Imaging characterization of an adult H3 K27M-altered diffuse midline glioma of the medulla oblongata with a confounding steroid response.

We report an uncommon, infratentorial localization of adult H3 K27M-altered diffuse midline glioma arising in a particularly rare site (medulla oblongata). In addition to this unusual presentation, the lesion exhibited a substantial contrast enhancement and size decrease after dexamethasone, generating diagnostic dilemmas. Histology, molecular details, advanced Magnetic Resonance imaging features and differential diagnoses are here described and discussed, as well as common misconceptions about steroid-sensitive mass lesions, and practical difficulties for clinicians involved in the process of making diagnosis.

Primary sellar melanocytoma: report of two cases treated at the same institution and their long-term outcome.

Sellar melanocytomas represent a small subgroup of primary melanocytic tumors arising from leptomeningeal melanocytes. They are benign, slow-growing tumors with a high risk of recurrence. We report two cases of sellar melanocytoma treated at the same institute. A 35-year-old woman presented with amenorrhea and an intrasellar mass with suprasellar extension simulating a hemorrhagic pituitary adenoma. The second case is a 51-year-old man with progressive visual loss and a recurrence of primary sellar and suprasellar melanocytoma. The first patient underwent gross total resection and the second patient underwent subtotal resection. Neither of them was treated with postoperative adjuvant therapies. The second patient had tumor regrowth 75 months after surgery; he therefore underwent gamma knife radiosurgery. Both patients are alive and well at the last follow-up (140 and 93 months, respectively).

A cervical solitary fibrous tumor with intramedullary invasion.

Solitary fibrous tumor is a tumor originating from the mesenchymal cells, which occurrence in the central nervous system is extremely rare and was described in few patients as to yet. We report on a 53-years old male patient presenting with right upper limb radicular pain and ipsilateral limbs paresis, who was diagnosed with a cervical spinal lesion which, after surgical resection, resulted to be a solitary fibrous tumor (SFT). We discuss imaging, clinical and histopathological findings to allow considering this tumor early in the differential diagnosis.

Pediatric cerebellar pilocytic astrocytoma presenting with spontaneous intratumoral hemorrhage.

Pilocytic astrocytomas (PAs) are benign glial tumors and one of the most common childhood posterior fossa tumors. Spontaneous intratumoral hemorrhage in PAs occurs occasionally, in about 8-20% of cases. Cerebellar hemorrhages in pediatric population are rare and mainly due to head injuries, rupture of vascular malformations, infections, or hematological diseases. We have investigated the still controversial and unclear pathophysiology underlying intratumoral hemorrhage in PAs. Bleeding in low-grade tumors might be related to structural abnormalities and specific angio-architecture of tumor vessels, such as degenerative mural hyalinization, "glomeruloid" endothelial proliferation, presence of encased micro-aneurysms, and glioma-induced neoangiogenesis. The acute hemorrhagic presentation of cerebellar PA in childhood although extremely uncommon is of critical clinical importance and necessitates promptly treatment. We described a case of hemorrhagic cerebellar PA in a 9-year-old child and reviewed the English-language literature that reported spontaneous hemorrhagic histologically proven cerebellar PA in pediatric patients (0-18 years). According to our analysis, the mortality was not related to symptom onset, tumor location, hemorrhage distribution, presence of acute hydrocephalous, and timing of surgery, while the GCS at hospital admission resulted to be the only statistically significant prognostic factor affecting survival outcome. The abrupt onset of signs and symptoms of acute hydrocephalous and consequent raised intracranial pressure are life-threatening conditions, which need emergent medical and neurosurgical treatments. At a later time, the identification of posterior fossa hemorrhage etiology is crucial to select the appropriate treatment and address the surgical strategy, optimizing the postoperative results.

Long-term outcomes after cosmetic customized prostheses and dermis fat graft in congenital anophthalmia: a retrospective multicentre study.

PURPOSE: To evaluate long-term outcomes of progressively enlarging cosmetic customized prostheses (CCP) early after birth followed by dermis fat graft (DFG), as a strategy of socket rehabilitation in children with clinical congenital anophthalmia (CCA). METHODS: Twenty patients with unilateral and two patients with bilateral CCA were enrolled. All patients were treated by inserting a CCP at the time of their first assessment which was then enlarged. Subsequently they underwent DFG. Differences in vertical palpebral aperture (VPA) and horizontal palpebral length (HPL), between affected and unaffected sides, were recorded at the first CCP fitting as well as before and after DFG. Satisfaction with cosmetic results, prosthetic retention, and complications rate were assessed. Magnetic resonance imaging of the orbit was performed in all patients before and after surgery. RESULTS: A significant decrease in the difference between the normal and the anophthalmic side of both PA and HPL was found over follow-up. Both VPA and HPL differences decreased by 47.6% (10.5 mm, range 1-28 mm) and by 7.1% (5.8 mm, range 0-18 mm), respectively. Satisfaction in terms of cosmetic outcomes proved to be very positive, being "very satisfied" for families and "satisfied" for physicians. Excellent retention of prostheses was observed in all cases. CONCLUSIONS: A rehabilitating strategy combining early CCP and further DFG proved to be a valuable approach in children with CCA, offering significant benefits in terms of socket expansion, prosthetic retention, psychological impact, and cosmetic outcomes.

Gene expression profiling in human corticotroph tumours reveals distinct, neuroendocrine profiles.

Adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas give rise to a severe endocrinological disorder, comprising Cushing's disease, with multifaceted clinical presentation and treatment outcomes. Experimental studies suggest that the disease variability is inherent to the pituitary tumour, thus indicating the need for further studies into tumour biology. The present study evaluated transcriptome expression pattern in a large series of ACTH-secreting pituitary adenoma specimens in order to identify molecular signatures of these tumours. Gene expression profiling of formalin-fixed, paraffin-embedded specimens from 40 human ACTH-secreting pituitary adenomas revealed the significant expression of genes involved in protein biosynthesis and ribosomal function, in keeping with the neuroendocrine cell profile. Unsupervised cluster analysis identified 3 distinct gene profile clusters and several genes were uniquely overexpressed in a given cluster, accounting for different molecular signatures. Of note, gene expression profiles were associated with clinical features, such as the age and size of the tumour. Altogether, the findings of the present study show that corticotroph tumours are characterised by a neuroendocrine gene expression profile and present subgroup-specific molecular features.

Metallothioneins are neuroprotective agents in lysosomal storage disorders.

OBJECTIVE: Lysosomal storage disorders (LSDs) are a broad class of inherited metabolic diseases caused by the defective activity of lysosomal enzymes. Central nervous system (CNS) manifestations are present in roughly 50% of LSD patients and represent an unmet medical need for them. We explored the therapeutic potential of metallothioneins (MTs), a newly identified family of proteins with reported neuroprotective roles, in the murine models of two LSDs with CNS involvement. METHODS: MT-1 overexpressing transgenic mice (MTtg) were crossed with the murine models of Batten and Krabbe diseases. Changes in the survival and manifestations of the disease in the MTtg setting were assessed. In addition, we analyzed the therapeutic effects of MT-1 CNS gene delivery in one of these LSD models. RESULTS: Constitutive expression of MT-1 exerted favorable phenotypic effects in both LSD models. MT-LSD mice showed a 5% to 10% increase in survival and slower disease progression as compared to not-transgenic LSD mice. Rescue of Purkinje cells from degeneration and apoptosis was also observed in the MT-LSD models. This phenotypic amelioration was accompanied by a modulation of the disease-associated activated inflammatory microglia phenotype, and by a reduction of oxidative stress. Importantly, for the clinical translation of our findings, the very same effects were obtained when MTs were delivered to brains by systemic AAV gene transfer. INTERPRETATION: MTs can be considered novel therapeutic agents (and targets) in LSDs and potentiate the effects of approaches aiming at correction of the disease-causing enzyme deficiency in the CNS. Ann Neurol 2018;83:418-432 Ann Neurol 2018;83:418-432.

Brain Gliomas: Multicenter Standardized Assessment of Dynamic Contrast-enhanced and Dynamic Susceptibility Contrast MR Images.

Purpose To evaluate the feasibility of a standardized protocol for acquisition and analysis of dynamic contrast material-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging in a multicenter clinical setting and to verify its accuracy in predicting glioma grade according to the new World Health Organization 2016 classification. Materials and Methods The local research ethics committees of all centers approved the study, and informed consent was obtained from patients. One hundred patients with glioma were prospectively examined at 3.0 T in seven centers that performed the same preoperative MR imaging protocol, including DCE and DSC sequences. Two independent readers identified the perfusion hotspots on maps of volume transfer constant (Ktrans), plasma (vp) and extravascular-extracellular space (ve) volumes, initial area under the concentration curve, and relative cerebral blood volume (rCBV). Differences in parameters between grades and molecular subtypes were assessed by using Kruskal-Wallis and Mann-Whitney U tests. Diagnostic accuracy was evaluated by using receiver operating characteristic curve analysis. Results The whole protocol was tolerated in all patients. Perfusion maps were successfully obtained in 94 patients. An excellent interreader reproducibility of DSC- and DCE-derived measures was found. Among DCE-derived parameters, vp and ve had the highest accuracy (are under the receiver operating characteristic curve [Az] = 0.847 and 0.853) for glioma grading. DSC-derived rCBV had the highest accuracy (Az = 0.894), but the difference was not statistically significant (P > .05). Among lower-grade gliomas, a moderate increase in both vp and rCBV was evident in isocitrate dehydrogenase wild-type tumors, although this was not significant (P > .05). Conclusion A standardized multicenter acquisition and analysis protocol of DCE and DSC MR imaging is feasible and highly reproducible. Both techniques showed a comparable, high diagnostic accuracy for grading gliomas. © RSNA, 2018 Online supplemental material is available for this article.

A novel composite type I collagen scaffold with micropatterned porosity regulates the entrance of phagocytes in a severe model of spinal cord injury.

Traumatic spinal cord injury (SCI) is a damage to the spinal cord that results in loss or impaired motor and/or sensory function. SCI is a sudden and unexpected event characterized by high morbidity and mortality rate during both acute and chronic stages, and it can be devastating in human, social and economical terms. Despite significant progresses in the clinical management of SCI, there remain no effective treatments to improve neurological outcomes. Among experimental strategies, bioengineered scaffolds have the potential to support and guide injured axons contributing to neural repair. The major aim of this study was to investigate a novel composite type I collagen scaffold with micropatterned porosity in a rodent model of severe spinal cord injury. After segment resection of the thoracic spinal cord we implanted the scaffold in female Sprague-Dawley rats. Controls were injured without receiving implantation. Behavioral analysis of the locomotor performance was monitored up to 55 days postinjury. Two months after injury histopathological analysis were performed to evaluate the extent of scar and demyelination, the presence of connective tissue and axonal regrowth through the scaffold and to evaluate inflammatory cell infiltration at the injured site. We provided evidence that the new collagen scaffold was well integrated with the host tissue, slightly ameliorated locomotor function, and limited the robust recruitment of the inflammatory cells at the injury site during both the acute and chronic stage in spinal cord injured rats. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1040-1053, 2017.

Dynamic contrast-enhanced and dynamic susceptibility contrast perfusion MR imaging for glioma grading: Preliminary comparison of vessel compartment and permeability parameters using hotspot and histogram analysis.

INTRODUCTION: Dynamic susceptibility contrast (DSC)-MRI is a perfusion technique with high diagnostic accuracy for glioma grading, despite limitations due to inherent susceptibility effects. Dynamic contrast-enhanced (DCE)-MRI has been proposed as an alternative technique able to overcome the DSC-MRI shortcomings. This pilot study aimed at comparing the diagnostic accuracy of DSC and DCE-MRI for glioma grading by evaluating two estimates of blood volume, the DCE-derived plasma volume (Vp) and the DSC-derived relative cerebral blood volume (rCBV), and a measure of vessel permeability, the DCE-derived volume transfer constant K(trans). METHODS: Twenty-six newly diagnosed glioma patients underwent 3T-MR DCE and DSC imaging. Parametric maps of CBV, Vp and K(trans) were calculated and the region of highest value (hotspot) was measured on each map. Histograms of rCBV, Vp and K(trans) values were calculated for the tumor volume. Statistical differences according to WHO grade were assessed. The diagnostic accuracy for tumor grading of the two techniques was determined by ROC analysis. RESULTS: rCBV, Vp and K(trans) measures differed significantly between high and low-grade gliomas. Hotspot analysis showed the highest correlation with grading. K(trans) hotspots co-localized with Vp hotspots only in 56% of enhancing gliomas. For differentiating high from low-grade gliomas the AUC was 0.987 for rCBVmax, and 1.000 for Vpmax and K(trans)max. Combination of DCE-derived Vp and K(trans) parameters improved the diagnostic performance of the histogram method. CONCLUSION: This initial experience of DCE-derived Vp evaluation shows that this parameter is as accurate as the well-established DSC-derived rCBV for glioma grading. DCE-derived K(trans) is equally useful for grading, providing different informations with respect to Vp.

Polycomb dysregulation in gliomagenesis targets a Zfp423-dependent differentiation network.

Malignant gliomas constitute one of the most significant areas of unmet medical need, owing to the invariable failure of surgical eradication and their marked molecular heterogeneity. Accumulating evidence has revealed a critical contribution by the Polycomb axis of epigenetic repression. However, a coherent understanding of the regulatory networks affected by Polycomb during gliomagenesis is still lacking. Here we integrate transcriptomic and epigenomic analyses to define Polycomb-dependent networks that promote gliomagenesis, validating them both in two independent mouse models and in a large cohort of human samples. We find that Polycomb dysregulation in gliomagenesis affects transcriptional networks associated with invasiveness and de-differentiation. The dissection of these networks uncovers Zfp423 as a critical Polycomb-dependent transcription factor whose silencing negatively impacts survival. The anti-gliomagenic activity of Zfp423 requires interaction with the SMAD proteins within the BMP signalling pathway, pointing to a novel synergic circuit through which Polycomb inhibits BMP signalling.

Suprasellar granular cell tumor of the neurohypophysis: surgical outcome of a very rare tumor.

PURPOSE: Granular cell tumors of the neurohypophysis are rare, solitary lesions, mostly presenting in the adult age. They rarely grow to a sufficient size to cause mass effect related symptoms and they may be found in most cases incidentally at autopsy. Because of their rarity as of now they have been described only as case reports or included in small clinical series. METHODS: We report a series of 11 patients, who underwent surgery for granular cell tumors of the neurohypophysis between 1996 and 2013 in a single center. RESULTS: Mean follow-up time after treatment was 92.2 months (range 9-231 months). Mean age at surgery was 40.7 years (range 12-66 years). There were 7 males (63.6 %) and 4 females (36.4 %). Main symptoms at presentation were: hyperprolactinemia (72.7 %), visual impairment (45.5 %) and headache (36 %). Except for 2 patients, all the others underwent surgery as primary treatment at our Institution, through a transsphenoidal (54.5 %) or a transcranial approach (45.5 %). Overall- and progression-free survival times for the entire series (calculated from the time of diagnosis) were 112.9 and 100.5 months respectively. There was one case of perioperative death in a patient who had undergone repeat transcranial surgery for residual tumor. CONCLUSIONS: Although extremely rare, granular cell tumors of the neurohypophysis have to be considered in the differential diagnosis of suprasellar masses, to avoid misleading interpretation and consequent wrong therapeutic management. Early diagnosis, extensive tumor removal, opportune indication of adjuvant radiotherapy are the keys to manage these cases.

Intracranial Melanotic Schwannomas.

STUDY AIMS: Melanotic schwannomas (MSs) are an extremely rare variant of nerve sheath tumor. Lesions are characterized by melanin-producing cells that resemble ultrastructural features of Schwann cells. The main location is the paraspinal thoracic region, followed by other extraneural locations such as skin, soft tissues, bone, and viscera. Craniofacial and intracranial lesions are extremely rare. They may occur either sporadically or related to familiar syndromes, such as neurofibromatosis type II and Carney complex, a rare multisystemic autosomal dominant hereditary syndrome. Despite the benign histologic appearance, these tumors can recur or metastasize, even after a long time. We provide an overview of the epidemiological, clinical, radiologic, and histopathologic characteristics of intracranial MSs, with particular emphasis on diagnostic and therapeutic strategies and related clinical outcomes. MATERIAL AND METHODS: We performed a literature review on MSs (1932-2012) regarding intracranial and other localization. An illustrative case is reported. RESULTS: To the best of our knowledge, 17 papers reporting 18 cases of intracranial MSs were previously published. All these studies are either case report or clinical series describing intracranial MSs. Therapeutic results and prognostic factors were reviewed. CONCLUSION: Radical surgical resection is considered the treatment of choice for MS, but treatment guidelines still do not exist. Radiotherapy seems to play an important role in reducing the risk of recurrence in the case of subtotal tumor resection. Despite the reported encouraging results, only anecdotal data are available in the pertinent literature. Future studies should focus on the role of radiotherapy as adjuvant treatment when radical surgical excision cannot be achieved.

Metallothioneins as dynamic markers for brain disease in lysosomal disorders.

OBJECTIVE: To facilitate development of novel disease-modifying therapies for lysosomal storage disorder (LSDs) characterized by nervous system involvement such as metachromatic leukodystrophy (MLD), molecular markers for monitoring disease progression and therapeutic response are needed. To this end, we sought to identify blood transcripts associated with the progression of MLD. METHODS: Genome-wide expression analysis was performed in primary T lymphocytes of 24 patients with MLD compared to 24 age- and sex-matched healthy controls. Genes associated with MLD were identified, confirmed on a quantitative polymerase chain reaction platform, and replicated in an independent patient cohort. mRNA and protein expression of the prioritized gene family of metallothioneins was evaluated in postmortem patient brains and in mouse models representing 6 other LSDs. Metallothionein expression during disease progression and in response to specific treatment was evaluated in 1 of the tested LSD mouse models. Finally, a set of in vitro studies was planned to dissect the biological functions exerted by this class of molecules. RESULTS: Metallothionein genes were significantly overexpressed in T lymphocytes and brain of patients with MLD and generally marked nervous tissue damage in the LSDs here evaluated. Overexpression of metallothioneins correlated with measures of disease progression in mice and patients, whereas their levels decreased in mice upon therapeutic treatment. In vitro studies indicated that metallothionein expression is regulated in response to oxidative stress and inflammation, which are biochemical hallmarks of lysosomal storage diseases. INTERPRETATION: Metallothioneins are potential markers of neurologic disease processes and treatment response in LSDs.

Primary lymphoma of the central nervous system--a diagnostic challenge.

Primary lymphoma of the central nervous system is a distinct diffuse large B-cell lymphoma confined to the nervous system. Whereas classical cases can be classified easily, differential diagnosis can be a challenge in particular in patients who had received treatment prior to biopsy. In the differential diagnosis, other tumours and inflammatory diseases of autoimmune and infectious aetiology need to be considered.

Solitary clival plasmocytomas: Misleading clinical and radiological features of a rare pathology with a specific biological behaviour.

BACKGROUND: Tumours of the clivus are exceptionally rare, representing a diagnostic and a therapeutic challenge. Clival solitary plasmocytomas have been described only as single case reports or included in small clinical series with other intracranial location. METHODS: Authors report clinical, radiological, and survival data of four patients, who underwent surgery for clival plasmocytomas between 1989 and 2012 in a single centre. Current knowledge about solitary plasmocytomas of the clivus are reviewed. RESULTS: Follow-up time was 54 months (range: 9-165). Mean age of patient was 57 years, no gender predilection was observed. Main symptoms were headache (75 %) and double vision (75 %), due to third or sixth cranial nerve palsy. Mean time to diagnosis was 8.2 months. All patients underwent surgery as primary treatment, through either a transsphenoidal (75 %) or a transmaxillary approach (25 %). In all cases adjuvant conventional radiotherapy was performed with a median delivered dose of 45 Gy. Only one case of progression into multiple myeloma was observed 13 months after surgery, and the patient died 9 months later. No other recurrences or progression were observed. Mean overall survival and progression free survival time were, respectively, 54 and 51.7 months. CONCLUSIONS: Although extremely rare, clival plasmocytomas have to be considered in the differential diagnosis of a solitary clival lesion. Biological and clinical features of these tumours strongly differ from those of similar lesions in other part of the body. Early diagnosis, extensive tumour removal, opportune indication of adjuvant treatment with radiotherapy and chemotherapy are the keys to manage these cases.

Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases.

OBJECTIVE: The prognosis of either pituitary carcinoma or aggressive pituitary adenoma resistant to standard therapies is poor. We assessed the efficacy of treatment with temozolomide, an oral second-generation alkylating agent, in a consecutive series of six patients with aggressive pituitary adenomas. DESIGN: This was a 1-year prospective study of temozolomide therapy in six consecutive patients with pituitary carcinoma (one case) or atypical pituitary adenoma (five cases) resistant to standard therapies. There were three males and three females. Age at enrollment ranged between 52 and 64 years. Temozolomide was given orally at a dose of 150-200 mg/m(2) per day for 5 days every 4 weeks for a maximum of 12 cycles. METHODS: Response assessment was based on measurable change in tumor size, as assessed on magnetic resonance imaging, and hormone levels. Response was defined as reduction of at least 50% of tumor size and hormone levels. RESULTS: Four patients completed the 12 cycles of temozolomide treatment, as planned. Two patients stopped the drug after 3 and 6 months respectively because of the progression of disease. Two patients responded to temozolomide, while the remaining two patients had stable disease. Immunohistochemistry for O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor sample showed a partial association with treatment response. CONCLUSIONS: Temozolomide treatment has a wide range of efficacy in patients with pituitary carcinoma or locally aggressive pituitary adenoma. Positive staining for MGMT seems likely to predict a lower chance of response.