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Abstract: We report a case of orbital metastasis from hepatocellular carcinoma and review the literature. A 45-year-old healthy male patient presented with proptosis due to an orbital mass. Histopathologic examination indicated that the tumor was a secondary from a hepatocellular carcinoma, and further investigations revealed the primary tumor in the liver. Hepatocellular carcinoma is a rare source of metastasis to the orbit, and to our knowledge, only 14 histopathologically proven cases have been reported previously. Proptosis was the most common presenting feature in the reviewed reports. A majority of patients had occult primary tumors at presentation and the diagnosis of the orbital mass was based on histopathologic features. [Copyright &y& Elsevier]

Purpose: Cancer stem cells (CSCs) reported in various tumors play a crucial role in tumorigenesis and metastasis of retinoblastoma (Rb). Following the efforts to reduce, replace, and refine the use of mammalian models, we aimed to establish a short-term xenograft for Rb to evaluate the CSC properties of CD133- Rb Y79 cells, using the well-established chick embryo chorioallantoic membrane (CE-CAM) assay.Methods: Y79 cells were cultured, labeled with two different dyes (CM-Dil Y79 and enhanced green fluorescent protein (eGFP)) and sorted for CD133- and CD133 + subsets. Two million cells from each of the labeled groups were transplanted onto the abraded CAM on embryonic day 7 (E7). On E14, the tumor nodule formation on CAM and spontaneous metastasis to the embryos were evaluated by confocal microscopy, in vivo imaging, and histology.Results: Y79 cells formed pink-white raised perivascular nodules with feeder vessels on the CAM with both the types of labeled CD133- cells. CD133- cells, when compared to CD133 + cells, demonstrated significantly larger tumor volume (40.45 ± 7.744 mm3 vs 3.478 ± 0.69 mm3, P = 0.0014) and higher fluorescence intensity (CM-Dil: AUF = 6.37 × 107 ± 7.7 × 106 vs 1.08 × 107 ± 1.6 × 106; P < 0.0001; eGFP: AUF = 13.94 × 104 ± 2.54 × 104 vs AUF = 1.39 × 104 ± 0.4 × 104; P = 0.0003). The metastatic potential of CD133- cells was also observed to be higher as noted by in vivo imaging and histopathology.Conclusion: This study highlights that CE-CAM is a feasible alternative nonmammalian model for evaluating tumorigenicity and metastatic potential of Y79 CSCs. Increased tumorigenicity and metastatic potential of CD133- subset of tumor cells substantiate their CSC properties. [ABSTRACT FROM AUTHOR]

Retinoblastoma (RB) is an intraocular childhood cancer develops due to inactivation of RB1 gene. Identification of RB1 genetic variants, correlating and confirming genetic test results with clinical outcomes are crucial for effective RB management. Retrospective study of 62 RB patients and 14 family members who underwent genetic testing either by next generation sequencing (NGS) or multiplex ligation-dependent probe amplification (MLPA) or by both for screening RB1 germline mutations present in peripheral blood. Mutational outcomes were correlated with clinical outcomes evaluated over a follow-up period of 12 months. Of the 62 patients, 35 (56%) had bilateral RB and 27 (44%) had unilateral RB. Out of 24 (52%) variants detected by NGS, 9 (37.5%) were novel and 15 (62.5%) were known in 46 probands. Six (18%) gross deletions were detected by MLPA in 34 probands. The mutation detection rate by NGS and MLPA in unilateral cases was 15% (n = 4) and 74% (n = 26) in bilateral cases. In patients with RB1 genetic mutations versus those without, the rate of primary enucleation (7 (12%) vs 18 (44%) eyes; p =.0008) was inversely proportional to tumor recurrence (25 (45%) vs 6 (15%) eyes; p =.002). There was no difference in the rate of globe salvage and metastasis, over a mean follow-up period of 12 months. The mutations screening is important for risk assessment in future siblings and offspring of RB patients and most important in unilateral RB for determining if hereditary or not hereditary RB. Its role in predicting clinical outcomes is yet to be determined. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of polycystic echinococcosis of the orbit caused by Echinococcus oligarthrus. Design: Interventional case report. Methods: A 14-year-old girl presented with a massive proptosis of the right eye of 9 years duration and loss of vision. The eye was phthisic, and a cystic mass was palpable. Computed tomography scan showed closely packed multiple orbital cysts with destruction of the medial orbital wall. Surgical exploration was performed. Results: The phthisic eye was enucleated. Dissection of the outer fibrous capsule yielded approximately 30 intact translucent white cysts of various sizes that were suggestive of polycystic echinococcosis. The diagnosis of echinococcosis was confirmed on histopathologic evaluation. The specific diagnosis of E oligarthrus was made on the basis of the presence of straight-backed hooks and central guards. Conclusion: Polycystic echinococcosis of the orbit caused by E oligarthrus is rare. It may be an entirely new entity or hitherto unrecognized form of orbital echinococcosis. [ABSTRACT FROM AUTHOR]

Drug resistance (DR) is one of the challenges in treating retinoblastoma (Rb) that warrants novel approaches. With the emerging evidence on the role of small extracellular vesicles (sEVs) as a drug-delivery carrier system, in this study, we derived the drug-resistant (DR) clones of Y79 cells and evaluated the efficacy of sEVs-loaded with carboplatin (sEVs-CPT) to reverse the chemoresistance. Drug-resistant clones of Y79 cells (DR-Y79) were systematically developed through sequential exposure to carboplatin (CPT), showcasing a sixfold increase in inhibitory concentration when compared to parental Y79 cells (IC 50 : 41.4 µg/mL and 6.2 µg/mL) (P<0.0001). These DR-Y79 cells show higher expression of ABCG2 and higher expression of DR genes than parental Y79 cells (P<0.0001). The sEVs were isolated from the conditioned media of Y79 cells using ultracentrifugation (UC) and characterized. Further, the sEVs were loaded with CPT and achieved higher encapsulation efficiency at one hour, and drug release of sEVs-CPT was highest at ∼80% at pH 5.0. The cytotoxicity of sEVs-CPT on Y79 cells and DR-Y79 was higher when compared to the CPT (IC50: 3.5 µg/mL vs 6.2 µg/mL; 23.1 µg/mL vs 41.2 µg/mL) (p<0.0001). This study demonstrates that sequential exposure to CPT generates DR clones of Y79 cells, which could serve as an appropriate model to evaluate the efficacy of drugs. The sEVs-CPT were highly effective in enhancing cytotoxicity in DR-Y79 cells, and appear to hold promise as a novel complimentary drug delivery system. [Display omitted] • Stable DR-Y79 clones were generated through sequential exposure to CPT, shows higher inhibitory concentration. • sEVs were isolated from conditioned media of Y79 cells and loaded with CPT. • The higher encapsulation efficiency was achieved at one hour than prolonged incubations. • The sEVs-CPT has higher cytotoxicity on DR-Y79 cells than CPT. [ABSTRACT FROM AUTHOR]

Purpose: Lacrimal gland (LG) dysfunction leading to dry eye syndrome (DES) is an important cause of ocular morbidity. One of the potential and promising long-term management therapies for restoration of LG function could be transplantation of autologous ex vivo expanded stem cells. The present study was aimed at exploring the 2D and 3D cultures of human LG, identifying inherent stem cells and evaluating their secretory potential.Methods: Fresh human lacrimal gland (HuLG) (n = 5) from patients undergoing therapeutic exenteration was harvested after ethical approval and informed consent. The gland was enzymatically digested and the isolated cells plated in Hepato-STIM media supplemented with l-glutamine, epidermal growth factor, fibroblast growth factor, and N-2 supplement. The native HuLG and the cultured spheres (DIV14-16) were evaluated for presence of stem cells (CD117 expression, quiescence, BrdU label retention, cell cycle, colony forming efficiency) and differentiation (secretion of tear proteins).Results: Under the established culture conditions, suspension 3D cultures of human “lacrispheres” could be maintained and propagated for 3-4 weeks. The spheres consist of both acinar as well as ductal cells with evidence of stem cells (0.8 ± 0.05% CD117+ cells), BrdU label retention (9.31 ± 0.41%), G0/G1 profile similar to native lacrimal cells at isolation (76.9 versus 79.9%) and colony forming units (3.1%). The lacrispheres also secreted quantifiable levels of tear proteins (lysozyme, lactoferrin, scIgA) into the conditioned media.Conclusion: The study provides promising, first-of-its-kind evidence for the generation of lacrispheres from fresh HuLG, with enriched population of stem cells and secretory competent differentiated cells. The dual properties of these spheres make them a highly suitable source of transplantable cells for restoring the structure and function of damaged lacrimal gland. [ABSTRACT FROM AUTHOR]

Background/aims To report the influence of histological features of corneal surface pannus following ocular surface burn on the outcome of cultivated limbal epithelial transplantation (CLET). Methods On retrospectively reviewing the medical records of the patients who underwent autologous CLET from April 2002 to June 2012 at L V Prasad Eye Institute, Hyderabad, India, we could trace the histological reports in only 90 records. These 90 records, besides clinical parameters, were reviewed for the influence of various histological features on the final outcome of CLET. Results The histological features include epithelial hyperplasia (21.1%), surface ulceration (2.2%), goblet cells (62.2%), squamous metaplasia (11.1%), active fibrosis (31.1%), severe inflammation (8.9%), multinucleated giant cells (3.3%), stromal calcification (8.9%) and active proliferating vessels (5.6%). Among these histological features, patients with either hyperplasia or calcification in their excised corneal pannus show an unfavourable outcome compared with patients without hyperplasia ( p=0.003) or calcification (p=0.018). A similar unfavourable outcome was not seen with other histological features and various clinical parameters. Conclusions Presence of either calcific deposits or hyperplasia in the excised corneal pannus provides poor prognostication; hence, a proper counselling of such patients is mandatory along with a close follow-up. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical features, histopathology, treatment, and outcomes of ciliary body medulloepithelioma. Design: Retrospective study. Participants: Forty-one patients with medulloepithelioma. Intervention: Cryotherapy, plaque radiotherapy, external beam radiotherapy, tumor removal by partial lamellar sclerouvectomy (PLSU), or enucleation. Main Outcome Measures: Metastasis and death. Results: Of 41 patients with ciliary body medulloepithelioma, the median age at diagnosis was 5 years. The mean tumor basal diameter was 11 mm, and the mean tumor thickness was 7 mm. Related features included secondary glaucoma (n = 18, 44%), iris neovascularization (n = 21, 51%), cataract (n = 19, 46%), lens subluxation (n = 11, 27%), lens coloboma (n = 8, 20%), retrolental neoplastic cyclitic membrane (n = 21, 51%), intratumoral cysts (n = 25, 61%), and extraocular extension (n = 4, 10%). There was systemic association with pleuropulmonary blastoma in 2 cases (5%). Primary tumor treatment included enucleation (n = 21, 60%), tumor removal by PLSU (n = 8, 23%), plaque radiotherapy (n = 3, 9%), external beam radiotherapy (n = 1, 3%), cryotherapy (n = 1, 3%), or palliative chemotherapy (n = 1, 3%). In 1 case, medulloepithelioma was diagnosed histopathologically after inadvertent evisceration for blind painful eye. Subsequent treatment for residual or recurrent tumor in cases treated conservatively/inappropriately (n = 15) was necessary in 7 cases (47%). Histopathology disclosed benign features in 6 cases (20%), malignant features in 24 cases (80%), teratoid features in 11 cases (37%), and nonteratoid features in 19 cases (63%). In the 26 enucleated eyes, other features included retrolental neoplastic cyclitic membrane (n = 18, 69%), neoplastic epiretinal membrane (n = 6, 23%), and persistent hyaloid artery (n = 6, 23%). Systemic metastasis occurred in 3 cases (8%) over a mean follow-up of 49 months, all of whom presented with extrascleral extension of tumor due to mean delay in diagnosis by 39 months. Conclusions: Medulloepithelioma most commonly occurs in children. Systemic association with pleuropulmonary blastoma rarely is found. Patients with extrascleral medulloepithelioma are at risk for metastasis. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

Abstract: A 36-year-old woman presented with progressive loss of vision in the left eye for 3 years, and rapid progression and painful protrusion of the eye for one month. Clinical evaluation revealed no light perception, severe proptosis and hypoglobus, optic atrophy, and optociliary shunt vessels. Orbital imaging showed a well-defined heterogeneous intraconal mass partially encasing the optic nerve. A clinical diagnosis of optic nerve sheath meningioma was made, and the tumor was completely excised along with enucleation, followed by postoperative adjuvant external beam radiotherapy. There was no local recurrence at 15 month follow-up. Histopathologically, the tumor was found to be arising from the optic nerve meninges with classical “stag-horn” pattern and abundant cellularity. Immunohistochemistry supported the histopathological diagnosis of hemangiopericytoma. Optic nerve meningeal hemangiopericytoma is extremely rare—only two such cases have been reported in the literature. [Copyright &y& Elsevier]

Objective: To report the clinicopathologic features of 4 opacified, single-piece, hydrophilic, acrylic intraocular lenses (IOLs) explanted from children who had undergone IOL implantation during infancy. Design: Observational case series. Participants: Four IOLs explanted from 4 eyes of 3 children for visually significant opacification were included in the study. Methods: The clinical details of each case were obtained to look for possible risk factors for IOL opacification. The explanted IOLs were subjected to gross examination, staining by alizarin red 1% for calcium, scanning electron microscopy, and energy-dispersive x-ray spectroscopy (EDS). Levels of calcium and phosphorous were analyzed in the serum of all cases and in the aqueous humor of 1 case. Main Outcome Measures: Morphologic features and composition of deposits. Results: Two cases had congenital cataract while one case was after bilateral lens sparing vitrectomy for retinopathy of prematurity. All underwent surgery during infancy with implantation of an IOL. The IOLs were explanted 8 months after surgery from 4 eyes of 3 children at the age of 17, 25, and 26. All the children received a single-piece hydrophilic acrylic IOL. The IOLs were in situ for an average duration of 13.86 months. The deposits were in the shape of a bicycle wheel on 3 IOLs and looked like fish eggs on 1 IOL. All deposits stained bright orange with alizarin red. On EDS, the deposits were found to be composed of calcium, phosphate, and silicone. Conclusions: The morphologic features and composition of IOL deposits in 2 cases were similar to those of earlier reports in adults. The hydrophilic nature of the IOL material, sulcus implantation, and postoperative inflammation may be possible risk factors for opacification. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Purpose To report the clinical outcomes of allogeneic cell-based therapy for bilateral corneal blindness due to limbal stem cell deficiency (LSCD). Methods This retrospective study included 28 eyes of 21 patients, at least 8 years of age, with bilateral and total LSCD, treated between 2001 and 2010. A limbal biopsy was obtained from the eye of an adult living related donor. The limbal epithelial cells were cultivated in the laboratory using a xeno-free explant culture technique and transplanted onto the recipient eye after 10-14 days. All transplant recipients received topical and systemic immunosuppressants. Results At a mean follow-up of 4.8±2.8 years, 20 (71.4%) eyes maintained a completely epithelised, avascular and stable corneal surface, and among them 13 (46.4%) eyes subsequently underwent a penetrating keratoplasty (PK). The Kaplan-Meier survival rate of the PK allograft was 76.9±11.7% at 1 year with a median survival of 3.3 years. Visual acuity improved to 20/60 or better in 19 (67.8%) eyes. No donor or recipient eyes developed serious ocular complications. Conclusions Allogeneic cultivated limbal epithelial transplantation, followed by PK when needed, can successfully restore the ocular surface and improve vision in patients with corneal blindness due to bilateral LSCD. [ABSTRACT FROM AUTHOR]

Abstract: Since the devastation of the European silk worm industry in the 19th century, microsporidia have been recognized as important organisms. An enormous literature is available on their biology, phylogeny, classification, disease profile, diagnosis, and treatment; however, it is only recently that ophthalmologists have begun to take note of these organisms. The last two decades have seen several publications related to ocular microsporidiosis, in particular those forms affecting the cornea. Both immunocompetent and immunocompromised patients are at risk of developing corneal infections that may range from self limiting mild keratoconjunctivitis to severe stromal keratitis recalcitrant to medical treatment. Exposure to soil, muddy water, and minor trauma are possible risk factors. Although reliable prevalence data are lacking, recent studies indicate a high prevalence of microsporidial keratoconjunctivitis in the rainy season, especially in India and other countries with similar climates. For instance, a high prevalence has been documented in Singapore. We bring together the information available on ocular microsporidiosis. [Copyright &y& Elsevier]

Context.--Cancer is known to have epigenetic inputs, with events like genomewide hypomethylation and genespecific hypermethylation of DNA. The DNA methyltransferase enzymes act as effectors of this reprogramming. A previous study revealed that hypomethylation at the DNA methyltransferase 3-like (DNMT3L) promoter could be a potential biomarker in cervical tumors. Because the pathobiology of ocular surface squamous neoplasia (OSSN) is similar to that of cervical tumors, we wanted to determine whether similar changes occur in the methylation pattern at the DNMT3L promoter in OSSN. Objective.--To evaluate the methylation status of the DNMT3L promoter in OSSN compared with healthy conjunctiva. Design.--We evaluated DNA methylation at the DNMT3L promoter in the tumor tissues of 6 patients with histologically proven OSSN and in healthy conjunctiva tissue from 7 individuals for controls using the sodium bisulfite-assisted conversion of genomic DNA. Extracted genomic DNA was treated with sodium bisulfite and amplified with specific primers for the DNMT3L promoter region. The specific polymerase chain reaction products were cloned and sequenced. Results.--The mean age of these patients was 50.2 years (range, 35-65 years). Histologically, 4 OSSN cases were invasive; 2 were intraepithelial. Healthy conjunctival tissues exhibited a methylated promoter region, whereas a variable loss of methylation was observed in all 6 OSSN cases. Conclusions.--We have, for the first time to our knowledge, identified loss of methylation at the DNMT3L promoter in OSSN cases, but its physiologic significance is yet to be understood. Further studies are warranted to substantiate our results. [ABSTRACT FROM AUTHOR]

Retinoblastoma (Rb) is the most common primary intraocular malignancy in children. It is brought about by the mutational inactivation of both alleles of RB1 gene in the developing retina. To identify the RB1 mutations, we analysed 74 retinoblastoma patients by screening the exons and the promoter region of RB1. The strategy used was to detect large deletions/duplications by fluorescent quantitative multiplex PCR; small deletions/insertions by fluorescent genotyping of RB1 alleles, and point mutations by PCR-RFLP and sequencing. Genomic DNA from the peripheral blood leucocytes of 74 Rb patients (53 with bilateral Rb, 21 with unilateral Rb; 4 familial cases) was screened for mutations. Recurrent mutations were identified in five patients with bilateral Rb, large deletions in 11 patients (nine with bilateral Rb and two with unilateral Rb), small deletions/ insertions were found in 12 patients all with bilateral Rb, and point mutations in 26 patients (14 nonsense, six splice site, five substitution and one silent change). Three mutations were associated with variable expressivity of the disease in different family members. Using this method, the detection rates achieved in patients with bilateral Rb were 44/53 (83%) and with unilateral Rb, 5/21 (23.8%). This approach may be feasible for clinical genetic testing and counselling of patients. [ABSTRACT FROM AUTHOR]

Context.-Ocular surface squamous neoplasia (OSSN) represents a spectrum of ocular surface tumors ranging from intraepithelial to invasive. The genesis of OSSN is multifactorial, possibly including human papillomavirus (HPV) infection, the role of which is controversial. Objective.-To evaluate the role of high-risk HPV16 and HPV18 in OSSN. Design.-Retrospective and prospective noncomparative case series. In this study, histologically proven cases of OSSN were evaluated in formalin-fixed, paraffin-embedded sections (n = 50) and fresh tissues (n = 7) for the presence of HPV by polymerase chain reaction using MY09/MY11 consensus primers, HPV16 and HPV18 typespecific primers, and in situ hybridization-catalyzed reporter deposition (ISH-CARD). Cervical tumors (n = 19) along with SiHa and HeLa cell lines served as positive controls for HPV analysis. Results.—The study included 48 patients with OSSN who accounted for 57 specimens, with a median patient age of 28.5 years (range, 1.5-70 years). These specimens included 36 squamous cell carcinomas and 21 conjunctival intraepithelial neoplasias. All of the cases were found to be negative for high-risk HPV using polymerase chain reaction and ISH-CARD assay, whereas the SiHa and HeLa cell lines were appropriately positive. Of the cervical tumors that served as positive controls, 18 were positive for HPV16, and 1 was positive for HPV18. Conclusions.—Sensitive, type-specific polymerase chain reaction for detection of HPV16 and HPV18, polymerase chain reaction assay for consensus HPV sequences, and ISH-CARD did not show the presence of high-risk HPV in OSSN. Thus, HPV appears to play no significant role in the etiology of OSSN in India. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stem cells (MSCs) lack major histocompatibility complex (MHC)-II and only show minimal MHC-I expression. Despite MSCs demonstrating T-cell anergy, there are no established methods to evaluate their suitability. It is crucial to evaluate the complete mismatch of MHC compatibility in view of the hypo-immunogenic nature and immunomodulatory properties of MSCs with respect to their proliferation potential (PP) and utility in terms of passage number. With bone marrow (BM) being the major source of MSCs, the use of these cells becomes even more complicated, due to many other receptors coming to fore and triggering alternative pathways. This prospective study included five BM aspirates for MSC cultures and five allogeneic peripheral blood mono nuclear cells (PBMNCs) from healthy volunteers. MHC compatibility was assessed by polymerase chain reaction-sequence specific primer (PCR-SSP). The PP and a T-cell response to MSCs was addressed in mixed cultures and evaluated on the basis of their stimulation index (SI). Allogeneic circulatory antibodies against the donor MSCs was performed by cytotoxicity assay. The PP of MSCs during interactions with PBMNCs (T-cells) demonstrated T-cell anergy and the response to circulatory antibodies was minimal, in consonance with other published reports. Although, the results are encouraging for potential clinical application of MSC transplantation, autologous is always preferable to allogeneic, at least until the long-term safety of these cells is established in clinical trials. [Copyright &y& Elsevier]

Abstract: We report three cases of renal cell carcinoma metastatic to the eye and orbit and review the relevant literature. The case reports of a 67-year-old man, a 58-year-old man, and a 23-year-old woman with metastatic renal cell carcinoma are described. The iris mass occurred in a 67-year-old man, a known case of renal cell carcinoma. Whereas the orbital metastasis in the 58-year-old man was the initial presenting sign in a hitherto undiagnosed patient, the orbital metastasis in the 23-year-old female patient was detected following nephrectomy for renal cell carcinoma. Renal cell carcinoma metastasizing to the eye and orbit are very rare, with only 68 cases reported previously. In patients presenting with atypical orbital or ocular masses, the possibility of renal cell carcinoma metastasis should be considered, especially if there is a history of previous renal disorder. Incisional biopsy with histopathological evaluation may be an important means to diagnose this condition and facilitate appropriate therapy. [Copyright &y& Elsevier]

Purpose: To describe the demographic features, clinical characteristics, and management in cases of childhood pterygium. Design: Observational case series. Methods: A retrospective review was done of 19 children (total 26 eyes) under the age of 16 years, consecutively presenting with pterygium and evaluated at a single tertiary care center between January 2000 and August 2011. The main outcome measures were clinical features, associated ocular or systemic diseases, approach towards its management, and histopathology of operated cases. Results: Of the 19 patients, 10 were girls and 9 were boys. The mean age at presentation was 10.63 ± 3.48 years (range 2–15 years). Seven patients (37%) had bilateral involvement. None of the cases had familial history. The median refractive astigmatism was found to be −0.5 diopter cylinder. All the eyes had primary pterygium, except 1, which was recurrent. The majority of the eyes (85%) were managed conservatively. Four eyes (15%) required surgery, where pterygium excision with conjunctival-limbal autograft with fibrin glue application was done. The follow-up of surgical cases ranged from 5 to 38 months (median 6 months). One operated case recurred 1 year after surgery. Conclusion: Development of pterygium is a possibility in younger age groups. No specific predisposing factors, either environmental or familial, were identified as contributing to childhood pterygium. The majority of the cases required conservative management. [ABSTRACT FROM AUTHOR]

Purpose: To report the clinical outcomes of penetrating keratoplasty (PK) after autologous cultivated limbal epithelial transplantation in eyes with limbal stem cell deficiency (LSCD) after ocular surface burns. Design: Retrospective case series. Methods: This study included 47 patients with unilateral LSCD treated by autologous cultivated limbal epithelial transplantation and PK between 2001 and 2010. PK was performed either along with (single-stage; n = 12) or at least 6 weeks after (2-stage; n = 35) limbal transplantation. The primary outcome measure was corneal allograft survival, and failure was defined clinically as loss of central graft clarity. Secondary outcomes were postoperative Snellen visual acuity and complications. Results: Most patients were young (mean age, 18 ± 11.4 years) males (76.6%) with LSCD resulting from alkali burns (78.7%) and with visual acuity less than 20/200 (91.5%). The mean follow-up was 4.2 ± 1.9 years. Kaplan-Meier corneal allograft survival rate at 1 year was significantly greater in eyes undergoing 2-stage limbal and corneal transplantation (80 ± 6%; median survival, 4 years) compared with single-stage limbal and corneal transplantation (25 ± 13%; median survival, 6 months; P = .0003). Visual acuity of 20/40 or better was attained by 71.4% of eyes with clear corneal grafts. Allograft failure occurred in 26 (60.5%) eyes as a result of graft rejection (57.7%), graft infiltrate (26.9%), or persistent epithelial defects (15.4%). Recurrence of LSCD was more common after single-stage (58.3%) than 2-stage (14.3%) surgery (P = .008). Conclusions: The 2-stage approach of autologous cultivated limbal epithelial transplantation followed by PK successfully restores ocular surface stability and vision in eyes with chronic ocular burns. The single-stage approach is associated with poorer clinical outcomes and should be avoided. [ABSTRACT FROM AUTHOR]

A growing body of research on extracellular vesicles (EVs) in cancer has revealed their novel and crucial activities in the progression of tumors while also paving the way for potential therapeutic interventions. It is now known that EVs are natural delivery vehicles for particular payloads of source cells, enabling them to influence diverse functions of cells both in healthy and malignant cells. In this review, we comprehensively summarize mechanistic insights into sEV roles in RB, the most frequent intraocular malignancy that affects the retina of young children. We also explore the therapeutic potential of sEVs as an emerging area as biomarkers and vehicles for targeted therapy. Additionally, we address the potential challenges and limitations of translating sEVs-based technologies into clinical practice.

Extracellular vesicles (EVs), defined as membrane-bound vesicles released from all cells, are being explored for their diagnostic and therapeutic role in dry eye disease (DED). We systematically shortlisted 32 articles on the role of EVs in diagnosing and treating DED. We cover the progress in the last 2 decades on the classification and isolation of EVs and their role in DED. The diagnostic predictability of exosomes was evaluated in Sjögren syndrome (SS) patients' tears, plasma, and saliva, where upregulation of inflammatory proteins was reported uniformly across studies. Also, we evaluate the therapeutic effects of MSC-derived EVs in in vitro and in vivo studies of SS and DED mouse models. A significant response occurs at a functional level with improved tear production and saliva flow rate and at a cellular level with reduced lymphocyte infiltration, improved corneal structural integrity, decreased epithelial cell apoptosis, and dampening of the inflammatory cytokine response. The proposed mechanisms of EV action include PD-L1, PRDM, NLRP-3, and Nf-kb pathways, and an increase in M2 macrophage phenotype. Current use of exosomes in DED is limited due to their cumbersome isolation techniqus. Further research on human subjects is needed, in addition to optimizing exosome isolation and delivery methods., Competing Interests: Declaration of Competing Interest Authors have nothing to disclose and have no conflicting interests., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: With the increased survival of retinoblastoma (RB) patients, it is important to evaluate the quality of life (QoL) of RB survivors as well as caregivers to provide comprehensive care to the children and caregivers. This study aims to assess the QoL of survivors of RB, as perceived by parents and the self-report by patients, through a pediatric QoL (PEDs-QoL) questionnaire., Methods: The study cohort included 86 RB survivors, 86 age-matched controls, and their primary carers. PedsQL 4.0 generic core scale and structured interview were administered. QoL in physical, social, emotional, and school health was evaluated and correlated with clinical and sociodemographic parameters., Results: The mean age of the RB survivors was 5.7 years with an M:F ratio of 1.1:1. Disease was bilateral in 79% of cases. About 45% (39/86) underwent enucleation, while others received combination therapy (16; 18%), chemotherapy (30; 34%), and radiation (1; 1%). As reported by parents, the QoL of physical health domain of RB survivors was 70.2 SD ± 27.8 and 96.15 ± 13 SD, emotional health was 72.1 ± 27.4 SD and 94.4 ± 12.5 SD, social health was 80.4 ± 24.9 SD and 98.6 ± 6.2 SD; and school health was 71.9 ± 2 6.5 SD and 96.1 ± 12.2 SD. As per the self-report perception, the QoL of physical health was 68.2 ± 27.8 SD and 96.2 ± 13 SD, emotional health was 66.2 ± 28.4 SD and 95.3 ± 12.5 SD, social health was 69.5 ± 24.9 SD and 98.7 ± 6.2 SD, and school health was 63.5 ± 26.5 SD and 95.1 ± 12.2 SD. There was a significant relationship between enucleation and QoL domains, where χ2 = 67.75, degrees of freedom (df) = 36, and P < 0.01. There was a significant association between vision in the better eye (6/18 or better = 8, 6/18-6/60 = 8, 3/60 or worse = 42) and QoL scores (χ2 = 95.36, df = 62, P < 0.01). There was a substantial association between socioeconomic status and QoL domains, where χ2= 88.5, df = 56, P < 0.01., Conclusion: The results of the study showed that the QoL of parents of RB survivors and self-proxy reports were negatively affected in many ways, including physical, social, emotional, and school-related dimensions. Despite the small differences, self-proxy reports indicated a lower QoL than the parents' group. The study findings indicate that there are notable correlations between enucleation and visual acuity less than 6/18, as well as socioeconomic status, with various aspects of QoL domains among individuals who have survived RB., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Aims: To examine whether the specific location of ocular adnexal lymphoma (OAL) and the American Joint Committee on Cancer (AJCC) TNM tumour stage are prognostic factors for mortality in the main OAL subtypes., Methods: Clinical and survival data were retrospectively collected from seven international eye cancer centres. All patients from 1980 to 2017 with histologically verified primary or secondary OAL were included. Cox regression was used to compare the ocular adnexal tumour locations on all-cause mortality and disease-specific mortality., Results: OAL was identified in 1168 patients. The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n=688, 59%); follicular lymphoma (FL) (n=150, 13%); diffuse large B-cell lymphoma (DLBCL) (n=131, 11%); and mantle cell lymphoma (MCL) (n=89, 8%). AJCC/TNM tumour-stage (T-stage) was significantly associated with disease-specific mortality in primary ocular adnexal EMZL and increased through T-categories from T1 to T3 disease. No associations between AJCC/TNM T-stage and mortality were found in primary ocular adnexal FL, DLBCL, or MCL. EMZL located in the eyelid had a significantly increased disease-specific mortality compared with orbital and conjunctival EMZL, in both primary EMZL and the full EMZL cohort. In DLBCL, eyelid location had a significantly higher disease-specific mortality compared with an orbital or lacrimal gland location., Conclusion: Disease-specific mortality is associated with AJCC/TNM T-stage in primary ocular adnexal EMZL patients. Lymphoma of the eyelid has the highest disease-specific mortality in primary EMZL, and in the full cohort of EMZL and DLBCL patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To identify the genes and pathways responsible for treatment resistance (TR) in retinoblastoma (RB) by analyzing serum small extracellular vesicles (sEVs) of patients with TR active RB (TR-RB) and completely regressed RB (CR-RB)., Methods: Serum-derived sEVs were characterized by transmission electron microscopy and nanoparticle tracking analysis. sEV transcriptome profiles of two TR-RB and one CR-RB with good response (>20 years tumor free) were compared to their age-matched controls (n = 3). Gene expression data were analyzed by the R Bioconductor package. The CD9 protein and mRNA expression of CD9, CD63, and CD81 were studied in five RB tumors and two control retinae by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction., Results: The isolated serum sEVs were round shaped and within the expected size (30-150 nm), and they had zeta potentials ranging from -10.8 to 15.9 mV. The mean ± SD concentrations of sEVs for two adults and four children were 1.1 × 1012 ± 0.1 and 5.8 × 1011 ± 1.7 particles/mL. Based on log2 fold change of ±2 and P < 0.05 criteria, there were 492 dysregulated genes in TR-RB and 184 in CR-RB. KAT2B, VWA1, CX3CL1, MLYCD, NR2F2, USP46-AS1, miR6724-4, and LINC01257 genes were specifically dysregulated in TR-RB. Negative regulation of apoptotic signaling, cell growth, and proton transport genes were greater than fivefold expressed only in TR-RB. CD9, CD63, and CD81 mRNA levels were high in RB tumors versus control retina, with increased and variable CD9 immunoreactivity in the invasive areas of the tumor., Conclusions: Serum sEVs could serve as a potential liquid biopsy source for understanding TR mechanisms in RB.

Purpose: The existing treatment options for dry eye disease (DED) due to lacrimal gland (LG) dysfunction are mainly palliative. Mesenchymal stem cells (MSCs) based therapies and 3D-LG organoids have been explored as a curative option for LG regeneration in animal models. Human LG epithelial cultures are previously established and, here, we aim to isolate and characterize the spindle-shaped cells obtained from primary human LG cultures in order to unveil its MSC property., Methods: Normal human lacrimal glands were obtained from individuals undergoing LG debulking surgery. The conditions for human LG-MSC culture were standardized to obtain pure population of LG-MSCs at passage 3. Population doubling time (PDT), expression of phenotypic markers, tri-lineage differentiation, colony forming potential, and gene expression analysis were carried out to assess the phenotypic and genotypic characteristics compared to bone marrow-MSCs (BM-MSCs)., Results: Our data show that these spindle-shaped cells exhibit similar phenotypic expression, colony-forming ability, and trilineage differentiation like BM-MSCs. Moreover, the gene expression also did not show any significant difference, except for increased IL1-β in LG-MSCs. The LG-MSCs do not express any lacrimal epithelial markers unlike LG tissue., Conclusions: This study reveals the first-time evidence for the presence of MSC population within the human LGs, and these cells might play a role in maintaining healthy microenvironment within normal LG and repair in diseased LGs.

Introduction: Retinoblastoma (Rb) is an early childhood intraocular tumor of the retina and is managed by multimodal therapeutic approaches. Recent advanced targeted delivery of chemotherapeutic drugs to the eye has improved the possibility of globe salvage. However, enucleation is inevitable for advanced and recurrent Rb. The cumulative knowledge of identification of newer molecular biology tools, exosomal cargo, role of cancer stem cells (CSCs), and its microenvironment in the progression of the diseases warrants a relook at the traditional treatment protocol and explore the feasibility of targeted therapies., Areas Covered: This review covers Rb pathobiology, novel molecular-targeted therapeutics, and strategies targeting Rb CSCs and provides an update on potential therapeutic targets such as second messengers and exosomal cargo., Expert Opinion: The emergence of early diagnosis and multimodality treatment protocols have significantly improved the clinical outcome of children with advanced Rb; however, the problem of tumor recurrence has not yet been overcome. Improved understanding of the molecular pathways, identification, and characterization of CSCs opens up new targeted therapy approaches. The contemporary evidence from other fields shows promising evidence that combining conservative treatment modalities with targeting therapies specific for CSCs in clinical practice is essential for achieving high globe salvage rate in Rb patients.

Purpose: To evaluate the efficacy of multimodal treatment in adenoid cystic carcinoma (ACC) of the lacrimal gland., Methods: A retrospective comparative case series of 40 consecutive patients with ACC of the lacrimal gland without systemic metastasis at the initial presentation and primarily managed by one of the 3 treatment protocols-surgery + external beam radiotherapy (EBRT) (group 1), surgery + EBRT + adjuvant chemotherapy (group 2), and neoadjuvant chemotherapy + surgery + EBRT + adjuvant chemotherapy (multimodal treatment) (group 3) at a tertiary care ocular oncology center. Local tumor control, eye salvage, and systemic metastasis were the primary outcome measures., Results: The age ranged from 11 to 72 (mean ± SD, 36 ± 13; median, 36) years with 26 (65%) male and 14 (35%) female patients. Twelve (30%) patients belonged to group 1, 8 (20%) to group 2, and 20 (50%) to group 3. Primary surgery included tumor excision in 36 (90%) and orbital exenteration in 4 (10%). Chemotherapy composed of cisplatin + 5 fluorouracil (5FU) for 6 cycles in 28 (70%) patients. Extended-field stereotactic EBRT with a dose of 5,000-6,000 cGy included the entire pretreatment extent of the tumor with a 10-mm margin all around, superior orbital fissure, inferior orbital fissure, cavernous sinus, and temporal fossa. Mean duration of follow up after completion of treatment was 58 ± 26 (range, 29-180; median, 60) months. In all, local tumor recurrence occurred in 10 (25%) patients at a mean of 38 ± 23 (range, 12-120; median, 24) months. Local tumor recurrence was noted in 5 (42%) patients in group 1, 2 (25%) in group 2, and 3 (15%) in group 3. Overall, eye salvage was possible in 34 (85%) patients, with visual acuity >20/40 in 28 (82%). Systemic metastasis occurred in 10 (25%) patients at a mean of 53 ± 28 (range, 12-120; median, 43) months. Eight (67%) patients in group 1, 1 (13%) in group 2, and 1 (5%) in group 3 developed systemic metastasis. Six (15%) overall, 5 (42%) in group 1 and 1 (13%) in group 2, died with systemic metastasis., Conclusions: Multimodal treatment with sequential neoadjuvant chemotherapy, followed by surgery, extended-field stereotactic EBRT, and adjuvant chemotherapy seems relatively more effective in providing local tumor control and eye salvage and in minimizing the risk of systemic metastasis in ACC of the lacrimal gland., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Dry eye disease (DED) is a common multifactorial disease of the tear film and the ocular surface. The problem of DED has gained attention globally, with millions of people affected by the disorder. Although the treatment strategies for DED have significantly evolved over time, most of the existing modalities fall under the category of standard palliative care when viewed from a long-term perspective. To address these limitations, different approaches have been explored by various groups to uncover alternative treatment strategies that can contribute to a full regeneration of the damaged lacrimal gland, which is responsible for producing the major aqueous component of the tear film. For this, multiple groups have investigated the role of lacrimal gland cells in DED based on their regenerating, homing, and differentiating capabilities. In this review, we discuss in detail the therapeutic mechanisms and regenerative strategies that can potentially be applied for lacrimal gland regeneration as well as their therapeutic applications. This review mainly focuses on aqueous deficiency dry eye disease (ADDE) caused by lacrimal gland dysfunction and possible future treatment strategies. The current key findings from cell and tissue-based regenerative therapy modalities that could be utilised to achieve lacrimal gland tissue regeneration are summarized. In addition, this review summarises the available literature from in vitro to in vivo studies, their limitations in relation to lacrimal gland regeneration and the possible clinical applications. Finally, current issues and unmet needs of cell-based therapies in providing complete lacrimal gland tissue regeneration are discussed., (Copyright © 2022. Published by Elsevier Inc.)

Exosomes are a subgroup of membrane-bound extracellular vesicles secreted by all cell types and present virtually in all biological fluids. The composition of exosomes in the same cell type varies in healthy and disease conditions. Hence, exosomes research is a prime focus area for clinical research in cancer and numerous age-related metabolic syndromes. Functions of exosomes include crucial cell-to-cell communication that mediates complex cellular processes, such as antigen presentation, stem cell differentiation, and angiogenesis. However, very few studies reported the presence and role of exosomes in normal physiological and pathological conditions of specialized ocular tissues of the eye and ocular cancers. The eye being a protected sense organ with unique connectivity with the rest of the body through the blood and natural passages, we believe that the role of exosomes in ocular tissues will significantly improve our understanding of ocular diseases and their interactions with the rest of the body. We present a review that highlights the existence and function of exosomes in various ocular tissues, their role in the progression of some of the neoplastic and non-neoplastic conditions of the eyes.

Purpose: Cancer stem cells (CSCs) are known to contribute to tumor relapses by virtue of their chemoresistance. With the knowledge that nanoformulations can overcome drug resistance, we evaluated the efficacy and cytotoxicity of clinical-grade carboplatin (CPT)- and etoposide (ETP)-loaded lactoferrin nanoparticles (Lf-Nps) on total, CD133-enriched (non-CSC), and CD133-depleted (CSC) populations of retinoblastoma (Rb) Y79 cells., Methods: Physicochemical properties of drug-loaded Lf-Nps were measured with transmission electron microscopy and attenuated total reflectance-Fourier transform infrared. The encapsulation efficiency, uptake, and release of drug-loaded Lf-Nps were measured using high-performance liquid chromatography and a UV-visible spectrophotometer. Cytotoxicity of the standard and drug-loaded Lf-Nps was evaluated by the MTT assay., Results: The mean (SD) size and encapsulation efficiency of Lf-CPT and Lf-ETP were 61.2 (3.94) nm, 60% and 45.15 (5.85) nm, 38%, respectively, and the drug release efficiency was highest at pH 6. The increased drug uptake and lower release of drug-loaded Lf-Nps were observed in CSC and non-CSC populations compared to their standard forms. The relative increase of drug uptake and sustained intracellular retention of the drug-loaded Lf-Nps compared to standard drugs showed an enhanced cytotoxicity up to 50%, especially in Rb Y79 CSCs (IC50: CPT, 230.3; Lf-CPT, 118.2; ETP, 198.1; and Lf-ETP, 129) compared to non-CSCs., Conclusions: Our study documents an increase in drug uptake, retention, and cytotoxicity of Lf-CPT and Lf-ETP on Y79 CSCs and non-CSCs as compared to their standard drugs in vitro. The reversal of chemoresistance in the CSC population by nanoformulation appears promising with the potential to pave the way for improved targeted therapy and better clinical outcomes.

Purpose: Xeroderma pigmentosum (XP) is an extreme hypersensitivity to sunlight causing skin freckling and pigmentary changes because of defective DNA repair mechanisms. The purpose of this article is to evaluate the spectrum of ocular and systemic features in XP at a tertiary eye care center in India over 32 years., Methods: Data from 418 eyes of 209 patients diagnosed with XP from 1987 to 2018 were reviewed retrospectively for demographics, complaints, ocular features, systemic associations, and their management., Results: Median age at diagnosis was 2 years (interquartile range, 0.5-5 years). A total of 124 patients (59.3%) were men. There was parental consanguinity in 74.4% cases. Common ocular complaints were photophobia (47.1%), ocular discomfort (45%), defective vision (36.6%), redness (13.4%), tissue growth (12%), white spot (11.2%), and pain (10.5%). At presentation, 43.5% had corneal scars (45.5% were located inferiorly and 70.9% covered visual axis). Corneal vascularization and limbal stem cell deficiency were noted in 37.4%. A total of 56% of patients had at least 1 tumor, and 6.7% had neurological abnormalities. At least 1 ocular surgery was performed in 37.8% of patients. Ophthalmic surgical interventions included tumor excision (23%), keratoplasty (13.4%), and nontumor ocular surface surgery (3.4%)., Conclusions: XP is a disorder that has high ocular morbidity in Indian patients. The recognition of common signs and symptoms and relative frequency of various ocular complications with time trends will help in managing and reducing the sequelae of this otherwise untreatable and progressive disease., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Metastasis-associated in colon cancer 1 (MACC1), one of the prognostic markers for colonic and other tumours was noted to be overexpressed in retinoblastoma (Rb) Y79 cancer stem cells. This prompted us to evaluate its expression in primary Rb tumour and serum samples with clinicopathologic correlation. The interacting partner, c-MET was also evaluated in primary tumour tissues to explore the activation of MACC1 signaling., Methodology: This study was done following institutional review board approval from participating institutes. Semiquantitative gene expression for MACC1 was evaluated using formalin-fixed paraffin-embedded sections and unfixed tumour samples from primary Rb cases ( n  = 44). Immunolocalization for MACC1 was assessed in primary Rb tumours ( n  = 22), bone marrow aspirates with metastasis ( n  = 3), and c-MET expression was also assessed in Rb tumours ( n  = 17). Serum MACC1 levels were analysed using enzyme-linked immunosorbent assay in samples collected from Rb patients undergoing enucleation ( n  = 31), Rb patients with proven clinical metastasis ( n  = 3), and compared to appropriate controls. Clinicopathologic correlation of MACC1 expression was analysed using the medical records with specific reference to histologic risk factors (HRF) for metastasis and differentiation., Results: High expression of MACC1 gene was noted in all the tumour samples ( n  = 44), more so in cases with versus without HRF ( p  < 0.0001). In cases with HRF, MACC1 and c-MET showed diffuse nuclear and cytoplasmic staining whereas it was predominantly cytoplasmic in cases without HRF. Mean immunoreactivity score of MACC1 and c-MET tissue immunolocalization revealed that cases with HRF showed significantly higher expression compared to cases without HRF ( p  < 0.05). Unlike the findings in colonic tumours, serum levels of MACC1 were lower in patients compared to normal controls., Conclusion: Overexpression of MACC1 and c-MET in retinoblastoma tissues, specifically those with risk factors for metastasis, suggests its role in proliferation and possibly in invasion. However, the current data do not support it to be a clinical prognostic marker in retinoblastoma tumours. The inverse serum expression is an intriguing finding, which warrants further studies especially in retinoblastoma.

Purpose: To characterize the clinical features of subtype-specific lacrimal gland lymphoma and their effect on patient survival., Design: Multicenter retrospective interventional case series., Methods: Patient data were collected from 6 international eye cancer centers from January 1, 1980, through December 31, 2017. All patients with histologically verified primary or secondary lymphoma of the lacrimal gland were included. Primary endpoints were overall survival (OS) and disease-specific survival (DSS)., Results: A total of 260 patients with lacrimal gland lymphoma were identified. The median age was 58 years and 52% of patients were men. Non-Hodgkin B-cell lymphomas constituted 99% (n = 258) and T-cell lymphomas constituted 1% (n = 2). The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n = 177, 68%), follicular lymphoma (FL) (n = 26, 10%), diffuse large B-cell lymphoma (DLBCL) (n = 25, 10%), and mantle cell lymphoma (MCL) (n = 17, 7%). Low-grade lymphomas (EMZL and FL) were most commonly treated with external beam radiotherapy (EBRT), whereas high-grade lymphomas (DLBCL and MCL) were treated with chemotherapy in combination with rituximab and/or EBRT. The prognosis was relatively good with a 5-year OS and DSS of 73.8% and 87.5%, respectively. Lymphoma subtype was a statistically significant predictor for DSS, with EMZL (5-year DSS: 93.4%) having the best prognosis and DLBCL (5-year DSS: 52.6%) having the poorest., Conclusions: This is the largest reported collection of data of subtype-specific lacrimal gland lymphoma. The subtype distribution of lacrimal gland lymphoma resembles that of the ocular adnexa. Prognosis is good and the histologic subtype is a significant predictor for disease-specific survival., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Backgrounds/aims: To date, this is the largest cohort study on extranodal marginal zone B-cell lymphoma (EMZL) of the ocular adnexa (OA). The aim of the study was to characterise the clinical features of OA-EMZL., Methods: A retrospective multicentre study involving seven international eye cancer centres. Data were collected from 1 January 1980 through 31 December 2017. A total of 689 patients with OA-EMZL were included., Results: The median follow-up time was 42 months. The median age was 62 years (range, 8-100 years), and 55 % (378/689 patients) of patients were women. The majority of patients (82%, 558/680 patients) were diagnosed with primary OA-EMZL with Ann Arbor stage IE (90%, 485/541 patients) and American Joint Committee on Cancer stage T2 (61%, 340/557 patients) at the time of diagnosis. The orbit (66%, 452/689 patients) and the conjunctiva (37%, 255/689 patients) were the most frequently involved anatomical structures. The 5-year, 10-year and 20-year disease-specific survival (DSS) were 96%, 91% and 90%, respectively. Stage IE patients treated with external beam radiation therapy (EBRT) as monotherapy (10-year DSS, 95%) were found to have a better DSS than stage IE patients treated with chemotherapy (10-year DSS, 86%). Stage IIIE/IVE patients treated with chemotherapy and rituximab had a better DSS (10-year DSS, 96%) than stage IIIE/IVE patients treated with chemotherapy without rituximab (10-year DSS, 63%)., Conclusions and Relevance: EMZL is a slow-growing tumour with an excellent long-term survival. Low-dose EBRT as monotherapy should be considered in localised OA-EMZL. Rituximab-based chemotherapy should be chosen in those patients with disseminated disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate and characterize the clinical features of subtype-specific orbital lymphoma., Design: Retrospective, interventional case series., Methods: The study included 7 international eye cancer centers. Patient data were collected from January 1, 1980 through December 31, 2017. A total of 797 patients with a histologically verified orbital lymphoma were included. The primary endpoints were overall survival, disease-specific survival, and progression-free survival., Results: The median age was 64 years, and 51% of patients (n = 407) were male. The majority of lymphomas were of B-cell origin (98%, n = 779). Extranodal marginal zone B-cell lymphoma (EMZL) was the most frequent subtype (57%, n = 452), followed by diffuse large B-cell lymphoma (DLBCL) (15%, n = 118), follicular lymphoma (FL) (11%, n = 91), and mantle cell lymphoma (MCL) (8%, n = 66). Localized Ann Arbor stage IE EMZL and FL were frequently treated with external beam radiation therapy. DLBCL, MCL, and disseminated EMZL and FL were primarily treated with chemotherapy. EMZL and FL patients had a markedly better prognosis (10-year disease-specific survival of 92% and 71%, respectively) than DLBCL and MCL patients (10-year disease-specific survival of 41% and 32%, respectively)., Conclusions: Four lymphoma subtypes were primarily found in patients with orbital lymphoma: EMZL, DLBCL, FL, and MCL. The histologic subtype was found to be the main predictor for outcome, with EMZL and FL patients having a markedly better prognosis than DLBCL and MCL., (Copyright © 2018 Elsevier Inc. All rights reserved.)

True exfoliation is a delamination of the superficial layer of anterior lens capsule, which appears as a transparent membrane in the anterior chamber. It is a rare occurrence, and most of the reported cases have been associated with a history of exposure to excessive heat, ocular trauma, or inflammation. We report pre- and post-operative anterior segment observations, surgical approach and histopathology of the excised lens capsule in a patient who presented with bilateral true exfoliation without any contributory history. This case highlights findings from light microscopy which demonstrated a lamellar separation of the anterior lens capsule and partial detachment of anterior capsule with reduced intensity of periodic acid Schiff's staining in the detached portion, confirming the diagnosis of true exfoliation., Competing Interests: There are no conflicts of interest.

Importance: To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort., Objective: To characterize the clinical features of OA-MCL., Design, Setting, and Participants: This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months., Main Outcomes and Measures: Overall survival, disease-specific survival, and progression-free survival were the primary end points., Results: Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region., Conclusions and Relevance: These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment.

Purpose: Despite advances in orbital radiotherapy (XRT), a significant proportion of patients develop ophthalmic complication like dry eye syndrome (DES). The study evaluates the prevalence of aqueous deficient DES (ADDE) and lacrimal gland (LG) changes through histologic evaluation and ex-vivo expansion potential postorbital XRT., Methods: With the approval of the institutional review board, medical records of patients who underwent orbital XRT as management protocol were reviewed for evidence of ADDE using DEWS (Dry Eye Workshop) 2007 criteria ( n = 51). HuLG was harvested from three of these patients who underwent subsequent orbital exenteration and used for histological studies/ex-vivo culture., Results: ADDE was noted in 47.07% of the patients, status postorbital XRT, with a prediction of nearly 50% developing it within 0.5 to 2.9 years. ADDE severity was grade 2 (18%), grade 3 (14%), and grade 4 (17%). Other comorbidities were radiation retinopathy (33.4%), radiation-induced cataract (24.9%), and radiation keratopathy (20.8%). Multivariate and univariate analysis showed that fraction of radiation and dose of radiation/fraction were significant risk factors; male gender and young age were protective factors. The post-XRT exenterated HuLG showed near-total effacement of histoarchitecture with intra/periductal and intra/interlobular fibrosis, loss of acini, and reduced secretory activity. The potential of the LG to expand and grow in culture was impaired with loss of stem cells as compared to normal HuLG., Conclusion: This study documents that orbital-XRT is associated with morphological and functional loss of lacrimal function in nearly 50% of the patients with a prediction of two-third developing ADDE by the end of 5 years., Translational Relevance: The study provides objective clinical evidence for DES development due to architectural/functional damage to the LG postorbital XRT. Based on recent findings that the LG can be cultured in-vitro, with preservation of stem cells and secretory potential, it would be logical to harvest a portion of LG before radiation, and expand and transplant it to rescue the damaged gland if indicated.

Purpose: To document subtype-specific clinical features of lymphoma of the eyelid, and their effect on patient outcome., Design: Retrospective observational case series., Methods: Patient data were collected from 7 international eye cancer centers from January 1, 1980 through December 31, 2015. The cases included primary and secondary lymphomas affecting the eyelid. Overall survival, disease-specific survival (DSS), and progression-free survival were the primary endpoints., Results: Eighty-six patients were included. Mean age was 63 years and 47 (55%) were male. Non-Hodgkin B-cell lymphomas constituted 83% (n = 71) and T-cell lymphomas constituted 17% (n = 15). The most common subtypes were extranodal marginal-zone lymphoma (EMZL) (37% [n = 32]), follicular lymphoma (FL) (23% [n = 20]), diffuse large B-cell lymphoma (DLBCL) (10% [n = 9]), mantle cell lymphoma (MCL) (8% [n = 7]), and mycosis fungoides (MF) (9% [n = 8]). EMZL had a female predilection (69% [22 of 32]), whereas MCL (71% [5 of 7]) and MF (88% [7 of 8]) had a male predominance. MCL (57% [4 of 7]), DLBCL (56% [5 of 9]), and MF (88% [7 of 8]) were frequently secondary lymphomas. Localized EMZL and FL were mostly treated with external beam radiation therapy, whereas DLBCL, MCL, and high Ann Arbor stage EMZL and FL were frequently treated with chemotherapy. DLBCL and MCL had a poor prognosis (5-year DSS, 21% and 50%, respectively), whereas EMZL, FL, and MF had a good prognosis (5-year DSS, 88%, 88% and 86%, respectively)., Conclusions: Lymphoma of the eyelid consists mainly of the lymphoma subtypes EMZL, FL, DLBCL, MCL, and MF. High-grade DLBCL and MCL, as well as MF, are frequently secondary eyelid lymphomas. The main predictor of outcome was the histologic subtype: EMZL, FL, and MF had a significantly better prognosis than MCL and DLBCL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: To date, the clinical features of the various subtypes of conjunctival lymphoma (CL) have not been previously evaluated in a large cohort., Objective: To characterize subtype-specific clinical features of CL and their effect on patient outcome., Design, Setting, and Participants: A retrospective multicenter study was performed. Patient data were collected from January 1, 1980, through December 31, 2010. The dates of the analysis were May 15, 2015, to August 20, 2015. The median follow-up period was 43 months. Seven eye cancer centers were involved in the study. In total, 268 patients with CL were identified, 5 of whom were excluded because of missing clinical data., Main Outcomes and Measures: Overall survival, disease-specific survival, and progression-free survival were the primary end points., Results: Two hundred sixty-three patients with CL were included in the study. Their mean age was 61.3 years, and 55.1% (145 of 263) were female. All lymphomas were of B-cell type. The most frequent subtype was extranodal marginal zone lymphoma (EMZL) (68.4% [180 of 263]), followed by follicular lymphoma (FL) (16.3% [43 of 263]), mantle cell lymphoma (MCL) (6.8% [18 of 263]), and diffuse large B-cell lymphoma (DLBCL) (4.6% [12 of 263). Conjunctival lymphoma commonly manifested in elderly individuals (age range, 60-70 years old), with EMZL having a female predilection (57.8% [104 of 180]) and MCL having a marked male predominance (77.8% [14 of 18]). Unlike EMZL and FL, DLBCL and MCL were frequently secondary diseases (41.7% [5 of 12] and 88.9% [16 of 18], respectively), with MCL showing a frequent occurrence of stage IVE lymphoma (61.1% [11 of 18]) and bilateral manifestation (77.8% [14 of 18]). Localized disease (stage IE or IIE) was commonly treated with external beam radiation therapy (EBRT) with or without chemotherapy, while widespread lymphoma (stage IIIE or IVE) and MCL of any stage were managed with chemotherapy with or without EBRT. Diffuse large B-cell lymphoma and MCL had a poor prognosis, with 5-year disease-specific survival of 55.0% and 9.0%, respectively, in contrast to EMZL (97.0%) and FL (82.0%). Further survival predictors included age (EMZL), sex (FL), and Ann Arbor staging classification (EMZL and FL). The American Joint Committee on Cancer TNM staging showed limited prognostic usefulness, only being able to predict survival for patients with DLBCL., Conclusions and Relevance: Conjunctival lymphoma consists of mainly 4 subtypes of B-cell non-Hodgkin lymphoma: EMZL, FL, MCL, and DLBCL. Mantle cell lymphoma is characterized by a particularly high frequency of secondary disease of stage IVE and bilateral manifestation. The histological subtype is the main outcome predictor, with MCL and DLBCL having a markedly poorer prognosis than EMZL and FL.

Importance: The clinical features of diffuse large B-cell lymphoma (DLBCL) subtype of ocular adnexal lymphoma have not previously been evaluated in a large cohort to our knowledge., Objective: To investigate the clinical features of ocular adnexal DLBCL (OA-DLBCL)., Design, Setting, and Participants: This retrospective international cooperative study involved 6 eye cancer centers. During 30 years, 106 patients with OA-DLBCL were identified, and 6 were excluded from the study. The median follow-up period was 52 months., Main Outcomes and Measures: Overall survival, disease-specific survival (DSS), and progression-free survival were the primary end points., Results: One hundred patients with OA-DLBCL were included in the study (median age, 70 years), of whom 54 (54.0%) were female. The following 3 groups of patients with lymphoma could be identified: primary OA-DLBCL (57.0%), OA-DLBCL and concurrent systemic lymphoma (29.0%), and ocular adnexal lymphoma relapse of previous systemic lymphoma (14.0%). Of 57 patients with primary OA-DLBCL, 53 (93.0%) had Ann Arbor stage IE disease, and 4 (7.0%) had Ann Arbor stage IIE disease. According to the TNM staging system, 43 of 57 (75.4%) had T2 tumors. Among all patients, the most frequent treatments were external beam radiation therapy with or without surgery (31.0%) and rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone (CHOP) or rituximab-CHOP-like chemotherapy with or without external beam radiation therapy (21.0%). The 5-year overall survival among the entire cohort was 36.0% (median, 3.5 years; 95% CI, 2.5-4.5 years). Relapse occurred in 43.9% (25 of 57) of patients with primary OA-DLBCL. Increasing T category of the TNM staging system was predictive of DSS (P = .04) in primary OA-DLBCL, whereas the Ann Arbor staging system was not. However, when taking all 100 patients into account, Ann Arbor stage was able to predict DSS (P = .01). Women had a longer median DSS than men (9.8 years; 95% CI, 1.9-17.7 years vs 3.3 years; 95% CI, 1.6-5.0; P = .03)., Conclusions and Relevance: Most patients with primary OA-DLBCL were seen with Ann Arbor stage IE and TNM T2 disease. The 5-year overall survival was between 2.5 and 4.5 years, which is the 95% CI around the median of 3.5 years in this cohort. Increasing T category appears to be associated with decreased DSS among patients with primary OA-DLBCL. When taking all patients into account, sex and Ann Arbor stage also seem to be DSS predictors.

To report the clinical characteristics and treatment outcome in six patients with chronic conjunctivitis due to Mycobacterium tuberculosis. In this retrospective observational case series, all patients with a diagnosis of conjunctival tuberculosis seen in our clinics between January 2000 and January 2010 were reviewed. The clinical presentation, diagnostic investigations and response to medical therapy and outcomes were analyzed. Six patients (age range 15-47 years) were diagnosed with conjunctival tuberculosis. The mean duration from onset of symptoms to diagnosis was 6.5 months (range 1-12 months). Of the six patients, two had ulceration, one had a nodulo-ulcerative lesion, one had bilateral nodular epibulbar masses, and one had a hypertrophied papillary lesion. Systemic signs of tuberculosis were noted in two patients--pleural effusion in one and preauricular and submandibular lymph node involvement in the other. All patients had resolution of symptoms after treatment with four-drug anti-tuberculosis therapy (ATT). None had ocular or systemic recurrences after completion of ATT. Tuberculosis of the conjunctiva can have varied clinical presentation. Although a rare entity, it should be suspected in non-responding chronic conjunctivitis. A high index of suspicion and clinical examination aided by appropriate microbiological and histopathological testing can help in early diagnosis and management.

We report a case of choroidal melanoma with features suggestive of orbital cellulitis. A 24-year-old Asian Indian male presented with a 20-day history of sudden loss of vision in the right eye. Edematous eyelids with complete mechanical ptosis, complete ophthalmoplegia, gross proptosis accompanied by massive chemosis, and prolapse of the inferior forniceal conjunctiva were noted. He denied perception of light in the right eye. The left eye was unremarkable. B-scan ultrasonography of the right eye showed a large dome-shaped mass filling the posterior segment suggestive of choroidal melanoma. Computed tomography confirmed those findings and showed no extraocular tumor extension. The patient was conservatively treated with systemic steroids following which the inflammation subsided. He underwent enucleation of the right eye and a diagnosis of spindle A cell choroidal melanoma was confirmed by histopathological examination. Although rare, orbital cellulitis is one of the presenting features of choroidal melanoma. Uveal melanoma-associated orbital cellulitis can be well controlled with systemic steroids, does not always indicate extraocular tumor extension, and can occur in spindle A cell melanomas.

The human lacrimal gland is an essential component of the lacrimal functional unit (LFU). Any perturbation of this unit can lead to the debilitating morbid condition called the dry eye syndrome (DES). The current line of therapy available for dry eye remains supportive and palliative with the patient being dependent on life long and frequent administration of lubricating eye drops. Even advanced therapies like punctual plugs, cyclosporine B administration, and salivary gland auto-transplantation have led to a limited success. Under these scenarios, the option of cell based therapy needs to be explored to provide better and long term relief to these patients. This review gives an overview of the efforts in lacrimal gland regeneration and examines the past and ongoing research in cell based therapies in animals as well as human lacrimal gland cultures. The authors discuss their first of its kind functionally viable human lacrimal gland in vitro culture system from fresh exenteration specimens. A brief overview of research in near future and the potential implications of lacrimal gland regenerative therapies have been discussed.

Advances in animal models of retinoblastoma have accelerated research in this field, aiding in understanding tumor progression and assessing therapeutic modalities. The distinct pattern of mutations and specific location of this unique intraocular tumor have paved the way for two types of models- those based on genetic mutations, and xenograft models. Retinoblastoma gene knockouts with an additional loss of p107, p130, p53 and using promoters of Nestin, Chx10, and Pax6 genes show histological phenotypic changes close to the human form of retinoblastoma. Conditional knockout in specific layers of the developing retina has thrown light on the origin of this tumor. The use of xenograft models has overcome the obstacle of time delay in the presentation of symptoms, which remains a crucial drawback of genetic models. With the advances in molecular and imaging technologies, the current research aims to develop models that mimic all the features of retinoblastoma inclusive of its initiation, progression and metastasis. The combination of genetic and xenograft models in retinoblastoma research has and will help to pave way for better understanding of retinoblastoma tumor biology and also in designing and testing effective diagnostic and treatment modalities.