Matthew C. Tate

Biology of angiogenesis and invasion in glioma

SummaryTreatment of adult brain tumors, in particular glioblastoma, remains a significant clinical challenge, despite modest advances in surgical technique, radiation, and chemotherapeutics. The formation of abnormal, dysfunctional tumor vasculature and glioma cell invasion along white matter tracts are believed to be major components of the inability to treat these tumors effectively. Recent insight into the fundamental processes governing glioma angiogenesis and invasion provide a renewed hope for development of novel strategies aimed at reducing the morbidity of this uniformly fatal disease. In this review, we discuss background biology of the blood brain barrier and its pertinence to blood vessel formation and tumor invasion. We will then focus our attention on the biology of glioma angiogenesis and invasion, and the key mediators of these processes. Last, we will briefly discuss recent and ongoing clinical trials targeting mediators of angiogenesis or invasion in glioma patients. The findings provide a renewed hope for those endeavoring to improve treatment of patients with glioma by providing a novel set of rational targets for translational drug discovery.

Preoperative multimodal motor mapping: a comparison of magnetoencephalography imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation.

OBJECT Direct cortical stimulation (DCS) is the gold-standard technique for motor mapping during craniotomy. However, preoperative noninvasive motor mapping is becoming increasingly accurate. Two such noninvasive modalities are navigated transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) imaging. While MEG imaging has already been extensively validated as an accurate modality of noninvasive motor mapping, TMS is less well studied. In this study, the authors compared the accuracy of TMS to both DCS and MEG imaging. METHODS Patients with tumors in proximity to primary motor cortex underwent preoperative TMS and MEG imaging for motor mapping. The patients subsequently underwent motor mapping via intraoperative DCS. The loci of maximal response were recorded from each modality and compared. Motor strength was assessed at 3 months postoperatively. RESULTS Transcranial magnetic stimulation and MEG imaging were performed on 24 patients. Intraoperative DCS yielded 8 positive motor sites in 5 patients. The median distance ± SEM between TMS and DCS motor sites was 2.13 ± 0.29 mm, and between TMS and MEG imaging motor sites was 4.71 ± 1.08 mm. In no patients did DCS motor mapping reveal a motor site that was unrecognized by TMS. Three of 24 patients developed new, early neurological deficit in the form of upper-extremity paresis. At the 3-month follow-up evaluation, 2 of these patients were significantly improved, experiencing difficulty only with fine motor tasks; the remaining patient had improvement to 4/5 strength. There were no deaths over the course of the study. CONCLUSIONS Maps of the motor system generated with TMS correlate well with those generated by both MEG imaging and DCS. Negative TMS mapping also correlates with negative DCS mapping. Navigated TMS is an accurate modality for noninvasively generating preoperative motor maps.

The long-term postsurgical prognosis of patients with pineoblastoma.

For this report, the authors comprehensively summarized the existing literature on patients with pineoblastoma and identified the variables and treatments that had an impact patient on outcomes.

Contemporary Management of Pineoblastoma

Pineoblastomas (PBs) represent the most aggressive of the pineal parenchymal tumors. Routine treatment consists of operative management of obstructive hydrocephalus and cerebrospinal fluid studies followed by maximal resection and adjuvant chemotherapy/radiotherapy, resulting in a median survival of 20 months. Important prognostic factors for survival of patients with PB include extent of resection, age at presentation, disseminated disease, and craniospinal radiotherapy. Novel strategies being evaluated for the treatment of PB include high-dose chemotherapy with autologous stem cell therapy, stereotactic radiosurgery, and histone deacetylase inhibitors.

Assessment of morbidity following resection of cingulate gyrus gliomas. Clinical article.

OBJECT The morbidity associated with resection of tumors in the cingulate gyrus (CG) is not well established. The goal of the present study is to define the short- and long-term morbidity profile associated with resection of gliomas within this region. METHODS Ninety consecutive patients with gliomas involving the CG were analyzed. Resections were classified by zones corresponding to functionally defined regions of the CG as follows: Zone I (perigenual, anterior), Zone II (midcingulate), Zone III (posterior), and Zone IV (retrosplenial). Basic demographic, imaging, operative details, and pre- and postoperative neurological examinations were recorded for each patient. Patients in whom neurological morbidity was documented during their initial postoperative examination who did not completely improve by the 6-month follow-up examination were considered to have a permanent deficit. For each patient with surgery-related morbidity, postoperative MR imaging and operative notes were reviewed, and the cortical regions incorporated in the surgical trajectory were recorded. The analysis was carried out for tumors confined to the CG (> 90% of tumor contained within the CG) as well as those involving the CG but extending into adjacent cortical structures. RESULTS Analysis of the entire patient cohort demonstrated that 29% of patients experienced a new or worsened neurological deficit immediately after surgery. The most common deficits were supplementary motor area (SMA) syndrome (20%), weakness (6%), and sensory changes (2%). All patients with an SMA syndrome in our series had intentional resection of SMA as part of the surgical approach. Patients with resections including Zone II or III had a higher rate of total morbidity and SMA syndrome than patients with Zone I resections (p < 0.05). Only 4% of patients had a persistent neurological deficit at 6 months postoperatively. A similar morbidity profile was observed in the subset analysis of patients with tumors confined to the CG, with no additional morbidity related to known cingulate-specific functions. CONCLUSIONS Resection of gliomas involving the CG can be performed with minimal, predictable long-term morbidity (< 5%). Surgical morbidity is primarily a function of surgical trajectory rather than the particular cingulate region resected.

Infected Rathke cleft cysts: distinguishing factors and factors predicting recurrence.

BACKGROUNDRathke cleft cysts (RCCs) are benign sellar lesions that are generally asymptomatic but sometimes warrant transsphenoidal drainage. Small case reports have described infected RCCs, but this phenomenon remains uncharacterized. OBJECTIVEWe reviewed RCCs over 23 years at our institution to determine factors predicting infection and recurrence. METHODSWe retrospectively reviewed the magnetic resonance images, laboratory results, microbiology, and pathology of 176 RCC patients (1985–2008) who underwent initial operation at our institution (n = 170) or at another institution followed by recurrence managed at our institution (n = 6). RESULTSThere were 3 RCC categories: cysts cultured intraoperatively during initial surgery (n = 21), cysts not cultured during initial surgery but cultured during subsequent surgery (n = 9), and cysts that were never cultured (n = 146). Cultured cysts were larger (1.6 vs 1.2 cm; P = .002) and had more frequent pituitary dysfunction (76% vs 30%; P < .001) than noncultured cysts. Restricted diffusion was also more common in cultured cysts (50% vs 0%; P = .02). Of cysts cultured at initial or subsequent surgery, 48% and 44%, respectively, had positive cultures (n = 14) and were treated with antibiotics. The most common organisms were Staphylococcus epidermidis (64%) and Propionibacterium acnes (57%). Kaplan-Meier recurrence rates were 13% (culture positive/antibiotic treated), 31% (culture negative/not antibiotic treated), and 9% (noncultured) (P = .002, cultured vs noncultured; P = .002, culture negative/not antibiotic treated vs non-cultured; P = .5 culture positive/antibiotic treated vs noncultured). CONCLUSIONSuspected RCC infection, regardless of culture results, is a strong predictor of recurrence and may warrant antibiotic treatment. With antibiotic treatment, the recurrence rate of infected RCC approaches that of noninfected cysts. The higher recurrence rates reported in other series may reflect underrecognition of occult infection.

Postnatal growth of the human pons: A morphometric and immunohistochemical analysis

Despite its critical importance to global brain function, the postnatal development of the human pons remains poorly understood. In the present study, we first performed magnetic resonance imaging (MRI)‐based morphometric analyses of the postnatal human pons (0–18 years; n = 6–14/timepoint). Pons volume increased 6‐fold from birth to 5 years, followed by continued slower growth throughout childhood. The observed growth was primarily due to expansion of the basis pontis. T2‐based MRI analysis suggests that this growth is linked to increased myelination, and histological analysis of myelin basic protein in human postmortem specimens confirmed a dramatic increase in myelination during infancy. Analysis of cellular proliferation revealed many Ki67+ cells during the first 7 months of life, particularly during the first month, where proliferation was increased in the basis relative to tegmentum. The majority of proliferative cells in the postnatal pons expressed the transcription factor Olig2, suggesting an oligodendrocyte lineage. The proportion of proliferating cells that were Olig2+ was similar through the first 7 months of life and between basis and tegmentum. The number of Ki67+ cells declined dramatically from birth to 7 months and further decreased by 3 years, with a small number of Ki67+ cells observed throughout childhood. In addition, two populations of vimentin/nestin‐expressing cells were identified: a dorsal group near the ventricular surface, which persists throughout childhood, and a parenchymal population that diminishes by 7 months and was not evident later in childhood. Together, our data reveal remarkable postnatal growth in the ventral pons, particularly during infancy when cells are most proliferative and myelination increases. J. Comp. Neurol. 523:449–462, 2015.

Surgical management of multicentric diffuse low-grade gliomas: functional and oncological outcomes

OBJECT Multicentric diffuse low-grade gliomas (DLGGs) are defined as widely separated lesions in different lobes or hemispheres where there is no anatomical continuity between lesions. This condition is rare and its clinicopathological characteristics have been scarcely described in the literature. Here, the authors report the first consecutive surgical series of multicentric DLGGs with functional and oncological outcomes. METHODS A retrospective review of patients surgically treated for histopathologically confirmed multicentric DLGGs between 2000 and 2012 was performed. Information regarding clinical features, surgical procedures, histopathological results, and clinical outcomes was collected and analyzed. RESULTS Five consecutive patients were included in this study. There were 3 men and 2 women, whose mean age was 27.4 years (range 23-35 years). The mean follow-up period after surgery was 46 months (range 11-138 months). Gross-total or subtotal resection was achieved in all cases, using a single surgery in 3 patients and a 2-stage surgery in 2 patients. There was no mortality or permanent morbidity associated with surgery. The Karnofsky Performance Scale score ranged between 90 and 100 in all cases. Adjuvant chemotherapy was administered in 2 patients because of tumor regrowth with no malignant transformation. CONCLUSIONS Multicentric DLGGs can be removed safely without inducing severe permanent neurological deficits. Interestingly, a single-stage resection of multiple lesions within different lobes may be performed if tumors are located in the same hemisphere. Therefore, the authors suggest considering surgery as the first therapeutic option for multicentric DLGGs, as in solitary DLGGs.

Safety and Efficacy of Motor Mapping Utilizing Short Pulse Train Direct Cortical Stimulation

Background/Aims: A major goal of intracranial surgery is to maximize resection while minimizing neurological morbidity, particularly motor dysfunction. Direct cortical stimulation (DCS) is a common intraoperative adjunct used to identify functional motor cortex. In this study, we report on the safety/efficacy of short pulse train DCS (direct cortical stimulation motor-evoked potential, dcMEP) for motor mapping and monitoring during intracranial surgery. Methods: A retrospective analysis of 29 patients undergoing elective craniotomy for lesions near the motor cortex was performed. dcMEP mapping (40-120 V, 500-1,000 Hz, 5-9 pulses/s, 1- to 3-ms interstimulus interval, monopolar, 50-μs pulse width) was performed either alone (n = 29) or in addition to standard DCS (n = 6). Outcome measures were positive MEPs and the presence of seizures during stimulation. dcMEP-based continuous corticospinal tract (CST) monitoring was also performed. Changes in stimulation threshold and new postoperative neurological deficits were recorded. Results: dcMEP mapping success was 96% and was not affected by preoperative motor status. Intraoperative seizure rates for dcMEP were 3% and were not related to preoperative seizure status. CST monitoring success rate was 96%, and changes in stimulation threshold were predictive of new permanent motor deficits. Conclusions: dcMEP is an effective method for mapping motor function and may prove useful for continuous CST monitoring.

Intraoperative Conversion from Endoscopic to Open Transcortical-Transventricular Removal of Colloid Cysts as a Salvage Procedure.

Objective: To describe the transcortical-transventricular as an intraoperative salvage procedure and its effect of operative time and outcome. Methods: Thirty-three patients were included in the study. Twenty patients had an endoscopic operation, five had a transcortical-transventricular approach, and eight underwent an interhemispheric approach for resection. Based on common cyst location in the roof of the third ventricle, we propose a simple classification of surgical operative zones based on relationships defined by the anterior column of the fornix, the septal vein, and the medial atrial vein. Results: Complete capsule removal was achieved in 35% of endoscopic operations, 100% of transcortical-transventricular operations, and 63% of the interhemispheric operations. Operative time was 176 minutes for endoscopic operations, whereas the operative time for cases that converted to the transcortical-transventricular approach was 190 minutes (p=0.39). Conclusion: A surgical-based classification of zones within the roof of the third ventricle that can be accessed with microsurgical techniques is proposed. Both endoscopic and microsurgical cyst aspiration and excision remain options. We believe that younger patients, patients with large cysts that fill the third ventricle, or those with recurrence after prior treatment would benefit from open transcortical excision as a safe and effective operative approach using modern image-guided systems. Consent was formally obtained or waived for all subjects present within this study.