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Background Pineal parenchymal tumors are exceedingly rare brain tumors responsible for less than 1% of all adult primary intracranial malignancies in the United States. In this study, we describe the clinicopathologic features, management, and outcomes of patients with pineal parenchymal tumor of intermediate differentiation (PPTID). Methods We describe a single-center, multidisciplinary team experience in managing PPTID patients over a 15-year period (January 2000 to January 2015) at The University of Texas MD Anderson Cancer Center (MDACC). Pathology was reviewed by the pathology collaborators (A.G. and G.N.F.) and retrospective chart review was performed for treatment and clinical outcomes. Results We identified 17 patients (9 male) with diagnosis of PPTID. Median age at diagnosis of PPTID was 37 years (range, 15-57 years). Follow-up ranged from 0.1 to 162.8 months with 6 reported deaths. Most patients presented with headaches and diplopia. Three patients had neuroaxial dissemination at initial diagnosis, and recurrence of tumor was common (7/16) despite treatment. Conclusions No clear prognostic factors were identified in this series. Extension of resection showed a trend toward improved survival. PPTID with neuroaxial dissemination benefits from aggressive initial treatment including craniospinal irradiation and adjuvant chemotherapy, whereas localized disease may be treated traditionally with maximum debulking followed by adjuvant radiotherapy alone. Long-term monitoring is recommended for neurotoxicity and/or late recurrence. [ABSTRACT FROM AUTHOR]

Background: Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. Methods: We describe a single-center multidisciplinary experience in ma naging PC patients over a 22-year period and review previously published PC series. Results: Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16-82 years), and the median time from PA to PC transformation was 5 years (range 1-2 9 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation aft er PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervo us system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most common ly used chemotherapy was TMZ, and TMZbased therapy was associated with the longest PFS in 12 (71%) c ases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year sur vival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. Conclusions: PC management benefits from multidisciplinary care and multimod ality therapy. TMZ-based regimens were associated with high survival rates and long disease contr ol. [ABSTRACT FROM AUTHOR]

Background: Virtually all low-grade gliomas (LGGs) will progress to high-grade gliomas (HGGs), including glioblastoma, the most common malignant primary brain tumor in adults. A key regulator of immunosuppression, fibrinogen-like protein 2 (FGL2), may play an important role in the malignant transformation of LGG to HGG. We sought to determine the mechanism of FGL2 on tumor progression and to show that inhibiting FGL2 expression had a therapeutic effect.Methods: We analyzed human gliomas that had progressed from low- to high-grade for FGL2 expression. We modeled FGL2 overexpression in an immunocompetent genetically engineered mouse model to determine its effect on tumor progression. Tumors and their associated microenvironments were analyzed for their immune cell infiltration. Mice were treated with an FGL2 antibody to determine a therapeutic effect. Statistical tests were two-sided.Results: We identified increased expression of FGL2 in surgically resected tumors that progressed from low to high grade (n = 10). The Cancer Genome Atlas data showed that LGG cases with overexpression of FGL2 (n = 195) had statistically significantly shorter survival (median = 62.9 months) compared with cases with low expression (n = 325, median = 94.4 months, P < .001). In a murine glioma model, HGGs induced with FGL2 exhibited a mesenchymal phenotype and increased CD4+ forkhead box P3 (FoxP3)+ Treg cells, implicating immunosuppression as a mechanism for tumor progression. Macrophages in these tumors were skewed toward the immunosuppressive M2 phenotype. Depletion of Treg cells with anti-FGL2 statistically significantly prolonged survival in mice compared with controls (n = 11 per group, median survival = 90 days vs 62 days, P = .004), shifted the phenotype from mesenchymal HGG to proneural LGG, and decreased M2 macrophage skewing.Conclusions: FGL2 facilitates glioma progression from low to high grade. Suppressing FGL2 expression holds therapeutic promise for halting malignant transformation in glioma. [ABSTRACT FROM AUTHOR]

Objectives: To report a case of primary rhabdomyosarcoma (RMS) of the pineal gland in an adult, as well as review the literature on this rare entity. Methods: The case is compared with previous reports of similar entities, with emphasis on this patient's characteristics and clinical presentation, investigations, and management. Results: Diagnosis of primary RMS of the pineal gland was based on the presence of strap cells and multinucleated myotube-like structures, as well as tumor cell expression of skeletal muscle markers consistent with myogenic differentiation. Multimodality treatment was initiated based on pediatric protocols. Unfortunately, the disease progressed on treatment, and the patient survived only 5 months from diagnosis. Conclusions: Pineal RMS is a rare disease with poor prognosis. Optimal management is unknown but likely to involve aggressive multimodality therapy. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. Although many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs), the mechanisms that regulate self-renewal and other oncogenic properties of GSCs are only now being unraveled. Here we showed that GSCs derived from GBM patient specimens express varying levels of the transcriptional repressor repressor element 1 silencing transcription factor (REST), suggesting heterogeneity across different GSC lines. Loss- and gain-of-function experiments indicated that REST maintains self-renewal of GSCs. High REST-expressing GSCs (HR-GSCs) produced tumors histopathologically distinct from those generated by low REST-expressing GSCs (LR-GSCs) in orthotopic mouse brain tumor models. Knockdown of REST in HR-GSCs resulted in increased survival in GSC-transplanted mice and produced tumors with higher apoptotic and lower invasive properties. Conversely, forced expression of exogenous REST in LR-GSCs produced decreased survival in mice and produced tumors with lower apoptotic and higher invasive properties, similar to HR-GSCs. Thus, based on our results, we propose that a novel function of REST is to maintain self-renewal and other oncogenic properties of GSCs and that REST can play a major role in mediating tumorigenicity in GBM. S TEM C ELLS 2012;30:405-414 [ABSTRACT FROM AUTHOR]

Production of neurons from non-neural cells has far-reaching clinical significance. We previously found that myoblasts can be converted to a physiologically active neuronal phenotype by transferring a single recombinant transcription factor, REST-VP16, which directly activates target genes of the transcriptional repressor, REST. However, the neuronal subtype of M-RV cells and whether they can establish synaptic communication in the brain have remained unknown. M-RV cells engineered to express green fluorescent protein (M-RV-GFP) had functional ion channels but did not establish synaptic communication in vitro. However, when transplanted into newborn mice cerebella, a site of extensive postnatal neurogenesis, these cells expressed endogenous cerebellar granule precursors and neuron proteins, such as transient axonal glycoprotein-1, neurofilament, type-III β-tubulin, superior cervical ganglia-clone 10, glutamate receptor-2, and glutamate decarboxylase. Importantly, they exhibited action potentials and were capable of receiving glutamatergic synaptic input, similar to the native cerebellar granule neurons. These results suggest that M-RV-GFP cells differentiate into glutamatergic neurons, an important neuronal subtype, in the postnatal cerebellar milieu. Our findings suggest that although activation of REST-target genes can reprogram myoblasts to assume a general neuronal phenotype, the subtype specificity may then be directed by the brain microenvironment. S C 2010;28:1839-1847 [ABSTRACT FROM AUTHOR]

Polypyrimidine tract-binding protein (PTB) is a nuclear factor that binds to the polypyrimidine tract of premRNA introns, where it is associated with negative regulation of RNA splicing and with exon silencing. We have previously demonstrated that PTB expression is increased during glial cell transformation and that this increase correlates with changes in the RNA splicing of the fibroblast growth factor receptor 1. In this paper we examine the specific cellular distribution of PTB expression in normal brain and in glial and neuronal tumors. Paraffin sections were stained by using a primary monoclonal antibody against PTB. Tissues that were analyzed included normal brain (n = 2) and tumors of various types (low-grade astrocytoma, n = 2; anaplastic astrocytoma, n = 2; glioblastoma, n = 4; medulloblastoma, n = 4; central neurocytoma, n = 2; dysplastic gangliocytoma, n = 1; ganglioglioma, n = 1; paraganglioma, n = 1). In glial cell populations the majority of astrocytes and oligodendrocytes were negative, but occasional positively staining cells were observed. Strongly positive PTB staining was observed in ependymocytes, choroid plexus epithelium, microglia, arachnoid membrane, and adenohypophysis, and weak staining was found in the neurohypophysis. In all cases vascular endothelium and smooth muscle stained strongly. In tumor samples, intense positive nuclear staining was observed in transformed cells of low-grade astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma, paraganglioma, and the glial population of both ganglioglioma and dysplastic gangliocytoma (the neuronal cells of both were negative). In medulloblastoma, neoplastic neuronal cells were positive, as were other cell lineages. In normal brain, all neuron populations and pineocytes were negative for PTB. We conclude that although glial cells show derepression of PTB expression, a similar mechanism is absent in both nonneoplastic neurons and in most neuronally derived tumor cells. Strong upregulation of PTB expression in tumor cells of glial or primitive neuroectodermal origin suggests involvement of this protein in cellular transformation. Whether PTB affects splicing of RNAs critical to cellular transformation or proliferation is an important question for future research. [ABSTRACT FROM AUTHOR]

Reports on the two cases of West Nile Encephalitis in patients who received hematopoietic stem cell transplants. Risk factor for acquiring symptomatic diseases; Efficacy of tacrolimus and corticosterids for chronic skin graft-versus-host diseases; Number of patients with severe encephalopathy.

Background: Oncolytic adenoviruses are promising therapies for the treatment of gliomas. However, untargeted viral replication and the paucity of coxsackie-adenovirus receptors (CARs) on tumor cells are major stumbling blocks for adenovirus-based treatment. We studied the antiglioma activity of the tumor-selective Delta-24 adenovirus, which encompasses an early 1 A adenoviral (E1A) deletion in the retinoblastoma (Rb) protein-binding region, and of the Delta-24-RGD adenovirus. Delta-24-RGD has an RGD-4C peptide motif inserted into the adenoviral fiber, which allows the adenovirus to anchor directly to integrins.Methods: CAR and integrin expression were examined by flow cytometry in six glioma cell lines and in normal human astrocytes (NHAs). Adenoviral vectors containing green fluorescent protein (GFP) (AdGFP and AdGFP-RGD) were used to infect glioma cell lines with high or low CAR expression. Viability of glioma cells infected with different adenoviruses was assessed by trypan blue staining. Adenovirus replication was quantified with the infection-dose replication assay. Athymic mice carrying glioma xenografts received intratumoral injections of Delta-24-RGD or Delta-24 and were followed for survival, which was analyzed by the Kaplan-Meier method and the log-rank test. All statistical tests were two-sided.Results: Half the glioma cell lines expressed low levels of CAR (defined as <50% of cells expressing detectable CAR); all lines expressed integrins in more than 50% of cells. Infection of U-87 MG cells (a low-CAR-expressing line) with AdGFP-RGD resulted in approximately six times more GFP-positive cells than infection with AdGFP. Delta-24-RGD was more cytopathic to both low- and high-CAR-expressing glioma lines than Delta-24, and it replicated more efficiently in both cell lines. In the xenografted mice, intratumoral injection of Delta-24-RGD was associated with longer survival than intratumoral injection of Delta-24 (P<.001, log-rank test). Furthermore, 60% of Delta-24-RGD-treated mice but only 15% of Delta-24-treated mice survived more than 4 months (difference = 45%, 95% CI = 21% to 68%).Conclusions: The antitumor activity of Delta-24-RGD suggests that it has the potential to be an effective agent in the treatment of gliomas. [ABSTRACT FROM AUTHOR]

Background The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis. Methods An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided. Results miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p–treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R2 = .303). Conclusions These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway. [ABSTRACT FROM PUBLISHER]