Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration.

In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent's ability to restore immunological function in the context of intended use.

Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype.

Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages.

Spinal Anaplastic Oligodendroglioma With Oligodendrogliomatosis: Molecular Markers and Management: Case Report.

BACKGROUND AND IMPORTANCE: Spinal cord oligodendrogliomas are rare tumors, with a reported incidence varying between 0.8% and 4.7% of all spinal cord tumors and just over 50 cases reported in the literature. Of these, only 9 cases are histologically defined as anaplastic oligodendrogliomas, with few having complete molecular characterization. The diffuse tumor spread that can occur along the subarachnoid space with secondary invasion of the leptomeninges is called oligodendrogliomatosis and is associated with poor outcome. CLINICAL PRESENTATION: A 68-year-old man with a history of lumbar stenosis status after lumbar decompression presented with new-onset right lower-extremity weakness. Magnetic resonance imaging demonstrated an intramedullary lesion from T9 to T12. During an attempted diagnostic biopsy, numerous intradural intramedullary lesions not present on magnetic resonance imaging were observed. Tissue biopsy demonstrated a 1p/19q-codeleted anaplastic oligodendroglioma with diffuse oligodendrogliomatosis. Postoperative treatment included 39.2-Gy radiation over 22 fractions from T1 to the bottom of the thecal sac with a boost to the T9-T12 area, the primary site of disease, to a total dose of 43.2 Gy in 24 fractions, followed by adjuvant temozolomide at a dose of 200 mg/m on days 1 to 5 in a 28-day cycle. At the 1-year follow-up, the patient demonstrated moderate neurological improvement. CONCLUSION: Management, prognosis, and use of molecular data in the decision-making algorithm for these patients are discussed, together with a review of all cases of primary intradural intramedullary spinal anaplastic oligodendrogliomas reported to date. Our study indicates that the combination of sequential treatment with radiation and temozolomide might provide a favorable outcome in the case of 1p/19q-codeleted spinal anaplastic oligodendrogliomas and that molecular analysis can be beneficial in guiding treatment strategies, although the impact of IDH mutations on these tumors is still unclear.

Fatal juvenile xanthogranuloma presenting as a sellar lesion: case report and literature review.

INTRODUCTION: Juvenile xanthogranuloma (JXG) is a histiocytic condition in the spectrum of non-Langerhans histiocytosis that preferentially affects children. Rarely this condition can involve the central nervous system (CNS) with devastating consequences. METHODS: The authors report the unique case of an 11-year-old child who initially presented with a sellar lesion without evidence of the cutaneous stigmata typical of JXG. She was later discovered to have JXG following initial diagnosis of granulomatous hypophysitis, with development of widespread intracranial disease and subsequent neurological deterioration. She underwent subtotal resection of her sellar lesion followed by whole brain radiation and systemic chemotherapy; however, she succumbed to her disseminated disease within 1 month of the JXG diagnosis. CONCLUSIONS: This is a rare case of fatal disseminated intracranial JXG without cutaneous manifestations. Additionally, the initial presentation as a sellar lesion is particularly unusual and seldom described in the literature.

The high mitotic count detected by phospho-histone H3 immunostain does not alter the benign behavior of angiocentric glioma.

Angiocentric glioma (AG) has been formally codified in the revised 2007 WHO Classification of Tumours of the Central Nervous System. AGs characteristically exhibit mixed features of ependymal and diffuse astrocytic differentiation and low proliferation rates, with Ki-67 labeling indices ranging from less than 1 to 5%. A single case with anaplastic recurrence and a labeling index of 10% has been reported. In the present study, we report a series of three AGs (Case 1: 4-year-old girl at right frontal lobe; Case 2: 4-year-old boy at left frontal lobe; Case 3: 9-year-old boy at right temporal lobe). Case 1 with elevated proliferation index (~10%) and increased mitotic activity (six mitoses per 10 high-power fields) on phospho-histone H3 (pHH3) immunostain at presentation, nonetheless, has shown protracted recurrence-free survival after 6 years of follow-up. So far, this is the first report for evaluating the mitotic activity in AGs using pHH3 immunostain.

Aggressive meningiomas involving the parotid gland.

Parotid masses remain challenging secondary to the great diversity of primary tumors that may arise in the salivary glands and propensity for regional and even distant metastases to occur in this region. Meningioma must also be considered in the differential diagnosis of parotid masses, whether from direct extension, metastases, or as an extracranial primary. We herein report 4 cases of aggressive meningioma involving the parotid gland and the pathologic considerations in evaluating these tumors.

Atypical teratoid/rhabdoid tumors in adults: a case report and treatment-focused review.

UNLABELLED: Atypical teratoid/rhabdoid tumor is predominantly a childhood tumor and has only been rarely reported in adults; therefore, treatment regimens are often extrapolated from the pediatric experience. Typically, children are treated with craniospinal radiation therapy which is often followed by systemic chemotherapy. Employing pediatric regimens to treat this tumor in adult patients poses a particular risk for myelosuppression, as the prescribed doses in pediatric protocols exceed those tolerated by adults, and conventional craniospinal radiation can be associated with prolonged myelotoxicity and a depletion of the bone marrow reserve in vertebrae of adults. Here we present a case of a woman with a pineal region atypical teratoid/rhabdoid tumor, an unusual adult cancer presenting in an atypical location. This is followed by a review of the disease in adult patients with an emphasis on treatment and suggestions to minimize myelotoxicity. KEYWORDS: Atypical rhabdoid tumor; AT/RT; Pineal tumor; Adult.

Progressive multifocal leukoencephalopathy in a patient with glioblastoma.

Malignant gliomas are aggressive malignancies which inevitably recur despite multimodality treatment. In a subset of patients who are longer term survivors of this disease, progressive radiologic worsening can also occur from late effects of radiation rather than recurrent tumor, a differential diagnosis that is commonly considered in this setting. However, other causes for radiologic progression are not as well recognized and could potentially confound management leading to incorrect treatment decisions. Progressive multifocal leukoencephalopathy (PML) is a rare infectious demyelinating disease of the central nervous system seen primarily in immunocompromised patients, the early diagnosis and treatment of which remains a challenge. Here, we report a case of a long term survivor with glioblastoma whose diagnostic and therapeutic management was confounded by the development of PML. We review the radiological features and clinical course of this patient to highlight the dramatic neurological course in the setting of a highly malignant tumor, and emphasize the unusual changes in diffusion weighted images, and the need for clinical suspicion for early diagnosis of PML.

Atypical teratoid/rhabdoid tumor of the pineal region in an adult.

An atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal tumor most often occurring in the posterior fossa in children younger than 3 years of age. Adult cases of AT/RT are very rare, and 27 cases with a diagnosis of either AT/RT or (malignant) rhabdoid tumor have been reported to date. The authors report an adult case of an AT/RT occurring in the pineal region with molecular cytogenetic and immunohistochemical confirmation. A 33-year-old woman presented with a 2-month history of headache and blurred vision progressing to diplopia, and was admitted emergently due to deteriorating mental status. An MR image showed a heterogeneously enhancing mass involving the posterior third ventricle and pineal region with mild hydrocephalus. She underwent a subtotal resection of the tumor and was then treated with chemoradiation. Thirteen months after surgery, she was still alive with radiological evidence of recurrence/residual lesions. Histological sections showed epithelioid cellular sheets of rhabdoid tumor cells with scattered mitotic figures. Immunohistochemically, the tumor cells were diffusely and strongly positive for epithelial membrane antigen and vimentin, and showed focal expression of glial fibrillary acidic protein, pancytokeratin, and neurofilament protein. Loss of nuclear immunoreactivity for INI1 protein was observed. Fluorescence in situ hybridization analysis showed monosomy 22. Histologically, this tumor consisted exclusively of epithelioid tumor cells with rhabdoid features. The differential diagnoses include rhabdoid glioblastoma, metastatic carcinoma, and rhabdoid meningioma. Molecular testing to identify monosomy 22 or deletions of the chromosome 22q11 containing the INI1/hSNF5 gene and/or immunohistochemical staining with INI1 antibody is of great importance for the diagnosis of this tumor.

Bilateral gonadoblastoma with dysgerminoma and pilocytic astrocytoma with WT1 GT-IVS9 mutation: A 46 XY phenotypic female with Frasier syndrome.

Frasier syndrome is characterized by a 46 XY disorder of sex development, nephropathy, and increased risk for gonadoblastoma due to Wilms tumor 1(WT1) mutation in the donor splice site of intron-9, resulting in the splice form +KTS. Germ cell tumors and gonadoblastomas have been reported previously in Frasier syndrome. We present the clinical, radiological, and genetic (WT1 mutation analysis) of a 46 XY phenotypic female with Frasier syndrome with bilateral gonadoblastoma with dysgerminoma who developed pilocytic astrocytoma.

Neuron-glia signaling in trigeminal ganglion: implications for migraine pathology.

OBJECTIVE: The goal of this study was to investigate neuronal-glial cell signaling in trigeminal ganglia under basal and inflammatory conditions using an in vivo model of trigeminal nerve activation. BACKGROUND: Activation of trigeminal ganglion nerves and release of calcitonin gene-related peptide (CGRP) are implicated in the pathology of migraine. Cell bodies of trigeminal neurons reside in the ganglion in close association with glial cells. Neuron-glia interactions are involved in all stages of inflammation and pain associated with several central nervous system (CNS) diseases. However, the role of neuron-glia interactions within the trigeminal ganglion under normal and inflammatory conditions is not known. METHODS: Sprague-Dawley rats were utilized to study neuron-glia signaling in the trigeminal ganglion. Initially, True Blue was used as a retrograde tracer to localize neuronal cell bodies in the ganglion by fluorescent microscopy and multiple image alignment. Dye-coupling studies were conducted under basal conditions and in response to capsaicin injection into the TMJ capsule. S100B and p38 expression in neurons and glia were determined by immunohistochemistry following chemical stimulation. CGRP levels in the ganglion were measured by radioimmunoassay in response to capsaicin. In addition, the effect of CGRP on the release of 19 different cytokines from cultured glial cells was investigated by protein microarray analysis. RESULTS: In unstimulated control animals, True Blue was detected primarily in neuronal cell bodies localized in clusters within the ganglion corresponding to the V3 region (TMJ capsule), V2 region (whisker pad), or V1 region (eyebrow and eye). However, True Blue was detected in both neuronal cell bodies and adjacent glia in the V3 region of the ganglion obtained from animals injected with capsaicin. Dye movement into the surrounding glia correlated with the time after capsaicin injection. Chemical stimulation of V3 trigeminal nerves was found to increase the expression of the inflammatory proteins S100B and p38 in both neurons and glia within the V3 region. Unexpectedly, increased levels of these proteins were also observed in the V2 and V1 regions of the ganglion. CGRP and the vesicle docking protein SNAP-25 were colocalized in many neuronal cell bodies and processes. Decreased CGRP levels in the ganglion were observed 2 hours following capsaicin stimulation. Using protein microarray analysis, CGRP was shown to differentially regulate cytokine secretion from cultured trigeminal ganglion glia. CONCLUSIONS: We demonstrated that activation of trigeminal neurons leads to changes in adjacent glia that involve communication through gap junctions and paracrine signaling. This is the first evidence, to our knowledge, of neuron-glia signaling via gap junctions within the trigeminal ganglion. Based on our findings, it is likely that neuronal-glial communication via gap junctions and paracrine signaling are involved in the development of peripheral sensitization within the trigeminal ganglion and, thus, are likely to play an important role in the initiation of migraine. Furthermore, we propose that propagation of inflammatory signals within the ganglion may help to explain commonly reported symptoms of comorbid conditions associated with migraine.

Papillary tumors of the pineal region: case report.

OBJECTIVE: The pineal region is a rare intracranial site for metastasis. We report three patients initially considered to have metastatic papillary adenocarcinoma to the pineal region. On review, these papillary, keratin-positive neoplasms meet the criteria for papillary tumor of the pineal region (PTPR). CLINICAL PRESENTATION: These neoplasms occurred in three women (age range, 37-55 yr). Imaging studies demonstrated well-circumscribed lesions in the pineal region. All patients presented with obstructive hydrocephalus and symptoms attributable to hydrocephalus and tectal compression. INTERVENTION: All three patients underwent near total microsurgical resection of the pineal region neoplasm, followed by adjuvant radiotherapy. The two patients with long-term follow-up (56-60 mo) have remained clinically stable without evidence of local or distant recurrence. The first two patients were initially diagnosed as having papillary metastatic carcinoma of unknown origin. The third patient was treated after the recent description of PTPR and met the histopathological diagnostic criteria. Retrospective pathological review of the previous two patients resulted in designation as PTPR. CONCLUSION: The morphological features of the tumors in our series, along with the clinical presentations, are similar to those in the original description of the PTPR. Our findings agree with the original hypothesis that the cells composing the PTPR are similar to ependymal cells of the subcommissural organ, thus furthering the hypothesis that the PTPR derives from a specialized ependymocyte associated with the subcommissural organ. The two patients with long-term follow-up (56-60 mo) have remained clinically stable without evidence of local or distant recurrence.

Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas.

Distinguishing between grade II and grade III diffuse astrocytomas is important both for prognosis and for treatment decision-making. However, current methods for distinguishing between grades based on proliferative potential are suboptimal, making identification of clear cutoffs difficult. In this study, we compared the results from immunohistochemical staining for phospho-histone H3 (pHH3), a specific marker of cells undergoing mitosis, with standard mitotic counts (number of mitoses/10 high-power fields) and MIB-1 labeling index values for assessing proliferative activity. We tested the relationship between pHH3 staining and tumor grade and prognosis in a retrospective series of grade II and III infiltrating astrocytomas from a single institution. The pHH3 index (per 1000 cells), MIB-1 index (per 1000 cells), and number of mitoses per 10 high-power fields were determined for each of 103 cases of grade II and III diffuse astrocytomas from patients with clinical follow-up. pHH3 staining was found to be a simple and reliable method for identifying mitotic figures, allowing a true mitotic index to be determined. The pHH3 mitotic index was significantly associated both with the standard mitotic count and with the MIB-1 index. Univariate analyses revealed that all 3 measurements of proliferation were significantly associated with survival. However, the pHH3 mitotic index accounted for a larger proportion of variability in survival than standard mitotic count or MIB-1/Ki-67 labeling index. After adjusting for age, extent of resection, and performance score, the pHH3 mitotic index remained an independent predictor of survival. Thus, pHH3 staining provides a simple and reliable method for quantifying proliferative potential and for the stratification of patients with diffuse astrocytomas into typical grade II and III groups. These results also suggest that pHH3 staining may be a useful method in other neoplasms in which accurate determination of proliferation potential is relevant to tumor grading or clinical treatment decision-making.

Textiloma (gossypiboma) mimicking recurrent intracranial tumor.

CONTEXT: Resorbable substances used to achieve hemostasis during neurosurgical procedures comprise 3 principal classes based on chemical composition: (1) gelatin sponge, (2) oxidized cellulose, and (3) microfibrillar collagen. Nonresorbable hemostatic aides include various forms of cotton and rayon-based hemostats (cottonoids and kites). Resorbable and nonresorbable hemostatic agents have been reported to cause symptomatic mass lesions, most commonly following intra-abdominal surgery. Histologic examination typically shows a core of degenerating hemostatic agent surrounded by an inflammatory reaction. Each agent exhibits distinctive morphologic features that often permit specific identification. Hemostat-associated mass lesions have been variously referred to as textilomas, gossypibomas, gauzomas, or muslinomas. OBJECTIVES: The aims of this study were to (1) identify cases of histologically proven cases of textiloma in neurosurgical operations, (2) characterize the specific hemostatic agent associated with textiloma formation, and (3) characterize the preoperative magnetic resonance imaging appearance of textiloma. DESIGN: Cases in which a textiloma constituted the sole finding on repeat surgery for recurrent brain tumor, or was a clinically significant component of a radiologically identified mass lesion together with residual tumor, constituted the study set. RESULTS: Five textilomas were identified and evaluated. The primary neoplasm was different in each case and included pituitary adenoma, tanycytic ependymoma, anaplastic astrocytoma, gliosarcoma, and oligodendroglioma. In all cases, preoperative magnetic resonance imaging suggested recurrent tumor. Textilomas included all categories of resorbable hemostatic agent. Other foreign bodies were present in some cases; the origin of these foreign bodies was traced to fibers shed from nonresorbable hemostatic material placed temporarily during surgery and removed before closure (cottonoids and kites). Inflammatory reactions included giant cells, granulomas, and fibroblastic proliferation. Microfibrillar collagen (Avitene) textilomas were associated with a striking eosinophil infiltration that was not seen with any other hemostatic agent. CONCLUSIONS: Hemostatic agents may produce clinically symptomatic, radiologically apparent mass lesions. When considering a mass lesion arising after intracranial surgery, the differential diagnosis should include textiloma along with recurrent tumor and radiation necrosis.

Cerebellar central liponeurocytoma.

Cerebellar liponeurocytoma is a rare, benign neuroepithelial tumor that occurs exclusively in the cerebellum of adults. Its salient histological features include advanced neuronal/neurocytic differentiation, focal vacuolated cells resembling mature adipose cells, low mitotic activity, and lack of endothelial proliferation and/or necrosis. The morphological appearance of this neoplasm can be confused with that of oligodendroglioma, neurocytoma, ependymoma, medulloblastoma, hemangioblastoma, metastatic renal cell carcinoma, and other clear cell carcinomas. Its full biological potential and histological features, however, have not been fully exploited due to the rarity of this tumor. The authors describe a case with clinical, imaging, histological, immunohistochemical, and ultrastructural features.

Epidermal growth factor receptor, cyclooxygenase-2, and BAX expression in the primary non-small cell lung cancer and brain metastases.

PURPOSE: The purpose is to identify biological markers that predict brain metastasis and treatment outcome in non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Samples were obtained from the primary tumors, lymph nodes, and brain metastases of 29 patients with NSCLC who had undergone resection of both the pulmonary tumors and the brain lesions. Samples from 29 patients matched for age, sex, and histology whose pulmonary tumors were resected served as controls. Samples were stained with H&E as well as immunohistochemical stains for epidermal growth factor receptor (EGFR), cyclooxygenase 2 (COX-2), and BAX. Comparisons were made between patients with and without brain metastasis. Independent investigators determined the percentage of positive cells. RESULTS: There was positive correlation in expression of all three biomarkers between primary lung tumors and lymph node metastases. Significantly higher levels of EGFR were found in lymph node metastases in the control group (P = 0.0147). COX-2 expression in brain lesions correlated with expression in primary tumors (P = 0.023). BAX levels were lower in poorly differentiated tumors in lymph node metastases in the control group (P = 0.01) and in brain metastases (P = 0.045). Low EGFR expression and high COX-2 expression in lymph node metastasis were associated with poorer treatment outcome. CONCLUSIONS: Expression of EGFR, COX-2, and BAX in primary lung tumors did not differ between patients with brain metastases from NSCLC and those without brain metastases. These three biomarkers cannot be used to predict brain metastasis. Studies of other biomarkers are under way in an effort to predict brain metastasis among patients with NSCLC.

Posterior fossa decompression for life-threatening tonsillar herniation in patients with gliomatosis cerebri: report of three cases.

OBJECTIVE AND IMPORTANCE: Gliomatosis cerebri (GC) is a rare type of primary brain tumor that diffusely infiltrates more than two lobes of the brain while the normal cerebral architecture is maintained. To the best of our knowledge, the association between an acquired tonsillar herniation and GC has never been reported. In this article, we describe three patients with progressive gliomatosis of the cerebellar hemispheres who subsequently showed signs and symptoms secondary to tonsillar herniation. Early recognition of this potentially life-threatening complication allowed us to recommend prompt surgical intervention. CLINICAL PRESENTATION: One patient with primary, or Type I, GC presented with suboccipital headaches, and two patients with secondary, or Type II, GC presented with the signs and symptoms of progressive myelopathy. Serial imaging studies demonstrated progressive involvement of the cerebellum, descent of the cerebellar tonsils through the foramen magnum, and cervicomedullary spinal cord compression. INTERVENTION: Once the tonsillar herniation was recognized, all three patients underwent posterior fossa decompression, a cervical laminectomy to the lowest level of the tonsillar herniation, and duraplasty. All three patients experienced immediate improvement in their conditions. CONCLUSION: Early recognition of tonsillar herniation, a possibly overlooked cause of death in patients with GC, allows for early surgical intervention as a potentially lifesaving procedure and significant improvement in the patient's condition.