Meningeal SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1)-deficient tumours: an emerging group of meningeal tumours.

AIMS: Bi-allelic inactivation of SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B member 1 (SMARCB1; also known as INI1) and loss of immunohistochemical expression of SMARCB1 define the group of SMARCB1-deficient tumours. Initially highlighted in malignant rhabdoid tumours, this inactivation has subsequently been observed in several intra and extracranial tumours. To date, primary meningeal SMARCB1-deficient tumours have not been described. We report two cases of meningeal SMARCB1-deficient tumours occurring in adults. METHODS: We performed immunohistochemical analyses, comparative genomic hybridization, fluorescence in situ hybridization and targeted next-generation sequencing. RESULTS: The first meningeal tumour was a solitary mass, composed of rhabdoid, adenoid, chordoid and sarcomatoid areas. The second case presented as multiple, bilateral, supra and infratentorial nodules, was composed of fusiform and ovoid cells embedded in a myxoid stroma. Tumour cells were positive for epithelial membrane antigen (EMA), vimentin and CD34 and negative for SMARCB1 and meningothelial, melanocytic, muscular, glial markers. In the first case, one allele of SMARCB1 was completely deleted, whereas in the second case, loss of expression of SMARCB1 was observed as a consequence of a homozygous deletion of SMARCB1. CONCLUSIONS: The phenotype and genotype of these two cases did not fit diagnostically with entities already known to be SMARCB1-deficient tumours. As both tumours shared common features, they are regarded as belonging to an emerging group of primary meningeal SMARCB1-deficient tumours, not described to date. To facilitate the identification and characterization of these tumours, we recommend SMARCB1 immunohistochemistry for primary meningeal tumours which are difficult to classify, especially if immunopositive for EMA and CD34.

Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. MATERIALS AND METHODS: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150-200 mg/m2 on days 1-5 every 28 days). RESULTS: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells. CONCLUSION: This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

Hyaline astrocytic inclusions in pediatric epilepsy: report of two cases.

Distinctive hyaline inclusion bodies in the cytoplasm of neocortical astrocytes were observed in surgical resection specimens of a frontal epileptic focus, in 2 patients aged 16 and 10 who had suffered intractable partial seizures since the age of 2 years. One case had minimal neurological impairment and no brain malformation on MRI and recovered completely following surgery. The second case had mental retardation and surgery reduced the frequency and generalization of seizures. In both cases, the astrocytic inclusions were strongly eosinophilic, hyaline and refractile. They were PAS negative. Electron microscopy in the first case, confirmed their granular osmiophilic structure. By immunohistochemistry, the inclusions were strongly positive for filamin in the first case, only some were weakly positive in the second case. They also variably expressed other proteins such as alpha-B-crystallin, GFAP, S-100 protein and cytoglobin. We compare our findings with previously reported cases and discuss the clinical significance of the inclusions and the pathophysiologic relevance of filamin A and other proteins accumulation in astrocytes.

Gliomatosis cerebri, imaging findings of 12 cases.

BACKGROUND AND PURPOSE: We report 12 cases of Gliomatosis cerebri (GC), a rare brain neoplasm, to define its semeiologic criteria. Literature was reviewed to clarify its physiopathology. PATIENTS AND METHODS: From 1997 to 2008, 12 histologically proven cases with GC were retrospectively reviewed. Of the 12 patients, nine were male. The mean age was of 54 years. Were performed CT-Scan (n=6), MRI (n=12), diffusion and perfusion weighted images (n=12 and n=4), MR Spectroscopy (n=3), a FDG and a Methionin PET-Scan (n=2 and n=3 respectively). RESULTS: Primary diagnosis was missed in six cases. Most frequent clinical signs were seizure and mental changes. Imaging criteria were: area of high signal intensity on FLAIR and T2-weighted images, involving three or more contiguous lobes with conserved architecture. Frequently a bilateral widespread invasion with involvment of the corpus callosum or the anterior white commissure or both was observed. At diagnosis and in the classical form (type I) of GC, no significant contrast enhancement and decreased rCBV were observed. Focal enhancement and increased rCBV were observed in the focal mass in type II GC. MR Spectroscopy showed an increase of the Cho/Cr ratio and a decrease in the NAA/Cr one. FDG PET showed in type I a decreased avidity for the FDG whereas in type II a increased avidity was observed. MET-PET showed an increased avidity for the tracer in a GC type II and a slight avidity in a GC type I. CONCLUSION: GC is a rare brain entity. Primary diagnosis is often missed. The imaging findings of GC I, a WHO grade III tumor, should be known and include classical MRI but also PWI, MRS and scintigraphic findings.

In vivo analysis of glial cell phenotypes during a viral demyelinating disease in mice.

C57 BL/6N mice injected intracranially with the A59 strain of mouse hepatitis virus exhibit extensive viral replication in glial cells of the spinal cord and develop demyelinating lesions followed by virus clearing and remyelination. To study how different glial cell types are affected by the disease process, we combine three-color immunofluorescence labeling with tritiated thymidine autoradiography on 1-micron frozen sections of spinal cord. We use three different glial cell specific antibodies (a) to 2',3' cyclic-nucleotide 3' phosphohydrolase (CNP) expressed by oligodendrocytes, (b) to glial fibrillary acidic protein (GFAP) expressed by astrocytes, and (c) the O4 antibody which binds to O-2A progenitor cells in the rat. These progenitor cells, which give rise to oligodendrocytes and type 2 astrocytes and react with the O4 antibody in the adult central nervous system, were present but rare in the spinal cord of uninfected mice. In contrast, cells with the O-2A progenitor phenotype (O4 + only) were increased in number at one week post viral inoculation (1 WPI) and were the only immunostained cells labeled at that time by a 2-h in vivo pulse of tritiated thymidine. Both GFAP+ only and GFAP+, O4+ astrocytes were also increased in the spinal cord at 1 WPI. Between two and four WPI, the infected spinal cord was characterized by the loss of (CNP+, O4+) oligodendrocytes within demyelinating lesions and the presence of O-2A progenitor cells and O4+, GFAP+ astrocytes, both of which could be labeled with thymidine. As remyelination proceeded, CNP immunostaining returned to near normal and tritiated thymidine injected previously during the demyelinating phase now appeared in CNP+ oligodendrocytes. Thus O4 positive O-2A progenitor cells proliferate early in the course of the demyelinating disease, while CNP positive oligodendrocytes do not. The timing of events suggests that the O-2A progenitors may give rise to new oligodendrocytes and to type 2 astrocytes, both of which are likely to be instrumental in the remyelination process.

Diagnostic and therapeutic pitfalls in neurosarcoidosis.

Neurosarcoidosis is a diagnostic challenge, especially in the absence of systemic involvement, even when cerebral biopsies show noncaseating granulomas. We report a patient with a pineal germinoma associated with a extensive peri- and intra- tumoural granulomatous reaction, who was first diagnosed as possible neurosarcoïdosis. A second patient was initially considered as suffering from Multiple Sclerosis. Brain biopsy showed typical granulomas and gallium scintigraphy revealed other locations of the disease. Unfortunately, he developed a severe, steroid-induced, epidural lipomatosis at the Th3-Th8 levels and died unexpectedly after surgical decompression. Granulomatous inflammation in a tissue obtained by biopsy from a midline lesion should be always considered for the differential diagnosis of germinoma. Corticosteroid-sparing immunosuppressant drugs should be used early in neurosarcoïdosis.

[Central nervous system involvement in Wegener's granulomatosis]. / Atteinte cérébrale au cours d'une maladie de Wegener.

INTRODUCTION: Wegener's granulomatosis (WG) is a systemic necrotizing vasculitis associated with c-ANCA antibodies. The involvement of the central nervous system in WG is uncommon and usually caused by in situ vasculitis, intracranial granuloma formation or contiguous invasion from extracranial sites. CASE REPORT: Here, we report on a tumour-like expansion of a severe nasosinusal WG into the brain, which was confirmed by brain biopsy examination. CONCLUSION: The positivity of positron emission tomography in our observation supports the potential role of such functional imaging in the staging, as well as in the follow-up of WG.

Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3.

Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors. During mouse development, HNF-6 is expressed in the epithelial cells that are precursors of the exocrine and endocrine pancreatic cells. We have investigated the role of HNF-6 in pancreas differentiation by inactivating its gene in the mouse. In hnf6(-/-) embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiation was impaired. The expression of neurogenin 3 (Ngn-3), a transcription factor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, we demonstrated that HNF-6 binds to and stimulates the ngn3 gene promoter. At birth, only a few endocrine cells were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and their beta cells were deficient in glucose transporter 2 expression. Adult hnf6(-/-) mice were diabetic. Taken together, our data demonstrate that HNF-6 controls pancreatic endocrine differentiation at the precursor stage and identify HNF-6 as the first positive regulator of the proendocrine gene ngn3 in the pancreas. They also suggest that HNF-6 is a candidate gene for diabetes mellitus in humans.

[Intraventricular schwannoma: a case report]. / Schwannome intraventriculaire: à propos d'un cas.

Ventricular schwannomas are very uncommon. We report such a tumor in the right lateral ventricle of a 16-year-old young man. The various etiopathogenic hypotheses are discussed.

Radiotherapy plus temozolomide in elderly patients with glioblastoma: a "real-life" report.

BACKGROUND: The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/- temozolomide regimens. METHODS: From 2003 to 2016, 104 patients ≥ 70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria. RESULTS: Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70-88), and the median Karnofsky performance status (KPS) was 70 (30-100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT + TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT + TMZ (P = 0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P = 0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26-0.86], P = 0.014), ii) RPA class (HR: 2.15 [1.17-3.95], P = 0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33-0.88], P < 0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor. CONCLUSIONS: These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

Atopic myelitis: a clinical, biological, radiological and histopathological diagnosis.

We describe a young patient with an unusual intramedullary lesion filled with eosinophils. The 21-year-old man developed chronic myelitis without optic neuritis or signs of systemic or infectious disease. A spinal biopsy was conducted because of the progressive extension and pseudo-tumoural aspect of the lesion. Histopathological analysis of the biopsy specimen revealed a severe inflammatory process with macrophages and numerous eosinophils. The eosinophil count in the blood and cerebrospinal fluid (CSF) were normal. Clinical, laboratory and radiological data did not correspond with the usual causes of eosinophilic myelitis. Abnormal mite antigen-specific IgE levels and features similar to Japanese cases of atopic myelitis suggested an allergic origin. Despite normal total IgE levels, this case may be the second case of atopic myelitis reported in a Caucasian patient. Striking differences with the first reported case are the absence of a typical history of atopy and normal total IgE levels. This case highlights that atopic myelitis should be considered in myelopathy occurring in Caucasian patients even in the absence of hyperIgEaemia.

Thymic lymphomas in interleukin 9 transgenic mice.

Transgenic mice overexpressing the interleukin 9 gene were generated to study the biological activity of this cytokine in vivo. Although no major histological or morphological modifications of the lymphoid system were observed in most animals, approximately 7% of transgenic mice developed thymic lymphomas at the age of 3-9 months. The tumor cells, which were clonal, with unique T cell rearrangements, were double positive for the expression of CD4 and CD8. The need for additional transforming events, suggested by the low incidence of spontaneous tumors, was further indicated by the high susceptibility of the transgenic animals to injections of low doses of N-methyl-N-nitrosourea, a chemical carcinogen with a thymic tropism. Expression of interleukin 9 was required for optimal tumor growth in vivo, as one of the tumors studied, which had lost the transgene, was much more efficiently transplanted into transgenic than in normal mice. Moreover, the in vitro proliferative activity of interleukin 9 on cell lines derived from such transgene-negative tumors suggests that an autocrine loop mediates the proliferation of these cells in vivo. Taken together, these results indicate that dysregulated IL-9 expression could be involved in the development of some T cell malignancies.

Metastasis of a small cell carcinoma from undetected origin to the pituitary gland--the otolaryngologist's view.

Tumour metastasis to the anterior pituitary-hypothalamic area is rare. We present a patient who had severe headache, bitemporal quadrant hemianopsia and an expanding mass in the sella turcica as revealed by MRI. Partial resection via a transsphenoidal approach was performed and postoperative radiation therapy was initiated. Immunohistochemical investigation identified the tumour as a metastatic small cell carcinoma whose primary site remained undetected for more than 12 months despite repeated oncological evaluations. We reviewed the literature on metastatic disease of the pituitary gland.

Granular Cell Tumor of the Pituitary Stalk: A Rare and Benign Entity.

Granular cell tumor of the pituitary stalk is an uncommon benign lesion that usually appears like a suprasellar mass with visual disturbances. This diagnosis should be considered with the discovery of neurohypophysis tumors. Histological confirmation remains essential. We describe one case of this rare entity and review the literature.

Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome.

Among tumors classified as pilocytic astrocytoma (PA) in the Johns Hopkins Hospital Department of Pathology files, we identified 18 cases with a distinctive monomorphous pilomyxoid histological pattern and a higher recurrence rate than that of PA with classical histological features (classical PA). The majority of the tumors occurred in infants and young children and involved the hypothalamic/chiasmatic region. The tumors were histologically similar to PA, but they were more monomorphous and more myxoid. Rosenthal fibers were not seen and only 1 of 18 tumors had eosinophilic granular bodies. At the end of the follow-up period, 6 patients were dead and 12 were alive with evidence of disease. Progression free survival (PFS) at 1 year was 38.7%. In comparison, we identified a control group of 13 classical PAs in the same age range and location as the study group. In this group, PFS at 1 year was 69.2%, which was significantly better than that for pilomyxoid tumors (p = 0.04). There was no CSF dissemination or death due to tumor progression among patients with classical PA. Eight of these patients are alive with recurrent disease, and 4 have no evidence of disease. While the monomorphous pilomyxoid tumors have some resemblance to classical PA, our results suggest that the former is a more aggressive variant or a separate entity that needs to be recognized for prognostic purposes.

Spinal neurenteric cyst presenting in infancy with chronic fever and acute myelopathy.

The authors describe the clinical, radiologic, and pathologic features of a neonatal spinal neurenteric cyst (NC) presenting with long-lasting fever and acute myelopathy, and compare this observation with other infants reported in the literature. This observation shows that NC must be considered in the differential diagnosis of acute myelopathy with persistent fever in infancy. Fever is attributed to degenerative changes in the NC, triggering inflammatory cell infiltration and tumor necrosis factor alpha secretion.

Effect of cyclosporin A on an experimental chronic viral infection of the central nervous system.

The effects of cyclosporin A (CsA) on neuropathological lesions induced by a chronic viral infection have been tested in the experimental model of the mouse hepatitis virus 3 (MHV3) infection. Daily injections of CsA (50 mg/kg) inhibited the expression of the MHV3-induced ependymitis, meningitis, hydrocephalus and vasculitis. The effect was preserved even if CsA treatment was initiated 15 days after virus infection but was lost if CsA treatment was given later on or for a shorter period of time. Viral titers in brains of chronically infected mice were not affected by CsA treatment. During the first week following MHV3 infection, CsA treatment increased both the percentage of acute death (31 vs. 10%) and the viral titers in brain and liver of infected mice. In this model, the timing of CsA treatment appeared critical for the balance between its beneficial effect on CNS lesions and the risk of increased acute mortality.