PURPOSE:To report treatment outcomes of orbital tumors associated with Erdheim-Chester disease and to highlight the importance of systemic work-up in patients presenting with bilateral proptosis. PATIENTS AND METHODS:Three patients with Erdheim-Chester disease, whose initial manifestation was bilateral proptosis, were retrospectively studied. The course of onset, clinical, imaging and histopathological features, systemic associations and response to treatment were reviewed. The main outcome measures were Hertel measurements and orbital tumor regression on imaging studies. RESULTS:All patients presented with bilateral non-pulsatile proptosis resistant to retropulsion and headeache without specific localization. Magnetic resonance imaging studies showed bilateral intraconal orbital tumors. Incisional biopsy of these tumors demonstrated CD68+, CD1a-, and S100- histiocytic infiltrates consistent with the diagnosis of Erdheim-Chester disease. The BRAFV600E mutation was found in all cases. Systemic work-up revealed asymptomatic bony involvement in the lower extremities, perirenal fibrosis, central nervous system and cardiac involvement. All patients initially received pegylated interferon-α2a, which resulted in excellent responses except for the orbital tumors. Two patients were then treated with vemurafenib, which resulted in rapid regression of the orbital lesions. CONCLUSION:Pegylated interferon-α was highly effective in the control of cardiac, perirenal, skeletal and cerebral involvement but not the orbital tumors. The infiltrative orbital lesions of Erdheim-Chester disease would appear more responsive to vemurafenib.

We trained a convolutional neural network (CNN) to classify H.E. stained microscopic images of focal cortical dysplasia type IIb (FCD IIb) and cortical tuber of tuberous sclerosis complex (TSC). Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. The microscopic review of routine stainings of such surgical specimens remains challenging. A digital processing pipeline was developed for a series of 56 FCD IIb and TSC cases to obtain 4000 regions of interest and 200.000 sub-samples with different zoom and rotation angles to train a CNN. Our best performing network achieved 91% accuracy and 0.88 AUCROC (area under the receiver operating characteristic curve) on a hold-out test-set. Guided gradient-weighted class activation maps visualized morphological features used by the CNN to distinguish both entities. We then developed a web application, which combined the visualization of whole slide images (WSI) with the possibility for classification between FCD IIb and TSC on demand by our pretrained and build-in CNN classifier. This approach might help to introduce deep learning applications for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.

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New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brain-barrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500μM freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment.

BACKGROUND:Although the morphology of central nervous system (CNS) germ cell tumours is very similar to that of gonadal germ cell tumours, some architectural changes may dominate the microscopic appearance of CNS germinomas leading to misdiagnosis at low-power magnification.METHODS:We report five cases of CNS germinoma demonstrating delicate pseudopapillary fronds on squash smear preparations.RESULTS:The age of the patients ranged from 5 to 21 years (mean 14). Three were female and two male. Three patients presented with symptoms of diabetes insipidus, including polydipsia and polyuria, while absence seizures, meaningless speech, hemiparesia, weight loss, insufficient breast development, amenorrhoea and symptoms of raised intracranial pressure were also encountered depending on the location of the tumours. Tumours were located in the hypophysis in two cases and in the suprasellar region in three. During the intra-operative pathological consultation, evenly distributed pseudopapillary or papillary structures formed the dominant pattern in the squash preparations of all cases. The neoplastic cells were characterized by pale variably vacuolated cytoplasm, pleomorphic nuclei with irregular membranes, and several prominent nucleoli. Variable numbers of small lymphocytes were also found.CONCLUSION:Intracranial germinomas may commonly exhibit a pseudopapillary pattern on squash smears that may cause misdiagnosis as neoplasms with papillary morphology. Careful examination of cellular details is essential in order to reach the correct diagnosis.

Mesial temporal lobe epilepsy (MTLE) is often characterized pathologically by severe neuronal loss in the hippocampus. In this study we investigated concomitant appearance of the pro-apoptotic and anti-apoptotic mechanisms in injured neurons in epileptic human hippocampi. Postsurgical hippocampal specimens of randomly selected 25 patients with MTLE were studied with standard immunohistochemical techniques to detect the below markers of cell death pathways: truncated Bid - tBid, mitochondrial translocation of Bax (markers of pro-apoptotic Bcl-2 protein activation) and nuclear translocation of AIF (caspase-independent pro-apoptotic pathway). For cell survival pathways, we investigated the expression of c-IAP1, c-IAP2 and Hsp70 (heat shock protein). Immunopositive cells were counted in different regions of the hippocampus. We also verified IAP (inhibitor of apoptosis) expression with Western blotting. The results were statistically compared with hippocampi from non-epileptic autopsy controls. In patient hippocampi, Bax and tBid immunoreactivity were significantly increased and Bax staining was consistent with mitochondrial translocation. AIF was not translocated to the nucleus. c-IAP1 and c-IAP2 were barely detectable in control hippocampi, whereas their expression was dramatically increased in the patients in all hippocampal subfields. Interestingly, these neurons were also positively co-labeled for tBid and translocated Bax. Hsp70 immunreactivity was significantly increased in all surviving neurons in patient hippocampi whereas degenerating neurons failed to express Hsp70. Our findings are consistent with both pro-apoptotic and anti-apoptotic mechanisms being active within the same hippocampal neurons of patients with MTLE, illustrating an ongoing struggle between cell death and survival mechanisms in neurons under stress.

Objective. Co-existence of Cushing disease and Rathke's cleft cyst (RCC) has been reported in a few cases in the literature so far. We herein describe a rare condition of Cushing disease that might originate from epithelium of RCC.Case. A 48-year-old woman was admitted to the hospital with complaints of headache, weakness, and weight gain. The patient underwent endoscopic transsphenoidal surgery due to Cushing disease. Histopathological examination revealed cyst contents and walls compatible with RCC, and normal adenohypophysis and neurohypophysis tissues. Immunohistochemical stainings with ACTH, GH, and prolactin were positive on the epithelium of the cyst.Conclusion. In our case, Cushing disease might he associated with hormonal activity derived from cyst wall of RCC or disappearance of a small microadenoma during surgical or pathological processing. According to the recent data, origin of this lesion and histogenetic link between RCC with Cushing disease could not be explained.

Context. This is a case of gonadotropinoma presented with Rathke's cleft cyst.Objective. We are presenting a case of gonadotropinoma along with Rathke's cleft cyst which is unique case as being male and symptomatic gonadotropin releasing adenoma. Method. A 51 year old man was referred to our institution for evaluation of impotence and loss of libido. His endocrine screening evaluations revealed hypopituitarism with low levels of blood cortisol and ACTH, and high levels of prolactin.Results. An endonasal transsphenoidal endoscopic approach was performed and upon inspection via endoscope the floor of sella was eroded and following dural incision soft dark colored tumor overflowed through sella. Pathology revealed gonadotropinoma with unexpected remnants of Rathke's cleft cyst.Conclusion. Pituitary adenomas and Rathke's cleft cysts have a common embryologic ancestry. Our case was a symptomatic gonadotropinoma consisting of multicystic component which was then demonstrated as Rathke's cleft cyst in pathological work up. is combination may be the result of a coincidence or Rathke's cleft cysts may be the origin of the pituitary adenomas.

Hypoxic ischemic brain damage presents significant mortality and morbidity rates in newborns. Various animal models of hypoxia-ischemia have made important contribution to the trial of pathogenesis and new treatment modalities. Seven day old rat hypoxia-ischemia model can be used to evaluate the effect of different agents. The complex role of nitric oxide and its antagonists in neonatal hypoxic ischemia has been widely known. However effects of L-arginine, an NO precursor, on apoptotic cell death in neonatal hypoxia-ichemia animal models have not been studied before. The aim of this study is to investigate the effects of the pre and post treaatment of L-arginine on apoptotic cell death in hypoxia-ischemia neonatal rat model. Seven-day-old rats were administered L-arginine intraperitoneally before and after hypoxic ischemia inflicted through right cartotid artery ligation and the exposed to 8 % oxygen. Apoptotic cell death was shown by Tunnel method after there-day recovery. Right hippocampal and striatal apoptotic cell death percentage in L-arginine post-treated group were significantly lower than those of vehicle groups, but no change was found in cortex. L-arginine pretreatment was found to have no effect on apoptotic cell death in the three brain regions. As a result, nitric oxide may play an important dual role in apoptotic cell death in neonatal hypoxicischemic brain injury. Pre-treatnent of L-arginine, a an NO precursor has not been proven to reduce apoptotic celll death, while early treatment after hypoxic ischemia has antiapoptotic effect on neurons in neonatal rat model.