Tumor-brain Interface Research Articles

Preoperative radiologic classification of convexity meningioma to predict the survival and aggressive meningioma behavior.

BackgroundA subgroup of meningioma demonstrates clinical aggressive behavior. We set out to determine if the radiological parameters can predict histopathological aggressive meningioma, and propose a classification to predict survival and aggressive meningioma behavior.MethodsA retrospective review of medical records was conducted for patients who underwent surgical resection of their convexity meningioma. WHO-2007 grading was used for histopathological diagnosis. Preoperative radiologic parameters were analyzed, each parameter was scored 0 or 1. Signal intensity on diffusion weighted MRI (DWI) (hyperintensity=1), heterogeneity on T1-weighted gadolinium enhanced MRI (heterogeneity=1), disruption of arachnoid at brain-tumor interface=1and peritumoral edema (PTE) on T2-weighted MRI (presence of PTE=1) and tumor shape (irregular shape=1). Multivariate logistic regression analyses were conducted to determine association of radiological parameters to histopathological grading. Kaplan-Meier and Cox regression models were used to determine the association of scoring system to overall survival and progression free survival (PFS). Reliability of the classification was tested using Kappa co-efficient analysis.ResultsHyperintensity on DWI, disruption of arachnoid at brain-tumor interface, PTE, heterogenicitiy on T1-weighted enhanced MRI and irregular tumor shape were independent predictors of non-grade I meningioma. Mean follow-up period was 94.6 months (range, 12-117 months). Median survival and PFS in groups-I, II and III was 114.1±1.2 and 115.7± 0.8, 88± 3.3 and 58.5±3.9, 43.2± 5.1 and 18.2±1.7 months respectively. In cox regression analysis model, age (P<0.0001, OR–1.039, CI-1.017-0.062), WHO non-grade-I meningioma (P=0.017, OR–3.014, CI-1.217-7.465), radiological classification groups II (P=0.002, OR–6.194, CI–1.956-19.610) and III (P<0.0001, OR–21.658, CI–5.701-82.273) were independent predictors of unfavorable survival outcomes.ConclusionsPreoperative radiological classification can be used as a supplement to the histopathological grading. Group-I meningiomas demonstrate benign radiological, histopathological and clinical features; group-III demonstrates aggressive features. Group-II meningiomas demonstrate intermediate features; the need for more aggressive follow-up and/or treatment should be further investigated.

Phosphorylation of NMDA 2B at S1303 in human glioma peritumoral tissue: implications for glioma epileptogenesis.

Peritumoral seizures are an early symptom of a glioma. To gain a better understanding of the molecular mechanism underlying tumor-induced epileptogenesis, the authors studied modulation of the N-methyl-d-aspartate (NMDA) receptor in peritumoral tissue. To study the possible etiology of peritumoral seizures, NMDA receptor expression, posttranslational modification, and function were analyzed in an orthotopic mouse model of human gliomas and primary patient glioma tissue in which the peritumoral border (tumor-brain interface) was preserved in a tissue block during surgery. The authors found that the NMDA receptor containing the 2B subunit (NR2B), a predominantly extrasynaptic receptor, is highly phosphorylated at S1013 in the neurons located in the periglioma area of the mouse brain. NR2B is also highly phosphorylated at S1013 in the neurons located in the peritumoral area from human brain tissue containing a glioma. The phosphorylation of the extrasynaptic NMDA receptor increases its permeability for Ca(2+) influx and subsequently mediates neuronal overexcitation and seizure activity. These data suggest that overexcitation of the extrasynaptic NMDA receptors in the peritumoral neurons may contribute to the development of peritumoral seizures and that the phosphorylated NR2B may be a therapeutic target for blocking primary brain tumor-induced peritumoral seizures.

O04 * DIFFUSION WEIGHTED MRI DISCRIMINATES PRIMARY CANCER TYPE AND OUTCOME IN BRAIN METASTASES

INTRODUCTION: Diffusion weighted MRI (DWI) is a powerful technique for non-invasive assessment of many solid cancers. We investigated whether pre-operative DWI characteristics of cerebral metastases correlate with patient outcomes. METHOD: Retrospective analysis of 76 metastases with DWI performed pre-operatively at 1.5T. Apparent Diffusion Coefficient (ADC) maps were generated and measurements were taken from the tumour, peritumoral region, across the brain-tumour interface (ADC transition coefficient or (ATC)) and in normal white matter. Outcome measures were overall survival (OS) and time to local recurrence (PFS). Tissue was assessed to determine cellularity. RESULTS: ADC changes in the tumour and peritumoral region differed between metastases of different primaries. Metastases with higher tumour ADC values were associated with longer OS and PFS. This was also demonstrated in the most common brain metastasis, lung adenocarcinoma (n = 36). Tumours with a sharp change in ADC across their boundary (high ATC) had a significantly shorter OS, 6.8 months (95% CI 5.3 - 8.4) as compared to those with a low ATC and hence diffuse boundary (11.2 months, 95% CI 8.3 - 14.0, Log rank Chi-Square = 4.19, p = 0.041). The ATC was the only imaging metric which independently predicted overall survival in multivariate analysis (hazard ratio 0.54, 95% CI 0.3 - 0.97, p = 0.04). Cellularity was positively related to ATC and inversely related to tumour ADC. CONCLUSION: DWI demonstrates changes in the tumour, tumour edge and peritumoral region which are not visible on routine MRI. ADC maps could be used to predict patient outcomes more accurately and plan surgical margins or stereotactic radiosurgery fields.

Correlation between magnetic resonance imaging grading and pathological grading in meningioma.

This study investigated the specific preoperative MRI features of patients with intracranial meningiomas that correlate with pathological grade and provide appropriate preoperative planning. From 2006 to 2012, 120 patients (36 men and 84 women, age range 20-89 years) with newly diagnosed symptomatic intracranial meningiomas undergoing resection were retrospectively analyzed in terms of radiological features of preoperative MRI. There were 90 WHO Grade I and 30 WHO Grade II or III meningiomas. The relationships between MRI features and WHO histopathological grade were analyzed and scored quantitatively. According to the results of multivariate logistic regression analysis, age ≥ 75 years, indistinct tumorbrain interface, positive capsular enhancement, and heterogeneous tumor enhancement were identified factors in the prediction of advanced histopathological grade. The prediction model was quantified as a scoring scale: 2 × (age) + 5 × (tumor-brain interface) + 3 × (capsular enhancement) + 2 × (tumor enhancement). The calculated score correlated positively with the probability of high-grade meningioma. This scoring approach may be useful for clinicians in determining therapeutic strategy and in surgical planning for patients with intracranial meningiomas.

Diffusion-weighted MRI characteristics of the cerebral metastasis to brain boundary predicts patient outcomes.

BackgroundDiffusion-weighted MRI (DWI) has been used in neurosurgical practice mainly to distinguish cerebral metastases from abscess and glioma. There is evidence from other solid organ cancers and metastases that DWI may be used as a biomarker of prognosis and treatment response. We therefore investigated DWI characteristics of cerebral metastases and their peritumoral region recorded pre-operatively and related these to patient outcomes.MethodsRetrospective analysis of 76 cases operated upon at a single institution with DWI performed pre-operatively at 1.5T. Maps of apparent diffusion coefficient (ADC) were generated using standard protocols. Readings were taken from the tumor, peritumoral region and across the brain-tumor interface. Patient outcomes were overall survival and time to local recurrence.ResultsA minimum ADC greater than 919.4 × 10-6 mm2/s within a metastasis predicted longer overall survival regardless of adjuvant therapies. This was not simply due to differences between the types of primary cancer because the effect was observed even in a subgroup of 36 patients with the same primary, non-small cell lung cancer. The change in diffusion across the tumor border and into peritumoral brain was measured by the “ADC transition coefficient” or ATC and this was more strongly predictive than ADC readings alone. Metastases with a sharp change in diffusion across their border (ATC >0.279) showed shorter overall survival compared to those with a more diffuse edge. The ATC was the only imaging measurement which independently predicted overall survival in multivariate analysis (hazard ratio 0.54, 95% CI 0.3 – 0.97, p = 0.04).ConclusionsDWI demonstrates changes in the tumor, across the tumor edge and in the peritumoral region which may not be visible on conventional MRI and this may be useful in predicting patient outcomes for operated cerebral metastases.

Magnetic resonance imaging findings of intracranial papillary meningioma: a study on eight cases

ObjectivesTo increase the awareness on intracranial papillary meningiomas (PMs) by presenting magnetic resonance imaging (MRI) findings on this disease. Materials and methodsThe MRI findings and clinical presentations of nine discrete lesions in eight patients with pathologically documented PMs were retrospectively analyzed. ResultsMost tumors occurred in young adults. The tumors originated from the convexity meninges in five cases and from the parasagittal regions in four cases. The tumor shape was irregular in six cases, lobulated in two cases, and round in one case. By MRI, nine masses were primarily isointense (n=5) or mildly hypointense (n=4) to gray matter on T1-weighted images and inhomogeneous hyperintense (n=3) or isointense (n=6) to the cortex on T2-weighted and fluid-attenuated inversion recovery images. On diffusion-weighted imaging, the signal intensity of the tumor was increased in all lesions compared with the adjacent parenchyma. Tumor and brain interfaces were unclear in seven cases, cyst formation was observed in eight tumors, scattered hemorrhage was observed in three tumors, signal voids due to vessels were visible in four cases, and eight tumors had moderate or marked irregular peritumoral edema. Enhancement was homogeneous (n=2) or heterogeneous (n=7), an area of focal nodular enhancement was observed in three lesions, and the dural tail sign was visible in seven cases. ConclusionAlthough PM is rare, it should be considered in the differential diagnosis when evaluating intracranial neoplasms. Younger patient age, as well as imaging features such as unclear tumor–brain interface, internal heterogeneity including cyst formation, irregular enhancement, signal voids of vessels, and marked peritumoral edema can help distinguish PM from typical benign meningiomas.

Molecular susceptibility weighted imaging of the glioma rim in a mouse model

Glioma is the most common and most difficult to treat brain cancer. Despite many efforts treatment, efficacy remains low. As neurosurgical removal is the standard procedure for glioma, a method, allowing for both early detection and exact determination of the location, size and extent of the tumor, could improve a patient's positive response to therapy. We propose application of susceptibility weighted molecular magnetic resonance imaging using, targeted contrast agents, based on superparamagnetic iron oxide nanoparticles, for imaging of the, glioma rim, namely brain-tumor interface. Iron oxide attached to the targeted cells increases, susceptibility differences at the boundary between tumor and normal tissue, providing the opportunity, to utilize susceptibility weighted imaging for improved tumor delineation. We investigated potential, enhancement of the tumor-brain contrast, including tumor core and rim when using susceptibility, weighted MRI for molecular imaging of glioma. There were significant differences in contrast-to-noise ratio before, 12 and 120min after contrast, agent injection between standard gradient echo pulse sequence and susceptibility weighted molecular, magnetic resonance imaging for the core-brain, tumor rim-core and tumor rim-brain areas. Currently, the most common MRI contrast agent used for glioma diagnosis is a non-specific, gadolinium-based agent providing T1-weighted enhancement. Susceptibility-weighted magnetic, resonance imaging is much less efficient when no targeted superparamagnetic contrast agents are, used. The improved determination of glioma extent provided by SWI offers an important new tool for, diagnosis and surgical planning.

Hyperostotic Esthesioneuroblastoma: Rare Variant and Fibrous Dysplasia Mimicker

A 65-year-old male presented with a 3-year history of orbital symptoms. An imaging-based diagnosis of fibrous dysplasia involving the skull base was made at another institution. CT showed a diffuse sinonasal mass and ground-glass appearance of the bones of the anterior skull base with bony defects and mucocele formation. MRI demonstrated an accompanying intracranial and orbital rind of soft tissue mass along the hyperostotic bones. FDG-PET showed corresponding intense hypermetabolism. Small cysts were observed at the tumor-brain interface. Biopsy revealed esthesioneuroblastoma with bone infiltration that is compatible with the hyperostotic variant of esthesioneuroblastoma. There are a few cases of hyperostotic esthesioneuroblastoma reported in the literature.

The rim pattern of meningioma on 3D FLAIR imaging: correlation with tumor-brain adhesion and histological grading.

We evaluated the rim patterns of intracranial meningiomas on nonenhanced (NE) and contrast-enhanced (CE) 3-dimensional fluid-attenuated inversion recovery (3D FLAIR) imaging on 3-tesla magnetic resonance (MR) imaging to clarify the associated imaging and pathological findings and the value of the rims in predicting tumor cleavability. Thirty-two patients with meningioma underwent tumor excision. We classified the rim patterns on 3D FLAIR, subdivided into "rim-NE," a rim with relatively low signal intensity on NE 3D FLAIR and "rim-CE," a rim with relatively high signal intensity on CE 3D FLAIR, into 4 grades by their extent from 0 (no rim visible) to 3 (rim visible over most of the tumor-brain interface) and correlated them with tumor size, grade of peritumoral brain edema, presence/absence of pial supply, grade of tumor-brain adhesion, and histological findings. On NE 3D FLAIR, "rim-NE" was graded 0 in 5 patients, one in 5, 2 in 6, and 3 in 16. On CE 3D FLAIR, "rim-CE" was graded 0 in one patient, one in 13, 2 in 4, and 3 in 14. The grade of "rim-NE" correlated negatively with the grade of brain edema (P = 0.023) and positively with surgical tumor-brain cleavability (P < 0.001). It also correlated with the amount of connective tissue at the tumor-brain interface histologically (P = 0.041). Furthermore, a lower grade of "rim-NE" was more often seen in atypical than benign meningioma (P = 0.003). Although "rim-CE" was more prominent in tumors with pial supply on digital subtraction angiography (DSA) (P = 0.002), it was not useful in predicting tumor-brain adhesion or histological tumor grading. The rim pattern of meningioma on NE 3D FLAIR can predict surgical cleavability and histological tumor grading. A higher grade of rim pattern on CE 3D FLAIR suggests prominent pial supply to the tumor but has no added value in predicting tumor-brain adhesion and histological tumor grading.

The reliability of routine clinical post-processing software in assessing potential diffusion-weighted MRI “biomarkers” in brain metastases

Background and PurposeDiffusion MRI characteristics have been used as biomarkers to guide prognosis in cerebral pathologies including brain metastases. The measurement of ADC is often described poorly in clinical and research studies with little detail given to the practical considerations of where to place ROIs, which post processing software package to use and how reproducible the resulting metrics will be. MethodWe investigated a series of 12 patients with brain metastases and preoperative DWI. Three post processing platforms were used. ROI were placed over the tumour, peritumoural region and across the brain-tumour interface. These recordings were made by a neurosurgeon and a neuroradiologist. Inter-intra-observer variability was assessed using Bland-Altman analysis. An exploratory analysis of DWI with overall survival and tumour type was made. ResultsThere was excellent correlation between the software packages used for all measures including assessing the whole tumour, selective regions with lowest ADC, the change of ADC across the brain-tumour interface and the relation of the tumour ADC to peritumoural regions and the normal white matter. There was no significant inter- or intra-observer variability for repeated readings. There were significant differences in the mean values obtained using different methodologies and different metrics had differing relationships to overall survival and primary tumour of origin. ConclusionDiffusion weighted MRI metrics offer promise as potential non-invasive biomarkers in brain metastases and a variety of metrics have been shown to be reliably measured using differing platforms and observers.

Factors associated with recurrence of postoperative meningioma: a clinical study of 138 patients

Abstract Background and purpose: As the postoperative recurrence of meningioma can have devastating effects, it is important to identify factors that can be used to predict this type of tumor recurrence. Material and methods: We have performed a retrospective study involving 138 patients who were surgically treated for intracranial meningioma between 2005 and 2010. The patient population consisted of 80 females and 58 males, with an age range of 23 to 77 years old (mean age = 52 years). We measured associations between meningioma recurrence and clinical features (age, sex, extent of resection, histological type), or radiological features (tumor size, location, shape, calcification, bone changes, brain tumor interface, tumor necrosis, and MRI enhancement). Results: We found statistically higher levels of postoperative meningioma recurrence in patients with high Simpson grade resections, high histological types, tumor diameters &gt; 5 cm, tumors located in the base of the skull or the parasagittal sinus, tumors with unclear border, irregular enhancements on MRI, edema around the tumor, bleeding and necrosis within the tumor, and irregularly shaped tumors (e.g., lobulated or mushroom-shaped). In addition, calcification, age, sex, bone change, and dural tail sign provided no predictive value. C onclusions: We have shown that histological type, degree of resection, bleeding, necrosis, edema, irregular enhancement, location, shape, size, and margin serve as strong predictors for the postoperative recurrence of meningioma tumors.

Miniaturized handheld confocal microscopy identifies focal brain invasion in a mouse model of aggressive meningioma.

Invasion of the brain parenchyma by a meningioma classified by histological criteria as World Health Organization (WHO) grade I meningioma, implies that the tumor has greater likelihood of recurrence and a biological behavior similar to the more aggressive WHO grade II meningiomas. It is therefore important to detect microscopic foci of brain invasion during surgery in order to maximize the resection and/or adapt imaging follow-up. In this study, we tested the sensitivity of two handheld confocal imaging devices to detect foci of brain invasion in two types of meningioma mouse models: in a genetically engineered mouse model and in a syngeneic xenograft model. Confocal imaging offered precise images of meningothelial and fibroblastic mouse meningiomas as well as malignant meningiomas, which corresponded exactly to the pathological findings. Imaging showed a sharp definition of the brain-tumor interface and enabled identification of embedded nerves and vessels. Importantly, in both mouse models used in this study, extension of tumor along Virchow-Robin spaces into adjacent brain was detected by imaging. In conclusion, this novel technique, following validation in clinical trials, may open new possibilities for use in operating rooms to influence both decision making during the surgery and planning for additional treatments.

Resistance-Sized Arteries Structure and Capillary Density Changes in Glioblastoma and Meningioma Peritumoral Brain Tissue

Background: Brain vessels play a relevant role in the development of malignant primary tumors. Previous studies performed in preclinical models of brain tumors demonstrated the irregular morphology of vessels in glioblastoma, characterized by multiple abnormalities in shape, permeability and relationship with the contacting structures, such as the basement membrane; however no data about microvascular structural alterations in the brain of patients affected by brain tumors have been previously reported. Methods: We studied small vessels structural alterations, microvascular rarefaction and vascular collagen content in the peritumoral brain tissue of two groups of patients, respectively affected by glioblastoma and by meningioma, who underwent a surgical operation in order to remove the tumor. The two groups of patients were matched for clinical, laboratory variables and risk factors, with the exception of sex. Results: Media to lumen ratio was significantly higher in patients with meningioma compared to patients affected by glioblastoma. Vessels in the brain surrounding glioblastomas show a less organized structure, as demonstrated by the thinner media, by the lower content in collagen and by the lower capillary density. Conclusions: For the first time, we used an in vitro ex vivo technique to analyze structural alterations of resistance sized arteries of peritumoral brain tissue at the radiological tumor-brain interface in patients affected by glioblastoma and meningioma. This approach, together with immunohistochemical evaluation of microvessel density, has supplied new data about the brain microcirculation. These findings can be the result of the aberrant angiogenic process that characterizes glioblastomas and can finally play a role in tumor growth. Further studies are needed to confirm our data, to identify the pathways that lead to this microvascular pattern and to identify possible clinical applications

Merging machines with microsurgery: clinical experience with neuroArm

It has been over a decade since the introduction of the da Vinci Surgical System into surgery. Since then, technology has been advancing at an exponential rate, and newer surgical robots are becoming increasingly sophisticated, which could greatly impact the performance of surgery. NeuroArm is one such robotic system. Clinical integration of neuroArm, an MR-compatible image-guided robot, into surgical procedure has been developed over a prospective series of 35 cases with varying pathology. Only 1 adverse event was encountered in the first 35 neuroArm cases, with no patient injury. The adverse event was uncontrolled motion of the left neuroArm manipulator, which was corrected through a rigorous safety review procedure. Surgeons used a graded approach to introducing neuroArm into surgery, with routine dissection of the tumor-brain interface occurring over the last 15 cases. The use of neuroArm for routine dissection shows that robotic technology can be successfully integrated into microsurgery. Karnofsky performance status scores were significantly improved postoperatively and at 12-week follow-up. Surgical robots have the potential to improve surgical precision and accuracy through motion scaling and tremor filters, although human surgeons currently possess superior speed and dexterity. Additionally, neuroArm's workstation has positive implications for technology management and surgical education. NeuroArm is a step toward a future in which a variety of machines are merged with medicine.

Galectin-1, a gene preferentially expressed at the tumor margin, promotes glioblastoma cell invasion

BackgroundHigh-grade gliomas, including glioblastomas (GBMs), are recalcitrant to local therapy in part because of their ability to invade the normal brain parenchyma surrounding these tumors. Animal models capable of recapitulating glioblastoma invasion may help identify mediators of this aggressive phenotype.MethodsPatient-derived glioblastoma lines have been propagated in our laboratories and orthotopically xenografted into the brains of immunocompromized mice. Invasive cells at the tumor periphery were isolated using laser capture microdissection. The mRNA expression profile of these cells was compared to expression at the tumor core, using normal mouse brain to control for host contamination. Galectin-1, a target identified by screening the resulting data, was stably over-expressed in the U87MG cell line. Sub-clones were assayed for attachment, proliferation, migration, invasion, and in vivo tumor phenotype.ResultsExpression microarray data identified galectin-1 as the most potent marker (p-value 4.0 x 10-8) to identify GBM cells between tumor-brain interface as compared to the tumor core. Over-expression of galectin-1 enhanced migration and invasion in vitro. In vivo, tumors expressing high galectin-1 levels showed enhanced invasion and decreased host survival.ConclusionsIn conclusion, cells at the margin of glioblastoma, in comparison to tumor core cells, have enhanced expression of mediators of invasion. Galectin-1 is likely one such mediator. Previous studies, along with the current one, have proven galectin-1 to be important in the migration and invasion of glioblastoma cells, in GBM neoangiogenesis, and also, potentially, in GBM immune privilege. Targeting this molecule may offer clinical improvement to the current standard of glioblastoma therapy, i.e. radiation, temozolomide, anti-angiogenic therapy, and vaccinotherapy.

Prediction of high-grade meningioma by preoperative MRI assessment

High-grade (World Health Organization grades II and III) meningiomas grow aggressively and recur frequently, resulting in a poor prognosis. Assessment of tumor malignancy before treatment initiation is important. We attempted to determine predictive factors for high-grade meningioma on magnetic resonance (MR) imaging before surgery. We reviewed 65 meningiomas (39 cases, benign; 26 cases, high-grade) and assessed four factors: (1) tumor-brain interface (TBI) on T1-weighted imaging (T1WI), (2) capsular enhancement (CapE), i.e., the layer of the tumor-brain interface on gadolinium-enhanced T1WI (T1Gd), (3) heterogeneity on T1Gd, and (4) tumoral margin on T1Gd. All four factors were useful in distinguishing high-grade from benign meningiomas, according to univariate analysis. On multivariate regression analysis, unclear TBI and heterogeneous enhancement were independent predictive factors for high-grade meningioma. In meningiomas with an unclear TBI and heterogeneous enhancement, the probability of high-grade meningioma was 98%. Our data suggest that this combination of factors obtained from conventional sequences on MR imaging may be useful to predict high-grade meningioma.

Ultrasound Elastography Special Issue

I am delighted to introduce this Elastography special issue as the first Ultrasound issue of 2012. It features five excellent ultrasound elastography papers that clearly demonstrate the very different applications of ultrasound elastography including liver fibrosis, regional anaesthesiology and brain tumour resection, also demonstrating the large breadth of clinical specialists who all are using this exciting technology: anaesthetists, neurosurgeons, physicists and radiologists. The first paper in this issue by Hoskins introduces and reviews the principles of ultrasound elastography and will be of interest to those wishing to learn more about the different ultrasound elastography techniques and their respective merits. The second paper is by Cournane et al. which reviews the current status of elastography phantoms for training and quality assurance purposes. It is suggested that there is a need for further development of such phantoms in order to ensure that these new diagnostic techniques are validated. Jaffer et al. question whether ultrasound elastography of the liver is ready to replace biopsy. They provide an excellent review of the advantages, limitations and clinical relevance of the three most investigated ultrasound elastography methods for the accurate assessment of liver fibrosis: transient elastography, realtime elastography and acoustic radiation force impulse. Chakraborty et al. investigate the role of ultrasound elastography in the differentiation of brain tumours from normal brain tissue. They found that the technique had a sensitivity of 100% and a specificity of 75% at detecting that tumour had a different stiffness to the brain when compared with surgical findings. The authors recommend, however, that the technique be used in combination with conventional B-mode ultrasound due to its limited ability at identifying the brain-tumour interface and the quality of fluid-filled cysts. Munirama et al. present the results from the first use of ultrasound elastography for regional anaesthesia in a Thiel cadaver model. It was found in this investigation that ultrasound elastography images were superior in visualizing dynamic spread of fluid as well as providing a better dose-response compared with B-mode, which offers the clinical user the potential to use smaller test doses that can be easily detected using ultrasound elastography. Learn more about this special elastography issue by reading the guest editorial by Pete Hoskins and William Svensson. There may be more to fetal sexing than meets the eye. Well, that is the message from Edwards’ and Thomson’s thought-provoking paper on using ultrasound to determine sex prenatally. In this special feature they discuss ambiguous genitalia and also highlight international concerns on the growing crime of gendercide. Fernandez et al. present an interesting case where cranial ultrasound detected grey matter heterotopia in a neonate, which was later correlated with magnetic resonance imaging findings. They describe the sonographic signs and suggest an extended investigation beyond the white matter and cortex. Two more articles are featured as part of the nowestablished ‘PoCUS Series’. Liteplo et al. describe the use of ultrasound for evaluating the hypotensive patient when every second counts. They review some of the suggested scanning protocols and algorithms. On the same theme, Pishe et al. discuss the value of ultrasound for the hypotensive patient when a cardiogenic cause is suspected. Our new international editor is John Hossack who joined us last November. Originally from Scotland, John is a

Preliminary investigation into the use of ultrasound elastography during brain tumour resection

Introduction Differentiation of brain tumours from normal brain, during surgical resection is, in part, based on their differing mechanical properties. Brain tumours have variable stiffness characteristics. Surgical evaluations on stiffness are, at best, subjective. Ultrasound elastography is a non-invasive method for imaging mechanical properties of tissues such as stiffness at depth. It is hypothesized that this technique may assist in differentiating tumour from the brain in an intraoperative setting. Methods This study evaluated the feasibility of the intraoperative use of ultrasound elastography during brain tumour resection. A total of 24 patients were recruited for the study. Surgical findings on tumour stiffness were compared with the elastogram findings. Furthermore, visibility of the brain-tumour interface on ultrasound echography compared with ultrasound elastography was analysed. Results Ultrasound elastography was found to have a sensitivity of 100% and specificity of 75% at detecting that tumour had a different stiffness to the brain when compared with surgical findings. The technique was also found to have a 100% sensitivity and specificity at the detection of intratumoral stiffness heterogeneity compared with surgical findings. The presence of fluid-filled cysts limited the quality of the elastograms. Ultrasound elastography did not detect the brain-tumour interface as accurately as conventional echography. Conclusion These findings suggest that ultrasound elastography in combination with conventional B-mode ultrasound may be a useful adjunct to differentiate tumour from the brain.

Characterization of Immune Cell Infiltration Into Canine Intracranial Meningiomas

Meningiomas are the most common intracranial tumors in dogs. A variety of inflammatory cells have been shown to invade these tumors in people, but little is known about interactions between the immune system and naturally occurring brain tumors in dogs. The purpose of this study was to investigate the presence of a variety of immune cell subsets within canine intracranial meningiomas. Twenty-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry with antibodies specific for CD3, CD79a, CD18, CD11d (αD), CD45RA, forkhead box P3, and Toll-like receptors 4 and 9. Immune cell infiltration was evident in all samples, with a predominance of CD3(+) T cells. Large numbers of CD18(+) microglia and macrophages were noted surrounding and infiltrating the tumors, and a subset of these cells within the tumor appeared to be CD11d(+). Scattered macrophages at the tumor-brain interface were TLR4(+) and TLR9(+). Rare CD79a(+) B cells were noted in only a small subset of tumors. Lesser numbers of lymphocytes that were CD11d(+), CD45RA(+), or FoxP3(+) were noted in a number of the meningiomas. Although the function of these cells is not yet clear, work in other species suggests that evaluation of this immune cell infiltrate may provide important prognostic information and may be useful in the design of novel therapies.

Intraoperative confocal microscopy in the visualization of 5-aminolevulinic acid fluorescence in low-grade gliomas

Greater extent of resection (EOR) for patients with low-grade glioma (LGG) corresponds with improved clinical outcome, yet remains a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5-ALA)-induced tumor fluorescence is a strategy that can improve EOR in gliomas, only glioblastomas routinely fluoresce following 5-ALA administration. Intraoperative confocal microscopy adapts conventional confocal technology to a handheld probe that provides real-time fluorescent imaging at up to 1000× magnification. The authors report a combined approach in which intraoperative confocal microscopy is used to visualize 5-ALA tumor fluorescence in LGGs during the course of microsurgical resection. Following 5-ALA administration, patients with newly diagnosed LGG underwent microsurgical resection. Intraoperative confocal microscopy was conducted at the following points: 1) initial encounter with the tumor; 2) the midpoint of tumor resection; and 3) the presumed brain-tumor interface. Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence. Ten consecutive patients with WHO Grades I and II gliomas underwent microsurgical resection with 5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to tumor infiltration on matched histological analyses. Intraoperative confocal microscopy can visualize cellular 5-ALA-induced tumor fluorescence within LGGs and at the brain-tumor interface. To assess the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation, and for LGGs in combination with intraoperative confocal microscopy and neuronavigation, a Phase IIIa randomized placebo-controlled trial (BALANCE) is underway at the authors' institution.