Vijay Anand P. Reddy

Histopathologic Risk Factors in Retinoblastoma in India

CONTEXT The presence of histopathologic risk factors is associated with development of metastasis in a patient with retinoblastoma. Adjuvant chemotherapy administered to such patients decreases the risk of metastasis. OBJECTIVE To analyze the incidence of histopathologic risk factors in our patient population and the clinical predictors of such risk factors. DESIGN This is a retrospective case series, with review of clinical data and histopathologic slides, in 142 consecutive eyes enucleated for retinoblastoma between 1996 and 2002. RESULTS Histopathologic risk factors were present in 54.2% of 142 eyes enucleated for retinoblastoma and included infiltration of iris (7%), ciliary body (9%), choroid (40%), optic nerve lamina cribrosa (11%), retrolaminar optic nerve (17%), optic nerve to the line of transection (8%), sclera (9%), and extrascleral structures (6%). On univariate analysis, histopathologic risk factors correlated with age greater than 24 months at presentation and with glaucoma and iris neovascularization at presentation. On multivariate logistic regression analysis, age greater than 24 months and iris neovascularization correlated with infiltration of the choroid, while iris neovascularization correlated with infiltration of the retrolaminar optic nerve. CONCLUSION Histopathologic risk factors are present in a significant proportion of patients enucleated for retinoblastoma and have identifiable clinical predictors.

Establishing Human Lacrimal Gland Cultures with Secretory Function

Purpose Dry eye syndrome is a multifactorial chronic disabling disease mainly caused by the functional disruptions in the lacrimal gland. The treatment involves palliation like ocular surface lubrication and rehydration. Cell therapy involving replacement of the gland is a promising alternative for providing long-term relief to patients. This study aimed to establish functionally competent lacrimal gland cultures in–vitro and explore the presence of stem cells in the native gland and the established in-vitro cultures. Methods Fresh human lacrimal gland from patients undergoing exenteration was harvested for cultures after IRB approval. The freshly isolated cells were evaluated by flow cytometry for expression of stem cell markers ABCG2, high ALDH1 levels and c-kit. Cultures were established on Matrigel, collagen and HAM and the cultured cells evaluated for the presence of stem cell markers and differentiating markers of epithelial (E-cadherin, EpCAM), mesenchymal (Vimentin, CD90) and myofibroblastic (α-SMA, S-100) origin by flow cytometry and immunocytochemistry. The conditioned media was tested for secretory proteins (scIgA, lactoferrin, lysozyme) post carbachol (100 µM) stimulation by ELISA. Results Native human lacrimal gland expressed ABCG2 (mean±SEM: 3.1±0.61%), high ALDH1 (3.8±1.26%) and c-kit (6.7±2.0%). Lacrimal gland cultures formed a monolayer, in order of preference on Matrigel, collagen and HAM within 15–20 days, containing a heterogeneous population of stem-like and differentiated cells. The epithelial cells formed ‘spherules’ with duct like connections, suggestive of ductal origin. The levels of scIgA (47.43 to 61.56 ng/ml), lysozyme (24.36 to 144.74 ng/ml) and lactoferrin (32.45 to 40.31 ng/ml) in the conditioned media were significantly higher than the negative controls (p<0.05 for all comparisons). Conclusion The study reports the novel finding of establishing functionally competent human lacrimal gland cultures in-vitro. It also provides preliminary data on the presence of stem cells and duct-like cells in the fresh and in-vitro cultured human lacrimal gland. These significant findings could pave way for cell therapy in future.

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.

Orbital retinoblastoma: Where do we go from here?

Diagnosis of orbital retinoblastoma traditionally carries a dismal prognosis. Although its incidence is less in the developed countries, it continues to contribute to an epidemic of extraocular disease at diagnosis in the developing world. Orbital retinoblastoma encompasses a wide range of distinct clinical entities with varying tumor load. There are no standard treatment protocols as of now but the current preferred management is multimodal with a combination of initial high-dose chemotherapy, surgery, external beam radiotherapy and prolonged chemotherapy for 12 cycles. Though orbital retinoblastoma is a catastrophic event, rapid advances on many fronts, especially the genetic, makes the future appear brighter than what it is now. This review looks at all the new frontiers that are in store in the near as well as the distant future. Looking at the ever expanding horizons makes one believe of a definite hope that one day we will conquer this disease as we have conquered many others in the past.

Orbital retinoblastoma: Present status and future challenges - A review

Orbital retinoblastoma is a catastrophic event traditionally carrying a dismal prognosis. Although its incidence is less in the developed countries it continues to be one of the major diagnosis at presentation in the developing world. Orbital retinoblastoma encompasses a wide range of distinct clinical entities with varying tumor load. There are no standard treatment protocols as of now but the current preferred management is multimodal with a combination of initial high-dose chemotherapy, surgery, external beam radiotherapy and prolonged chemotherapy for twelve cycles. In spite of progress on all fronts including surgical, medical, diagnostic, genetic and rehabilitative with improving survival rates, however, lack of access to medical facilities, lack of education about the need for early medical attention and cultural resistance to enucleation continue to contribute to an epidemic of extra ocular disease at diagnosis in the developing world. This review introduces the various terminologies used in the spectrum of orbital retinoblastoma, discusses in details the clinical aspects and management protocols, current status and the future directions.

RB1 gene mutations in retinoblastoma and its clinical correlation

PURPOSE To find correlation between the type of mutations observed and the severity of the disease using multiple techniques like polymerase chain reactions (PCR), quantitative multiplex PCR, sequencing and RNA analysis. METHODS Prospective, observational study. Patients who had been screened for mutations in the RB1 gene were included in the study. Patient details including demographic data; age and sex, laterality, international classification of intraocular retinoblastoma (ICIOR) staging, modality of management, histopathology high risk factors if the eyes were enucleated and metastasis rate were assessed. RESULTS Seventy four patients were studied. Fifty three patients had bilateral and 21 unilateral disease. Complete genetic data was analyzed for 74 patients and complete clinical correlation was established for all the 49 patients with mutations. Of the total mutations identified, 11/49 (22.4%) of patients had large deletions, 12/49 (24.5%) had small deletions or insertions, 14/49 (28.6%) had nonsense mutations, 7/49 (14.3%) had splice mutations and 5/49 (10.2%) of patients had missense mutations. Four cases were familial. Group E ICIOR stage at presentation was noted in 40% of patients with large deletions, 33% with small deletions whereas 38.5% with splice mutations and 44.4% of patients with missense mutations presented with Group B ICIOR. Twenty five percentages of eyes with large deletions had high risk features on histopathology and one patient among these developed metastasis. CONCLUSION Current laboratory testing of RB1 mutations may be feasible in determining the severity of the disease and patient counseling. The study provides a starting point for looking at correlations.

Evisceration in Unsuspected Intraocular Tumors

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

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.

Neoadjuvant Systemic Chemotherapy in the Management of Extensive Eyelid Sebaceous Gland Carcinoma: A study of 10 Cases.

Purpose: To report the efficacy of neoadjuvant systemic chemotherapy in the management of eyelid sebaceous gland carcinoma (SGC). Methods: Retrospective study of 10 patients that received neoadjuvant systemic chemotherapy (Cisplatin/Carboplatin and 5-Fluorouracil) for eyelid SGC. Results: The mean age at presentation of eyelid SGC was 58 years (median, 55 years; range, 45 to 72 years). There were 6 females and 4 males. The mean tumor basal diameter was 36 mm (median, 31 mm, range, 20 to 65 mm), with orbital tumor extension in 9 cases. On the basis of TNM Classification, the tumors were classified as T3 (n = 10), N1 (n = 6), and M1 (n = 2). The mean number of cycles of neoadjuvant systemic chemotherapy per patient was 3 (median, 3; range, 3 to 4). The mean percentage reduction of tumor basal diameter after neoadjuvant chemotherapy was 74% (median, 80%; range, 30% to 100%). None of them had any major systemic side-effects of neoadjuvant chemotherapy. Postchemotherapy, surgical treatment for residual tumor was performed in 7 cases. Five cases underwent excision biopsy and 2 cases with residual orbital component underwent eyelid-sparing orbital exenteration. No tumor recurrence was noted in any of the 7 cases at a mean follow-up period of 18 months (median, 14 months; range, 3 to 63 months). One patient died due to systemic metastasis. Conclusion: Neoadjuvant systemic chemotherapy is effective and safe in the management of eyelid sebaceous gland carcinoma.

Distant metastatic retinoblastoma without central nervous system involvement.

Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births. Metastatic retinoblastoma is rare in developed countries, with a reported range from 4.8% in the United States to 5.8% in the United Kingdom. However, the frequency reported from developing countries varies from 9 to 11% at presentation. The mortality is very high owing to late presentations, delayed diagnosis compounded by socio-economic factors. The management of metastatic retinoblastoma is evolving, but it is still a challenge in pediatric oncology. We present a case of an extensive skeletal metastasis that initially presented as a massive orbital retinoblastoma.