Publications by authors named "Hayyam Kiratli"

117 Publications

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

Pediatr Blood Cancer 2021 Jun 15;68(6):e28963. Epub 2021 Mar 15.

The Goldschleger eye institute, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.

Introduction: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment.

Method: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication.

Results: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy.

Conclusion: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.
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http://dx.doi.org/10.1002/pbc.28963DOI Listing
June 2021

Current Management of Conjunctival Melanoma Part 2: Treatment and Future Directions.

Turk J Ophthalmol 2020 12;50(6):362-370

Hacettepe University Faculty of Medicine, Department of Ophthalmology, Ocular Oncology Unit, Ankara, Turkey.

Conjunctival melanoma is a rare disease which requires tailored management in most cases. The mainstays of treatment can be classified as surgery, topical chemotherapy, radiotherapy, cryotherapy, and other emerging treatment modalities. Herein we review conventional approaches as well as more recently introduced treatment options, together with advances in molecular biology in this particular disease.
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http://dx.doi.org/10.4274/tjo.galenos.2020.22567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802095PMC
December 2020

Current Management of Conjunctival Melanoma Part 1: Clinical Features, Diagnosis and Histopathology.

Turk J Ophthalmol 2020 10;50(5):293-303

Hacettepe University Faculty of Medicine, Department of Ophthalmology, Ocular Oncology Service, Ankara, Turkey.

Conjunctival melanoma is a rare disease which makes up approximately 5% of ocular melanomas. The lesion may occur de novo or originate from a pre-existing nevus or primary acquired melanosis. Biomicroscopy is of paramount importance in diagnosis and follow-up of the disease, while other diagnostic modalities serve as supplementary tools. Many clinical and histopathological risk factors have been reported for prognosis. This review aims to address the clinical findings, differential diagnosis, diagnostic tools, prognostic factors, and staging of this disease.
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http://dx.doi.org/10.4274/tjo.galenos.2020.38096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610047PMC
October 2020

Single shot echo planar imaging (ssEPI) single shot turbo spin echo (ssTSE) DWI of the orbit in patients with ocular melanoma.

Br J Radiol 2021 Feb 22;94(1118):20200825. Epub 2020 Dec 22.

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

Objectives: Diffusion weighted imaging (DWI) has become important for orbital imaging. However, the echoplanar imaging (EPI) DWI has inherent obstacles due to susceptibility to magnetic field inhomogeneities. We conducted a comparative study assessing the image quality of orbits in a patient cohort with uveal melanoma (UM). We hypothesized that single shot turbo spin echo (ssTSE) DWI would have better image quality in terms of less distortion and artifacts and yield better tissue evaluation compared to ssEPI-DWI.

Methods: ssEPI-DWI and ssTSE-DWI of orbits were obtained from 50 patients with uveal melanoma who were prospectively enrolled in the study. Distortion ratio (DR), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), diffusion signal properties, and apparent diffusion coefficient (ADC) values were collected and compared between ssEPI-DWI and ssTSE-DWI. Two reviewers evaluated and compared the geometric distortion, susceptibility and ghosting artifacts, resolution, demarcation of ocular mass, and overall quality.

Results: A higher DR was found in ssEPI-DWI compared to ssTSE-DWI ( < 0.001). SNR and CNR were lower for the temporal lobe cortex ( ≤ 0.004), but higher for melanoma in ssEPI-DWI than ssTSE-DWI ( ≤ 0.037). Geometric distortion and artifacts were more common in ssEPI-DWI ( < 0.001). Resolution ( ≤ 0.013) and overall quality ( < 0.001) were better in ssTSE-DWI. Ocular masses were demarcated better on ssEPI-DWI ( ≤ 0.002). Significant negative correlations between T1 and T2 signal intensities ( = -0.369, ≤ 0.008) and positive correlations between T2 and both DWI signal intensities ( = 0.686 and < 0.001 for ssEPI-DWI, = 0.747 and < 0.001 for ssTSE-DWI) were revealed.

Conclusion: With less geometric distortion and susceptibility artifacts, better resolution, and overall quality, ssTSE-DWI can serve as an alternative to ssEPI-DWI for orbital DWI.

Advances In Knowledge: ssTSE-DWI can be a better alternative of diffusion imaging of orbits with less susceptibility artifact and geometric distortion compared to ssEPI-DWI.
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http://dx.doi.org/10.1259/bjr.20200825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934310PMC
February 2021

Primary Ciliary Body Marginal Zone Lymphoma Presenting as Hemorrhagic Hypopyon.

Ocul Immunol Inflamm 2020 Oct 16:1-4. Epub 2020 Oct 16.

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

: Our purpose is to report a patient with primary unilateral ciliary body marginal zone lymphoma who initially presented with hemorrhagic hypopyon.Methods: Retrospective review of the clinical, imaging, and immunohistopathological features of the case was performed.: A 59-year-old man was referred with right anterior uveitis of unknown etiology which was unresponsive to systemic treatment. Slit-lamp biomicroscopy showed normotensive hemorrhagic hypopyon in that eye. Anterior segment ultrasound biomicroscopy revealed an iridociliary mass lesion. Because an anterior chamber paracentesis was noncontributory, a diagnostic cyclectomy was performed. Histopathological evaluation showed that the neoplastic cells were positive for CD20, lambda light chain, and BCL 2. BCL 6, CD10, CD5, SOX11, kappa, and Cyclin D1 stains were negative. The final diagnosis was extranodal marginal zone lymphoma of the ciliary body.: Although rare, ciliary lymphoma may be a cause of intractable anterior uveitis. Repeat biopsies could be carried out when there is a high level of clinical suspicion.
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http://dx.doi.org/10.1080/09273948.2020.1815798DOI Listing
October 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

Comparison of intravitreal melphalan with and without topotecan in the management of vitreous disease in retinoblastoma.

Jpn J Ophthalmol 2020 Jul 23;64(4):351-358. Epub 2020 May 23.

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

Purpose: To evaluate clinical outcomes and enucleation rates after intravitreal melphalan (IVM) alone and after IVM combined with intravitreal topotecan (IVT) for the treatment of vitreous disease, and to a lesser extent subretinal and retrohyaloid seeds, in patients with retinoblastoma.

Study Design: A retrospective analysis of 77 eyes of 72 consecutive patients.

Methods: Demographic data, classification of tumors, seed type (dust, sphere or cloud) before injection and at the end of follow-up, injection type (IVM or IVM+IVT), doses of IVM and IVT, number of injections, follow-up time, enucleation status and side effects were recorded. Cox regression analysis and log-rank test for Kaplan-Meier curves were performed.

Results: Of 77 eyes, 40 received IVM alone (group 1) and 37 received IVM+IVT (group 2). Enucleation rates were 62.5% (n=25) in group 1 and 10.8% (n=4) in group 2 (p=0.001). Median eye survival was 23.6 months in group 1 and 25.6 months in group 2. Mantel-Cox test revealed statistically significant differences between Kaplan-Meier curves of group 1 and 2 (p=0.022). Multiple Cox regression analysis showed a significantly elevated enucleation rate associated with: IVM only treatment group (p=0.019) and pre-injection cloud type of seeding (p=0.014).

Conclusion: The combined use of intravitreal melphalan and topotecan provides significantly better results in terms of avoiding enucleation and vitreal and subretinal seed control.
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http://dx.doi.org/10.1007/s10384-020-00743-2DOI Listing
July 2020

Global Retinoblastoma Presentation and Analysis by National Income Level.

JAMA Oncol 2020 05;6(5):685-695

Imam Hussein Cancer Center, Karbala, Iraq.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.

Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.

Design, Setting, And Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.

Main Outcomes And Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.

Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).

Conclusions And Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
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http://dx.doi.org/10.1001/jamaoncol.2019.6716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047856PMC
May 2020

Corneal Relapse of Peripheral T-Cell Lymphoma Under Systemic Chemotherapy.

Cornea 2018 Dec;37(12):1593-1595

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

Purpose: To report a patient who developed unilateral corneal stromal infiltration while undergoing systemic chemotherapy for multinodal peripheral T-cell lymphoma not otherwise specified.

Methods: Clinical, imaging, and immunohistopathological features of a 40-year-old woman who presented with a stromal haze in the right cornea were reviewed.

Results: At initial presentation, her visual acuity in the right eye was 20/40. Slit-lamp examination showed stromal infiltration located mainly in the inferotemporal peripheral cornea without epithelial or limbal involvement. Immunohistochemical examination of the incisional biopsy specimen revealed CD3, CD5, and CD8 neoplastic lymphocytes suggestive of T-cell lymphoma. The corneal lesion and disseminated lymphadenopathy did not respond to various combinations of several cycles of systemic chemotherapy. Remission was achieved only after allogeneic bone marrow transplantation. The corneal infiltrates almost totally regressed within 6 months, and she maintained 20/20 visual acuity thereafter. She did not have any systemic or ocular recurrence during 6 years of posttransplantation follow-up.

Conclusions: In this rare case of systemic multinodal peripheral T-cell lymphoma, corneal stromal infiltration was the only ocular manifestation. Prompt corneal biopsy enabled the appropriate diagnosis. Development and persistence of corneal infiltration despite systemic chemotherapy may be a warning sign for resistance to treatment.
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http://dx.doi.org/10.1097/ICO.0000000000001759DOI Listing
December 2018

Retrospective analysis of primarily treated group D retinoblastoma.

Graefes Arch Clin Exp Ophthalmol 2018 Nov 30;256(11):2225-2231. Epub 2018 Jun 30.

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

Purpose: To assess the effectiveness of intra-arterial chemotherapy (IAC), intravenous chemotherapy (IVC), and their combination in the management of group D retinoblastoma.

Methods: This was a retrospective, interventional, comparative, and non-randomized clinical study, including all eyes with primarily treated group D retinoblastoma managed in a single institution from February 2010 to July 2016. Patient demographics, treatment modality (primary enucleation, intravenous chemotherapy, intra-arterial chemotherapy alone or intravenous, and intra-arterial chemotherapy), additional need for consolidation treatments or intravitreal melphalan (IVM) injections, and follow-up time were recorded. The main outcome measure was ocular survival rate after various treatment modalities.

Results: Of 87 eyes of 83 consecutive cases, 9 eyes (10.3%) were primarily enucleated, 37 (42.6%) eyes received IVC, 30 (34.5%) eyes had IAC, and 11 (12.6%) eyes were treated with IVC followed by IAC. After a mean 81.1 ± 75.2 weeks of follow-up, enucleation rates were 56.8% in the IVC group, 23.3% in the IAC group, and 36.6% in the IVC + IAC group (p = 0.021). There was no significant difference of ocular survival estimates among these 3 groups at 2 or 5 years (p = 0.998, p = 0.986). With logistic regression analysis, age; gender; disease laterality; administration of IVM, TTT, or cryotherapy; mean dose of IVM; follow-up time; and number of IAC or IVC cycles were not significantly related to the enucleation rate (p > 0.05 for all variables).

Conclusions: Our experience showed that in group D patients, primary IAC achieved ocular survival in 76.7% of eyes, and less need for local consolidation treatments, whereas following primary IVC ocular survival was 43.2%.
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http://dx.doi.org/10.1007/s00417-018-4051-4DOI Listing
November 2018

Mesenchymal Chondrosarcoma of the Lacrimal Gland.

Ophthalmic Plast Reconstr Surg 2018 May/Jun;34(3):e77-e79

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

A 23-year-old woman presented with right-sided painless proptosis that developed in 12 months. MRI studies demonstrated a well-delineated tumorous enlargement of the right lacrimal gland with homogenous signal intensity and compressing the globe. The tumor was removed totally and in 1 piece with the tentative diagnosis of a pleomorphic adenoma. Pathologic examination revealed biphasic neoplastic elements, which were composed of the cartilaginous matrix and small round cell component. Immunohistopathological examination showed positive CD99 staining and negative reaction to S100, panCK, and CD15. The patient then received a total of 64 Gy orbital radiotherapy in 32 fractionations. There has been no recurrence or metastasis during 14 months of follow up. This case showed that mesenchymal chondrosarcoma may arise from the lacrimal gland and must be considered in the differential diagnosis of lacrimal gland tumors in young adults.
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http://dx.doi.org/10.1097/IOP.0000000000001054DOI Listing
July 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

Sequential development of dermatofibrosarcoma protuberans in the forehead and eyelid.

Can J Ophthalmol 2017 12 23;52(6):e228-e230. Epub 2017 Jun 23.

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

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http://dx.doi.org/10.1016/j.jcjo.2017.04.007DOI Listing
December 2017

Ciliary Body Mesectodermal Leiomyoma Diagnosed by Fine Needle Aspiration Biopsy.

Ocul Oncol Pathol 2017 Sep 15;3(3):199-203. Epub 2017 Feb 15.

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

Aims: To describe the clinical, imaging, cytopathological, and immunohistochemical features of mesectodermal leiomyoma of the ciliary body diagnosed by fine needle aspiration biopsy in a patient who denied any major intervention without prior pathological verification.

Methods: The clinical, imaging, and cytopathological records of the patient were retrospectively reviewed. A fine needle aspiration biopsy with a 25-G needle was performed after tailoring a scleral flap.

Results: Examination of the cell blocks prepared from the aspirate demonstrated cells with granular cytoplasms and large nuclei. Immunohistochemical studies showed positive smooth muscle actin, desmin, h-caldesmon, CD56, and neuron-specific enolase stainings, suggesting both neurogenic and myogenic differentiation. Reactions for HMB-45, S-100, panCK, epithelial membrane antigen, glial fibrillary acidic protein, and CD68 were negative. Because the tumor continued to enlarge, fractionated stereotactic radiotherapy at the dose of 3,000 cGy was delivered, which reduced the size of the mass by 40% in 5 years.

Conclusions: This case demonstrated that the diagnosis of mesectodermal leiomyoma of the ciliary body can be established with fine needle aspiration biopsy and that stereotactic radiotherapy can be successfully used to induce tumor regression.
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http://dx.doi.org/10.1159/000454863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649313PMC
September 2017

Orbital exenteration: Institutional review of evolving trends in indications and rehabilitation techniques.

Orbit 2018 Jun 17;37(3):179-186. Epub 2017 Oct 17.

a Ocular Oncology Service, Department of Ophthalmology , Hacettepe University School of Medicine , Ankara , Turkey.

Purpose: To determine the changes in indications for orbital exenteration over 20 years and to assess its impact on patient survival. Evolving techniques of rehabilitation of the orbit in our institution were also evaluated.

Methods: This was a retrospective review of hospital records of patients who underwent orbital exenteration from 1995 to 2015 in a tertiary care center. Data extracted included primary location of the tumor, preoperative treatments, interval between initial diagnosis and exenteration, status of surgical margins, presence of metastatic disease, and postoperative survival. The types of prosthesis utilized over the years were also reviewed. Cox regression analysis was performed for categorical variables. Kaplan-Meier analysis was used to estimate post-exenteration survival.

Results: Over a 20-year period, orbital exenteration was performed on 100 orbits of 100 patients. The mean age was 39.4 years (range: 2 months to 90 years). The most common indications among 98 malignant causes were retinoblastoma, squamous cell carcinoma, basal cell carcinoma, extraocular extension of uveal melanoma, and conjunctival melanoma. Postoperative survival was significantly related to age and tumor location but independent from gender, surgical margin, histopathological diagnosis, previous treatment modality, and preoperative interval. In the whole cohort, 1-year and 5-year survival rates were 97% and 84%, respectively.

Conclusions: Exenteration appears to be life-saving in children with orbital extension of retinoblastoma. While patients exenterated for malignant eyelid tumors have the best chance of survival, those with orbital extension of uveal melanoma and adenoid cystic carcinoma of the lacrimal gland have the worst prognosis.
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http://dx.doi.org/10.1080/01676830.2017.1383466DOI Listing
June 2018

Circumferential Ciliary Body Cysts Presenting as Acute Pigment Dispersion and Ocular Hypertension.

Ocul Immunol Inflamm 2018 15;26(8):1261-1263. Epub 2017 Sep 15.

a Department of Ophthalmology , Başkent University, Faculty of Medicine , Ankara , Turkey.

Purpose: To report a case of circumferential neuroepithelial cyst of the ciliary body presenting with pigment dispersion (PD) and ocular hypertension.

Case Report: 48-year-old female patient presented with a complaint of pain in the left eye. On examination, visual acuity of the left eye was 0.9, and the intraocular pressure was 48 mmHg. Biomicroscopic anterior segment examination of the left eye revealed 4+ pigmented cells in the anterior chamber. Active PD from the pupillary region at 11 o'clock was noticed at the time of the examination. Ultrasound biomicroscopy demonstrated 360º cystic lesions of the ciliary body in the left eye. The patient was diagnosed as neuroepithelial cyst of the ciliary body.

Conclusion: Our case is unique as it is the first case of circumferential neuroepithelial ciliary body cyst presenting with acute PD and ocular hypertension.
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http://dx.doi.org/10.1080/09273948.2017.1343856DOI Listing
December 2018

Unusual presentations of Carney Complex in patient with a novel PRKAR1A mutation.

Neuro Endocrinol Lett 2017 Aug;38(4):248-254

Hacettepe University, Faculty of Medicine, Department of Endocrinology and Metabolism, Ankara, Turkey.

Carney Complex (CNC) is a multiple neoplasia syndrome characterized by skin tumors and pigmented lesions, myxomas, and various endocrine tumors. The aim of this case report was to describe a case of CNC with a novel PRKAR1A mutation. A man aged 46 years with a medical history of surgery for cardiac myxomas at the age of 39 was admitted to our hospital because of four newly-developed heart masses. The histologic examination confirmed cardiac myxomas. He had many presentations of CNC such as growth hormone (GH) and prolactin (PRL)-secreting mixed pituitary adenoma, benign thyroid nodule, large-cell calcifying Sertoli cell tumor (LCCST), and superficial angiomyxoma. A bilateral adrenalectomy was performed because the laboratory findings suggested primary pigmented nodular adrenocortical disease (PPNAD). The pathologic examination revealed a focal unilateral PPNAD, unilateral nonpigmented adrenocortical nodule, and bilateral adrenal medullary hyperplasia. Two years after the second cardiac operation, an interatrial septum-derived tumor was detected. An atrial myxoma was confirmed with histologic studies. Based on these findings, the patient was confirmed to have CNC. A novel insertion mutation in the type 1A regulatory subunit of the cAMP-dependent protein kinase A gene (PRKAR1A) in exon 2 was detected in our patient through genetic analysis. The presence of multiple myxomas and endocrine abnormalities should be an indication to physicians to further investigate for CNC. Herein, we described a case of CNC with a novel mutation in exon 2 of the PRKAR1A gene with typical and atypical clinical features.
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August 2017

An international survey of classification and treatment choices for group D retinoblastoma.

Int J Ophthalmol 2017 18;10(6):961-967. Epub 2017 Jun 18.

Istanbul University, Cerrahpasa Medical Faculty & Oncology Institute, Istanbul 34303, Turkey.

Aim: To determine which IIRC scheme was used by retinoblastoma centers worldwide and the percentage of D eyes treated primarily with enucleation versus globe salvaging therapies as well as to correlate trends in treatment choice to IIRC version used and geographic region.

Methods: An anonymized electronic survey was offered to 115 physicians at 39 retinoblastoma centers worldwide asking about IIRC classification schemes and treatment patterns used between 2008 and 2012. Participants were asked to record which version of the IIRC was used for classification, how many group D eyes were diagnosed, and how many eyes were treated with enucleation versus globe salvaging therapies. Averages of eyes per treatment modality were calculated and stratified by both IIRC version and geographic region. Statistical significance was determined by Chi-square, ANOVA and Kruskal-Wallis tests using Prism.

Results: The survey was completed by 29% of physicians invited to participate. Totally 1807 D eyes were diagnosed. Regarding IIRC system, 27% of centers used the Children's Hospital of Los Angeles (CHLA) version, 33% used the Children's Oncology Group (COG) version, 23% used the Philadelphia version, and 17% were unsure. The rate for primary enucleation varied between 0 and 100% and the mean was 29%. By IIRC version, primary enucleation rates were: Philadelphia, 8%; COG, 34%; and CHLA, 37%. By geographic region, primary enucleation rates were: Latin America, 57%; Asia, 40%; Europe, 36%; Africa, 10%, US, 8%; and Middle East, 8%. However, systemic chemoreduction was used more often than enucleation in all regions except Latin America with a mean of 57% per center (<0.0001).

Conclusion: Worldwide there is no consensus on which IIRC version is used, systemic chemoreduction was the most frequently used initial treatment during the study period followed by enucleation and primary treatment modality, especially enucleation, varied greatly with regards to IIRC version used and geographic region.
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http://dx.doi.org/10.18240/ijo.2017.06.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515152PMC
June 2017

Stereotactic Radiosurgery and Fractionated Stereotactic Radiation Therapy for the Treatment of Uveal Melanoma.

Int J Radiat Oncol Biol Phys 2017 05 17;98(1):152-158. Epub 2017 Feb 17.

Department of Radiation Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. Electronic address:

Purpose: To evaluate treatment results of stereotactic radiosurgery or fractionated stereotactic radiation therapy (SRS/FSRT) for uveal melanoma.

Methods And Materials: We retrospectively evaluated 181 patients with 182 uveal melanomas receiving SRS/FSRT between 2007 and 2013. Treatment was administered with CyberKnife.

Results: According to Collaborative Ocular Melanoma Study criteria, tumor size was small in 1%, medium in 49.5%, and large in 49.5% of the patients. Seventy-one tumors received <45 Gy, and 111 received ≥45 Gy. Median follow-up time was 24 months. Complete and partial response was observed in 8 and 104 eyes, respectively. The rate of 5-year overall survival was 98%, disease-free survival 57%, local recurrence-free survival 73%, distant metastasis-free survival 69%, and enucleation-free survival 73%. There was a significant correlation between tumor size and disease-free survival, SRS/FSRT dose and enucleation-free survival; and both were prognostic for local recurrence-free survival. Enucleation was performed in 41 eyes owing to progression in 26 and complications in 11.

Conclusions: The radiation therapy dose is of great importance for local control and eye retention; the best treatment outcome was achieved using ≥45 Gy in 3 fractions.
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http://dx.doi.org/10.1016/j.ijrobp.2017.02.017DOI Listing
May 2017

An orbital perivascular epithelioid cell tumor in a 7-year-old boy: case report and review of the literature.

J AAPOS 2017 Aug 30;21(4):325-328.e1. Epub 2017 May 30.

Department of Pediatric Oncology, Hacettepe University, Cancer Institute, Ankara, Turkey.

We report the case of a 7-year-old boy who presented with a swollen right eye. Magnetic resonance imaging revealed a right intraconal orbital mass with intense contrast enhancement. Incisional biopsy led to a diagnosis of perivascular epithelioid cell tumor (PEComa). Sirolimus was initiated but discontinued at the third week of treatment because the tumor had progressed. A minor regression of the tumor was seen after six cycles of systemic chemotherapy. Previously reported cases of PEComa were benign in nature, and full remission was achieved with surgical excision. In the present case the tumor was malignant and responded only slightly to systemic chemotherapy.
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http://dx.doi.org/10.1016/j.jaapos.2017.05.022DOI Listing
August 2017

INTRAVITREAL DEXAMETHASONE (OZURDEX) IMPLANT FOR RADIATION MACULOPATHY SECONDARY TO STEREOTACTIC RADIOTHERAPY FOR POSTERIOR UVEAL MELANOMA.

Retin Cases Brief Rep 2019 ;13(4):352-356

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

Purpose: To evaluate the efficacy of 0.7 mg intravitreal dexamethasone implant in the treatment of radiation maculopathy after stereotactic radiotherapy for posterior uveal melanoma.

Methods: Retrospective chart review of seven eyes of seven consecutive patients was performed. Extracted data included age, sex, initial and follow-up visual acuities and central macular thickness values, intraocular pressure, follow-up time, number of implants, and time elapsed from radiotherapy to implantation. Main outcome measures were visual acuity and central macular thickness. Glaucoma, cataract formation, or systemic side effects, if any, were recorded.

Results: Female to male ratio was 4:3. Mean age was 49.9 ± 17.0 (range: 27-73). Initial mean visual acuity was 20.4 ± 12.5 Early Treatment Diabetic Retinopathy Study letters and initial central macular thickness measured 514.1 ± 135.1 μm on spectral domain optical coherence tomography. All patients except one showed improvement in visual acuity and a mean improvement of 7.4 ± 6.2 letters was observed in the whole group (range: 0-16). The mean reduction in central macular thickness was 226.7 ± 157.0 μm after a mean 9.1 ± 3.4 months of follow-up. On average, implantation of intravitreal dexamethasone was performed 35.2 ± 16.5 months after radiotherapy. Four patients were treatment naive and three had previous intravitreal bevacizumab injections with limited response. Ozurdex reimplantations were performed in four patients and the mean number of injections was 1.7 ± 0.8. Mean time to reimplantation was 5.0 ± 2.12 months. Only one patient developed posterior subcapsular cataract and all patients had intraocular pressures within normal limits. No systemic side effects were observed.

Conclusion: In our experience, intravitreal implantation of 0.7 mg dexamethasone is an anatomically, and to a lesser extent functionally effective procedure for radiation maculopathy after stereotactic radiotherapy for posterior uveal melanoma.
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http://dx.doi.org/10.1097/ICB.0000000000000593DOI Listing
March 2020

Intravitreal chemotherapy in the management of vitreous disease in retinoblastoma.

Eur J Ophthalmol 2017 Jun 2;27(4):423-427. Epub 2017 Jan 2.

Department of Pediatric Oncology, Hacettepe University School of Medicine, Ankara - Turkey.

Purpose: To evaluate the therapeutic outcome of intravitreal melphalan injection in the management of vitreous disease in patients with retinoblastoma. We particularly aimed to assess whether higher melphalan dose with lower number of injections was more effective and associated with fewer side effects.

Methods: This retrospective, interventional, noncomparative, and nonrandomized study included 39 eyes of 37 patients. Vitreous seeds were classified as dust, sphere, and cloud types. Intravitreal injections were performed through pars plana free of any visible tumor using 30-G needle. Response of the seeds (disappearance, conversion into inactive debris, or progression) and enucleation rate were determined as outcome measures.

Results: All patients previously received systemic or intra-arterial chemotherapy. Vitreous seeding was primary in 54% of eyes and secondary in 46% of eyes. Vitreous seeds were classified as dust in 9 (23.1%) eyes, sphere in 24 (61.5%) eyes, and cloud in 6 (15.4%) eyes. Melphalan dose varied between 20 and 40 µg and 20 (51.3%) eyes received >30 µg. The total number of injections was 70 (range 1-5, mean 1.8 per eye). Various types of regression were obtained in 27 (69.2%) eyes. Sphere-type seeds were the most responsive to melphalan. Nonresponse and disease progression were noted in 12 (30.8%) eyes. After a mean follow-up of 11.8 months, 17 (44%) eyes were enucleated. Vitreous hemorrhage (18%) and retinal pigment epithelial alterations (8%) were the most common side effects.

Conclusions: Intravitreal melphalan at 30-40 µg in 1 or 2 injections proved effective in 69.2% of eyes with vitreous disease.
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http://dx.doi.org/10.5301/ejo.5000921DOI Listing
June 2017

Uveal Melanoma: Current Trends in Diagnosis and Management.

Turk J Ophthalmol 2016 Jun 6;46(3):123-137. Epub 2016 Jun 6.

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

Uveal melanoma, which is the most common primary intraocular malignancy in adults, arises from melanocytes within the iris, ciliary body and choroid. The diagnosis is based principally on clinical examination of the tumor with biomicroscopy and indirect ophthalmoscopy and confirmed by diagnostic techniques such as ultrasonography, fundus fluorescein angiography and optical coherence tomography. The clinical diagnosis of posterior uveal melanomas can be made when the classical appearance of a pigmented dome-shaped mass is detected on dilated fundus exam. Uveal melanomas classically show low to medium reflectivity on A-scan ultrasonography and on B-scan ultrasonography the tumor appears as a hyperechoic, acoustically hollow intraocular mass. Management of a suspicious pigmented lesion is determined by its risk factors of transforming into a choroidal melanoma, such as documentation of growth, thickness greater than 2 mm, presence of subretinal fluid, symptoms and orange pigment, margin within 3 mm of the optic disc, and absence of halo and drusen. Advances in the diagnosis and local and systemic treatment of uveal melanoma have caused a shift from enucleation to eye-conserving treatment modalities including transpupillary thermotherapy and radiotherapy over the past few decades. Prognosis can be most accurately predicted by genetic profiling of fine needle aspiration biopsy of the tumor before the treatment, and high-risk patients can now be identified for clinical trials that may lead to target-based therapies for metastatic disease and adjuvant therapy which aims to prevent metastatic disease.
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http://dx.doi.org/10.4274/tjo.37431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076295PMC
June 2016

In vivo Confocal Microscopy in Differentiating Ipilimumab-Induced Anterior Uveitis from Metastatic Uveal Melanoma.

Case Rep Ophthalmol 2016 Sep-Dec;7(3):126-131. Epub 2016 Sep 9.

Ocular Oncology Service, Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey.

This report aims to describe the facilitating role of in vivo confocal microscopy in differentiating inflammatory cells from a metastatic process in a patient with uveal melanoma and multiple systemic metastases who developed anterior uveitis while under ipilimumab treatment. A 43-year-old woman developed systemic metastases 11 months after treatment of amelanotic choroidal melanoma in her right eye with 30 Gy fractionated stereotactic radiotherapy. She first received temozolomide and then 4 cycles of ipilimumab 3 mg/kg/day. After the third cycle, severe anterior uveitis with coarse pigment clumps on the lens was seen in the left eye. Her left visual acuity declined from 20/20 to 20/80. Confocal microscopy revealed globular keratic precipitates with hyperreflective inclusions and endothelial blebs all suggestive of granulomatous uveitis. The uveitic reaction subsided after a 3-week course of topical corticosteroids, and her visual acuity was 20/20 again. Although uveal melanoma metastatic to the intraocular structures of the fellow eye is exceedingly rare and metastasis masquerading uveitis without any identifiable uveal lesion is even more unusual, it was still mandatory to rule out this distant possibility in our particular patient who already had widespread systemic metastases. Confocal microscopy was a useful complementary tool by identifying the inflammatory features of the keratic precipitates.
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http://dx.doi.org/10.1159/000448730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073655PMC
September 2016

Evaluation of the 'Hedgehog' signaling pathways in squamous and basal cell carcinomas of the eyelids and conjunctiva.

Oncol Lett 2016 Jul 25;12(1):467-472. Epub 2016 May 25.

Department of Pathology, Hacettepe University School of Medicine, 06100 Ankara, Turkey.

The purpose of the present study was to assess the role of hedgehog signaling pathway in the carcinogenesis of eyelid skin and conjunctival epithelial malignant tumors. The study was conducted on specimens from 41 patients with cutaneous eyelid basal cell carcinoma, 22 with bulbar conjunctival squamous cell carcinoma, 12 with bulbar conjunctival intraepithelial neoplasia. Major molecules of Hedgehog signaling pathway (Sonic Hedgehog [Shh] and Patched-1 [Ptch-1] and Glioma-associated oncogene [Gli-1]) were evaluated in paraffin-embedded tissue specimens using immunohistochemical staining. For each specimen, the percentage (<10%, 10-50%, >50%) and the intensity of the immunohistochemical staining (graded from 0 to 3) were calculated and the scores obtained by multiplication of two values were analyzed using the Kruskall-Wallis test. Shh and Ptch-1 expression levels were statistically significantly lower in the basal cell carcinoma group compared with the squamous cell carcinoma group (P=0.043 for Shh; P=0.030 for Ptch-1). In the conjunctival squamous cell carcinoma group, the Ptch-1 score was 0 in ~25% of specimens and the Gli-1 score was ≤2 in ~45% of cases. In the conjunctival intraepithelial neoplasia group, the Ptch-1 score was ≥2 in 66% of specimens, the Gli-1 score was ≤2 in ~92% of cases. Ptch-1 mutations contribute to the development of cutaneous eyelid basal cell carcinoma. The present study provides evidence that alterations in hedgehog signaling pathways may lead to transformation of the conjunctival intraepithelial neoplasia into invasive squamous cell carcinoma.
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http://dx.doi.org/10.3892/ol.2016.4625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907170PMC
July 2016

Malignant transformation of retinocytoma treated with intra-arterial chemptherapy.

Can J Ophthalmol 2016 Jun;51(3):e105-7

Ocular Oncology Service, Department of Ophthalmology, Hacettepe University School of Medicine, Ankara, Turkey.

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http://dx.doi.org/10.1016/j.jcjo.2015.12.023DOI Listing
June 2016

Management of anaplastic lymphoma kinase positive orbito-conjunctival inflammatory myofibroblastic tumor with crizotinib.

J AAPOS 2016 06;20(3):260-3

Hacettepe University School of Medicine, Sihhiye, Ankara, Turkey.

Inflammatory myofibroblastic tumor (IMT) is a distinct mesenchymal neoplasm of myofibroblastic spindle cells associated with an inflammatory infiltrate formed by lymphocytes, eosinophils, and plasma cells in a myxoid or collagenous stroma. This tumor has a predilection for children and young adults and most commonly occurs in the lungs, retroperitoneum, abdomen, and pelvis. Ocular and orbital involvement is exceedingly rare. We describe a case of IMT in a 7-year-old girl involving the cornea, conjunctiva, and the anterior orbit treated with crizotinib, resulting in complete tumor remission.
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http://dx.doi.org/10.1016/j.jaapos.2016.01.009DOI Listing
June 2016

Orbital Extension of an Unsuspected Choroidal Melanoma Presumably through an Aqueous Tube Shunt.

Ocul Oncol Pathol 2016 Apr 25;2(3):144-7. Epub 2015 Nov 25.

Department of Ophthalmology, Kozluk State Hospital, Batman, Turkey.

Aims: To report a patient with unrecognized small macular melanoma, who gradually developed neovascular glaucoma that was treated with an Ahmed valve. We presume that tumor cells gained access to the orbit through this aqueous drainage device.

Methods: The medical records pertaining to 5 different centers, the results of imaging studies, the clinical course of the patient and histopathological findings were retrospectively reviewed.

Results: A 61-year-old man presented with a blind and painful proptotic right eye. Retinal hemorrhage had been suspected 3 years earlier and followed accordingly thereafter. Yearly performed MRI studies demonstrated the steady growth of the hemorrhagic lesion/tumor. Meanwhile, he developed neovascular glaucoma first treated unsuccessfully with cyclocryotherapy then with implantation of an Ahmed valve. Right proptosis became evident within a year, and a final MRI study revealed a large retrobulbar mass. Orbital exenteration was performed and histopathological examination showed intraocular and orbital epithelioid cell melanoma. Tumor cells were also found within the reservoir of the Ahmed valve. The patient died of widespread metastases 1 year later.

Conclusions: Ahmed valve implantation in an eye with unsuspected macular choroidal melanoma may ultimately be associated with extraocular extension and orbital tumor formation.
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http://dx.doi.org/10.1159/000441726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881271PMC
April 2016

Orbital Malignant Peripheral Nerve Sheath Tumor With Heterologous Elements in a 15-Year-Old Girl.

J Pediatr Ophthalmol Strabismus 2016 Apr 23;53 Online:e12-4. Epub 2016 Apr 23.

A 15-year-old girl presented with painful proptosis in the right eye. Imaging studies demonstrated an inferiorly located orbital mass. Histopathological examination of the exenteration specimen was consistent with malignant peripheral nerve sheath tumor. This case is a rare example of orbital malignant peripheral nerve sheath tumor presumably arising from the infraorbital nerve with heterologous histologic elements.
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http://dx.doi.org/10.3928/01913913-20160406-02DOI Listing
April 2016