI findings in preoperative, intraoperative, and 3 months postoperative stage were compared. Adjunctive value of iMRI in improving resection rates of adenoma, postoperative endocrinological outcomes, need for adjuvant radiotherapy, and postoperative cerebrospinal fluid leak rates was assessed. Results High-field 3 Tesla iMRI helped us to detect residues in 24 (48%) patients and iMRI-guided second look surgery increased our GTR rates from initial 52 to 80% and also helped us to identify and achieve 100% GTR in intrasellar residues and parasellar residues that were medial to medial carotid tangential line. With better resection rates, need for adjuvant radiotherapy was also reduced and only 2% received adjuvant radiotherapy. Average increase in surgical time with the use of iMRI was 38.78 minutes without any side effects pertaining to prolonged surgery. Conclusion High-field iMRI is a useful adjunct in assessment and improvement in extent of resection of PA by endoscopic transsphenoidal surgery. Also, it was found beneficial in preserving normal anatomical gland and, thus, reducing the need for postoperative adjuvant hormonal and radiation therapy

Differential Expression Of Igfbp Isoforms In Astrocytoma: Prognostic Value Of Igfbp-2,-3, And-5 In Glioblastoma Patients

Insulin-like growth factor binding proteins (IGFBP) are known to modulate the actions of insulin-like growth factors (IGF) mainly by controlling the amount of free IGF that can bind to its receptors. IGFBP are also known to regulate cell survival in an IGF-independent pathway. However, they can have a complex bidirectional effect on tumorigenesis. Among the various IGFBP, the expression and role of IGFBP2 in gliomas has been extensively studied. In an earlier gene-expression profiling study on the various grades of astrocytoma, we identified the upregulation of IGFBP-2, - 5, and -7 in glioblastoma tumors. In order to establish a role for all the IGFBP isoforms in the progression and prognosis of astrocytoma, we analyzed the gene expressions of IGFBP-1 to –5, -7 to -10, and -L1 by real-time quantitative polymerase chain reaction (RT-PCR) and IGFBP-2, -3, -4, -5, and -7 by immunohistochemistry (IHC) in a cohort of 50 diffusely infiltrating astrocytoma tissues. There were greater than two-fold upregulations in the transcript levels of IGFBP-2, -3, and -4 and in the majority of glioblastomas (GBM) relative to anaplastic astrocytomas (AA). On the other hand, IGFBP-5 and -7 were upregulated in the majority of malignant astrocytomas (AA and GBM). In contrast to these observations, IGFBP-9 transcript levels were found to be downregulated in both AA and GBM tumors. Overexpression of IGFBP -2, -3, -4, –5, and -7 was observed by IHC maximally in the tumor cells of GBM. Notably, we found that in an independent set of GBM patients, expression of IGFBP-2 alone and coexpression of IGFBP-2 and -5 in the tumor were indicative of shorter survival. In addition, when IGFBP-3 coexpressed with epidermal growth factor receptor, it indicated shorter patient survival. Our study suggested associations between IGFBP-2, -3, -4, -5, and -7 and malignant transformation in diffusely infiltrating astrocytomas, with maximal expression in GBM. We also showed that overexpression of IGFBP-2, -3, and -5 isoforms portended poor prognosis in GBM patients