Metastatic Lung Cancer Masquerading as Endophthalmitis.

A 41-year-old man presented to the emergency department with a painful and red left eye associated with chronic vision loss. He had a history of homelessness and polysubstance abuse including intravenous drug use. Fundus examination revealed several cream-colored lesions encroaching on the macula of the right eye, and a total retinal detachment with secondary neovascular glaucoma in the left eye. Further work-up with imaging and endobronchial ultrasound-guided fine needle aspiration revealed stage IV epidermal growth factor receptor (EGFR) mu- tant (L858R) lung adenocarcinoma with brain, bone, adrenal, lymph node and bilateral choroid- al metastases. Herein we present a case of metastatic lung cancer masquerading as endophthalmitis.

Tumor Control and Visual Acuity Outcomes in Vitreoretinal Lymphoma with and without Sub-Retinal Pigment Epithelium Infiltration: Analysis of 125 Eyes of 70 Patients at a Single Ocular Oncology Center.

PURPOSE: To investigate outcomes in vitreoretinal lymphoma (VRL) presenting with or without sub-retinal pigment epithelial (sub-RPE) infiltration. DESIGN: Retrospective, comparative analysis. SUBJECTS: Patients with VRL at a single center from January 1, 1984, through July 30, 2018. METHODS: Record review was conducted for clinical features, treatments, and outcomes of tumor control, visual acuity (VA), and death. MAIN OUTCOME MEASURES: Ocular tumor control and VA outcome. RESULTS: The study involved 168 eyes of 95 patients with VRL, of which 45 (27%) eyes of 32 patients had sub-RPE infiltration. Comparison (of patients with vs. without sub-RPE infiltration) showed similar presenting features of mean patient age (65 vs. 68 years, P = 0.30), percentage of males (53% vs. 56%, P = 0.83), white race (84% vs. 87%, P = 0.77), bilateral ocular involvement (78% vs. 75%, P = 0.80), and VA of 20/40 or better (40% vs. 50%, P = 0.30), 20/50 to 20/200 (42% vs. 31%, P = 0.20), or worse than 20/200 (18% vs. 19%, P = 0.99). Lymphoma subtype was diffuse large B cell (59% vs. 52%) or unspecified (41% vs. 44%, P = 0.85). Follow-up data were available for 125 eyes of 70 patients. Overall treatment included systemic chemotherapy (53% vs. 64%, P = 0.29), intravitreal chemotherapy (59% vs. 28%, P = 0.005), and external beam radiotherapy (59% vs. 94%, P < 0.001). Initial ocular tumor control occurred (91% vs. 94%, P = 0.68) with subsequent recurrence (35% vs. 17%, P = 0.07). Outcomes at final follow-up (mean 24 vs. 25 months, P = 0.82) revealed ocular tumor complete regression (68% vs. 86%, P = 0.03), partial regression (3% vs. 7%, P = 0.44), or active persistent or recurrent disease (29% vs. 7%, P = 0.002). Final VA was 20/40 or better (39% vs. 53%, P = 0.18), 20/50 to 20/200 (26% vs. 34%, P = 0.53), or worse than 20/200 (34% vs. 13%, P = 0.007). Vitreoretinal lymphoma was associated with central nervous system lymphoma (41% vs. 59%, P = 0.13) or systemic lymphoma (16% vs. 21%, P = 0.60). Death occurred (63% vs. 54%, P = 0.51) at mean age (69 vs. 69 years, P = 0.94). CONCLUSION: Sub-RPE infiltration in VRL is associated with more persistent or recurrent ocular tumor and poorer VA outcome, but no difference in frequency of central nervous system/systemic lymphoma or death. Further studies are required to determine whether earlier, more aggressive, or prolonged ocular therapy for patients with VRL presenting with sub-RPE infiltration could improve these factors.

Case report: an intriguing sign in a patient with an inferior rectus muscle granular cell tumor.

RATIONALE: Occurrence of granulosa cell tumors (GCTs) in the eye are rare and may be diagnosed by imaging examination and immune-histochemical studies. Two common signs of a rectus muscle tumor are the proptosis of the eye ball and the complaint of bi-ocular diploma. PATIENT CONCERNS: A 45-year-old man visited our ophthalmology department with an about a 3-year history of vertical diplopia. His visual acuity when looking forward was normal but was severely low when gazing upward. DIAGNOSIS: Histopathological analysis demonstrated that the encapsulated tumor contained large nested or cord-like cells with small nuclei and abundant eosinophilic cytoplasmic particles. Immunohistochemistry showed that tumor cells strongly expressed CD68, S100 and vimentin, were weakly positive for Ki67, and negative for CK. The tumor was diagnosed as a GCT. INTERVENTIONS: The tumor was surgically removed via a transconjunctival approach along inferior rectus muscle. OUTCOMES: The severe loss of acuity when gazing upward was ameliorated after surgery, but global mobility did not improve. Long-term follow-up was still needed. LESSONS: Ophthalmologists should be aware that when a patient's visual acuity is normal when looking forward but severely low when gazing upward, it may be a sign of a GCT of the inferior rectus muscle.

Ocular Human Papillomavirus Infections.

CONTEXT: - Human papillomavirus (HPV) has a well-known role in the pathogenesis of squamous cell carcinoma and precursor lesions of the cervix, anogenital region, and head and neck, but its role in the development of squamous neoplasms of the eye, particularly the conjunctiva, remains unclear. OBJECTIVE: - To review recent evidence implicating HPV in the pathophysiology of ocular lesions. DATA SOURCES: - Published articles obtained from a PubMed search of the English literature were the primary sources for this review. CONCLUSIONS: - The low-risk HPV types 6 and 11 appear to play a role in the development of at least a subset of conjunctival squamous papillomas. The role of HPV in the pathogenesis of pterygium and ocular surface squamous neoplasia is less well defined. There is evidence to suggest that HPV may be a cofactor in the development of these lesions, acting in concert with ultraviolet radiation and/or human immunodeficiency virus infection in a subgroup of cases.

Combined treatment of primary vitreoretinal lymphomas significantly prolongs the time to first relapse.

BACKGROUND: Vitreoretinal lymphomas belong to the family of central nervous system (CNS) lymphomas. The optimal approach for the treatment of isolated primary vitreoretinal lymphoma is unclear because of the lack of large comparative clinical series. Combination of intravitreal and systemic chemotherapy is recommended in many reports. The aim of our retrospective study was to compare the survival rate and prognosis of patients with vitreoretinal lymphoma with and without CNS involvement. METHODS: Twenty patients with vitreoretinal lymphomas were observed between the years 2004and2016, 10 patients with primary vitreoretinal lymphoma and 10 with primary CNS lymphoma. To compare survival rates, we included 53 patients diagnosed with primary CNS lymphoma without vitreoretinal involvement between the years 2002and2011 from our haemato-oncology department. RESULTS: The 5-year survival rate was estimated 71% in patients with vitreoretinal lymphoma in our observation. Significantly longer 5-year overall survival (P˂0.01) was observed in patients with vitreoretinal lymphoma compared with patients with primary CNS lymphoma without vitreoretinal involvement. Progression-free survival was almost equal in both groups of patients with primary vitreoretinal lymphoma and primary CNS lymphoma (P=0.363). The relapse of lymphoma was frequent (50%-60%) with the median time to first relapse of 31 months. Combined treatment (local and systemic) in patients without CNS involvement significantly prolonged progression-free survival in our study (P˂0.05). CONCLUSION: Combined treatment of primary vitreoretinal lymphoma significantly delays the relapse of lymphoma compared with local therapy alone. Intraocular involvement brings significant positive prognostic value when overall survival is compared.

[Ocular dermoids and microphthalmia in a juvenile sheep]. / Okuläre Dermoide und Mikrophthalmie bei einem Jungschaf.

A 6-month-old Leine sheep was presented because of dermal tissue located on the left eye. During the first examination, the animal was clinically silent, apart from the deformed eye. A corneal and conjunctival dermoid and blindness of the left eye were diagnosed. Over a period of a year, the animal displayed conjunctivitis and inflammation of the affected eye. Furthermore, the sheep did not develop according to its age. During histopathological examination of the euthanized animal, microphthalmia and aphakia of the left eye were found in addition to the dermoids. Dermoids are described in humans and in different domestic animals. They can be combined with other congenital malformations. In sheep, dermoids are rarely diagnosed or reported in the literature.

9.4T and 17.6T MRI of Retinoblastoma: Ex Vivo evaluation of microstructural anatomy and disease extent compared with histopathology.

BACKGROUND: Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. PURPOSE: To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. STUDY TYPE: Prospective case series. POPULATION: Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). FIELD STRENGTH/SEQUENCE: In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. ASSESSMENT: After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). RESULTS: Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 µm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 µm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. DATA CONCLUSION: Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.

Clinical behavior of intraocular teratoid medulloepithelioma in two-related Quarter Horses.

The objective of this paper is to describe clinical behavior, histopathologic features, and immunohistochemical staining of two-related horses with intraocular teratoid medulloepithelioma. Two-related Quarter Horses with similar intraocular masses presented to the UF-CVM Comparative Ophthalmology Service for evaluation and treatment. The first horse, a 3-year-old gelding, had glaucoma and a cyst-like mass in the anterior chamber. Enucleation was performed. Histopathology revealed a teratoid medulloepithelioma. The tumor was considered to be completely excised. Fifteen months later, the gelding presented with swelling of the enucleated orbit and local lymph nodes with deformation of the skull. Cytology revealed neuroectodermal neoplastic cells. Necropsy confirmed tumor metastasis. Six weeks later, a 9-year-old mare, a full sibling to the gelding, presented for examination. An infiltrative mass of the iris and ciliary body was found that extended into the anterior, posterior, and vitreal chambers. Uveitis was present, but secondary glaucoma was not noted. Enucleation was performed and the histopathologic diagnosis was also teratoid medulloepithelioma. The mare has had no recurrence to date, 2 years following enucleation. Metastasis of intraocular teratoid medulloepithelioma is possible. Staging is recommended in cases where the diagnosis of teratoid medulloepithelioma is confirmed. Surveillance of full siblings is recommended until more information regarding etiology is known.

The Evolving Functions of Autophagy in Ocular Health: A Double-edged Sword.

Autophagy plays an adaptive role in cell survival, development, differentiation and intracellular homeostasis. Autophagy is recognized as a 'self-cannibalizing' process that is active during stresses such as starvation, chemotherapy, infection, ageing, and oxygen shortage to protect organisms from various irritants and to regenerate materials and energy. However, autophagy can also lead to a form of programmed cell death distinct from apoptosis. Components of the autophagic pathway are constitutively expressed at a high level in the eye, including in the cornea, lens, retina, and orbit. In addition, the activation of autophagy is directly linked to the development of eye diseases such as age-related macular degeneration (ARMD), cataracts, diabetic retinopathy (DR), glaucoma, photoreceptor degeneration, ocular tumours, ocular infections and thyroid-associated ophthalmopathy (TAO). A high level of autophagy defends against external stress; however, excessive autophagy can result in deterioration, as observed in ocular diseases such as ARMD and DR. This review summarizes recent developments elucidating the relationship between autophagy and ocular diseases and the potential roles of autophagy in the pathogenesis and treatment of these diseases.

Optical eye tracking system for real-time noninvasive tumor localization in external beam radiotherapy.

PURPOSE: External beam radiotherapy currently represents an important therapeutic strategy for the treatment of intraocular tumors. Accurate target localization and efficient compensation of involuntary eye movements are crucial to avoid deviations in dose distribution with respect to the treatment plan. This paper describes an eye tracking system (ETS) based on noninvasive infrared video imaging. The system was designed for capturing the tridimensional (3D) ocular motion and provides an on-line estimation of intraocular lesions position based on a priori knowledge coming from volumetric imaging. METHODS: Eye tracking is performed by localizing cornea and pupil centers on stereo images captured by two calibrated video cameras, exploiting eye reflections produced by infrared illumination. Additionally, torsional eye movements are detected by template matching in the iris region of eye images. This information allows estimating the 3D position and orientation of the eye by means of an eye local reference system. By combining ETS measurements with volumetric imaging for treatment planning [computed tomography (CT) and magnetic resonance (MR)], one is able to map the position of the lesion to be treated in local eye coordinates, thus enabling real-time tumor referencing during treatment setup and irradiation. Experimental tests on an eye phantom and seven healthy subjects were performed to assess ETS tracking accuracy. RESULTS: Measurements on phantom showed an overall median accuracy within 0.16 mm and 0.40° for translations and rotations, respectively. Torsional movements were affected by 0.28° median uncertainty. On healthy subjects, the gaze direction error ranged between 0.19° and 0.82° at a median working distance of 29 cm. The median processing time of the eye tracking algorithm was 18.60 ms, thus allowing eye monitoring up to 50 Hz. CONCLUSIONS: A noninvasive ETS prototype was designed to perform real-time target localization and eye movement monitoring during ocular radiotherapy treatments. The device aims at improving state-of-the-art invasive procedures based on surgical implantation of radiopaque clips and repeated acquisition of X-ray images, with expected positive effects on treatment quality and patient outcome.

Risk factors for intraocular involvement in patients with primary central nervous system lymphoma.

To determine the risk factors for intraocular involvement in patients with primary central nervous system lymphoma (PCNSL), a retrospective chart review was performed on 136 patients who were pathologically diagnosed with PCNSL. The patients were investigated for demographics, clinical manifestation, and the profile of immunohistochemical tumor biomarkers, as well as for the presence of intraocular involvement of lymphoma at diagnosis or during follow-up. The mean age of the entire cohort was 58.6 ± 12.4 years, and the mean follow-up period was 31.1 ± 30.8 months. Twenty-nine (21 %) patients had an intraocular involvement, among which 20 (69 %) patients presented with intraocular involvement at diagnosis of PCNSL and 9 (31 %) patients developed intraocular involvement after a mean period of 32.4 ± 33.6 months. Of the patients with intraocular involvement, 8 (28 %) had no visual symptom at the diagnosis of ocular invasion. Between those with and without intraocular involvement, no significant differences were found with respect to the age, sex, and follow-up period as well as cerebrospinal fluid spread and bone marrow involvement. Among the immunohistochemical biomarkers, the Ki-67 proliferation index was significantly higher in patients with intraocular involvement than in patients without (P = 0.021), but the other investigated biomarkers did not show a significant difference between the two groups. A Ki-67 level ≥80 % was a risk factor for the intraocular involvement in patients with PCNSL (odds ratio, 2.63). Median overall survival was 39.0 months in the entire cohort and was not significantly different between those with and without intraocular involvement (P = 0.959).

Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide).

PURPOSE: To explore the safety and tolerability of combining two epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent). The purpose of such combination is to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy. METHODS: A Phase I clinical trial enrolling patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site. This trial was conducted with full Institutional Review Board approval and was registered with the National Institutes of Health under the clinicaltrials.gov identifier NCT00925132. Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg three times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred. Each cycle lasted 6 weeks, and patients could receive up to six cycles. Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Twenty patients were initially enrolled, with 17 receiving treatment. The median age was 56 years. Eleven (65%) were male, and 6 (35%) were female. Eleven (64.7%) had cutaneous melanoma, 4 (23.5%) had ocular melanoma, and 2 (11.8%) had mucosal melanoma. All patients received at least one treatment cycle and were evaluable for toxicity. Patients received a median of two 6-week treatment cycles (range 1-6). None of the patients experienced DLT. MTD was not reached. Adverse events attributed to treatment included grade 3 lymphopenia (24%), anemia (12%), neutropenia (12%), and fatigue (12%), as well as grade 2 leukopenia (30%), neutropenia (23%), nausea (23%), and lymphopenia (18%). The most common reason for study discontinuation was disease progression. CONCLUSIONS: This triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well tolerated by the cohort and appeared safe to be continued in a Phase II trial. No DLTs were observed, and MTD was not reached.

Propranolol and periocular capillary hemangiomas: assessment of refractive effect.

PURPOSE: To assess the effects of systemic propranolol on refractive error in infants with periocular capillary hemangiomas. METHODS: A single-center study of consecutive patients with capillary hemangiomas treated with systemic propranolol. Refractive data were analyzed using Long's matrix formalism and the methods of Harris and Kaye. RESULTS: Seventeen patients were included. At 6 months postoperatively, hemangioma size reduced from 3,214 to 1,806 mm(3) (standard deviation: 4,122 to 2,441). Mean refractive error in the affected eye significantly reduced: -1.25/0.38 × 36 (95% confidence intervals: -5.08/1.20 × 90 to 1.64/1.43 × 180, P = .048) with a smaller change (P = .06) in the unaffected eye of -1.01/+0.31 × 3.16 (95% confidence intervals: -4.02/+1.12 × 180 to +1.49/+0.51 × 90). CONCLUSIONS: Propranolol produced a clinically significant reduction in the infants' refractive error and anisometropia. The reduction in the total refractive error and anisometropia has not been evident in previous analyses, which have concentrated on the change in the "cylinder" as the principal outcome measure.

Carboplatin +/- topotecan ophthalmic artery chemosurgery for intraocular retinoblastoma.

PURPOSE: Carboplatin administered systemically or periocularly can result in dramatic and prompt regression of retinoblastoma. However, both routes are rarely curative alone and have undesirable side effects. We aimed to assess the efficacy and toxicity of carboplatin +/- topotecan delivered by ophthalmic artery chemosurgery whereby chemotherapy is infused into the eye via the ophthalmic artery. METHODS: This retrospective, IRB-approved study investigated retinoblastoma patients whom received carboplatin +/- topotecan ophthalmic artery chemosurgery. Patient survival, ocular survival, hematologic toxicity, ocular toxicity, second cancer development and electroretinogram response were all evaluated. RESULTS: 57 carboplatin +/- topotecan infusions (of 111 total) were performed in 31 eyes of 24 patients. The remaining infusions were melphalan-containing. All patients were alive and no patient developed a second malignancy at a median follow up of 25 months. The Kaplan-Meier estimate of ocular survival at two years was 89.9% (95% confidence interval [CI], 82.1-97.9%) for all eyes. Grade 3 or 4 neutropenia developed in two patients and one patient developed metastatic disease. By univariate analysis, neither increasing maximum carboplatin/topotecan dose nor cumulative carboplatin/topotecan dose was associated with statistically significant reduction in the electroretinogram responses. CONCLUSION: Carboplatin +/- topotecan infusions are effective for ophthalmic artery chemosurgery in retinoblastoma: they demonstrate low hematologic and ocular toxicity and no statistically significant influence on electroretinogram responses, and used in conjunction with melphalan-containing OAC, demonstrate excellent patient survival and satisfactory ocular survival.

Proptosis congénita secundaria a teratoma orbitario. Estudio clinicopatológico / Congenital proptosis secondary to orbital teratoma. Clinicopathological study

Caso clínico: Recién nacido masculino con proptosis secundaria a tumor retroorbitario. La exploración oftalmológica mostró úlcera corneal, perforación, hernia del iris, oftalmoplejia y retracción palpebral. Se realizó estudio anatomopatológico con diagnóstico de teratoma maduro. Discusión: El teratoma congénito maduro es una neoplasia germinal con presencia de elementos maduros de las tres capas germinales. Es una lesión poco frecuente en la órbita que debe ser incluida en los diagnósticos diferenciales cuando se encuentra un tumor retroorbitario congénito(AU)

Case report: A newborn male with right proptosis secondary to a retroocular mass. Ophthalmological examination also showed corneal ulcer and perforation, iris hernia, total ophthalmoplegia, chemosis and eyelid retraction. The histopathologydiagnosis was mature teratoma. Discussion: Teratomas are tumors composed of a mixture of mature tissues consisting of 3 germ layers. Congenital teratomas of the orbit are very rare and should be included as a possibility in cases with a primary tumor in the orbit(AU)

Flashes, floaters and fuzz.

Flashing lights (photopsia) and floaters are common visual phenomena and patients frequently present to hospital with these symptoms. This article provides a guide for the non-specialist to the different pathologies that may result in photopsia and floaters.

RB1 in cancer: different mechanisms of RB1 inactivation and alterations of pRb pathway in tumorigenesis.

Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species-and cell type-specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107, and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer.

Loss of Hfe leads to progression of tumor phenotype in primary retinal pigment epithelial cells.

PURPOSE: Hemochromatosis is a disorder of iron overload arising mostly from mutations in HFE. HFE is expressed in retinal pigment epithelium (RPE), and Hfe(-/-) mice develop age-related iron accumulation and retinal degeneration associated with RPE hyperproliferation. Here, the mechanism underlying the hyperproliferative phenotype in RPE was investigated. METHODS: Cellular senescence was monitored by ß-galactosidase activity. Gene expression was monitored by real-time PCR. Survivin was analyzed by Western blot and immunofluorescence. Migration and invasion were monitored using appropriate kits. Glucose transporters (GLUTs) were monitored by 3-O-methyl-D-glucose uptake. Histone deacetylases (HDACs) were studied by monitoring catalytic activity and acetylation status of histones H3/H4. RESULTS: Hfe(-/-) RPE cells exhibited slower senescence rate and higher survivin expression than wild type cells. Hfe(-/-) cells migrated faster and showed greater glucose uptake and increased expression of GLUTs. The expression of HDACs and DNA methyltransferase (DNMTs) also was increased. Similarly, RPE cells from hemojuvelin (Hjv)-knockout mice, another model of hemochromatosis, also had increased expression of GLUTs, HDACs, and DNMTs. The expression of Slc5a8 was decreased in Hfe(-/-) RPE cells, but treatment with a DNA methylation inhibitor restored the transporter expression, indicating involvement of DNA methylation in the silencing of Slc5a8 in Hfe(-/-) cells. CONCLUSIONS: RPE cells from iron-overloaded mice exhibit several features of tumor cells: decreased senescence, enhanced migration, increased glucose uptake, and elevated levels of HDACs and DNMTs. These features are seen in Hfe(-/-) RPE cells as well as in Hjv(-/-) RPE cells, providing a molecular basis for the hyperproliferative phenotype of Hfe(-/-) and Hjv(-/-) RPE cells.

The absence of Brm exacerbates photocarcinogenesis.

Brm is an ATPase subunit of the SWI/SNF chromatin-remodelling complex. Previously, we identified a novel hotspot mutation in Brm in human skin cancer, which is caused by exposure to ultraviolet radiation (UVR). As SWI/SNF is involved in DNA repair, we investigated whether Brm-/- mice had enhanced photocarcinogenesis. P53+/- and Brm-/-p53+/- mice were also examined as the p53 tumor suppressor gene is mutated early during human skin carcinogenesis. Mice were exposed to a low-dose irradiation protocol that caused few skin tumors in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumors compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumors that arose early in Brm-/- p53+/- mice had a higher growth rate. Brm-/- did not prevent UVR-induced apoptotic sunburn cell formation, which is a protective response. Unexpectedly, Brm-/- inhibited UVR-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumor suppressing capability.