Efficacy and safety of intravitreal methotrexate for vitreo-retinal lymphoma - 20 years of experience.

Vitreo-retinal lymphoma (VRL) is the most common intraocular lymphoma and is highly associated with central nervous system (CNS) lymphoma (CNSL), both posing a therapeutic challenge. We investigated patients' characteristics, efficacy and safety of intravitreal methotrexate (MTX) injections and their outcomes over 20 years. The records of 129 patients diagnosed between 1997 and 2018 were retrospectively reviewed. Lymphoma involved both the CNS and vitreo-retina (49%), solely the CNS (37%) or solely the vitreo-retina (14%). In all, 45·5% of the patients with CNSL either presented with VRL or developed it after a mean (±SE) of 85·7 (7·3) months. In all, 66·0% of the patients diagnosed with VRL either presented with CNSL or developed it after a mean (±SE) 42·6 (7·6) months. The 81 patients with VRL (134 eyes) received a mean (±SD) of 19 (7) injections; however, only 5 (4) injections were needed to reach complete remission. Local recurrence occurred in two of the 81 patients. Overall, 80·2% of eyes had an initial moderate-severe visual loss, and >50% of them improved. Reversible keratopathy was the most prevalent side-effect. A total of 18·5% developed intraocular pressure (IOP) elevation due to angle neovascularisation after 16 injections, which could be reversed with prompt intravitreal injection of bevacizumab. Intravitreal MTX injections are a safe and effective treatment for VRL. Fewer injections (15) may offer similar results with fewer side-effects.

Visual assessment of commercial drivers in the South West Region of Cameroon.

BACKGROUND: Driving is a visually intensive task. In Cameroon, where the burden of road traffic deaths is high, visual assessment is not universally performed before the issuance of driver licenses. This study aims to assess the visual status of commercial drivers (CDs) in the southwestern region of Cameroon, and to find its relation to road traffic crashes (RTCs). METHODS: This work was a cross-sectional community-based study on CDs in Limbe and Buea. Questionnaires were used to assess sociodemographic parameters, the incidence of RTCs, and self-reported visual status. Visual acuity (VA) was measured using a standard Snellen chart at 6 m. Statistical analysis was performed using descriptive methods: frequencies, the paired Student's t-test, and the chi-square test. RESULTS: Two hundred seven CDs were enrolled in this study, all of which were male, with a mean age of 41.8 ± 12.1 years. A total of 15.0% had undergone an eye exam prior to licensure, and 3.4% had undergone an eye exam within the past 10 years. The VA in the better-seeing eye of participants was less than 6/9 and 6/12 in 14.1 and 10.6% of CDs, respectively. Seventy-five percent of CDs with self-reported poor vision and 95% of CDs with VA < 0.5 had a history of RTCs compared to 55.8% of CDs with self-reported good vision and 55.7% of CDs with VA ≥ 0.5 (p < 0.05). Injuries from RTCs were more common in CDs with self-reported poor vision (81.1%) and in those with VA < 0.5 (90.5%) compared to CDs who self-reported good vision (55.8%) and those with VA ≥ 0.5 (55.7%) (p < 0.05). CONCLUSIONS: A large proportion of CDs did not undergo a visual assessment before the issuance or renewal of their driver licenses. A substantial number of CDs had poor vision in their better-seeing eye and suffered from RTCs and related injuries, which suggests that the visual status of CDs in Cameroon is related to the gruesome number of road traffic crashes and deaths in the country. Therefore, concerned authorities should consider making vision tests a necessary requirement for the obtention of driver licenses.

VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report.

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.

The impact of monocular vision on motor function and quality of life in survivors of retinoblastoma.

BACKGROUND: Monocular vision has been found to have a negative effect on children's motion processing and motor functions. Yet, knowledge of motor function of survivors of retinoblastoma (RB) with monocular vision (due to enucleation, for example) is limited. This study examined motor function and its relationship to visual-related and health-related quality of life (HRQOL) in survivors of RB with monocular vision. PROCEDURE: Parents of 27 survivors of RB, who underwent an enucleation of one eye resulting in monocular vision, and of 21 typically developing children between the ages of 6 and 12, were administered questionnaires relating to their children's motor function (DCDQ), as well as vision-related function (CVFQ) and HRQOL (PedsQL). RESULTS: Of the 27 survivors of RB, 7 (25.6%) were found to have difficulties in motor functions, compared with 1 (4.8%) child in the control group. The difficulties were faced mainly in daily function requiring control during movement, including jumping, running, and ball playing. Additionally, significant correlations were found between motor functions and children's QOL. Finally, survivors of RB with monocular vision were found to have lower QOL, specifically physical- and school-related QOL. CONCLUSION: Survivors of RB who have monocular vision have a higher rate of decreased motor function and lower QOL. These results point to a need for ongoing assessment of survivors of RB to allow timely detection of motor deficits and to institute appropriate therapeutic interventions.

Peripapillary distribution of Muller cells within the retinal nerve fiber layer in human eyes.

The purpose of this study was to describe the distribution of Muller cell within the peripapillary retinal nerve fiber layer (RNFL) in human eyes. Eleven unpaired normal postmortem eyes were recruited into this study. Each eye was sectioned using the "umbrella technique" to obtain a concentric peripapillary ring centered on the optic disc, with a diameter of 3.0 mm. Immunohistochemistry with anti- CRALBP stained Muller cell within each ring. The RNFL thickness measurements around the peripapillary ring were: 262.5, 339.4, 285.4 and 347.5 µm for the temporal, superior, nasal and inferior quadrants, respectively. Muller cell were found to be unevenly distributed in the peripapillary RNFL of normal eyes. The relative Muller cell staining to the thickness of each measured segment (16.6%, 15.2%, 21.3%, and 17.9% for the temporal, superior, nasal and inferior quadrants, respectively) showed a significant increase in the nasal quadrant. The RNFL thickness measurements obtained using imaging techniques reflect the amount of axonal tissue present in this layer. In this study we highlight that around 20% of RNFL thickness is composed of non-axonal contents which do not represent neuronal tissue, nor are they necessarily lost in the glaucomatous process. More so, the ratio of the Muller cell component to the total RNFL thickness varies around the peripapillary RNFL ring, demonstrating the lowest relative content of Muller cell superiorly and the highest content nasally. Further studies should compare the amount and distribution of Muller cell in normal versus glaucomatous eyes.

Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases.

BACKGROUND: Mucin 13 (MUC13) is a cell surface glycoprotein aberrantly expressed in a variety of epithelial carcinomas. Thus far, the role of MUC13 in various diseases remains elusive. To the best of our knowledge, this is the first study to examine the potential of MUC13 as a serum biomarker in a variety of carcinomas and other conditions. METHODS: We developed a recombinant MUC13 protein, mouse monoclonal antibodies and enzyme immunoassay (ELISA) for MUC13. We used this assay to measure MUC13 levels in the supernatants of cancer cell lines and a large cohort of serum samples from healthy and diseased individuals. RESULTS: MUC13 is secreted from cancer cell lines, with highest levels found in ovarian cancer cell lines. MUC13 levels in human sera were significantly increased in patients with renal failure and 20%-30% of patients with ovarian, liver, lung and other cancers. MUC13 was also elevated in 70% of patients with active cutaneous melanoma, but not uveal melanoma. Furthermore, we identified significant MUC13 elevations in the serum of patients with vasculitis (ANCA-positive) autoantibodies, but not in those with inflammatory bowel disease. CONCLUSIONS: Serum MUC13 is frequently elevated not only in a variety of malignant cases but also in some benign pathologies, thus appearing to be a non-specific disease biomarker. Nonetheless, serum MUC13 is clearly highly elevated in some carcinoma patients, and its relationship with tumor progression in this context warrant further research. Future studies that examine the correlation between serum MUC13 levels to stage of cancer could elucidate prognostic potential.

[ADVANCES IN THE TREATMENT OF RETINOBLASTOMA AT HADASSAH IN THE LAST THREE DECADES].

INTRODUCTION: Retinoblastoma (RB) is a malignant tumor presenting in the eyes of infants and children, which endangers life, the eye and vision. The treatment of RB has undergone marked changes in recent years, and great progress has been made in our ability to preserve eyes. Over the last three decades most Israeli patients with RB have been treated in the National Specialty Ocular Oncology Service at the Hadassah-Hebrew University Medical Center in Jerusalem. AIMS: To describe advances in the primary treatment of RB with an emphasis on eye-preserving treatments. METHODS: The study included a retrospective cohort of patients who were diagnosed and treated at our center over the last three decades. Review of patients' records was approved by the Hadassah IRB. RESULTS: From 1988 to 2014 we diagnosed 290 children (138 girls - 47.6%). The mean age at diagnosis (±SE) was 18.1±1.2 months, median 12.5 months. RB was unilateral in 55.6% of the cases, bilateral in 41.3% and unilateral multifocal in 3.1%. There was an even distribution of disease severity (IRB grouping). Since the advent of IV chemotherapy (IVC) there has been a decrease in the rate of eye enucleation from ~90% to ~30% of the children until the year 2000 with a stable rate thereafter. In the years 1990-2000 there was an increase followed by a decrease in the use of primary external beam radiotherapy (EBRT), and a parallel small increase in the use of brachytherapy from the mid '90s until today. The recently introduced novel treatments - intravitreal (IVitC) and intra-arterial chemotherapy (IAC) - were used as a complimentary treatment to IVC, and not yet as a single primary modality until 2014. CONCLUSIONS: IVC replaced the need to enucleate in most of the cases, but 30% of children still require a primary enucleation. DISCUSSION: IVC usually requires additive treatments (thermal-cryotherapy, trans-pupillary thermotherapy - TTT, brachytherapy and/or local chemotherapy - IVitC and IAC) and with the use of multi-modal therapy many eyes can be preserved. In the period reported in the current manuscript, the use of IAC as a primary treatment approach was only used in isolated cases. In Summary, There have been significant advances in our ability to save eyes, and the field continues to progress.

The Pediatric Choroidal and Ciliary Body Melanoma Study: A Survey by the European Ophthalmic Oncology Group.

PURPOSE: To collect comprehensive data on choroidal and ciliary body melanoma (CCBM) in children and to validate hypotheses regarding pediatric CCBM: children younger than 18 years, males, and those without ciliary body involvement (CBI) have more favorable survival prognosis than young adults 18 to 24 years of age, females, and those with CBI. DESIGN: Retrospective, multicenter observational study. PARTICIPANTS: Two hundred ninety-nine patients from 24 ocular oncology centers, of whom 114 were children (median age, 15.1 years; range, 2.7-17.9 years) and 185 were young adults. METHODS: Data were entered through a secure website and were reviewed centrally. Survival was analyzed using Kaplan-Meier analysis and Cox proportional hazards regression. MAIN OUTCOME MEASURES: Proportion of females, tumor-node-metastasis (TNM) stage, cell type, and melanoma-related mortality. RESULTS: Cumulative frequency of having CCBM diagnosed increased steadily by 0.8% per year of age between 5 and 10 years of age and, after a 6-year transition period, by 8.8% per year from age 17 years onward. Of children and young adults, 57% and 63% were female, respectively, which exceeded the expected 51% among young adults. Cell type, known for 35% of tumors, and TNM stage (I in 22% and 21%, II in 49% and 52%, III in 30% and 28%, respectively) were comparable for children and young adults. Melanoma-related survival was 97% and 90% at 5 years and 92% and 80% at 10 years for children compared with young adults, respectively (P = 0.013). Males tended to have a more favorable survival than females among children (100% vs. 85% at 10 years; P = 0.058). Increasing TNM stage was associated with poorer survival (stages I, II, and III: 100% vs. 86% vs. 76%, respectively; P = 0.0011). By multivariate analysis, being a young adult (adjusted hazard rate [HR], 2.57), a higher TNM stage (HR, 2.88 and 8.38 for stages II and III, respectively), and female gender (HR, 2.38) independently predicted less favorable survival. Ciliary body involvement and cell type were not associated with survival. CONCLUSIONS: This study confirms that children with CCBM have a more favorable survival than young adults 18 to 25 years of age, adjusting for TNM stage and gender. The association between gender and survival varies between age groups.

Genotype-phenotype correlation in the presentation of retinoblastoma among 149 patients.

In this work, we describe the association between a germline RB1 mutation and disease presentation characteristics of retinoblastoma. The study evaluates a retrospective cohort of 164 of the 295 patients with retinoblastoma who were treated at a single center between 1988 and 2013 and who were referred for genetic evaluation. Peripheral blood was evaluated for RB1 mutations via Multiplex Ligation-dependent Probe Amplification (MLPA), sequencing, and detection of recurrent CpG transition mutations. Patients with an RB1 mutation were compared to patients without a mutation, regarding epidemiological factors and clinical presentation. Genetic analysis was completed for 149 patients. An RB1 mutation was identified in 76 children (51.0%) including 90.0% of the bilateral patients, and 19.8% of the unilateral unifocal patients (24.7% if we include the unilateral multifocal cases). The most common mutations were a stop codon (38.2%), a splicing error (19.7%) and a large deletion (15.8%). The mutation type correlated only with sex (Likelihood ratio, p = 0.0240) and with macular involvement (Likelihood ratio, p = 0.0591 and Fisher's exact one tail test p = 0.0459 for more macular involvement if there are germline mutations). It did not correlate with laterality, with the reason for referral, or with diagnosis age. However, identification of a mutation was more common in babies diagnosed under one year of age (Likelihood ratio, p < 0.0001). In conclusion, we were surprised that our genetic tests have also found mutations in 24.7% of patients with unilateral retinoblastoma in addition to most of the bilateral children. These unilateral patients with a germline mutation have an increased risk for other cancers throughout their lives, and their first-degree relatives have an increased risk for retinoblastoma. Therefore, genetic testing for RB1 mutation should be offered to all patients, including the unilateral cases.

Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability.

Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/ß-catenin signaling pathway.

Treatment of conjunctival palpebral lesions using ruthenium plaque brachytherapy "Sandwich Technique".

OBJECTIVE: Treatment of palpebral conjunctival lesions is problematic due to late diagnosis, difficult surgical approach, and the need to preserve eyelid integrity. We describe our treatment experience using plaque brachytherapy in the "sandwich technique." DESIGN: A retrospective study. PARTICIPANTS: We reviewed the medical records of patients treated by plaque brachytherapy for conjunctival lesions at the Hadassah Medical Center between January 1, 2013, and January 1, 2024, and included in the analysis patients treated for palpebral conjunctival lesions. METHODS: Ruthenium plaque was sutured to the palpebral conjunctiva. The matching nonradioactive "dummy" plaque was sutured to the external eyelid to flip the tarsal's curvature. RESULTS: The study cohort included 5 patients, 2 men (40%) and 3 women (60%) at a median age of 68.11 years (range: 47-79.7 years). Three patients had conjunctival melanoma (60%), 1 had sebaceous carcinoma (20%), and 1 had extensive carcinoma in situ (20%). All lesions were in the left upper eyelid. Median follow-up was 37.6 months (range: 18.7-110.6 months). Four patients demonstrated a complete response (80%), while one had a partial response (20%). There was local recurrence in 1 patient (20%), and 1 patient had new foci elsewhere (20%). All patients had full local control after adding local treatments. One patient developed metastatic disease and died (20%). All patients had manageable madarosis and conjunctival scars. CONCLUSIONS: Treatment of palpebral conjunctival lesions using "sandwich" plaque brachytherapy is safe and effective. To the best of our knowledge, this treatment was never described before, and we believe it should be added to our armamentarium.

Homozygosity mapping reveals null mutations in FAM161A as a cause of autosomal-recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 45 genes. Using homozygosity mapping, we identified a ∼4 Mb homozygous region on chromosome 2p15 in patients with autosomal-recessive RP (arRP). This region partially overlaps with RP28, a previously identified arRP locus. Sequence analysis of 12 candidate genes revealed three null mutations in FAM161A in 20 families. RT-PCR analysis in 21 human tissues revealed high levels of FAM161A expression in the retina and lower levels in the brain and testis. In the human retina, we identified two alternatively spliced transcripts with an intact open reading frame, the major one lacking a highly conserved exon. During mouse embryonic development, low levels of Fam161a transcripts were detected throughout the optic cup. After birth, Fam161a expression was elevated and confined to the photoreceptor layer. FAM161A encodes a protein of unknown function that is moderately conserved in mammals. Clinical manifestations of patients with FAM161A mutations varied but were largely within the spectrum associated with arRP. On funduscopy, pallor of the optic discs and attenuation of blood vessels were common, but bone-spicule-like pigmentation was often mild or lacking. Most patients had nonrecordable electroretinographic responses and constriction of visual fields upon diagnosis. Our data suggest a pivotal role for FAM161A in photoreceptors and reveal that FAM161A loss-of-function mutations are a major cause of arRP, accounting for ∼12% of arRP families in our cohort of patients from Israel and the Palestinian territories.

Vitreoretinal lymphoma: Central nervous system lymphoma risk with unilateral or bilateral ocular tumour. A multicentre collaboration.

OBJECTIVES: To investigate the risk of developing central nervous system (CNS) lymphoma in patients with vitreoretinal lymphoma (VRL) presenting with unilateral versus (vs.) bilateral ocular involvement. METHODS: Retrospective, multicentre cohort study from January 1, 1984 to December 31, 2020. RESULTS: There were 218 eyes of 127 patients with isolated VRL of the confirmed or presumed diffuse large B-cell subtype in the absence of known CNS or systemic lymphoma. Overall, mean patient age at presentation was 67 years (median 68, range 22-93 years), with 52 (40%) male, and 118 (90%) Caucasian. By univariate Cox regression analysis, two factors were predictive of decreased risk for development of CNS lymphoma, including initial presentation with unilateral VRL (versus bilateral VRL) (HR 0.5 [0.2-0.9], p = 0.02) and use of systemic chemotherapy for initial treatment of isolated ocular disease (HR 0.2 [0.1-0.6], p = 0.002). Both factors remained significant on multivariate and competing risk analyses. Progression from unilateral to bilateral VRL, patient age at presentation, and ocular structures involved (vitreous, subretinal space, subretinal pigment epithelial space) were not significantly associated with CNS lymphoma risk. CONCLUSION: Initial presentation with unilateral VRL and treatment of isolated VRL with systemic chemotherapy were associated with lower risk of developing CNS lymphoma. Further study is required to determine whether select patients with isolated VRL might benefit from systemic chemotherapy in the prevention of CNS lymphoma.

sIL-2R- an Immuno-biomarker for Prediction of Metastases in Uveal Melanoma.

BACKGROUND/AIM: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. High serum levels of soluble IL-2 receptor (sIL-2R) have been reported in acute inflammations and metastatic cancers. This study evaluated the potential of high/increasing sIL-2R levels in predicting metastases. PATIENTS AND METHODS: The study included a total of 1,546 sera samples of subjects from three groups: 119 healthy controls (73 subjects), 566 UM 10 year (10y) disease-free (DF) (220 patients), 861 metastatic UM (268 patients). Patients were followed-up biannually with liver ultrasound and liver function tests for the presence of metastases (Mets). Blood samples to measure the levels of sIL-2R were obtained at the time of primary diagnosis, soon after initial treatment (enucleation, brachytherapy), every 6 months, 10 years from diagnosis, at Mets confirmation by CT, and after additional treatments. RESULTS: Significantly higher sIL-2R levels were detected in the Mets patients compared to healthy controls and 10y DF patients. Compared to the upper limit of the normal levels of sIL-2R, 1,000 U/ml, its levels in metastatic UM were 61%, 25% in 10y DF UM, and 6.25% in the controls. High levels of sIL-2R in metastatic patients, decreased significantly post treatments. Individual kinetics of markers, indicated similar trends of sIL-2R compared to osteopontin and S-Protein 100, predicting metastases, which were confirmed on liver imaging. CONCLUSION: Significantly higher sIL-2R levels were evident in all UM patients with Mets. Significant increases in sIL-2R levels on serial evaluations indicated and predicted UM Mets, enabling earlier treatment of Mets, to improve survival.

Participation in daily activities and quality of life in survivors of retinoblastoma.

PURPOSE: To assess the participation and health-related quality of life (HRQOL) of survivors of childhood retinoblastoma (RB). PATIENTS AND METHODS: Parents of 46 survivors of childhood RB between the ages of 2-18 were administered questionnaires relating to their children's participation (CFFS) and HRQOL (CHQ and PedsQL) and children were administered the PedsQL. Results of the HRQOL were compared to population-based norms. RESULTS: The overall QOL of survivors of RB was similar to that of age norms. However, parents' rating of their children's general and emotional health was lower than that of age norms, and survivors reported lower QOL related to school. Survivors of bilateral RB participated less in daily activities and had lower emotional QOL compared to those with unilateral RB, and parents of children who had an eye enucleated reported that their children had lower self-esteem. The level of participation was related to the perceived QOL. CONCLUSION: Our results indicate that children who are survivors of RB have an overall QOL that is similar to their age-peers. However, subgroups of survivors appear to have unique difficulties that require continued follow-up and intervention. Focus should be placed on their participation in daily activities both in the community and at school.

Consensus Recommendations for the Diagnosis of Vitreoretinal Lymphoma.

PURPOSE: To provide recommendations for diagnosis of vitreoretinal lymphoma (VRL). METHODS: Literature was reviewed for reports supporting the diagnosis of VRL. A questionnaire (Delphi 1 round) was distributed to 28 participants. In the second round (Delphi 2), items of the questionnaire not reaching consensus (75% agreement) were discussed to finalize the recommendations. RESULTS: Presenting symptoms include floaters and painless loss of vision, vitreous cells organized into sheets or clumps. Retinal lesions are usually multifocal creamy/white in the outer retina. Other findings include retinal lesions with "leopard-skin" appearance and retinal pigment epithelium atrophy. Severe vitreous infiltration without macular edema is the most likely presentation. Diagnostic vitrectomy should be performed. Systemic corticosteroid should be discontinued at least 2 weeks before surgery. An interleukin (IL)-10:IL-6 ratio > 1, positive mutation for the myeloid differentiation primary response 88 gene and monoclonality are indicators of VRL. Multi-modal imaging (optical coherence tomography, fundus autofluorescence) are recommended. CONCLUSIONS: A consensus meeting allowed the establishment of recommendations important for the diagnosis of VRL.

Limbal stem cell deficiency after topical mitomycin C therapy for primary acquired melanosis with atypia.

PURPOSE: To describe the incidence, characteristics, risk factors, and clinical outcome of limbal stem cell deficiency (LSCD) resulting from topical treatment with mitomycin C (MMC) for primary acquired melanosis (PAM) with atypia. DESIGN: Retrospective, observational case series. PARTICIPANTS: Patients with LSCD who had been managed with topical MMC for PAM with atypia at the Ocular Oncology Service at the Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, between 2000 and 2007. METHODS: Retrospective chart review of all patients with PAM with atypia was performed. Impression cytologic analysis of the corneal and conjunctival epithelium was performed in patients suspected of having LSCD. MAIN OUTCOME MEASURES: Evaluation of risk factors for LSCD, including demographic characteristics, MMC dosage, and length of treatment; and clinical and visual outcome of patients diagnosed with LSCD. RESULTS: Limbal stem cell deficiency was identified in 5 (23.8%) of 21 patients. The mean age+/-standard deviation of the 5 patients was 61.8+/-12.7 years compared with 43.7+/-16.1 years in patients in whom this complication did not develop (P = 0.025). Longer treatment periods of MMC were noted in eyes in which LSCD developed (78.4+/-24.8 days) compared with eyes without LSCD (37.7+/-3.1 days; P = 0.07). In 3 patients, spontaneous partial resolution of the LSCD was noted. CONCLUSIONS: High-dose topical MMC for PAM with atypia may be associated with a relatively high incidence of LSCD. Mitomycin C concentration and treatment regimen should be reevaluated to improve the safety of this treatment protocol.

New techniques for drug delivery to the posterior eye segment.

Ocular drug delivery has become an increasingly important field of research especially when treating posterior segment diseases of the eye, such as age-related macular degeneration, diabetic retinopathy, posterior uveitis and retinitis. These diseases are the leading causes of vision loss in developed countries which require repeated long-term administration of therapeutic agents. New drugs for the medication of the posterior ocular segment have emerged, but most drugs are delivered by repeated intravitreal injections associated with ocular complications. Advances in ocular drug delivery system research are expected to provide new tools for the treatment of the posterior segment diseases, providing improved drug penetration, prolonged action, higher efficacy, improved safety and less invasive administration, resulting in higher patient compliance. This review provides an insight into the recent progress and trends in ocular drug delivery systems for treating posterior eye segment diseases, with an emphasis on transscleral iontophoresis.

The importance of cytokines analysis in the diagnosis of vitreoretinal lymphoma.

PURPOSE: To evaluate the efficacy of the different diagnostic tests for vitreoretinal lymphoma (VRL). METHODS: A cohort of 150 patients with a presumed diagnosis of VRL. Vitrectomy samples were analysed for cytology, monoclonality [polymerase chain reaction (PCR)] and cytokine levels, and anterior chamber taps were analysed for cytokine levels. Vitreoretinal lymphoma (VRL) was diagnosed after confirming the clinical suspicion with vitreal or brain cytology. RESULTS: Vitreoretinal lymphoma (VRL) was diagnosed in 78 patients. Vitreal cytology was positive for 53/132 patients (40.2%), 36/53 had positive cytology from both the eye and the brain. Additional 25 patients had positive brain cytology. Vitreal PCR for monoclonality was positive for 32/91 patients (35.2%). Vitreal cytokine levels of interleukin (IL)-10/IL-6 were >1 for 47/110 patients (43.1%). For cytology, PCR and cytokine analysis, the respective sensitivity was 73.6%, 46.0% and 81.4%, and the accuracy of the tests was 85.6%, 60.4% and 80.9%, respectively. All three tests were available for 79 patients. In this subset, for cytology, PCR and cytokine analysis the respective sensitivity was 79.5%, 41.0% and 82.1%, respectively, and the accuracy of the tests was 89.9%, 60.8% and 81.0%, respectively. CONCLUSION: Cytokines analysis has an important role in the diagnosis of VRL. We suggest analysing cytokines levels in all cases suspected of VRL along with cytology and PCR analysis.