Intravitreal Topotecan for Vitreous Seeds in Retinoblastoma: A Long-term Review of 91 Eyes.

PURPOSE: To study the long-term efficacy of intravitreal topotecan (IVT) for vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence. DESIGN: Retrospective, non-comparative, interventional study. PARTICIPANTS: Ninety-one eyes of 90 patients with retinoblastoma treated between January 2013 and April 2019. METHODS: Patients with recurrent or refractory vitreous seeds after completion of intravenous or intra-arterial chemotherapy were treated with IVT (30 µg/0.15 ml) by the safety-enhanced technique. The injection was repeated every 4 weeks until the regression of seeds. Patients with a minimum follow-up of 12 months were included in the analysis. MAIN OUTCOME MEASURES: Primary outcome measures were vitreous seed regression and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence after treatment with IVT, vision salvage, and complications of IVT. RESULTS: The median age of the patients was 18 months, with most having group D (n = 58 [64%]) and group E (n = 26 [29%]) retinoblastoma. Vitreous seeds were refractory in 46 eyes (51%) and recurrent in 45 eyes (49%). A total of 317 IVT injections were administered, with the median being 3 injections. The median number of IVT injections required was 2.5 injections for dust, 3 injections for sphere, and 5 injections for cloud morphologic features. Recurrence of vitreous seeds after IVT was seen in 17 eyes (19%) at a mean follow-up of 7.9 months. At a mean follow-up 34 months, vitreous seed regression was achieved in 88 eyes (97%) and eye salvage was achieved in 77 eyes (85%). Older age (P = 0.018) and recurrence of retinal tumor (15/17 eyes; P < 0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 eyes (9%). CONCLUSIONS: Intravitreal topotecan at an every 3- to 4-week regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphologic features correspond to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence after treatment with IVT. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Does Multimodal Treatment Improve Eye and Life Salvage in Adenoid Cystic Carcinoma of the Lacrimal Gland?

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.

The Management of Ocular Surface Squamous Neoplasia (OSSN).

The rise of primary topical monotherapy with chemotherapeutic drugs and immunomodulatory agents represents an increasing recognition of the medical management of ocular surface squamous neoplasia (OSSN), which may replace surgery as the standard of care in the future. Currently, there is no consensus regarding the best way to manage OSSN with no existing guidelines to date. This paper seeks to evaluate evidence surrounding available treatment modalities and proposes an approach to management. The approach will guide ophthalmologists in selecting the most appropriate treatment regime based on patient and disease factors to minimize treatment related morbidity and improve OSSN control. Further work can be done to validate this algorithm and to develop formal guidelines to direct the management of OSSN.

Unilateral Frontalis Suspension With Silicone Sling Without Levator Extirpation in Congenital Ptosis With Marcus Gunn Jaw Winking Synkinesis.

PURPOSE: To evaluate the efficacy of unilateral tarso-frontalis silicone sling without levator extirpation or disinsertion in dampening the jaw wink in patients with congenital ptosis associated with Marcus Gunn Jaw Winking synkinesis phenomenon. METHODS: Retrospective review of medical records of all patients of congenital ptosis with moderate to severe Marcus Gunn jaw winking synkinesis who underwent unilateral tarsofrontal silicone sling surgery without extirpation of the levator muscle were retrospectively reviewed. Data were collected about the pre- and the postoperative severity of the ptosis and the amount of Marcus Gunn jaw winking excursion. RESULTS: Twenty-three patients were included in the study. Mean postoperative follow up duration was 31.2 (range 6-208) weeks. The severity of the preoperative jaw wink was mild (<2 mm excursion) in 0 patient, moderate (2-5mm) in 15 (65%) patients, and severe (>5 mm eyelid excursion) in 8 (35%) patients. Postoperatively, 20 (87%) patients had mild residual jaw wink, 3 (13%) patients had moderate jaw wink and none of the patient had severe residual jaw wink. CONCLUSION: Unilateral tarsofrontal silicone sling without disinsertion or extirpation of the levator can reduce the severity of the jaw wink excursion in patients with congenital ptosis with moderate to severe preoperative Marcus Gunn jaw winking synkinesis.

Establishing and characterizing lacrispheres from human lacrimal gland for potential clinical application.

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.

An update on ocular adnexal lymphoma.

Ocular adnexal lymphoma (OAL) is a relatively common lesion in the practice of ophthalmic oncology. Although OALs are usually primary tumors, secondary involvement of the ocular adnexae by systemic lymphoma is also possible. The clinical and radiological features of OAL are non-specific. Thorough morphological evaluation, aided by immunostaining, cytogenetic studies and molecular testing, are necessary for accurate diagnosis.

Forget Me Not: A Case of Gossypiboma (Textiloma) Mimicking an Orbital Tumor.

Retained foreign bodies are not infrequent following surgical procedures and are associated with medico-legal issues. Gossypiboma following ocular surgeries is rare but should be included in the differential diagnosis of a postoperative patient presenting with pain or mass. We report on one such case of gossypiboma following surgical excision of lacrimal gland.

Clinicopathologic features of orbital immunoglobulin G4-related disease (IgG4-RD): a case series and literature review.

BACKGROUND: Involvement of orbital structures by immunoglobulin G4-related disease (IgG4-RD) is not uncommon. We conducted this study to evaluate the clinicopathologic features of orbital IgG4-RD. MATERIAL/METHODS: This was a retrospective, clinicopathologic study. Clinical records, light microscopic features, results of immunostaining with IgG & IgG4 and laboratory findings were reviewed in 16 patients diagnosed with orbital IgG4-RD. RESULTS: Eleven patients had a bilateral disease, and the lacrimal gland was involved in 14. Dense sclerosis, plasma cell aggregates and dense lymphoplasmacytic infiltrate were seen in all patients. Serum IgG4 titre was elevated in 12 patients. Nine patients responded completely to glucocorticoid treatment. Five patients had a relapse on discontinuation of treatment. CONCLUSION: Orbital IgG4-RD is a distinct clinicopathologic entity requiring increased awareness and needs to be differentiated from other orbital lymphoproliferative lesions.

Management and outcome of retinoblastoma with vitreous seeds.

PURPOSE: To report the treatment response of retinoblastoma with vitreous seeds to high-dose chemotherapy coupled with periocular carboplatin. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Consecutive patients with retinoblastoma with vitreous seeds managed over 10 years at a comprehensive ocular oncology center and followed up for at least 12 months after the completion of treatment were included in this study. Institutional review board approval was obtained. INTERVENTION: High-dose chemotherapy with a combination of vincristine, etoposide, and carboplatin in patients with focal vitreous seeds and additional concurrent periocular carboplatin in patients with diffuse vitreous seeds. MAIN OUTCOME MEASURES: Tumor regression, vitreous seed regression, and eye salvage. RESULTS: After excluding the better eye of bilateral cases, 101 eyes of 101 patients were part of the final analysis. All the patients belonged to Reese-Ellsworth group VB, but on the International Classification of Retinoblastoma (ICRB), 21 were group C, 40 were group D, and 40 were group E. The mean basal diameter of the largest tumor was 11.8 ± 4.7 mm. Mean tumor thickness was 7.5 ± 4.0 mm. Vitreous seeds were focal in 21 eyes and diffuse in 80 eyes. Chemotherapy cycles ranged from 6 to 12 (median, 6). Seventy-three eyes with diffuse vitreous seeds received a 15-mg posterior sub-Tenon carboplatin injection (range, 1-13 mg; median, 6 mg). Follow-up duration ranged from 13.4 to 129.2 months (median, 48 months). External beam radiotherapy (EBRT) was necessary in 33 eyes with residual tumor, vitreous seeds, or both. In all, 20 eyes (95%) with ICRB group C retinoblastoma, 34 eyes (85%) with group D retinoblastoma, and 23 eyes (57.5%) with group E retinoblastoma were salvaged. Of 77 eyes that were salvaged, 74 (96%) had visual acuity of 20/200 or better. Twenty-four of 33 chemotherapy failures (73%) regressed with EBRT. None of the patients demonstrated second malignant neoplasm or systemic metastasis. Factors predicting tumor regression and eye salvage were bilateral retinoblastoma and absence of subretinal fluid. Factors predicting vitreous seed regression were absence of subretinal fluid and subretinal seeds. CONCLUSIONS: Intensive management with primary high-dose chemotherapy and concurrent periocular carboplatin, and EBRT selectively in chemotherapy failures, provides gratifying outcome in retinoblastoma with vitreous seeds.

Exome sequencing reveals the likely involvement of SOX10 in uveal melanoma.

PURPOSE: To identify the spectrum of somatic mutations in an Asian Indian patient with uveal melanoma (UM) without metastasis using exome sequencing. CASE REPORT: A 49-year-old man from India was diagnosed as having cilio-choroidal (uveal) melanoma (UM), without metastasis, in his right eye with the help of magnetic resonance imaging. This was later confirmed by histopathological evaluation. Two individuals from India with non-neoplastic blind eyes were recruited as controls. The affected eyes from the UM patient and the two control individuals were enucleated, and uveal tissues were collected. DNA was extracted from uveal tissue, and the matched blood sample from each of the three individuals was followed by exome sequencing. Statistical and bioinformatic analyses were done to identify somatic mutations and their putative associations with UM. Thirty-one somatic mutations (25 amino acid altering) in protein-coding (exonic) regions were detected in the UM patient. Of the amino acid-altering somatic mutations, 16 mutations were predicted to be candidate mutations relevant to UM. Somatic mutations, putatively causal for UM, were identified in GNAQ, SF3B1, and SOX10. CONCLUSIONS: Somatic mutations in GNAQ and SF3B1 genes were probable drivers of UM in the Indian patient; these were also reported earlier in some White patients. In addition, a frameshift deletion of 20 base pairs has been identified in SOX10 in the UM patient. Somatic mutations in SOX10, a transcription factor, which acts upstream of microphthalmia-associated transcription factor and synergizes with microphthalmia-associated transcription factor, was identified in some melanoma cell lines. The transcription factor SOX10 was found to have an essential role in melanocyte development and pigmentation. Our finding of the frameshift deletion (p.H387fs) in exon 4 of SOX10 in UM provides an important insight and complements earlier findings of mutations in GNAQ and SF3B1 on the genomic basis of UM.

Orbital immunoglobulin-G4-related disease: case series and literature review.

Immunoglobulin-G4-related disease (IgG4-RD) is a distinct group of diseases characterized by elevated serum IgG4 titres and infiltration of affected organs by IgG4-positive plasma cells. IgG4-RD can involve any ocular adnexal tissue. They have a distinct prognosis and pattern of tissue involvement and hence need to be differentiated from orbital lesions with similar clinicopathological features. We report three cases of IgG4-RD and review the literature extensively discussing various aspects of this novel entity.

Orbital myxofibrosarcoma: a clinicopathologic correlation of an extremely rare tumor.

Myxofibrosarcoma (MFS) is an extremely rare tumor of the orbit, with only 3 cases reported in the literature, although it is one of the most frequent sarcomas arising from extremities in the elderly patients. The scarcity of literature regarding orbital MFS poses a challenge in its diagnosis and management. A new case of orbital MFS, its clinicopathologic correlation, and management with a brief review of literature is reported.

Primary, orbital, malignant extra-renal, non-cerebral rhabdoid tumour.

Malignant rhabdoid tumour is a rare tumour outside the kidney and central nervous system. Orbital and intraocular malignant rhabdoid tumour is particularly rare with very few reports in published literature. Given the aggressiveness of this tumour and resistance to conventional chemotherapy, it is important to differentiate this tumour from other, less aggressive tumours that may have similar clinicoradiological or light microscopic features. We report one such case in a 6-week-old male child with its clinicoradiological and histopathologic features, differential diagnosis and also review the literature on the same.

The black lacrimal sac: a clinicopathological correlation of a malignant melanoma with anterior lacrimal crest infiltration.

Primary lacrimal sac melanoma is an extremely rare clinical entity with fewer than 25 cases reported in the literature. We present a well-documented case of lacrimal sac melanoma with anterior lacrimal crest infiltration and discuss the clinical, radiological and histopathological features along with surgical challenges and treatment.

Targeted therapy in ophthalmic oncology: The current status.

There have been rapid advancements in the field of ocular oncology for the diagnosis and management of intraocular, adnexal, and orbital tumors. Targeted therapy is in the forefront of medical research in all fields including ocular oncology. Targeted therapy include drugs that target specific genetic mutations, pathways or proteins involved in the development of cancer. In contrast to traditionally used chemotherapy, drugs used in targeted therapy are highly specific for tumor cells and preserve the function of normal cells. This review aims to familiarize ophthalmologists with the drugs that are currently approved or undergoing clinical trials for use in ocular oncology. Targeted therapy is particularly useful for locally advanced or metastatic tumors, including but not limited to eyelid and periocular basal cell carcinoma, periocular cutaneous and conjunctival squamous cell carcinoma, ocular adnexal lymphoma, conjunctival melanoma, and uveal melanoma. The results are promising with improved survival outcomes and better tolerability than chemotherapeutic drugs.

Ciliary body medulloepithelioma: analysis of 41 cases.

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.

Adenoid cystic carcinoma of the lacrimal gland: role of nuclear survivin (BIRC5) as a prognostic marker.

AIMS: This study aimed to evaluate the expression of nuclear survivin in adenoid cystic carcinoma (ACC) of the lacrimal gland and to determine if this expression is associated with histopathological features, markers of apoptosis and proliferation or clinical outcomes. METHODS AND RESULTS: Immunohistochemical staining for survivin, p53, Ki-67 and Bcl-2 was analyzed in 55 cases of ACC of lacrimal gland. Thirty-one cases (56.3%) expressed nuclear survivin. All cases expressed p53, Ki-67 and Bcl-2. Eleven cases (35.5%) had a high nuclear survivin score (NS-SCORE) and 20 cases (64.5%) had a low NS-SCORE. Cases with a high NS-SCORE had a shorter progression-free survival (PFS) (P < 0.0001), higher expression of Ki-67 (P < 0.005) and a solid tumour pattern >30% (P < 0.005). CONCLUSION: Nuclear expression of survivin impacts prognosis significantly and is thus a promising prognostic marker in ACC of the lacrimal gland.

Endoscopically guided minimally invasive bypass tube intubation without DCR: evaluation of drainage and objective outcomes assessment.

AIM: To report a series of 15 consecutive patients with complete proximal bicanalicular obstructions managed with endoscopically guided minimally invasive placement of bypass tubes without a dacryocystorhinostomy (DCR), their indications, interventions, complications and objective and uniform assessment of outcomes. MATERIAL AND METHODS: Fifteen consecutive patients presenting with complete proximal bicanalicular obstructions were included in a retrospective, non-comparative case series. Medical records were reviewed for demographic data, etiology, symptoms at presentation, type of bypass tube used, length of the tubes, duration of follow-up, class of lacrimal drainage, patency of the tube, resolution of symptoms, complications and their outcomes. RESULTS: The mean age at presentation was 18.7 years (range: 10-32 years). The most common indication was punctal agenesis (46.6%) followed by complete proximal bicanalicular block secondary to trauma (26.6%). All patients presented with epiphora. The most common bypass tube was a straight Jones variety (60%). The mean length of the bypass tubes was 21 mm (range 19-24 mm). All patients were followed up for a mean duration of 9.6 months following surgery (range 7-13 months). The majority of the patients were post-operatively objectively classified into type I lacrimal drainage (66.6%). At the last follow-up, the success rate was 86.6%. None of the tubes extruded but were removed in two patients due to peritubal soft tissue infection and conjunctival pressure necrosis. CONCLUSION: Endoscopically guided minimally invasive placement of a bypass tube without DCR is an easier and effective alternative to the traditional conjunctivodacryocystorhinostomy and is likely to help in avoiding major complications of tube extrusion and malpositions seen with the latter procedure. Objective evaluation of lacrimal drainage helps in typifying and uniformly assessing the outcomes.

Endoscopic guided single self-linking silicone stent in pediatric external dacryocystorhinostomy.

AIMS: To study the efficacy of a new technique of single self-linking silicone stent exclusively in pediatric external dacryocystorhinostomy (DCR) and to report the new use and advantages of endoscopic guidance for the same. MATERIAL AND METHODS: Prospective interventional case series, including 11 eyes of ten patients with nasolacrimal duct obstruction. Data collected included demographic data, clinical presentation, laterality, status of lids and puncta, syringing findings, probing interpretations, types and duration of intubation. Consecutive pediatric patients with post-saccal obstruction who underwent an external dacryocystorhinostomy were included. Exclusion criteria included patients who had undergone a DCR in the past by any route via external, endonasal or transcanalicular. Primary outcome measures were stent retention and ease of stent removal. Secondary outcome measures were anatomic patency of the passage and resolution of symptoms. RESULTS: There were three male and seven female patients. Mean age was 9.4 years (range 6-15). A total of 11 procedures were carried out. Following placement of self-linked stents, the removal was done at a mean duration of 13.2 weeks (range:12-16 weeks). None of the patients had a stent prolapse during this period. All stents were removed in the outpatient without the use of general anesthesia with minimal endoscopic guidance. A minimum follow-up of three months following removal was considered for final analysis. Follow-up ranged from three months to six months after tube removal. The anatomical and functional success rate was 91%. There was one anatomical failure three months following tube removal and the remaining patients were free of symptoms at the last follow-up. CONCLUSIONS: Self-linking stents are a useful modality in pediatric patients not only to prevent stent prolapse but also to allow easy removal with minimum discomfort. Endoscopic guidance is a useful addition to this technique.