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Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rhTNFSF10 (rhTRAIL), and rhBMP4. All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies.

Objective The collision of pituitary adenoma and craniopharyngioma is extremely rare and thus there remains a paucity of data. Methods We described a patient from our institution. We also performed a systematic review and subsequent quantitative synthesis of the literature (n = 21) and our institutional case to yield an integrated cohort, and a descriptive analysis was carried out. Results Twenty-two patients (15 males and 7 females) were included in the integrated cohort. The median age was 47.0 years (range, 8–75 years). The tumor subtypes were 5 somatotropic, 5 lactotropic, 4 nonfunctioning, 3 gonadotropic, 2 corticotropic, 1 plurihormonal, and 1 silent subtype 3 for pituitary adenomas, and 19 adamantinomatous, 2 papillary, and 1 unknown subtype for craniopharyngiomas. Three different radiographic patterns were observed: solid mass with cystic component (n = 5), coexistence of two distinct solid components (n = 3), and a mixed-intensity solid mass (n = 5). The first 2 were consistent with histologically separate collision, whereas the third was consistent with histologically admixed collision. Among 19 patients in whom the postoperative course was recorded, a secondary intervention was required in 14 (73.7%) because of tumor progression or residual. The recurrence rate after gross total resection was 33.3%. Postoperative hormone replacement was required in 33.3%. The 10-year cumulative overall survival was 73.1%. Conclusions Most craniopharyngiomas were adamantinomatous. There are 2 types of collisions: separated and admixed. Tumor control, overall survival, and endocrinologic remission are more challenging to achieve than for solitary tumors, but gross total resection of both tumors is important for satisfactory tumor control.

OBJECTIVE The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR). METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed. RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234). CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

Purpose To examine the occurrence of glioma-related preoperative seizures (GPS) and post-operative seizure control (PSC) with respect to patients characteristics including five commonly tested tumor molecular markers (TMMs). Methods A single-center retrospective cohort study of patients with glioma evaluated at the Mayo Clinic, Florida between 2016 and 2018. Results 68 adult patients (mean age = 51-years, 45-males) were included. 46 patients had GPS. 57 patients underwent intra-operative electrocorticography during awake craniotomy-assisted glioma resection. All patients underwent glioma resection (53, gross-total resection) with histologies of pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 4), oligodendroglioma (n = 14), anaplastic astrocytoma (n = 16), anaplastic oligodendroglioma (n = 1), and glioblastoma (n = 31). 31 (67%) patients had PSC (median follow-up = 14.5 months; IQR = 7–16.5 months). IDH1 mutation (IDH1mut) was present in 32, ARTX retention in 53, MGMT gene promotor methylation in 15, 1p/19q co-deletion in 15, and over-expression of p53 in 19 patients. Patients with IDH1mut were more likely to have GPS (p = 0.037) and PSC (p = 0.035) compared to patients with IDH1 wild-type. Patients with MGMT gene promoter methylation were also likely to have PSC (p = 0.032). GPS or PSC did not differ by age, sex, extent of surgery, glioma grade, location, and histopathological subtype, p53 expression, ARTX retention, or 1p/19q co-deletion status. Conclusions GPS and PSC may be associated with IDH1 mutation and MGMT gene promoter methylation status but not other glioma characteristics including tumor grade, location, or histopathology. Prospective studies with larger sample size are needed to clarify the exact mechanisms of GPS and PSC by the various TMMs to identify new treatment targets.

Objective The purpose of this article was to provide a combined pathologic and radiologic review of previous pathologically diagnosed facial nerve "hemangiomas" to confirm that these lesions are most characteristic of venous malformations rather than neoplasms. Study Design Retrospective radiologic, clinical, and histopathologic review of all patients with a previous pathologically diagnosed facial nerve hemangioma of the temporal bone who underwent computed tomography or magnetic resonance imaging (MRI) were included. A consensus radiologic review for characteristic features and pathologic analysis was performed. Materials and Methods A panel of 4 neuroradiologists retrospectively analyzed CT and MRI exams for 11 facial nerve hemangiomas and provided a consensus agreement on the characteristic imaging features. Concurrently, two neuropathologists reevaluated archived tissue specimens from these lesions and applied additional immunohistochemical and histochemical stains including D240, CD31, smooth muscle actin (SMA), Verhoeff Van Gieson (VVG) and glucose transporter 1 (GLUT1). Results Lesions were composed of dilated vascular spaces with a simple, CD31-positive endothelial lining and a smooth muscle component. All lesions were negative for markers found in arterial and lymphatic malformations and infantile hemangiomas. They had characteristic radiologic features previously ascribed to facial nerve hemangiomas. Namely, these lesions are typically T1 isointense or hypointense and T2 hyperintense relative to cerebral cortex and heterogeneously enhance on MRI. Bony canal expansion and erosion, intralesional calcification, and intracranial extension are common. Conclusions On the basis of this radiologic and pathologic review, these lesions are best characterized as venous malformations. Level of Evidence 4.

Mutations in the telomerase reverse transcriptase promoter (TERTp) region have been associated with worse prognosis in some cancers. Meningiomas are the most common type of primary central nervous tumors, and evaluation of the prognostic significance of TERTp mutations across the literature is lacking. The aim of this study was to pool all current evidence to assess for clinical relevance of TERTp mutations in meningioma and survival effect. Searches of seven electronic databases from inception to September 2018 were conducted following the appropriate guidelines. Two hundred and twenty seven articles were identified for screening. Hazard ratio (HR) and mean difference (MD) statistics were obtained and pooled utilizing both fixed- and random-effect (RE) models. Meta-regression was utilized to determine potential sources of heterogeneity and statistical influence. A total of five retrospective observational cohort studies describing 532 meningioma patients satisfied selection criteria. The incidence of TERTp mutations was 8%, and was associated with significantly worse prognosis (HR 3.79; P = 0.005) and significantly shorter overall survival (MD 59.8 months; P = 0.037) by RE modelling. Meningioma grade was not significantly associated with a TERTp mutation effect, however, preliminary meta-regression trends indicated this may be significant once greater statistical power is achieved. The current evidence indicates the presence of a TERTp mutation in meningioma can be associated with worse prognosis, and shorter overall survival. Routine detection in greater numbers will allow for further validation, as well as delineate the effect across histological grades. By identifying this subgroup of meningioma patients early in management, it may support more frequent follow-up and aggressive management to optimize survival outcomes.

Neurofibromatosis type-1 is a familial genetic syndrome associated with a predisposition to develop peripheral and central nervous system neoplasms. We have previously reported on a subset of gliomas developing in these patients with morphologic features resembling subependymal giant cell astrocytoma, but the molecular features of these tumors remain undefined. A total of 14 tumors were studied and all available slides were reviewed. Immunohistochemical stains and telomere-specific FISH were performed on all cases. In addition, next-generation sequencing was performed on 11 cases using a platform targeting 644 cancer-related genes. The average age at diagnosis was 28 years (range: 4–60, 9F/5M). All tumors involved the supratentorial compartment. Tumors were predominantly low grade (n = 12), with two high-grade tumors, and displayed consistent expression of glial markers. Next-generation sequencing demonstrated inactivating NF1 mutations in 10 (of 11) cases. Concurrent TSC2 and RPTOR mutations were present in two cases (1 sporadic and 1 neurofibromatosis type-1-associated). Interestingly, alternative lengthening of telomeres was present in 4 (of 14) (29%) cases. However, an ATRX mutation associated with aberrant nuclear ATRX expression was identified in only one (of four) cases with alternative lenghtening of telomeres. Gene variants in the DNA helicase RECQL4 (n = 2) and components of the Fanconi anemia complementation group (FANCD2, FANCF, FANCG) (n = 1) were identified in two alternative lenghtening of telomere-positive/ATRX-intact cases. Other variants involved genes related to NOTCH signaling, DNA maintenance/repair pathways, and epigenetic modulators. There were no mutations identified in DAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots of IDH1, IDH2, or BRAF. A subset of subependymal giant cell astrocytoma-like astrocytomas are alternative lenghtening of telomere-positive and occur in the absence of ATRX alterations, thereby suggesting mutations in other DNA repair/maintenance genes may also facilitate alternative lenghtening of telomeres. These findings suggest that subependymal giant cell astrocytoma-like astrocytoma represents a biologically distinct group that merits further investigation.

OBJECTIVE Multiple meningiomas (MMs) occur in as many as 18% of patients with meningioma, and data on progression-free survival (PFS) are scarce. The objective of this study was to explore the influence of the number of lesions and clinical characteristics on PFS in patients with WHO grade I meningiomas. METHODS The authors retrospectively reviewed the records of all adults diagnosed with a meningioma at their three main sites from January 2009 to May 2020. Progression was considered the time from diagnosis until radiographic growth of the originally resected meningioma. A secondary analysis was performed to evaluate the time of diagnosis until the time to second intervention (TTSI). Univariable and multivariable analyses were conducted to assess whether the number of lesions or any associated variables (age, sex, race, radiation treatment, tumor location, and extent of resection) had a significant impact on PFS and TTSI. RESULTS Eight hundred thirty-eight patients were included. Use of a log-rank test to evaluate PFS and TTSI between a single and multiple lesions showed a significantly shorter progression for MM (p < 0.001 and p < 0.001, respectively). Multivariable Cox regression analysis showed significantly inferior PFS on MM compared to a single lesion (hazard ratio [HR] 2.262, 95% confidence interval [CI] 1.392–3.677, p = 0.001) and a significantly inferior TTSI for patients with MM when compared to patients with a single meningioma (HR 2.377, 95% CI 1.617–3.494, p = 0.001). By testing the number of meningiomas as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350, 95% CI 1.074–1.698, p = 0.010) and TTSI was significantly inferior as well (HR 1.428, 95% CI 1.189–1.716, p < 0.001). African American patients had an inferior PFS when compared to non-Hispanic White patients (HR 3.472, 95% CI 1.083–11.129, p = 0.036). CONCLUSIONS The PFS of meningiomas appears to be influenced by the number of lesions present. Patients with MM also appear to be more prone to undergoing a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions. These results show a decreased PFS for each additional lesion present, as well as a shorter PFS for MM compared to a single lesion. When assessing associated risk factors, African American patients showed an inferior PFS, whereas older age and adjuvant therapy with radiation showed an improved PFS.

BACKGROUND: The pathogenesis of glioma-related seizures (GRS) is poorly understood. Here in, we aim to identify putative molecular pathways that lead to the development of GRS. METHODS: We determined brain transcriptome from intraoperative human brain tissue of patients with either GRS, glioma without seizures (non-GRS), or with idiopathic temporal lobe epilepsy (iTLE). We performed transcriptome-wide comparisons between disease groups tissue from non-epileptic controls (non-EC) to identify differentially-expressed genes (DEG). We compared DEGs to identify those that are specific or common to the groups. Through a gene ontology analysis, we identified molecular pathways enriched for genes with a Log-fold change ≥1.5 or ≤−1.5 and p-value

Introduction/Objective Maximizing surgical resection in gliomas, while avoiding compromising non-infiltrated tissue, is associated with survival benefit. Current methodologies are suboptimal in providing rapid, intraoperative molecular characterization of tissue. We address this unmet need by using desorption electrospray ionization mass spectrometry (DESI-MS) for the intraoperative molecular assessment of gliomas. Methods/Case Report This prospective study uses intraoperative DESI-MS analysis of fresh tissue to evaluate IDH mutations via 2-hydroxyglutarate intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles in less than three minutes. Blinded review of the tissue smears by a neuropathologist is used to validate IDH mutation status and TCP estimates. Results (if a Case Study enter NA) Presently, 529 biopsies from 85 enrolled patients have been collected and analyzed at two institutions. TCP assessment based on NAA intensity in 203 biopsies at the first institution yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP estimates via characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Ongoing validation of the methodology is being performed at a second institution, where we have collected 282 biopsies from 36 patients. IDH mutation assessment of the first 15 patients indicate 100% sensitivity, specificity, and accuracy. Conclusion This study represents the first and largest study using DESI-MS for the intraoperative evaluation of IDH status and TCP measurement in gliomas. Prospectively, we propose to modify our DESI-MS system to allow estimation of IDH mutation status and TCP in surgical cavities without the need for a biopsy by placing a surgical material along the margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. We envision molecular analysis by DESI-MS as a complementary technique to histopathology capable of providing additional clinical information in near real-time.

Background Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. Methods We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. Results GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. Conclusions SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

OBJECTIVE High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic. METHODS The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS). RESULTS Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19–76) years were included in the analysis. Eighteen patients had H3 K27M mutation–positive tumors, and 12 had H3 K27M mutation–negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation–positive tumors (p = 0.017). CONCLUSIONS Although H3 K27M mutant–positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant–positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant–negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.

BackgroundOligodendroglioma is genetically defined by concomitant IDH (IDH1/IDH2) mutation and whole-arm 1p/19q codeletion. Codeletion of 1p/19q traditionally evaluated by fluorescence in situ hybridization (FISH) cannot distinguish partial from whole-arm 1p/19q codeletion. Partial 1p/19q codeletion called positive by FISH is diagnostically a “false-positive” result. Chromosomal microarray (CMA) discriminates partial from whole-arm 1p/19q codeletion. Herein, we aimed to estimate the frequency of partial 1p/19q codeletion that would lead to a false-positive FISH result.MethodsFISH 1p/19q codeletion test probe coordinates were mapped onto Oncoscan CMA data to determine the rate of partial 1p/19q codeletion predicted to be positive by FISH. Diffuse astrocytic gliomas with available CMA data (2015–2018) were evaluated and classified based on IDH1-R132H/ATRX/p53 immunohistochemistry, IDH/TERT promoter targeted sequencing, and/or CMA according to classification updates. Predicted false-positive cases were verified by FISH whenever possible.ResultsThe overall estimated false-positive FISH 1p/19q codeletion rate was 3.6% (8/223). Predicted false positives were verified by FISH in 6 (of 8) cases. False-positive rates did not differ significantly (P = .49) between IDH-mutant (4.6%; 4/86) and IDH-wildtype (2.9%; 4/137) tumors. IDH-wildtype false positives were all WHO grade IV, whereas IDH-mutant false positives spanned WHO grades II-IV. Testing for 1p/19q codeletion would not have been indicated for most false positives based on current classification recommendations.ConclusionSelective 1p/19q codeletion testing and cautious interpretation for conflicting FISH and histopathological findings are recommended to avoid potential misdiagnosis.

Epstein-Barr virus–associated smooth-muscle tumors are rare tumors seen in immunocompromised patients. Most cases occur in the context of AIDS and organ transplantation, and very rarely in the setting of congenital immunodeficiency, with only 5 case reports of the latter published so far in the literature. The authors report the case of a previously healthy 8-year-old girl with headaches and precocious puberty who was found to have a large skull base lesion. There was a synchronous left adrenal lesion. She underwent resection of the skull base lesion and a left adrenalectomy. Thorough evaluation for immunodeficiency was negative for a known congenital immunodeficiency syndrome. She had a short course of intravenous immunoglobulin and has had no recurrence of disease or new lesions in the 17 months since presentation. Continued surveillance for the development of opportunistic infections and new or recurrent lesions is warranted in this case. Repeat surgery for surgically accessible tumors or chemoradiation would be recommended for any additional lesions.

BACKGROUND Intraoperative detection of residual tumor and isocitrate dehydrogenase (IDH) mutations can assist in maximizing surgical resection beyond contrast enhancing margins and guide intraoperative surgical decision making for glioma patients. We aimed to evaluate the use of desorption electrospray ionization-mass spectrometry (DESI-MS) for intraoperative assessment of IDH mutations and estimation of tumor cell percentage (TCP). METHODS This is a prospective study using intraoperative DESI-MS analysis of freshly obtained tissue samples to evaluate IDH mutations via 2-hydroxyglutarate (2-HG) intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles. These IDH mutation and TCP estimates were subsequently validated by a senior neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of TCP in 203 margin and core biopsies based on NAA intensity yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP assessment based on characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Further validation of the methodology is being performed in an ongoing collaboration with Mayo Clinic-Jacksonville, where we have collected 178 biopsies from 24 patients. Preliminary results of IDH mutation assessments indicate 100% sensitivity, specificity, and accuracy. DISCUSSION/CONCLUSION We present a novel system to allow intraoperative evaluation of IDH status and to guide surgical resection by TCP measurement from tissue biopsies. Prospectively, we propose to modify our DESI-MS system by placing a surgical material (e.g. cottonoid) along the surgical margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. This will allow the retention of the spatial distribution of diagnostic molecules while analyzing a wall of the surgical cavity without the need for biopsy.

Arachnoid web (AW) is a rare phenomenon that has only been described in small case reports and case series, 1 most commonly presenting with upper motor neuron signs and subtle radiographic findings, such as the classically described “scalpel sign.” 2 In this report, we demonstrate the use of imaging and operative techniques that have not been previously shown in the literature as a video for AW. These include high-definition magnetic resonance imaging (MRI) sequences for preoperative diagnosis, use of intraoperative ultrasonography for identification of adhesions, and operative technique for AW fenestration ( Video 1 ). The patient consented to this manuscript. A 64-year-old female patient developed progressive difficulty with balance and ambulation that particularly worsened over the last 4 months associated with tingling and numbness in the bilateral lower extremities. Physical examination revealed spastic gait and upper motor neuron signs in the lower extremities along with left foot drop. MRI revealed a chronic noncontrast-enhancing intramedullary lesion, along with a spinal cord indentation at the level T6 with an associated fiber between the cord and the posterior dura. Surgical intervention was performed with the use of intraoperative fluoroscopy and ultrasound for real-time identification of the surgical site and the AW. Under the microscope, the dura was incised while preserving the arachnoid. The AW was carefully dissected, leaving the portions that were tethered onto the cord. Two weeks postoperatively, the patient's gait was markedly improved, with resolved neurologic function in the lower extremities. Follow-up MRI at 3 months demonstrated resolved medullary syrinx and normalization of the spinal cord contour.

Intraventricular tumors are rare and comprise a variety of histological entities. They may be found throughout the ventricular system, which is comprised broadly of the lateral ventricles, third ventricle, cerebral aqueduct, and fourth ventricle. Given the widespread and varied topography of the ventricular system, its presence in the supratentorial and infratentorial compartments, as well as its diverse cellular constituency, it is not surprising that tumors arising from this complex are quite heterogeneous in location, clinical consequence, and biological behavior. The diverse nature of intraventricular tumors makes their classification more challenging than the standard intra-axial versus extra-axial categorization applied to many central nervous system lesions.

Objective:To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS).Methods:Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 × 107 (single dose) to 1 × 108 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis.Results:Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients.Conclusions:Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials.Classification of evidence:This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe.

Herein we present the case of a 42-year-old man who presented with an anterior mediastinal mass, which was found to represent a mature teratoma. Within it, there was a secondary somatic malignant glial neoplasm with mitotic activity and necrosis, compatible with glioblastoma. He experienced early local recurrence and lymph node metastasis, but is alive and well 3 1/2 years after diagnosis. Neither the teratoma nor the glioblastoma components had abnormalities of chromosome 12, which may implicate that this teratoma was more closely related to those arising along the midline of infants and children (type I germ cell tumor) than to the typically malignant testicular examples, which often contain mixed germ cell elements (type II germ cell tumor).

Hypothalamic hamartomas are rare tumors that typically present in childhood, often with gelastic seizures, precocious puberty, or as a manifestation of Pallister-Hall syndrome. Neurofibrillary tangles are cytoplasmic aggregates of hyperphosphorylated tau that are best recognized in Alzheimer disease, other tau-associated neurodegenerative diseases, or as part of aging, but occasionally may be seen in low-grade neoplasms with a ganglion cell component as gangliocytoma or ganglioglioma. Herein, we report a case of hypothalamic hamartoma with neurofibrillary tangles.

Intraneural ganglion cysts are non-neoplastic collections of mucinous material within the epineurium of peripheral nerves. We present a rare case of 2 intraneural ganglion cysts in separate nerves of the foot, originating from different joints within the same joint complex. Our findings add to the large body of evidence supporting the unifying articular (synovial) theory. We emphasize the importance of delineating the cyst morphology and origins using high-resolution magnetic resonance imaging before surgery and searching for and resecting the articular branch or branches during surgery.

Gliosarcoma is an uncommon variant of glioblastoma, which commonly demonstrates dural attachment. However, skull base invasion is rarely seen with this entity. Herein, we report a 44-year-old female patient diagnosed with primary intracranial gliosarcoma extensively invading the skull base and muscles of mastication. She presented to our institution with a three-month history of difficult right jaw opening and retro-orbital pressure and one week of severe right-sided postauricular headache. Head CT demonstrated a 6 cm mass with marked bony erosion. Brain MRI at a one-week interval more clearly characterized tumor extension through the right orbit and muscles of mastication, with overall growth to 7 cm and worsening midline shift. The patient underwent a right frontotemporal craniotomy for gross total resection. Pathology confirmed the diagnosis of gliosarcoma, IDH-wildtype (WHO grade IV). Her postoperative course was uneventful and she was discharged at preoperative neurologic baseline. To our knowledge, this is the third reported case of a primary intracranial gliosarcoma with direct invasion of skull base, brain parenchyma, and extracranial compartment. However, this is the first report case of primary GS invading the surrounding musculature and orbit. This case report highlights the rapid aggressiveness of gliosarcomas and further a prior undescribed radiographic and anatomic finding of skull base invasion with this entity.

We describe the case of a 29-year-old male who presented with new-onset seizures. He was subsequently found to have an orbital encephalocele containing a focus of pilocytic astrocytoma. We believe that this is the first report of a pilocytic astrocytoma located within the orbit that did not originate from the optic pathway. It is also the first case of a pilocytic astrocytoma completely contained within an encephalocele. This case suggests a close pathological examination of encephaloceles for underlying diseases.

Intracranial melanotic schwannomas (IMSch) are extremely rare nerve sheath tumors with features of Schwann cells that produce melanin. After a thorough review of the available literature since 1967, we report not only the 20th case of IMSch but a comprehensive modern-era analysis of radiographic and histological key-points to be considered when diagnosing and treating patients with this rare known entity. This is the case of a 43 years-old woman who presented with severe headaches 9 years ago (2008). At that time, MRI of the brain showed a 1.5 × 1.4 cm lesion at the level of the left cerebellar peduncle without any evidence of edema, mass effect or hydrocephalus. Given that the patient was neurologically intact, a conservative management with serial MRIs was recommended. Patient stopped following up due to the absence of symptoms. Over the course of the past year, patient noted mild left sided hearing loss and facial weakness, as well as some balance instability that progressed over the last 3 months. Given the presentation and progression of these signs and symptoms, a new MRI was performed in which considerable growth of the lesion was identified, measuring 2.5 × 2.8 × 2.6 cm with mass effect on the pons and the inferior fourth ventricle. She underwent a far lateral approach without a C1 hemilaminectomy for the resection of this lesion. Final pathology was consistent with a non-psammomatous melanotic schwannoma (NPMS) with areas of necrosis. Besides this case, only two other cases of IMSch with findings of necrosis have been reported in the literature, all of them reporting a subtotal resection. Evaluation of all previously reported cases of IMSch shows a male prevalence with a 1.6:1 male to female ratio. IMSch is radiographically T2 hypointense and can be differentiated from Schwannomas that are classically T2 hyperintense. In this case, only a subtotal resection was feasible due to the tumor’s overwhelming inherent attachment to vital structures such as cranial nerves (CN), brainstem, and vasculature. While MSch is considered histologically benign, several factors including localization, surrounding structures, the rate of growth, tumor volume resection and histological necrosis should be considered in determining prognosis and further adjuvant treatment planning.

Introduction Vestibular schwannoma (VS) behavior following subtotal resection (STR) is highly variable. Overall progression rates have been reported as high as 44%, and optimal treatment is controversial. Correspondingly, identification of a reliable clinical or pathologic marker associated with progression after STR would help guide decision-making. Methods A prospectively maintained institutional VS registry from 1999 to 2014 was retrospectively reviewed for sporadic VS patients who underwent primary STR without preceding stereotactic radiosurgery (SRS) by a single neurosurgery-neurotology team. Primary endpoints included tumor progression and postoperative facial nerve function. Pathologic specimens were stained for Ki67, CD68, S100, and SOX10 and were quantitated by digital imaging analysis. Macrophage density was defined as the ratio of CD68+ macrophages to S100+ macrophages and Schwannian tumor cells. Clinical outcomes were correlated with pathologic markers. Results Forty-six patients met the study inclusion criteria. Thirteen (28%) progressed during a mean 57 months of follow-up (range 15–149). Favorable postoperative facial nerve function (House–Brackmann I–II) was achieved in 37 (80%). CD68+ cells were present at significantly higher concentrations in tumors that progressed (p = 0.03). Higher macrophage density was significantly associated with both tumor progression (p = 0.02) and unfavorable facial nerve function (p = 0.02). Ki67 percent positivity was not significantly associated with either primary endpoint (p = 0.83; p = 0.58). Conclusions Macrophage density may provide an important marker for individuals at the highest risk for progression of VS after STR, potentially prompting closer surveillance or consideration for upfront SRS following STR. This finding supports preceding conclusions that an intratumoral macrophage-predominant inflammatory response may be a marker for tumor growth and a potential therapeutic target.

Objective: To understand the pathologic and clinical correlates of patients with chronic meralgia paresthetica (MP) undergoing lateral femoral cutaneous nerve (LFCN) neurectomy. Methods: A retrospective cohort approach was utilized to identify 7 patients undergoing LFCN neurectomy for intractable pain. Control autopsied LFCN was obtained. Clinical, radiologic, and electrophysiologic features were reviewed. Results: In identified cases, preoperative symptoms included severe lateral thigh pain and numbness. The duration of symptoms prior to surgery ranged from 2 to 15 years. Body mass index (BMI) varied from 20 kg/m 2 to 44.8 kg/m 2 (normal–morbidly obese), with 6 out of 7 patients being obese. No patients were diabetic. Focal nerve indentation at the inguinal ligament was seen intraoperatively and on gross pathology in 4 of 7 cases. Multifocal fiber loss, selective loss of large myelinated fibers, thinly myelinated profiles, regenerating nerve clusters, perineurial thickening, and subperineurial edema were seen. None of these features were observed in control nerve. Morphometric analysis confirmed loss of large myelinated fibers with small and intermediate size fiber predominance. Five patients had varying degrees of intraneural and epineurial inflammation. Six of 7 reported improved pain after neurectomy, sometimes dramatic. Conclusions: Patients with chronic MP and intractable pain have an LFCN mononeuropathy with loss of nerve fibers. Pathologic and clinical study supports a compressive pathogenesis as the primary mechanism. Abnormal nerve inflammation coexists and may play a role in pathogenesis. These selected patients typically benefited from neurectomy at a site of inguinal ligament compression. Classification of Evidence: This study provides Class IV evidence that patients with chronic MP LFCN neurectomy experience improvement in MP-related pain.

Prolactinomas are primarily treated with medical therapy. Given the efficacy of dopamine agonists (DAs), surgery has remained a second-line treatment option. Despite medical therapy, some tumors display resistance and/or patients maybe intolerant of DA and require alternative treatment options. We examined the indications, efficacy, and safety of pituitary surgery for the treatment of prolactinomas.We performed a retrospective analysis of all patients who had surgery for a prolactinoma at our institution from January 1993 to October 2014.Seventy-eight patients (46 females, mean age 32 years) with a median follow-up of 12 months were analyzed. Macroprolactinomas accounted for 65% (51/78) of tumors. The most common indication for surgery in microprolactinomas was medication intolerance (37%, 10/27) and medication failure (33%, 17/51) in macroprolactinomas. DA therapy had been tried in 76% (59/78) patients prior to surgery. Following surgery, long-term remission was seen in 72% (18/25) of micro-adenomas and 20% (10/49) of macro-adenomas (32% [10/32] in those without cavernous sinus invasion). Despite persistent disease in those with macro-adenomas (34% [13/38]) were able to remain off medication. Early surgical failure was more common in males (P = .004) and those with large (P≤.001) or atypical (P = .003) adenomas.Surgery can result in prolonged remission in 72% of microprolactinomas. Despite lower remission rates among macroprolactinomas, a third of patients with persistent disease did not require medical therapy. Therefore, surgery remains an alternative effective treatment option, particularly for those who are intolerant or resistant to medical therapy.ACTH = adrenocorticotropic hormone CI = confidence interval CSF = cerebrospinal fluid DA = dopamine agonist IQR = interquartile range MIB-1 = methylation inhibiting binding protein-1 VF = visual field.

OBJECTIVEDesmoid-type fibromatosis (DTF) presents a therapeutic dilemma. While lacking metastatic potential, it is a locally aggressive tumor with a strong propensity for occurrence near nerve(s) and recurrence following resection. In this study, the authors introduce the association of an occult neuromuscular choristoma (NMC) identified in patients with DTF.METHODSAfter experiencing a case of DTF found to have an occult NMC, the authors performed a retrospective database review of all other cases of biopsy-proven DTF involving the extremities or limb girdles in patients with available MRI data. Two musculoskeletal radiologists with expertise in peripheral nerve imaging reviewed the MRI studies of the eligible cases for evidence of previously unrecognized NMC.RESULTSThe initial case of a patient with an occult sciatic NMC is described. The database review yielded 40 patients with DTF—18 (45%) in the upper limb and 22 (55%) in the lower limb. Two cases (5%) had MRI findings of NMC associated with the DTF, one in the proximal sciatic nerve and the other in the proximal tibial and sural nerves.CONCLUSIONSThe coexistence of NMC may be under-recognized in a subset of patients with extremity DTF. This finding poses implications for DTF treatment and the likelihood of recurrence after resection or biopsy. Further study may reveal crucial links between the pathogenesis of NMC and DTF and offer novel therapeutic strategies.

Introduction Pineoblastomas are uncommon primitive neuroectodermal tumors that occur mostly in children; they are exceedingly rare in adults. Few published reports have compared the various aspects of these tumors between adults and children. Methods The authors report a series of 12 pineoblastomas in adults from 2 institutions over 24 years. The clinical, radiologic, and pathologic features and clinical outcomes were compared with previously reported cases in children and adults. Results Patient age ranged from 24 to 81 years, and all but 1 patient exhibited symptoms of obstructive hydrocephalus. Three patients underwent gross total resection, and subtotal resection was performed in 3 patients. Diagnostic biopsy specimens were obtained in an additional 6 patients. Pathologically, the tumors had the classical morphologic and immunohistochemical features of pineoblastomas. Postoperatively, 10 patients received radiotherapy, and 5 patients received chemotherapy. Compared with previously reported cases, several differences were noted in clinical outcomes. Of the 12 patients, only 5 (42%) died of their disease (average length of survival, 118 months); 5 patients (42%) are alive with no evidence of disease (average length of follow-up, 92 months). One patient died of unrelated causes, and one was lost to follow-up. Patients with subtotal resections or diagnostic biopsies did not suffer a worse prognosis. Of the 9 patients with biopsy or subtotal resection, 4 are alive, 4 died of their disease, and 1 died of an unrelated hemorrhagic cerebral infarction. Conclusions Although this series is small, the data suggest that pineoblastomas in adults have a less aggressive clinical course than in children.

Perineural spread is a well-known mechanism of dissemination of head and neck malignancies. There are few reports of melanoma involving the brachial plexus in the literature. To their knowledge, the authors report the first known case of perineural spread of malignant melanoma to the brachial plexus. Clinicoradiological and anatomopathological correlation is presented, highlighting the importance of peripheral nerve communications in perineural spread.

Objective: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4–immunoglobulin G (IgG) serologic testing. Methods: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. Results: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)–positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. Conclusions: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS.

Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition.

Background Metastatic disease is a well-known sequela of malignant peripheral nerve sheath tumors (MPNSTs). Metastic spread to the brain is unusual. Case Description A 56-year-old man was found to have a high grade MPNST of the sciatic nerve. Despite en-bloc excision of the sciatic nerve mass and local radiation postoperatively, he developed pathologically confirmed systemic metastases. He was found to have lung nodules and received chemotherapy 25 months after the diagnosis, and 32 months after the initial diagnosis, he presented with left leg weakness and sensory changes and was found to have a lesion of the frontal lobe for which he received palliative radiation. He developed systemic metastases and died 35 months after initial presentation. We retrospectively reviewed the charts of 179 patients treated at our institution with MPNSTs since 1994. This was the only case of a pathology proven brain metastasis, resulting in an incidence of 0.5%. Literature review revealed 21 cases. The mean age was found to be 37.5 years, and mean survival after development of a brain metastasis was 9.9 months. Conclusions Brain metastases from MPNSTs are very rare and represent a poor prognosis, with survival after brain metastasis reported to be approximately 10 months. Early and effective initial diagnosis and treatment of MPNSTs likely represent the best opportunity for increased overall survival.

To describe imaging characteristics of neuromuscular choristomas (NMC) and to differentiate them from fibrolipomatous hamartomas (FLH).Clinical and imaging characteristics of six patients with biopsy-proven NMC and six patients with FLH were reviewed by musculoskeletal, a pediatric, and two in-training radiologists with a literature review to define typical magnetic resonance imaging features by consensus. Five radiology trainees blinded to cases and naive to the diagnosis of NMC and a musculoskeletal-trained radiologist rated each lesion as having more than or less than 50% intralesional fat, as well as an overall impression using axial T1 images. Sensitivity, specificity, accuracy, and interobserver agreement kappa were determined.Typical features of NMC include smoothly tapering, fusiform enlargement of the sciatic nerve or brachial plexus elements with T1 and T2 signal characteristics closely following those of muscle. Longitudinal bands of intervening low T1 and T2 signal were often present and likely corresponded to fibrous tissue by pathology. Four of five patients with long-term follow-up (80%) developed aggressive fibromatosis after percutaneous or surgical biopsy. Nerve fascicle thickening often resulted in a "coaxial cable" appearance similar to classic FLH, however, using a cutoff of50% intralesional fat allowed for differentiation with 100% sensitivity by all reviewers and 100% specificity when all imaging features were utilized for impressions. Agreement was excellent with all differentiating methods (kappa 0.861-1.0).NMC can be confidently differentiated from FLH and malignancies using characteristic imaging and clinical features. When a diagnosis is made, biopsy should be avoided given frequent complication by aggressive fibromatosis.

Oligodendroglial tumors may rarely display striking desmoplasia resulting in unusual histologic patterns that have not been completely characterized. We reviewed the clinicopathologic findings of 7 such cases. Patients included 4 men and 3 women. Mean age at the time of primary surgery was 49 years (range, 31 to 57 y). All tumors were of World Health Organization grade III (4 anaplastic oligodendrogliomas and 3 anaplastic oligoastrocytomas). Characteristic morphologic features included tumor nests/nodules with surrounding fibrosis/ desmoplasia (n = 5), cords/single-cell infiltration (n = 2), mini-gemistocytes (n = 5), endothelial hypertrophy (n = 6), and necrosis (n = 1). Mean mitotic index was 9 mitoses per 10 high-power fields. Immunohistochemical studies demonstrated immunoreactivity for PDGFRα 1 to 3 + (5 of 6), PDGFRβ 3 + (n = 3 of 3), and EGFR 1 to 2 + (n = 5 of 6). p53 protein expression was 1-2+ and MIB-1 labeling index was moderate. Four tumors showed 1p19q codeletion, 1 tumor showed 1p deletion only, and 2 tumors showed intact 1p19q loci. t(1:19) was identified in 2 (of 3) tested cases, both also with 1p19q codeletion, and was absent in the case with 1p loss only. IDH1R132H mutant protein was detected in 3 (of 6) cases, and an IDH mutation (R132S) was identified in an additional case by pyrosequencing. Clinical follow-up was available in 6 (of 7) patients (mean follow-up of 64.2 mo). Five (of 6) developed recurrence/progression at a mean interval of 49.2 months after primary diagnosis. Only 1 patient died of disease, 22.5 months after primary diagnosis. Oligodendroglial tumors with prominent desmoplasia are rare. Most cases demonstrate 1p19q codeletion and IDH1 mutations, and behave as expected for anaplastic oligodendroglial tumors.

Sciatic nerve endometriosis (EM) is a rare presentation of retroperitoneal EM. The authors present 2 cases of catamenial sciatica diagnosed as sciatic nerve EM. They propose that both cases can be explained by perineural spread of EM from the uterus to the sacral plexus along the pelvic autonomie nerves and then further distally to the sciatic nerve or proximally to the spinal nerves. This explanation is supported by MRI evidence in both cases. As a proof of concept, the authors retrieved and analyzed the original MRI studies of a case reported in the literature and found a similar pattern of spread. They believe that the imaging evidence of their institutional cases together with the outside case is a very compelling indication for perineural spread as a mechanism of EM of the nerve.

Oncolytic measles virus strains are currently being evaluated in several clinical trials including glioblastoma and ovarian cancer, while clinical application in breast cancer is in development. The role of poliovirus receptor-related 4 (PVRL4), as a measles virus receptor, has been well documented. However the regulation of PVRL4 is not well understood. Immunohistochemistry and western blot analysis shows increased PVRL4 protein levels in glioblastoma and breast tumor clinical samples with no significant change in PVRL4 mRNA levels detected by qRT-PCR, suggesting that PVRL4 is likely post-transcriptionally regulated. Genes can be post-transcriptionally regulated by miRNAs by binding to the 3’UTR of the targeted mRNA causing translational repression or degradation. Thus, we sought to investigate the potential role of miRNAs in PVRL4 post-transcriptional regulation. Algorithms from microRNA. org and RegRNA, predicted that, from the miRNAs that are reportedly down-regulated in glioblastoma and breast cancer, miR-31 and miR-128 binds the 3’UTR of PVRL4. Indeed, luciferase binding assays demonstrated miR-31 and-128binding to the 3’UTR of PVRL4, suggesting that PVRL4 is a miRNA targeted gene. QRT-PCR studies validated that miR-31 and miR-128 are down-regulated in glioblastoma and breast tumor clinical samples, further supporting the hypothesis that PVRL4 are post-transcriptionally regulated by miRNAs. In order to understand the effects of the respective miRNAs on PVRL4 and thus on measles virus infectivity, a viral strain (Leonard et. al, 2010, J. Virol.) that exclusively utilizes PVRL4 as its receptor was employed to infect the cancer cell lines followed by evaluation of virus infectivity via measles viral nucleoprotein (N-protein) levels. Subsequent gain -and loss-of-function experiments showed that overexpression of miR-31and miR-128, via lentiviral-vector transduction, down-regulated the endogenous levels of PVRL4 and measles virus infectivity, while transduction of lentiviral-vectors expressing PVRL4 restored measles virus infectivity. The functional affects were reversed or increased upon transduction with the complementary anti-miRs-128 and anti-miR-31. These results are being further validated in ongoing in vivo mouse models where cancer cell lines stably transduced with miR-128, miR-31 or anti-miR-128, anti-miR-31, are transplanted in mice to evaluate tumor size and survival rates upon measles virus infection. These data suggest that PVRL4 is post-transcriptionally regulated by miR-128 and miR-31, and thus, these represent possible miRNA targets that could modulate PVRL4 levels in order to enhance oncolytic measles virus infectivity.This research is supported by P50 CA 108961-7, P50 CA 136393-4, P50 CA 116201-7 and R01 CA 136547-4.

Background High frequencies of the BRAF V600E mutation have been reported in pleomorphic xanthoastrocytoma (PXA). Recently, a BRAF V600E mutation-specific antibody has been developed and validated. We evaluated the immunohistochemical (IHC) detection of BRAF V600E mutation in PXA by comparing to gold standard molecular analysis and investigating the interobserver variability of the IHC scoring. We performed BRAF V600E IHC in 46 cases, of which 37 (80%) cases had sufficient tumor tissue for molecular analysis. IHC detection was performed using monoclonal mouse antibody VE1 (Spring Bioscience). IHC slides were scored independently by four reviewers blind to molecular data, including a primary (gold standard) and three additional reviewers. BRAF V600E mutation status was assessed by allele-specific polymerase chain reaction (PCR) with fragment analysis. Results All 46 cases showed interpretable BRAF V600E IHC results: 27 (59%) were positive (strong cytoplasmic staining), 19 (41%) were negative (6 of these cases with focal/diffuse weak cytoplasmic staining, interpreted as nonspecific by the primary reviewer). By molecular analysis, all 37 cases that could be tested had evaluable results: 22 (59%) cases were positive for BRAF V600E mutation and were scored as “IHC-positive”, and 15 (41%) were negative (including 11 cases scored as “IHC-negative” and 4 cases scored as negative with minimal nonspecific staining). IHC detection of BRAF V600E mutant protein was congruent in all 37 cases that were successfully evaluated by molecular testing (sensitivity and specificity of 100%). Agreement for IHC scoring among the 4 reviewers was almost perfect (kappa 0.92) when cases were scored as “positive/negative” and substantial (kappa 0.78) when minimal nonspecific staining was taken into account. Conclusions We conclude that detection of BRAF V600E mutation by immunohistochemistry is highly sensitive and specific. BRAF V600E IHC interpretation is usually straightforward, but awareness of possible nonspecific staining is necessary and training is recommended. It is a practical rapid method that may avoid the need of labor-intensive molecular testing and may be most valuable in small biopsies unsuitable for molecular analysis.

OBJECTIVE: In pregnant women, the pituitary is enlarged and the prolactin (PRL) secreting cells increase in size and number. This PRL cell hyperplasia is associated with hyperprolactinemia. The aim of the present work was to investigate adenohypophysial vascularization and immunoexpression of vascular endothelial growth factor (VEGF) in pituitaries of pregnant and post-partum women and compare the results with age-matched adenohypophyses of non-pregnant women who had no endocrine diseases. DESIGN: Pituitaries (n=18) obtained by autopsy from female patients of reproductive age who had died during pregnancy, after abortion or during post-partum were immunostained for CD-34 and VEGF using the streptavidinbiotin-peroxidase complex method. RESULTS: The results showed that microvessel densities and VEGF immunoexpression in the adenohypophyses of pregnant and post-partum women were similar to those found in the control pituitaries. CONCLUSION: It can be concluded that pituitary enlargement and PRL cell hyperplasia in pregnant women may occur without neovascularization and increased VEGF immunoexpression.