Publications by authors named "Figen Söylemezoğlu"

137 Publications

Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial.

Epilepsia 2021 Jun 5;62(6):1416-1428. Epub 2021 May 5.

Department of Neuropathology, Institute of Neurology, University College London, London, UK.

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme.

Methods: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients.

Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases.

Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.
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http://dx.doi.org/10.1111/epi.16899DOI Listing
June 2021

Temporal encephaloceles can be missed in patients with refractory temporal lobe epilepsy.

Epilepsy Res 2021 Jul 20;173:106640. Epub 2021 Apr 20.

Hacettepe University Faculty of Medicine, Department of Neurology, Ankara, Turkey.

Temporal encephaloceles (TEs) are one of the cause of refractory temporal lobe epilepsy (TLE). We reviewed the neuroimaging and video-electroencephalography (EEG) records of epilepsy patients who underwent temporal lobectomy in our center to investigate frequency of TEs. We retrospectively reevaluated 294 patients who underwent epilepsy surgery in our tertiary epilepsy centre between January 2010 and March 2019 and included 159 patients (78 females, 49 %; 81 males) who had temporal lobectomy. Preoperatively, TEs were reported in 3 of 159 patients (1 female, 2 males). After reevaluation 4 more patients with TEs (1 female, 3 males) were added. The ratio of TE in patients who underwent temporal lobectomy increased from 1.8 % (n=3) to 4,4 % (n=7). The median ages were 18 (range 16-22) versus 10 years (range 5-17) at habitual seizure onset and the median of epilepsy duration was 5 (range 3-15) versus 175 (range 11-25) years between patients with and without TE. Habitual seizure onset age was significantly higher (p =, 007) in the patients with encephalocele and epilepsy duration was shorter (p =, 003) than patients without encephalocele. The ictal EEG records of all patients TE rhythmic delta activity which is suggested neocortical temporal lobe onset seizures. 4 of 7 patients' PET imaging showed temporal lobe hypometabolism compatible with ipsilateral to the TEs. The three patients underwent anterior temporal lobectomy without amygdalohippocampectomy and others had anterior temporal lobectomy with amygdalohippocampectomy. We suggested that there might be some clues for temporal encephalocele, an easily overlooked cause in patients with nonlesional temporal lobe epilepsy.TLE patients with TE had relatively late onset of epilepsy and rhythmic delta activity on ictal EEG. Also, temporal hypometabolism on PET may be a useful key to suspicion of TE.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106640DOI Listing
July 2021

Primary intracranial germ cell tumors in children 36-year experience of a single center.

J Cancer Res Ther 2020 Oct-Dec;16(6):1459-1465

Department of Pediatric Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Purpose: Intracranial germ cell tumors (ICGCTs) comprise approximately 0.4%-3% of all brain tumors. In this study, we aim to evaluate clinical characteristics, treatment and outcomes of patients with ICGCT.

Patients And Methods: All patients with ICGCT diagnosed in Hacettepe University's Pediatric Oncology Department between January 1980 and January 2016 were evaluated, retrospectively.

Results: We identified 52 patients (male/female: 2.46) diagnosed with ICGT. Median age was 140 months. The median duration of symptoms was 3 months. Patients with endocrine symptoms were diagnosed later than others (P = 0.028). The primary site was pineal region in 20 patients, nonpineal region in 32 which included six bifocal involvements. Pineal location was more common in boys than girls (P = 0.02). Histopathological diagnosis was germinoma in 28 patients, nongerminomatous malignant germ cell tumors in 14 and immature teratoma in 4. The mean age for germinoma was higher than that of nongerminomatous tumors (P = 0.032). Patients treated with surgery and radiotherapy and chemotherapy. Median follow-up time was 52.5 months. Thirty-six patients were alive for 12-228 months. Relapsed/progressive disease was observed in 11 patients. Nongerminomatous tumors more frequently showed relapse/progression than germinoma (P = 0.06). Five-year overall and event-free survival rates for the whole group were 72.6% and 57.2%, respectively. Overall and event-free survival rates for germinoma were better than malignant nongerminomatous tumors.

Conclusion: Although the ratio of ICGCTs to central nervous system tumors in our series was similar to western countries, some clinical features such as tumor location were similar to cases from East Asian countries. Although similar protocols were used survival rates lower than developed western and eastern developed countries.
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http://dx.doi.org/10.4103/jcrt.JCRT_314_18DOI Listing
December 2020

High-grade neuroepithelial tumor with medulloepithelioma-like areas out of the central nervous system in an infant with hemihypertrophy: a unique association.

Turk J Pediatr 2020 ;62(5):836-842

Departments of Pediatric Oncology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Background: High-grade neuroepithelial tumor with areas resembling medulloepithelioma was diagnosed in an infant with coccygeal and inguinal masses. Hemihypertrophy is associated with Wilms tumor, hepatoblastoma and pancreatic tumors in children.

Case: The authors report on the first case of peripheral HNET associated with hemihypertrophy in an infant, with special discussion on histopathological differential diagnosis and management of this rare and highly malignant tumor.

Conclusions: HNET should be included into the list of hemihypertrophy associated tumors. Complete surgical excision with free margins is essential for the successful treatment of such cases and should be tried in suitable cases at the time of diagnosis. Continued treatment should be decided individually on a case to case basis.
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http://dx.doi.org/10.24953/turkjped.2020.05.017DOI Listing
January 2020

Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers.

J Neuropathol Exp Neurol 2020 10;79(10):1054-1064

Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Tuberous sclerosis complex (TSC) is a monogenetic disease that arises due to mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC are cortical malformations referred to as cortical tubers. These tubers are frequently associated with treatment-resistant epilepsy. Some of these patients are candidates for epilepsy surgery. White matter abnormalities, such as loss of myelin and oligodendroglia, have been described in a small subset of resected tubers but mechanisms underlying this phenomenon are unclear. Herein, we analyzed a variety of neuropathologic and immunohistochemical features in gray and white matter areas of resected cortical tubers from 46 TSC patients using semi-automated quantitative image analysis. We observed divergent amounts of myelin basic protein as well as numbers of oligodendroglia in both gray and white matter when compared with matched controls. Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder. In conclusion, myelin pathology in cortical tubers extends beyond the white matter and may be linked to cognitive dysfunction in TSC patients.
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http://dx.doi.org/10.1093/jnen/nlaa090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559237PMC
October 2020

International consensus classification of hippocampal sclerosis and etiologic diversity in children with temporal lobectomy.

Epilepsy Behav 2020 11 1;112:107380. Epub 2020 Sep 1.

Department of Pediatric Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey. Electronic address:

Introduction: The distribution of hippocampal sclerosis (HS) subtypes, according to the classification of the International League Against Epilepsy (ILAE), has been reported mainly in adult patients. We aimed to review the pathological findings in children who had anterior temporal lobectomy accompanied with amygdalohippocampectomy, in view of the current classification, and evaluate postsurgical outcome with respect to HS subtypes in childhood.

Methods: Seventy children who underwent temporal resections for treatment of medically refractory epilepsy, with a minimum follow-up of 2 years, were included; the surgical hippocampus specimens were re-evaluated under the HS ILAE classification.

Results: Neuropathological evaluations revealed HS type 1 in 38 patients (54.3%), HS type 2 in 2 (2.8%), HS type 3 in 21 patients (30%), and no HS in 9 patients (12.9%). Of 70 patients, 23 (32.9%) had dual pathology, and the most common pattern was HS type 3 with low-grade epilepsy-associated brain tumors (LEAT). The distribution of HS types with respect to age revealed that HS type 3 and no HS subgroups had significantly more patients younger than 12 years, compared with those of HS type 1 (90.5%, 77.8% vs 47.4%, respectively). History of febrile seizures was higher in HS type 1. Prolonged/recurrent febrile seizures were most common in patients 12 years and older, whereas LEAT was the most common etiology in patients under 12 years of age (p < 0.001). Patients with HS type 1 had longer duration of epilepsy and an older age at the time of surgery compared with patients with HS type 3 and no HS (p: 0.031, p: 0.007). At final visit, 74.3% of the patients were seizure-free. Seizure outcome showed no significant difference between pathological subtypes.

Conclusions: Our study presents the distribution of HS ILAE subtypes in an exclusively pediatric series along with long-term seizure outcome. The study reveals that the leading pathological HS subgroup in children is HS type 1, similar with adult series. Hippocampal sclerosis type 2 is significantly less in children compared with adults; however, HS type 3 emerges as the second most predominant group because of dual pathology, particularly LEAT. Further studies are required regarding clinicopathological features of isolated HS in pediatric cohort. Seizure-free outcome was favorable and similar in all HS types in children. The proportion of HS types may be better defined in pediatric patients with temporal resections, as the current HS ILAE classification becomes more widely used, and may help reveal the surgical and cognitive outcome with respect to HS types.
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http://dx.doi.org/10.1016/j.yebeh.2020.107380DOI Listing
November 2020

Recurrence of a Totally Excised Cavernous Venous Malformation 25 Years Later.

Ophthalmic Plast Reconstr Surg 2021 Mar-Apr 01;37(2):e59-e60

Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey.

Recurrence of cavernous venous malformation is exceedingly rare. In 1995, a 16-year-old woman was referred for left axial proptosis. Her left visual acuity was 20/200, and there were choroidal folds in the OS. MRI studies showed a well-circumscribed retrobulbar intraconal mass in the left orbit. The tumor was totally removed with intact capsule through a transconjunctival orbitotomy and proved to be a cavernous venous malformation. In 2020, at the age of 41 years and 25 years after the operation, she again presented with left proptosis. Imaging results were very similar to those at first presentation. This tumor was also extirpated in its entirety via an inferior forniceal orbitotomy with the histopathologic diagnosis of a cavernous venous malformation. Her final left visual acuity remained 20/50. Women with orbital cavernous venous malformations, especially those who undergo surgical removal at a relatively young age are advised to have long-term follow up complemented with occasional imaging studies.
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http://dx.doi.org/10.1097/IOP.0000000000001751DOI Listing
April 2021

Deep White Matter Lesions with Persistent Diffusion Restriction on MRI as a Diagnostic Clue: Neuroimaging of a Turkish Family with Hereditary Diffuse Leukoencephalopathy with Spheroids and Literature Review.

Ann Indian Acad Neurol 2020 May-Jun;23(3):280-288. Epub 2020 Jun 10.

Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Background: Hereditary diffuse leukoencephalopathy with spheroids (HDLS), first described in 1984 is a rare disorder. Generally, it presents at adulthood with dementia, motor impairment, extrapyramidal abnormalities, and epilepsy. Definitive diagnosis is made by brain biopsy. Neuroimaging studies have revealed confluent white matter lesions predominantly in the frontal lobes, corpus callosum, and corticospinal tracts on conventional magnetic resonance imaging. Only a few reports showed diffusion restriction in the cerebral white matter; furthermore, rarer reports emphasized persistent foci of diffusion restriction as a diagnostic imaging marker.

Objective: Herein, we have aimed to illustrate the first biopsy-proven Turkish HDLS pedigree consisting of 18 persons in 3 generations which contained 4 affected individuals.

Materials And Methods: Four individuals in the pedigree of HDLS [two affected patients (patient III-1 and patient III-2) and two unaffected individuals (patient II-4 and patient III-5)] were investigated with conventional MRI and Diffusion-weighted imaging (DWI) using 1.5 Tesla (T) scanner. All four individuals were evaluated via neurological examinations and Mini-Mental State Examination. Brain biopsy study was performed on patient III-2. Finally, an extensive literature review involving pathology investigations and neuroimaging studies of HDLS patients was conducted.

Results: DWIs of two investigated patients showed deep white matter lesions with persistent diffusion restriction. Computed tomography imaging showed punctate mineralization in the lesions. Biopsy specimens of patient III-2 demonstrated axonal spheroids which were typical for HDLS.

Conclusions: Via the presentation of our pedigree and literature review, we suggest HDSL as a first-line differential diagnosis in patients with undiagnosed adult-onset familial leukoencephalopathy, in particular, those with MRI lesions of frontal white matter and centrum semiovale associated with foci of diffusion restriction and mineralization. Finally, we think that the persistence of the diffusion restriction in deep white matter lesions should be kept in mind as a crucial neuroimaging sign for HDLS.
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http://dx.doi.org/10.4103/aian.AIAN_474_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313596PMC
June 2020

Clinical Characteristics, Management, and Treatment Outcomes of Primary Hypophysitis: A Monocentric Cohort.

Horm Metab Res 2020 Apr 8;52(4):220-227. Epub 2020 Apr 8.

Department of Endocrinology and Metabolism, Hacettepe University Medical School, Ankara, Turkey.

Primary hypophysitis (PH) is a rare autoimmune inflammatory disease of the pituitary gland. The aim of the study was to evaluate clinical characteristics, disease management, and outcomes of cases with PH. Medical records of PH patients admitted to Hacettepe University Hospital between 1999 and 2017 were analyzed retrospectively. Paraffin-embedded pathology blocks were obtained for both re-examination and IgG4 immunostaining. Twenty PH patients (15 females, 5 males) were evaluated. Mean age at diagnosis was 41.5±13.4 years. Some form of hormonal disorder was present in 63.2% of cases, hypogonadism (66.6%) being the most common. Panhypopituitarism was present in 36.8%. All patients had pituitary gland enlargement on magnetic resonance imaging; stalk thickening and loss of neurohypophyseal bright spot were present in 17.6 and 23.5%, respectively. Lymphocytic hypophysitis was the most common histopathological subtype (50%). Among pathology specimens available for IgG and IgG4 immunostaining (n=10), none fulfilled the criteria for IgG4-related hypophysitis. Four patients were given glucocorticoid treatment in diverse protocols; as initial therapy in 3. Sixteen cases underwent surgery, 7 of whom due to neuro-ophthalmologic involvement. Only 1 patient was observed without any intervention. Reduction of pituitary enlargement was seen in all surgical and glucocorticoid treated cases. None of the surgical patients showed hormonal improvement while one case in glucocorticoid group improved. PH should be considered in the differential diagnosis of sellar masses causing hormonal deficiencies. MRI findings are usually helpful, but not yet sufficient for definitive diagnosis of PH. Treatment usually improves symptoms and reduces sellar masses while hormonal recovery is less common.
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http://dx.doi.org/10.1055/a-1113-7777DOI Listing
April 2020

Same same but different: A Web-based deep learning application revealed classifying features for the histopathologic distinction of cortical malformations.

Epilepsia 2020 03 20;61(3):421-432. Epub 2020 Feb 20.

Institute of Neuropathology, University Hospitals, Erlangen, Germany.

Objective: The microscopic review of hematoxylin-eosin-stained images of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex remains challenging. 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. We trained a convolutional neural network (CNN) to classify both entities and visualize the results. Additionally, we propose a new Web-based deep learning application as proof of concept of how deep learning could enter the pathologic routine.

Methods: A digital processing pipeline was developed for a series of 56 cases of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex to obtain 4000 regions of interest and 200 000 subsamples with different zoom and rotation angles to train a neural network. Guided gradient-weighted class activation maps (Guided Grad-CAMs) were generated to visualize morphological features used by the CNN to distinguish both entities.

Results: Our best-performing network achieved 91% accuracy and 0.88 area under the receiver operating characteristic curve at the tile level for an unseen test set. Novel histopathologic patterns were found through the visualized Guided Grad-CAMs. These patterns were assembled into a classification score to augment decision-making in routine histopathology workup. This score was successfully validated by 11 expert neuropathologists and 12 nonexperts, boosting nonexperts to expert level performance.

Significance: Our newly developed Web application combines the visualization of whole slide images with the possibility of deep learning-aided classification between focal cortical dysplasia IIb and tuberous sclerosis complex. This approach will help to introduce deep learning applications and visualization for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.
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http://dx.doi.org/10.1111/epi.16447DOI Listing
March 2020

Combination of Paclitaxel and R-flurbiprofen loaded PLGA nanoparticles suppresses glioblastoma growth on systemic administration.

Int J Pharm 2020 Mar 24;578:119076. Epub 2020 Jan 24.

Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey. Electronic address:

Malignant gliomas are highly lethal. Delivering chemotherapeutic drugs to the brain in sufficient concentration is the major limitation in their treatment due to the blood-brain barrier (BBB). Drug delivery systems may overcome this limitation and can improve the transportation through the BBB. Paclitaxel is an antimicrotubule agent with effective anticancer activity but limited BBB permeability. R-Flurbiprofen is a nonsteroidal antienflammatory drug and has potential anticancer activity. Accordingly, we designed an approach combining R-flurbiprofen and paclitaxel and positively-charged chitosan-modified poly-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) and to transport them to glioma tissue. NPs were characterized and, cytotoxicity and cellular uptake studies were carried out in vitro. The in vivo efficacy of the combination and formulations were evaluated using a rat RG2 glioma tumor model. Polyethylene glycol (PEG) modified and chitosan-coated PLGA NPs demonstrated efficient cytotoxic activity and were internalized by the tumor cells in RG2 cell culture. In vivo studies showed that the chitosan-coated and PEGylated NPs loaded with paclitaxel and R-flurbiprofen exhibited significantly higher therapeutic activity against glioma. In conclusion, PLGA NPs can efficiently carry their payloads to glioma tissue and the combined use of anticancer and anti-inflammatory drugs may exert additional anti-tumor activity.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119076DOI Listing
March 2020

Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.

Acta Neuropathol 2020 01 28;139(1):193-209. Epub 2019 Sep 28.

Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.
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http://dx.doi.org/10.1007/s00401-019-02078-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477753PMC
January 2020

A case of atypical macroprolactinoma presenting with pituitary apoplexy during pregnancy and review of the literature.

Gynecol Endocrinol 2020 Feb 7;36(2):109-116. Epub 2019 Aug 7.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Hacettepe University School of Medicine, Ankara, Turkey.

Pituitary apoplexy (PA) during pregnancy is a rare acute clinical situation which could have life-threatening consequences. Here we reported a case of 26-year-old nulliparous woman presenting with PA at the second trimester of her pregnancy. We also have reviewed reported cases of PA during pregnancy and conducted a detailed discussion on presenting symptoms, underlying pituitary pathology, management of apoplexy during pregnancy and outcomes.
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http://dx.doi.org/10.1080/09513590.2019.1650339DOI Listing
February 2020

Poorly differentiated chordoma: review of 53 cases.

APMIS 2019 Sep;127(9):607-615

Department of Pathology, Hacettepe Unıversity, Ankara, Turkey.

Poorly differentiated chordoma (PDC) is a newly described variant of chordomas, which is not considered as a subtype yet, but has its own distinct features in terms of morphology, immunohistochemical and molecular characteristics, and clinical outcome. To provide a brief review of clinical, morphological, immunohistochemical, and molecular features of poorly differentiated chordoma. PubMed search using keyword 'poorly differentiated chordoma'. A critical review of all studies with a total of 53 cases using inclusion criteria of involvement of axial skeleton (vertebra and clivus), INI1 loss (either with the aid of immunohistochemistry or various molecular techniques), and immunohistochemical brachyury expression. PDC is characterized by a young population with slight female predominance, clivus/cervix location, multinodular sheets of epithelioid cells with eosinophilic cytoplasm and prominent pleomorphism, and loss of SMARCB1/INI1 expression, which can be demonstrated both with immunohistochemical and molecular studies, and is unexpected for other types of chordoma. However, classical chordomas lacking SMARCB1/INI1 expression were also reported and how to classify these cases has not been addressed yet. This unique entity is a candidate to be recognized and distinguished from other types of chordoma or SMARCB1-deficient tumors which are clinically important differential diagnoses that represent a challenging task for the pathologists.
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http://dx.doi.org/10.1111/apm.12978DOI Listing
September 2019

Neuroprotective effect of L-arginine in a neonatal rat model of hypoxic-ischemia.

Int J Neurosci 2019 Nov 9;129(11):1139-1144. Epub 2019 Jul 9.

Department of Pediatrics, Neonatology, School of Medicine, Gazi University , Ankara , Turkey.

The aim of the present study is to investigate the neuroprotective effects of l-Arginine (l-arg) in the seven-day-old rat hypoxia-ischemia model. L-Arginine ( = 10) or saline ( = 8) was administered intraperitoneally to seven-day-old rats before hypoxia-ischemia. In addition, 18 seven-day-old rats were given l-Arginine ( = 10) or saline ( = 8) after hypoxic-ischemic insult. Neuronal apoptosis was investigated by terminal dUDP-biotin nick end-labeling (TUNEL) following three days of recovery. The ratios of right side numerical density to the sum of right and left sides' numerical densities (right apoptosis index) were calculated for every brain region in rats receiving l-arginine and they were compared with the vehicle groups. Right side apoptosis indexes of the hippocampus (mean ± SD; 35.0 ± 16.1) and striatum (41.9 ± 16.0) were significantly decreased in the l-Arginine post-treatment groups when compared to vehicles (61.0 ± 17.0 and 62.4 ± 27.0 respectively) ( < 0.05). There was no significant difference in the right apoptosis indexes of the cortex between l-Arginine post-treated group and the vehicle group. There were also no significant differences between the right side apoptosis indexes of the l-Arginine pretreatment groups and those of the vehicle group in any of the three regions ( > 0.05). It is concluded that neuronal apoptosis due to hypoxic-ischemic injury may likely to be reduced by post-treatment of l-Arginine in the neonatal rat model and l-Arginine provides a new possibility for neuroprotective strategies based on NO production.
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http://dx.doi.org/10.1080/00207454.2019.1636794DOI Listing
November 2019

Pharmacoresistant seizures in neurofibromatosis type 1 related to hippocampal sclerosis: Three case presentation and review.

J Clin Neurosci 2019 Jun 5;64:14-17. Epub 2019 Apr 5.

Department of Neurology, School of Medicine, Hacettepe University Hospitals, Ankara, Turkey. Electronic address:

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder, with an estimated prevalence of 1 in 3000-4000 people. Seizures occur 4-7% of individuals with NF1, mostly due to associated brain tumors or cortical malformations. Hippocampal sclerosis (HS) in the patients with NF1 has been reported very rarely and only 15 patients were found in review of English literature. We presented here 3 additional patients with NF1 and intractable seizures due to hippocampal sclerosis; in whom one of them underwent epilepsy surgery and he is seizure free for 5 years after right temporal lobectomy.
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http://dx.doi.org/10.1016/j.jocn.2019.03.055DOI Listing
June 2019

MicroRNA519d and microRNA4758 can identify gangliogliomas from dysembryoplastic neuroepithelial tumours and astrocytomas.

Oncotarget 2018 Jun 15;9(46):28103-28115. Epub 2018 Jun 15.

Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Glioneuronal tumours, including gangliogliomas and dysembryoplastic neuroepithelial tumours, represent the most common low-grade epilepsy-associated brain tumours and are a well-recognized cause of intractable focal epilepsy in children and young adults. Classification is predominantly based on histological features, which is difficult due to the broad histological spectrum of these tumours. The aim of the present study was to find molecular markers that can be used to identify entities within the histopathology spectrum of glioneuronal tumours. The focus of this study was on microRNAs (miRNAs). miRNAs are important post-transcriptional regulators of gene expression and are involved in the pathogenesis of different neurological diseases and oncogenesis. Using a miRNA array, miR-519d and miR-4758 were found to be upregulated in gangliogliomas (n=26) compared to control cortex (n=17), peritumoural tissue (n=7), dysembryoplastic neuroepithelial tumours (n=9) and astrocytomas (grade I-IV; subependymal giant cell astrocytomas, n=10; pilocytic astrocytoma, n=15; diffuse astrocytoma grade II, n=10; grade III, n=14 and glioblastoma n=15). Furthermore, the PI3K/AKT3/P21 pathway, which is predicated to be targeted by miR-519d and miR-4758, was deregulated in gangliogliomas. Functionally, overexpression of miR-519d in an astrocytic cell line resulted in a downregulation of (P21) and an increase in cell proliferation, whereas co-transfection with miR-4758 counteracted this effect. These results suggest that miR-519d and miR-4758 might work in concert as regulators of the cell cycle in low grade gliomas. Furthermore, these miRNAs could be used to distinguish gangliogliomas from dysembryoplastic neuroepithelial tumours and other low and high grade gliomas and may lead to more targeted therapy.
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http://dx.doi.org/10.18632/oncotarget.25563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021349PMC
June 2018

Poorly Differentiated Chordomas Showing Loss of INI1/SMARCB1: A Report of 2 Rare Cases With Diagnostic Implications.

Int J Surg Pathol 2018 Oct 6;26(7):637-643. Epub 2018 Apr 6.

2 Hacettepe University, Ankara, Turkey.

Poorly differentiated chordomas are rare musculoskeletal tumors. Case 1. A 42-year-old lady presented with quadriparesis of 2 months' duration. Radiologic imaging disclosed a soft tissue mass in her left prevertebral- and paravertebral cervical region. Case 2. A 4-year-old male child presented with neck pain and restricted head movements of 1-year duration. Radiologic imaging revealed a contrast enhancing, paraspinal soft tissue mass in his cervical region. Microscopic examination in both the cases revealed a cellular malignant tumor composed of moderate to markedly pleomorphic cells with interspersed mitotic figures, along with focal myxoid change and necrosis. By immunohistochemistry, tumor cells in both cases were diffusely positive for pan cytokeratin (AE1/AE3) and brachyury, whereas these were negative for INI1/SMARCB1. Tumor cells in the second case were also positive for glypican3. The first case developed pulmonary metastasis, while the second case developed recurrence. Poorly differentiated chordomas are uncommon tumors, invariably characterized by loss of INI1. These tumors can be rarely seen in adults and need to be differentiated from their diagnostic mimics, in view of treatment implications and their relatively aggressive clinical outcomes.
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http://dx.doi.org/10.1177/1066896918768043DOI Listing
October 2018

Professionalism in Pathology: The Turkish Experience.

Arch Pathol Lab Med 2018 04;142(4):433

Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.

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http://dx.doi.org/10.5858/arpa.2017-0452-LEDOI Listing
April 2018

Heightened CXCR4 and CXCL12 expression in NF1-associated neurofibromas.

Childs Nerv Syst 2018 05 17;34(5):877-882. Epub 2018 Feb 17.

Department of Medical Biology and Genetics, Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey.

Background: Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited disorder that affects both the skin and the nervous system. NF1 occurs due to the mutations in the NF1 gene. Neurofibromas are the most common Schwann cell-based tumors in NF1 patients, which are mainly categorized into dermal and plexiform neurofibromas. Studies on different tumor types demonstrate that CXCR4 expression increases in tumor tissues and is linked to metastasis and cancer progression.

Purpose: In the present study, we aimed to analyze the gene expression of CXCR4, and its ligand CXCL12, in human neurofibromas.

Methods: Eight NF1 patients aged between 5 and 37 (2 males, 6 females) were selected. The patient group comprised 1 plexiform neurofibroma, 1 pheochromocytoma, and 6 dermal neurofibromas. Following pathological examination and diagnosis, tumors were co-stained with antibodies against Schwann cell marker S100 and target molecule CXCR4. CXCR4 expression in Schwann cell-based tumors was detected at the protein level. RNA isolated from the same tumors was used for RT-PCR-based studies to measure the quantitative expression of CXCR4 and CXCL12.

Results: CXCR4 gene expression increased 3- to 120-fold and CXCL12 gene expression increased 33- to 512-fold in all human Schwann cell-based tumors.

Conclusion: In order to validate the role of CXCR4 and its relationship with CXCL12 in NF1, future studies should be performed with additional tumors and different tumor types.
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http://dx.doi.org/10.1007/s00381-018-3745-6DOI Listing
May 2018

Primary Diffuse Large B-Cell Lymphoma of the Ciliary Body.

Ocul Immunol Inflamm 2019 15;27(3):407-409. Epub 2018 Jan 15.

b Pathology Department , Hacettepe University School of Medicine , Ankara , Turkey.

: To report an unusual case of an eye with primary ciliary body lymphoma which came to enucleation allowing detailed histopathological examination. : A 50-year-old man presented with a painful loss of vision in the left eye. The clinical, imaging, and immunohistopathological features of this case were reviewed. : The vision in the left eye was light perception. There were keratic precipitates, an irregular and thickened iris with neovascularization. Imaging studies disclosed a ciliary body mass extending into the anterior chamber. The eye was enucleated and immunohistopathological examination showed positive staining with CD20, BCL-2, MUM1, and CD10. Staining with BCL-6 was weak and S100 and HMB45 expressions were negative. Occasional CD3+ reactive T cells were present. The Ki-67 index was 80-90%. All these results suggested diffuse large B-cell lymphoma. : Diffuse large B-cell lymphoma may primarily arise from the ciliary body and can develop without systemic or central nervous system disease.
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http://dx.doi.org/10.1080/09273948.2017.1415362DOI Listing
December 2019

A young girl with severe cerebral fungal infection due to card 9 deficiency.

Clin Immunol 2018 06 4;191:21-26. Epub 2018 Jan 4.

Department of Pediatric Immunology, Hacettepe University Children's Hospital, Ankara, Turkey.

Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.
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http://dx.doi.org/10.1016/j.clim.2018.01.002DOI Listing
June 2018

A case of idiopathic granulomatous hypophysitis.

Hormones (Athens) 2017 Jul;16(3):331-332

Ege University, Faculty of Medicine, Endocrinology Department, Izmir, Turkey.

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http://dx.doi.org/10.14310/horm.2002.1752DOI Listing
July 2017

Subependymal giant cell astrocytomas in Tuberous Sclerosis Complex have consistent biallelic inactivation, and no mutations.

Oncotarget 2017 Nov 8;8(56):95516-95529. Epub 2017 Sep 8.

Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Subependymal giant cell astrocytomas (SEGAs) are rare, low-grade glioneuronal brain tumors that occur almost exclusively in patients with tuberous sclerosis complex (TSC). Though histologically benign, SEGAs can lead to serious neurological complications, including hydrocephalus, intractable seizures and death. Previous studies in a limited number of SEGAs have provided evidence for a biallelic two-hit inactivation of either , resulting in constitutive activation of the mechanistic target of rapamycin complex 1 pathway. The activating V600E mutation is a common genetic alteration in low grade gliomas and glioneuronal tumors, and has been reported in SEGAs as well. In the present study, we assessed the prevalence of the V600E mutation in a large cohort of TSC related SEGAs (n=58 patients including 56 with clinical TSC) and found no evidence of either V600E or other mutations in To confirm that these SEGAs fit the classic model of two hit or inactivation, we also performed massively parallel sequencing of these loci. Nineteen (19) of 34 (56%) samples had mutations in , 10 (29%) had mutations in , while 5 (15%) had no mutation identified in / The majority of these samples had loss of heterozygosity in the same gene in which the mutation was identified. These results significantly extend previous studies, and in agreement with the Knudson two hit mechanism indicate that biallelic alterations in and less commonly, are consistently seen in SEGAs.
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http://dx.doi.org/10.18632/oncotarget.20764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707039PMC
November 2017

Microembolism of single cortical arterioles can induce spreading depression and ischemic injury; a potential trigger for migraine and related MRI lesions.

Brain Res 2018 01 26;1679:84-90. Epub 2017 Nov 26.

Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey; Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey; Neuroscience Center, Massachusetts General Hospital, Harvard University, Boston, USA. Electronic address:

Increasing epidemiological evidence suggests an association between migraine with aura (MA) and cardiovascular events. There is experimental as well as clinical evidence implying cerebral microembolism as a potential trigger for MA attacks. Microembolism may also account for some of the ischemic MRI lesions more commonly observed in MA than in general population. Limited size of clinically-silent MRI lesions suggests isolated occlusion of a small vessel. However, it is not known whether selective thrombosis of a small arteriole (e.g. single mouse penetrating arteriole - PA), can induce cortical spreading depression (CSD), the putative cause of migraine aura and, hence, trigger an MA attack. For this, we mimiced thrombosis of a small vessel caused by microembolism by selectively occluding a PA just before diving into the cortex (radius; 10-25 µm) in the mouse. Clotting was induced with FeCl applied focally over the PA by a glass micropipette for 3 min. DC potential changes were recorded and the alterations in cortical blood flow were monitored by laser speckle contrast imaging. Mice were kept alive for 1-4 weeks and brain sections were stained with H&E or luxol-fast blue to evaluate changes induced by PA occlusion. We found that single PA occlusion consistently triggered a CSD originating from the tissue around the PA soon after occlusion and induced delayed, small ischemic lesions within territory of the affected vessel a few weeks later. These findings suggest that cerebral microembolism can lead to MA attacks and may account for some of the silent brain lesions.
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http://dx.doi.org/10.1016/j.brainres.2017.11.023DOI Listing
January 2018

Novel Anatomic Mapping of Pelvic Plexus at Prostatic and Periprostatic Region on Fresh Frozen Cadaveric Setting.

Urol J 2017 Nov 4;14(6):5064-5067. Epub 2017 Nov 4.

Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey.

Purpose: We aimed to investigate the exact localization of neural pathway and the frequency of nerve fibers, which are located in the pelvic facial layers in the prostate and periprostatic regions.

Materials And Methods: We used four fresh frozen cadavers in this trial. Anatomical layers of anterior rectus fascia and abdominal rectus muscle were dissected to reach the retropubic area. Prostate, visceral and parietal pelvic fascia, levator ani muscle and puboprostatic ligaments were identified. Nine tissue samples, each 1x1 cm in size, were obtained from each cadaver and grouped separately. The locations of these samples are as follows. Group G I from 12 o'clock (apical region), G II from right prostatic apex, G III from 2 o'clock, G IV from right far pelvic lateral, G V from 5 o'clock, G VI from 7 o'clock, GVII from left far pelvic lateral, G VIII from 10 o'clock and G IX from left prostatic apex. Nerve distribution, frequency and diameters of these 9 groups were compared to each other.

Results: 36 specimens were obtained from 4 cadavers. Mean number of nerve fibers was 14.1. The number of nerve fibers in each location were not statistically different from each other (P = .9). Mean nerve diameter was 89.1 µm. Mean diameter of nerves was statistically different between groups II, III IV and VI and VIII (P = .001). No difference was seen amongst others.

Conclusion: The distributions of nerve fibers at prostate and peri-prostatic region were homogeneous while the nerve diameters varied amongst the different regions.
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http://dx.doi.org/10.22037/uj.v14i6.3734DOI Listing
November 2017

Immunopathology in drug resistant mesial temporal lobe epilepsy with different types of hippocampal sclerosis.

Int J Neurosci 2018 May 16;128(5):421-428. Epub 2017 Nov 16.

a Department of Neurology, Faculty of Medicine , Hacettepe University , Ankara , Turkey.

Purpose: There is evidence that autoimmunity has a specific role in temporal lobe seizures of limbic encephalitis patients. Our aim in this study was to investigate any histopathological clues of autoimmune process in refractory temporal lobe epilepsy (TLE) patients with different pathologically proven hippocampal sclerosis (HS) types.

Methods: 22 patients who had undergone epilepsy surgery due to mesial TLE-HS were included. The sera of patients are tested for neuronal antibodies to N-methyl-D-aspartate receptors (NMDAR), leucine-rich, glioma inactivated 1 (LGI1), contactin-associated protein 2 (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid B receptor (GABAR) and glutamic acid decarboxylase (GAD). Pathological and immunohistochemical investigations including neuronal nuclei (NeuN), NMDAR, GAD, glial fibrillary acidic protein (GFAP), CD8-CD3 lymphocytes and immunoglobulin G (IgG) were done. Patients were grouped according to type of HS. Clinical features and immunohistochemical changes were defined in these groups.

Results: Available sera of 15 patients did not have any neuronal antibodies. Thirteen of 22 patients had HS type 1, three had HS type 2 and two had HS type 3. According to immunohistochemical investigations CD3 and CD8 T cell infiltration was more prominent in the hippocampus of patients with classical HS (International League Against Epilepsy (ILAE) Type 1 HS) and there was a significant negative correlation between epilepsy duration and numbers of CD3-CD8 lymphocytes in temporal lobe parenchyma.

Conclusion: The role of T cell-mediated immunopathology and immunopathological difference in a variety of drug resistant TLE-H2S patients was suggested. These findings can be helpful in understanding the epileptogenicity of HS.
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http://dx.doi.org/10.1080/00207454.2017.1389928DOI Listing
May 2018

Postherpetic Anti-N-methyl-D-aspartate Receptor Encephalitis after Hemispherotomy in a Patient with Intractable Startle Epilepsy.

Neuropediatrics 2018 02 22;49(1):63-67. Epub 2017 Sep 22.

Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Herpes simplex encephalitis (HSE) has been increasingly reported after neurosurgical procedures, mostly after tumor resections in patients with a prior history of HSE. Early detection and appropriate treatment are essential to prevent high mortality of the disease; however, there are diagnostic difficulties due to nonspecific prodromal symptoms. In addition, anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been reported after HSE as an immunological relapse. Here, we report a case of postherpetic anti-NMDAR encephalitis following right hemispherotomy for intractable startle-induced seizures, to emphasize the importance of early diagnosis and appropriate treatment. To our knowledge, this is the first reported case of anti-NMDAR encephalitis after postoperative HSE, and the third reported case of hemispherotomy as a curative treatment for startle epilepsy.
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http://dx.doi.org/10.1055/s-0037-1606640DOI Listing
February 2018

A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles.

J Control Release 2017 09 3;261:187-198. Epub 2017 Jul 3.

Department of Neurosurgery, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

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.
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http://dx.doi.org/10.1016/j.jconrel.2017.06.032DOI Listing
September 2017