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This brief report displays comprehensive details of health services provided by Children's Welfare Teaching Hospital, medical city, Baghdad. In 2010; 366 children with newly diagnosed cancer were admitted for treatment, two thirds were leukemia and lymphoma cases followed by other solid tumors except brain tumors. With this large number of patients; there are shortcomings in provision of health services in many aspects including professional manpower, infrastructure, diagnostic and therapeutic facilities, supportive and palliative care. The previous wars and sanction and the current instability of the country added to the socioeconomic difficulties of the families jeopardizing the appropriate therapy and ultimately the poor treatment outcome. Since 2003 an international collaboration had a major contribution in many aspects like provision of drugs and medical supplies, attendance of scientific workshops, and updating doctor's knowledge and experience through telemedicine programs which resulted in decreasing the induction mortality in acute lymphoblastic leukemia from 24% in the year 2007% to 10% in 2010 after introduction of pre-phase steroids and in acute promyelocytic leukemia from 95% to 5% after introduction of all trans-retinoic acid. A collaborative work with Rome University resulted in changing diagnosis of 20% of pathological samples sent there for reevaluation. Iraqi pediatric oncologists still need real attempts to improve infrastructure and human resources in addition to twinning programs with internationally recognized cancer centers to face these management challenges.

Objective: To examine ocular outcomes and survival after proton irradiation in patients with peripapillary and parapapillary melanomas ineligible for the Collaborative Ocular Melanoma Study., Methods: A total of 573 patients who received proton irradiation from January 4, 1985, through December 24, 1997, for tumors located within 1 disc diameter of the optic nerve, and therefore ineligible for the Collaborative Ocular Melanoma Study, were evaluated. Cumulative rates of vision loss in the treated eye, eye loss, melanoma-related mortality, and tumor recurrence were estimated using the Kaplan-Meier method., Results: Most (53.4%) tumors abutted the optic disc; median distance from the tumor to the macula was 0.5 disc diameters. By 5 years after proton therapy, radiation papillopathy had developed in 56.8% and maculopathy in 60.4% of patients. Of 450 patients with a baseline visual acuity of 20/200 or better in the treated eye, vision was retained in 54.9% at 2 years after irradiation. This decreased to 20.3% by 5 years after treatment, although 56.2% had visual acuity of counting fingers or better. Five- and 10-year rates of local recurrence were 3.3% and 6.0%, respectively. Enucleation rates were 13.3% at 5 years and 17.1% at 10 years after treatment. Melanoma-related mortality rates were similar to those in our larger cohort of patients (24.0% at 15 years)., Conclusions: Proton irradiation should be considered for treating patients with tumors contiguous to the optic disc. Although visual acuity is compromised, some preservation is possible (counting fingers or better in many patients). Eye conservation is likely, with low rates of tumor recurrence and no increased risk of metastasis.

Context: Advanced cases of retinoblastoma are treated with chemoreduction followed by enucleation. Further adjuvant therapy is recommended in patients with known pathologic risk factors (PRFs)., Objectives: To determine the PRFs in enucleated specimens after chemoreduction and their association for adverse events of recurrence, metastasis, or death., Design: This was a retrospective study of 77 enucleation specimens from patients treated between January 2000 and September 2008 with prior chemoreduction that were accessioned in the pathology department of a tertiary referral cancer center with an average follow-up of 24 months. Various PRFs were noted and their association with the development of an adverse event was recorded., Results: Of 77 patients, (male to female ratio, 51∶26), the incidence of overall PRF was 51.9%, and retrolaminar optic nerve invasion (32.5%), optic nerve cut margin (12.9%), massive choroidal invasion (26%), scleral invasion (23.4%), vitreous seedings (44.2%), and anterior segment invasion (20.8%). Undifferentiated tumor (>60%) was seen in 60.3% of cases (41 of 68 patients with differentiation available). Adverse event occurred in 18 of 72 patients with available follow-up (25%). Retrolaminar optic nerve invasion, optic nerve cut margin involvement, and scleral invasion were independent prognostic factors predicting the occurrence of an adverse event. Undifferentiated tumor (>60%) was a significant risk factor in univariate analysis, which is the unique feature in this study., Conclusions: Classic PRF with the addition of a predominant presence from the undifferentiated component were associated with adverse outcomes in retinoblastoma treated with anterior chemotherapy. The latter may represent chemoresistant clones and more intensive adjuvant chemotherapy may be warranted in these patients.

Background: Few studies have suggested that routine bone marrow (BM) and cerebrospinal fluid (CSF) evaluation is not needed in all patients with retinoblastoma. Although the International Retinoblastoma Staging System was developed recently, there remain no clear stage-specific guidelines with regard to the need for BM and CSF evaluations as part of the metastatic workup for patients with retinoblastoma., Methods: This is a retrospective study analyzing results of CSF cytology and BM evaluation at presentation/diagnosis in patients with retinoblastoma registered at our center from June, 2003 to June, 2009. Only cases with both BM biopsy and lumbar puncture were included., Results: Of the 259 evaluable patients, 18 (7%) were positive for metastasis either in CSF and/or BM. Although 7 of these had overt metastasis at presentation (stage IV), 1 belonged to stage II and 10 to stage IIIa. No stage 0 or I patient tested positive despite presence of histopathologic high-risk factors., Conclusions: This is the largest study evaluating the role of metastatic workup in patients with retinoblastoma at presentation. We conclude that CSF and BM evaluation is not required in patients with stage 0 and I retinoblastoma at presentation. No definitive recommendation could be made for stage II patients; while stage III and IV patients must certainly be evaluated.

Objective: Little is known about the incidence of secondary neoplasms among survivors of retinoblastoma in Japan. The objective of our study was to analyze the cumulative incidence rate of secondary neoplasms following retinoblastoma and to investigate the risk factors of developing secondary neoplasms., Methods: We conducted a retrospective cohort study of 754 retinoblastoma patients who visited the National Cancer Center Hospital in Tokyo between 1964 and 2007. The cumulative incidence rate curves were drawn using the competing risk method and compared with the Gray's test. Using competing risk regression analysis, multivariate analysis estimated the subdistribution hazard ratio of factors related to the development of secondary neoplasms., Results: The median length of follow-up was 108 months (0-594 months). Twenty-one (2.8%) patients developed 23 secondary neoplasms in total. The cumulative incidence rates of secondary neoplasms after retinoblastoma treatment were 2.4% at 10 years after diagnosis, 4.3% at 20 years, 6.4% at 30 years and 19.1% at 40 years. Ten patients (1.3%) died and 723 (95.9%) were alive without developing secondary neoplasms. The subdistribution hazard ratios of hereditary retinoblastoma and external beam irradiation were 4.85 (95% confidence interval = 0.74-31.85) and 4.76 (95% confidence interval = 0.69-33.09), respectively., Conclusions: We demonstrated the cumulative incidence rate of secondary neoplasms following retinoblastoma in Japan. The subdistribution hazards ratios of hereditary retinoblastoma and external beam irradiation were high but not significant because of statistical power. The long-term follow-up of retinoblastoma survivors is warranted to understand secondary neoplasm risk.

Survival of retinoblastoma is >90% in developed countries but there are significant differences with developing countries in stage at presentation, available treatment options, family compliance, and survival. In low-income countries (LICs), children present with advanced disease, and the reasons are socioeconomic and cultural. In middle-income countries (MICs), survival rates are better (>70%), but there is a high prevalence of microscopically disseminated extraocular disease. Programs for eye preservation have been developed, but toxicity-related mortality is higher. Although effective treatment of microscopically extraocular disease improved the outcome, worldwide survival will be increased only by earlier diagnosis and better treatment adherence., (Copyright © 2010 Wiley-Liss, Inc.)

Purpose: Initial response of intraocular retinoblastoma to chemotherapy has encouraged primary chemotherapy instead of primary enucleation for eyes with clinical features suggesting high risk of extraocular extension or metastasis. Upfront enucleation of such high-risk eyes allows pathologic evaluation of extraocular extension, key to management with appropriate surveillance and adjuvant therapy. Does chemotherapy before enucleation mask histologic features of extraocular extension, potentially endangering the child's life by subsequent undertreatment?, Methods: We performed retrospective analysis of 100 eyes with advanced retinoblastoma enucleated with, or without, primary chemotherapy, in Beijing Tongren Hospital, retrospectively, from October 31, 2008. The extent of retinoblastoma invasion into optic nerve, uvea, and anterior chamber on histopathology was staged by pTNM classification. The treatment groups were compared for pathologic stage (Cochran-Armitage trend test) and disease-specific mortality (competing risks methods)., Results: Children who received chemotherapy before enucleation had lower pTNM stage than primarily enucleated children (P = .01). Five patients who received pre-enucleation chemotherapy died as a result of extension into brain or metastasis. No patients who had primary enucleation died. For children with group E eyes, disease-specific survival (DSS) was lower with pre-enucleation chemotherapy (n = 45) than with primary enucleation (n = 37; P = .01). Enucleation longer than 3 months after diagnosis was also associated with lower DSS (P < .001)., Conclusion: Chemotherapy before enucleation of group E eyes with advanced retinoblastoma downstaged pathologic evidence of extraocular extension, and increased the risk of metastatic death from reduced surveillance and inappropriate management of high-risk disease, if enucleation was performed longer than 3 months after diagnosis.

Retinoblastoma patients have a strongly increased risk of second malignancies, and survivors with a third or subsequent malignancy are increasingly observed. However, it has not been examined whether survivors who developed a second malignancy have a greater risk of a subsequent malignancy. On the basis of the Dutch retinoblastoma registry, the risk of a third malignancy was compared with cancer risk in the Dutch population. Cox model analysis with a time-dependent covariate was used to compare the subsequent malignancy risk and survival among patients with and without a second malignancy. Risk of a third malignancy was increased 8-fold compared with the general population. The hazard ratio (HR) of a third malignancy after a second malignancy was more than 7-fold increased compared to the risk of a second malignancy after retinoblastoma. Radiotherapy increased the risk 3-fold. A third malignancy was associated with worse survival compared with survival of patients only diagnosed with a second malignancy (HR=5.0). Survivors of retinoblastoma who already developed a second primary malignancy have an even higher risk of subsequent primary malignancies than retinoblastoma survivors without a second malignancy. Treating physicians and patients should be aware of this higher risk., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Purpose: To determine the therapeutic effect of oncolytic adenovirus H101 on retinoblastoma in vitro and in vivo., Methods: The expression of coxsackievirus-adenovirus receptor (CAR) in human retinoblastoma cell line HXO-RB(44) was determined by RT-PCR, Western blot, immunofluorescence, and immunocytochemistry staining. Appropriate multiplicity of infection was determined using flow cytometry in retinoblastoma cells with green fluorescent protein-expressing adenovirus (AdGFP). The viability of HXO-RB(44) cells treated with H101 or AdGFP was measured using a cell counting kit-8-based procedure. Viral proliferation in vitro was measured by end point dilution titration and real-time PCR. Cell cycle and apoptotic activity of HXO-RB(44) were analyzed by flow cytometry. NOD-SCID mice bearing retinoblastoma xenografts were treated with intratumoral injection of H101, AdGFP, or PBS. Tumor volume and survival time were recorded. Immunohistochemistry for adenoviral fiber protein and Western blot for adenoviral Hexon protein of retinoblastoma xenografts were performed to evaluate H101 virus replication in vivo., Results: HXO-RB(44) cells expressed CAR and were sensitive to adenoviral infection. HXO-RB(44) cells treated with H101 had reduced cell viability compared with AdGFP-treated cells (P < 0.01). Abundant replication of H101 in HXO-RB(44) cells resulted in G(2)/M-phase arrest and finally tumor cell lysis, but the apoptosis pathway was not activated. Tumor-bearing mice treated with H101 had reduced tumor burdens and prolonged survival times compared with PBS and AdGFP controls (both P < 0.01). Immunohistochemical and Western blot examination revealed widespread replication of H101 within the tumor., Conclusions: These results suggest that H101 effectively inhibits the growth of retinoblastoma cells in vitro and in mice and may serve as a novel therapy for retinoblastoma.

Purpose: To describe the incidence and survival rate of patients with retinoblastoma in Taiwan over a 25-year period, from 1979 to 2003., Methods: Cases of retinoblastoma have been reported to the Taiwan National Cancer Registry (TNCR) since 1979. Retinoblastoma data from 1979 to 2003 were retrieved from the TNCR databank for analysis of both the incidence and survival rate. Trends in the incidence rate were estimated by calculating the annual percentage change (APC)., Results: From 1979 to 2003, a total of 380 patients (182 [47.9%] females) with retinoblastoma were identified. Of the 380 cases, 359 patients (94.5%) were diagnosed before 5 years of age. The average annual age-standardized incidence rate was 4.45 per million in children under 10 years of age and 8.58 per million in children under 5 years of age. There was a significant increasing trend in the incidence rate over the study period with an APC of 2.3% (P=0.035). Before the implementation of Taiwan's National Health Insurance (NHI) Program in 1995, the mean age at diagnosis was 4.8+/-13.3 years and the 5-year survival rate was 74.7%. After implementation of the NIH Program, the mean age at diagnosis decreased to 1.6+/-2.1 years (P<0.001) and the 5-year survival rate increased to 84.7% (P=0.063)., Conclusions: We report the first population-based study on retinoblastoma in Taiwan. There was a significant increasing trend in the incidence rate from 1979 to 2003. Since the implementation of Taiwan's NHI, the mean diagnostic age decreased.

Background: Little is known about the impact of retinoblastoma (RB) on the health status of survivors in terms of disabilities and worries, both of which may restrict participation in activities of daily life., Methods: In this population-based cross-sectional study, content analysis was used to extract data on perceived restrictions and worries, from semi-structured interviews held with 156 RB survivors aged 8-35 years. The International Classification of Functioning Disabilities and Health (ICF) was used as a framework., Results: Of all survivors, 55% perceive RB-related restrictions in daily life activities (school, professional career, mobility, self-care, intimate relationships). Young/adolescent survivors (6%) and adult survivors (15%) frequently report anxiety about developing a second primary tumor (SPT). Compared with the general population, RB survivors did not differ in rates of employment or marital status. However, special educational services were more frequently offered, and the level of completed education was lower., Conclusion: RB has influenced the lives of most survivors and, even though their prognosis was good, illness-related restrictions are common. Especially fear of developing SPT and of further loss of vision are important life-long problems, and many survivors had special education needs. The ICF might serve as a bridge between families and professionals, because this classification may facilitate early detection of problems., (Copyright 2009 Wiley-Liss, Inc.)

This study examined long-term cause-specific mortality among 998 Dutch retinoblastoma survivors, diagnosed from 1862 to 2005, according to follow-up time, treatment and heredity. After a median follow-up of 30.8 years, only cause-specific mortality for second malignancies among hereditary retinoblastoma survivors was statistically significantly increased with 12.8-fold. Risk of death from second malignancies among non-hereditary survivors was not increased. Mortality rates of second malignancy among hereditary patients were non-significantly elevated with 1.6-fold for treated with radiotherapy, compared to those treated otherwise. Standardised mortality ratios (SMRs) for second malignancy among hereditary patients increased during the first three decades after retinoblastoma diagnosis. Whereas these risks decreased after three decades, the absolute excess risk (AER) increased significantly, up to 23.2 excess cases per 1000 patients/year after five decades of follow-up. Fifty years after retinoblastoma diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. Very long-term follow-up of retinoblastoma patients revealed an emerging excess risk of mortality in hereditary retinoblastoma survivors. This implies that lifelong follow-up is needed, whereas at the same time, patients and their physicians must be alerted to the increased second malignancy risks.

Objective: To investigate the risk of cataract extraction among adult retinoblastoma survivors., Design: A retrospective cohort study was performed on retinoblastoma survivors who received the diagnosis from 1914 to 1984 and were interviewed in 2000. Lens doses were estimated from radiotherapy records. The cumulative time interval to cataract extraction between dose groups was compared using the log-rank test and Cox regression., Results: Seven hundred fifty-three subjects (828 eyes) were available for analysis for an average of 32 years of follow-up. During this period, 51 cataract extractions were reported. One extraction was reported in an eye with no radiotherapy compared with 36 extractions in 306 eyes with 1 course of radiotherapy and 14 among 38 eyes with 2 or 3 treatments. The average time interval to cataract extraction in irradiated eyes was 51 years (95% confidence interval [CI], 48-54) following 1 treatment and 32 years (95% CI, 27-37) after 2 or 3 treatments. Eyes exposed to a therapeutic radiation dose of 5 Gy or more had a 6-fold increased risk (95% CI, 1.3-27.2) of cataract extraction compared with eyes exposed to 2.5 Gy or less., Conclusions: The results emphasize the importance of ophthalmologic examination of retinoblastoma survivors who have undergone radiotherapy. The risk of cataract extraction in untreated eyes with retinoblastoma is comparable with the risk of the general population.

Background: Although screening for familial retinoblastoma has been shown to be beneficial we suspected that such screening programs may be less than optimal in developing countries (DC)., Methods: Retrospective cohort study comparing patients with familial retinoblastoma from five centers in DC (Argentina, Brazil, Turkey, Jordan, and Venezuela) versus a reference center in the USA., Results: Ninety-two (32 from the USA and 60 from DC) patients were included. Forty-one (44.6%) patients avoided enucleation, 42 (45.7%) had 1 eye removed, and 9 (9.8%) underwent bilateral enucleation. Eleven (11.9%) had major pathology risk factors at enucleation. There were no cases of metastatic disease at diagnosis. Detection via screening was significantly less common in DC than in the USA (23.3% vs. 71.8%, P < 0.0001). Patients in DC were diagnosed at a significantly later age and with more advanced intraocular disease that led to increased risk of bilateral enucleation. Patients detected by screening in DC were significantly younger at diagnosis, had less advanced intraocular disease, better ocular preservation rates and survival results than those whose retinoblastoma was not detected via early screening. Five-year pEFS was 0.92 for the patients treated in the USA and 0.81 for the patients in DC (P = 0.42). Seven events occurred (extraocular relapse four in patients from DC and second malignancies in three)., Conclusions: Patients with familial retinoblastoma are less likely to be diagnosed by screening in DC and had higher morbidity and mortality caused by recurrent extraocular retinoblastoma., ((c) 2009 Wiley-Liss, Inc.)

Background: Metastatic spread in retinoblastoma is a rare occurrence in developed countries but still associated with a poor prognosis., Patients and Methods: Medical records of all metastatic retinoblastoma diagnosed during a 20-year period were retrospectively reviewed., Results: Six patients out of 104 presented a metastatic disease with an incidence at diagnosis of 2%. Three had a metastatic disease at diagnosis, one patient a trilateral retinoblastoma and two a metastatic spread after enucleation. All but one were sporadic retinoblastoma. Central nervous system (CNS) involvement was reported in five patients, while one patient had an intraorbital lesion, and bone and bone marrow spread. Different treatment strategies were administered based on local treatment plus chemotherapy and radiotherapy with or without high-dose chemotherapy. An ifosfamide/carboplatin/etoposide regimen was administered in three patients resulting in a partial response. Out of six patients, four died, and two patients are alive at 60 and 63 months from diagnosis. Both children with a long follow-up were treated with high-dose chemotherapy. All but one of the patients with CNS involvement died; the survivor was a patient with pineal involvement., Conclusion: This retrospective review confirms a curable strategy based on local treatment and conventional plus high-dose chemotherapy. Patients with CNS involvement remain incurable.

Introduction: Retinoblastoma is a very rare disease. There were 30 cases of retinoblastoma diagnosed and treated at National University Hospital (NUH)., Materials and Methods: A retrospective chart review was performed on the medical records of 30 patients who were diagnosed with retinoblastoma between 1995 and 2008 at the Department of Paediatrics, National University Hospital, Singapore., Results: The median age at diagnosis was 1.6 years (range, 0-5.9) with a median follow-up of 1.8 years (range, 0.1 to 11.6). The median time from presenting signs to the time of diagnosis was 5.2 months (range, 0-25.2). Common presenting signs of retinoblastoma were identified; the most common of which were leukocoria (50.0%), squinting (13.3%), poor vision (10.0%), strabismus (6.6%) and unknown (33.3%). Of the 30 patients, 10 were from Singapore whilst the other 20 patients were from the surrounding countries. Twelve patients had bilateral disease at the time of diagnosis, while 18 had unilateral disease. Staging information was available in 27 patients. Enucleation was performed in 25 of 30 patients. Radiation therapy was given in 3 patients in 1995 (bilateral disease), 2001 (bilateral disease) and 2003 (unilateral disease). At the time of analysis, 19 patients were alive with no evidence of disease. Overall 5-year survival for the cohort was 88.1% [95% confidence interval (CI), 88.0-100] and event-free survival for the whole cohort was 74.2% (95% CI, 55.8-92.6)., Conclusion: In our limited experience, the importance of collaboration and standardisation of the staging system, raising awareness and education of primary healthcare providers and parents are strongly stressed.

Objective: To describe the clinical and pathological features of patients with retinoblastoma and microscopic scleral invasion., Methods: We reviewed all pathology slides of patients with microscopic scleral invasion who were included in 3 prospective treatment protocols (1988-2007). All patients received adjuvant chemotherapy (moderately intensive chemotherapy in the first 2 protocols or a more intensive combination in the third one). Only patients with cut-end invasion received orbital radiotherapy., Results: Thirty-two of 386 patients had enucleated eyes with intrascleral (21 cases) and transscleral (11 cases) invasion. Of these cases, 20 had tumor invading the optic nerve beyond the lamina cribrosa, with 6 of these having tumor at the surgical margin. Sixteen were treated with moderately intensive chemotherapy and 16 received a higher-intensity regimen. Five-year overall survival was 0.77. Seven patients had an extraocular relapse (central nervous system metastasis, n = 4; systemic metastasis, n = 2; and involving the orbit, n = 3, isolated in 1 and combined with central nervous system disease in 2). All patients who had a relapse died. Patients receiving the intensive regimen had a significantly better outcome (P = .007)., Conclusions: Microscopic scleral invasion might be a risk factor for extraocular relapse, and more intensive chemotherapy results in improved survival for these patients.

Background: Subsequent malignant neoplasms are a major cause of premature death in survivors of hereditary retinoblastoma. Radiotherapy further increases the risk of death. Mortality information is limited among long-term survivors who were irradiated for hereditary retinoblastoma., Methods: We examined cause-specific mortality among 1854 retinoblastoma survivors who were diagnosed from January 1, 1914, through December 31, 1996, at two US institutions. Standardized mortality ratios (SMRs) were calculated by use of US mortality data to estimate expected numbers of deaths. The relative rates (RRs) of mortality due to subsequent malignant neoplasms associated with multiple risk factors were evaluated with Poisson regression models. Cumulative mortality from subsequent malignant neoplasms was calculated by treating other causes of death as competing risks., Results: A total of 151 deaths due to subsequent malignant neoplasms occurred among 1092 hereditary retinoblastoma survivors (SMR = 35, 95% confidence interval [CI] = 30 to 41) compared with 12 deaths among 762 nonhereditary retinoblastoma survivors (SMR = 2.5, 95% CI = 1.3 to 4.4). In this extended follow-up of retinoblastoma survivors, we found no evidence of excess mortality from non-neoplastic causes compared with the general population. However, excess mortality from subsequent malignant neoplasms (particularly sarcomas, melanomas, and cancers of the brain and other parts of the nervous system) among hereditary retinoblastoma survivors extended beyond 40 years after retinoblastoma diagnosis. The additional 13 years of follow-up since our last mortality study revealed a previously unreported increased risk of death due to cancers of the corpus uteri (primarily sarcomas) and confirmed the previously reported elevated risk of death from lung cancer among hereditary retinoblastoma survivors. Among hereditary and nonhereditary retinoblastoma survivors, the relative rates of mortality from subsequent malignant neoplasm were higher in those who had been treated with radiotherapy than in those who had not. Cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 25.5% (95% CI = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors., Conclusions: The temporal patterns of site-specific excess risks of subsequent malignant neoplasms in retinoblastoma survivors should inform screening programs designed for the early detection and treatment of subsequent malignant neoplasms.

Background: Patients who refuse therapy against medical advice may be at risk of adverse health outcomes. We analyzed the impact of therapy refusal and its effect on the survival of retinoblastoma patients., Patients and Methods: 165 consecutive untreated retinoblastoma patients admitted to the CM-Hospital, between 1993-2000 were evaluated retrospectively. Survival outcomes and its association with delays and tumor staging were analyzed using Kaplan-Meier and Cox-Regression., Results: Of the 165 cases, 78 cases (47,3%) were assigned to the "No-Refusal-Group"; 52 cases (31,5%) to "Temporary-Refusal-Group," 30 cases (18,2%) to "Definite-Refusal-Group." Survival rates of patients who temporarily refused were significantly lower than those who did not refuse the therapy (p < 0.05). Progression of tumor stage was highly associated with temporary-refusal (p < 0.0005). In the Cox-Regression model, clinical staging of tumor was highly associated, whereas admission delay and treatment delay were slightly associated with the overall survival (p < 0.05, adjusted-hazard-ratio 6.321, 1.031,1.025, respectively). The clinical staging is the strongest variable associated with patient survival outcome. Delay >or= 6 months between first sign and admission is highly associated with tumor progression (p < 0.0005)., Conclusions: First, the high level of therapy refusal in a developing country like Indonesia has an adverse effect on the survival outcome of retinoblastoma patients. Second, the change of the tumor stage from intraocular to extraocular is the most adverse predictive factor for survival. Third, the advanced stage of the tumor is caused by long delay to admission. In a developing country the parents of many young patients refuse to accept the recommended therapy and therefore the tumor may reach a critical stage for the prognosis.

Purpose: To determine the impact of subtle differences (most notably in their classification of group E eyes) in two published versions of the ICRB (Philadelphia and the Children's Hospital Los Angeles)., Methods: Analysis of a series of 96 eyes with intra-ocular retinoblastoma., Results: The disparate criteria of the 2 published ICRB schemas affected group assignment of 5.2% of the eyes (25% of the group E eyes)., Conclusion: Discrepancies need to be reconciled to ensure accurate and uniform application of the ICRB.

Background/aims: Retinoblastoma is a highly malignant eye tumour in children with different survival rates across the world. The aims of this study are to determine the globe and patient survival in children with retinoblastoma in a major referral centre in Iran., Methods: 156 eyes of 105 consecutive patients with retinoblastoma were enrolled from 2001 to 2007. All demographic data, family history, presenting symptoms, duration of symptoms, ocular findings and treatment modalities that were used for the patients were collected. For patient survival, event was defined as death and for globe survival as enucleation., Results: The mean age at diagnosis was 28.5 months (unilateral 27.4 months; bilateral 30 months). Five patients had a positive family history. Fifty-two per cent of the cases were unilateral, and 48% were bilateral. The most common presenting sign was leucocoria (64.8%) followed by strabismus (28.2%). Enucleation was done primarily for 75.9% of unilateral cases and 34.3% of bilateral cases. Secondary enucleation was necessary in 5.6% and 7.8% of unilateral and bilaterally involved eyes respectively. Sixty-nine (44.2%) of 156 eyes were salvaged by different globe preserving modalities (unilateral 18.5%; bilateral 57.9%). The Kaplan-Meier survival estimate for globe preservation according to International Classification of Retinoblastoma (ICRB) was 100% for group A eyes, 93.5% for group B, 86.7% for group C, 57.1% for group D and 0% for group E eyes. Kaplan-Meier estimates for patients survival were 100% at 1 year, 94.8% at 3 years and 83.1% at 5 years., Conclusion: Progress in methods of treatment, early detection of the disease and prompt referral to specialised centres have led to improved outcomes for patients with retinoblastoma in terms of globe and patients' survival rates even in developing countries.

Background: The purpose of this study was to determine the survival of retinoblastoma in the USA over a 30-year period from 1975 to 2004 using a systematic review of existing databases., Methods: Nine hundred and ninety-two cases of retinoblastoma (International Classification of Oncology (ICDO-3) codes C69.2 (retina) and C69.9 (eye, NOS)) were derived from the Surveillance, Epidemiology and End Results (SEER) program database in the USA from 1975 to 2004. All 17 current SEER registries were utilised to allow for optimal patient volume for statistical analysis. Survival rates were calculated by the Kaplan-Meier method and differences evaluated with logrank and Wilcoxon tests. Cause of death was obtained and reviewed for all deceased patients. All retinoblastoma patient records were reviewed for treatments given and occurrence of second malignant neoplasms., Results: There were a total of 990 distinct patients with retinoblastoma. Almost all cases (99.1%) were reported by the hospitals, and histopathological confirmation was available in 87.7% of cases. Over the period of 30 years (1975-2004), the 5-year observed actuarial survival rate increased from 92.3% (1975-84) to 93.9% (1985-94) to 96.5% (1995-2004). The difference in rates was statistically significant (Wilcoxon = 6.2393, p = 0.0442). The proportion of cases treated with radiotherapy first increased from 20.5% in 1975-9 to 34.6% in 1985-9 and then sharply decreased to 6.5% in 2000-4., Conclusions: Over the last 30 years, there has been a gradual improvement in 5-year survival of children with retinoblastoma in the USA.

Purpose: The aim of this study is to analyze the results and the complications of radiotherapy in the treatment of retinoblastoma., Patients and Methods: Between 1994 and 2004, 40 children received radiotherapy for a retinoblastoma in Salah Azaiz Institute. The average age of the patients was 36 months (four to 132 months). There were 16 girls and 24 boys. Sixteen children presented a bilateral disease and 24 children a unilateral disease. Twenty eyes and thirty-six orbital cavities in 40 children with retinoblastoma were treated by radiotherapy. One child with a unilateral anterior retinoblastoma was treated with 106 ruthenium brachytherapy. External radiotherapy has been used to treat the 39 patients. In 20 cases the irradiation was conservative and in 36 cases postoperatively. The latter (n=36) presented at least one risk factor of relapses noted in the histological examination. The average dose was 44 Gy (1.8 to 2 Gy per fraction, five fractions weekly). This radiotherapy was associated with chemotherapy in 24 cases., Results: Thirty-five children were followed with an average follow-up of 53 months (3-108 months). The average delay of relapses was of 10 months (two to 26 months). We found four orbital relapses and seven metastasis in nine children. The conservation of the eye with a useful visual field was noted in 18 cases among the 20 conservative irradiated eyes. The major therapeutic complication was the growth defect of the bones face. A femoral bone sarcoma was noted five years after the end of the irradiation and chemotherapy in one case., Conclusion: If the radiotherapy offers the advantage of the functional conservation and the improvement of the local control, its indications are more and more restricted in favor of the other therapeutic methods (chemotherapy, thermochemotherapy) and this considering the iatrogene risk. The development of new techniques of brachytherapy and the progresses of the conformational radiotherapy appear to reduce considerably this risk.

Aim: This paper describes the treatment and survival of 1576 children with retinoblastoma in Great Britain diagnosed 1963-2002., Methods: Survival rates were analysed according to period of diagnosis and tumour laterality., Results: Survival was calculated by calendar period of diagnosis, 1963-1982 and 1983-2002. For both unilateral and bilateral retinoblastoma, survival improved between the two periods. The survival curves for the two periods were significantly different: for unilateral retinoblastoma p<0.00001, for bilateral p<0.01. For unilateral cases, the estimated 5-year survival rates rose from 85% for those diagnosed in 1963-1967 to 97% for those diagnosed in 1998-2002. The equivalent rates for bilateral cases were 88% and 100%., Conclusion: Survival rates were already high at the start of the study period. They increased with changes in treatment regimens.

Purpose: Since 1997, our institute has used neoadjuvant chemotherapy for intraocular retinoblastoma. However, some of the patients showed signs of recurrence months to years later. We therefore attempted to determine the prognostic factors of treatment outcomes and survival in our patients., Methods: We reviewed 90 patients treated from 1997 to 2006. The following information was recorded: demographic and ophthalmological data, clinical classification, histopathological data, and treatment methods and outcomes., Results: Enucleation was avoided in two of 57 eyes in the unilateral group. Sixteen of 54 eyes in the bilateral group were salvaged by systemic chemotherapy with local treatment. There was no difference in histopathological findings between the two groups. Nine of 57 patients in the unilateral group demonstrated poor outcomes, compared with four of 27 in the bilateral group. Significant poor prognostic factors for survival were optic nerve head invasion, orbital involvement, abnormal results on bone marrow aspiration, lumbar puncture, bone scan, and group E or F classification., Conclusions: The 15% mortality rate in our patients is slightly higher than that reported in developed countries. Delayed diagnosis and treatment is the main cause of avoidable deaths. Improving education of both clinicians and parents would increase survival rates in this potentially fatal disease.

Purpose: Chemotherapy resistance is a problem in the treatment of advanced retinoblastoma (RB). Since basic fibroblast growth factor (bFGF) is a survival factor for neural precursor cells, bFGF was evaluated as a growth and chemoresistance factor in RB., Methods: bFGF expression was analyzed in the LH-betaTag transgenic mouse model of RB and human RB cell lines by immunofluorescence, RT-PCR, and Western blot. Proliferation and apoptosis (TUNEL) assays were performed., Results: bFGF levels significantly increased during tumorigenesis in transgenic RB, as a function of tumor status (P = 0.005). PCR and confocal microscopy confirmed that the human cell lines and primary tumors expressed bFGF. bFGF was localized to vascular and tumor cells and rarely to glial cells. Exogenous 18-kDa bFGF induced proliferation in two RB cell lines (WERI and Y79). Western blot analysis demonstrated 34-, 22-, and 18-kDa isoforms in transgenic RB and both cell lines. In TUNEL assays, chemoresistance to carboplatin-induced apoptosis was observed in the Y79 line, which expressed a higher ratio of high (34 kDa)- to low-molecular-weight bFGF isoforms, compared with the WERI line. Similar to other bFGF tumor studies, exogenous low-molecular-weight (18 kDa) bFGF (1 ng) significantly enhanced carboplatin-induced apoptosis in the more chemosensitive WERI, but not the chemoresistant Y79 line., Conclusions: RB tumors produce significant amounts of bFGF, and the differential production and response to isoforms of bFGF may have implications for invasive tumor growth and chemoresistance.

Purpose: To evaluate the clinical features and management of diffuse infiltrating retinoblastoma., Design: Retrospective case series., Participants: Thirty-four eyes in 32 patients., Methods: The patients' records were reviewed for patient and tumor features, ocular management, histopathologic findings, and patient survival., Main Outcome Measures: Clinical features, tumor management, and patient survival., Results: Of 1507 patients with retinoblastoma, only 32 (2%) were classified with diffuse infiltrating retinoblastoma. The mean age at diagnosis was 4 years (range 1.5-16 years). The referring diagnoses included retinoblastoma (26 eyes, 76%), uveitis (3, 9%), Coats disease (1, 3%), trauma (1, 3%), and unspecified retinal problem (3, 9%). The anterior segment displayed tumor seeds on the corneal endothelium (8, 24%), cornea stromal edema (3, 9%), pseudohypopyon (11, 32%), hyphema (3, 9%), iris neovascularization (17, 50%), and iris tumor nodules (6, 18%). The posterior segment revealed extensive ill-defined retinoblastoma infiltrating the retina for a mean basal diameter of 20 mm and overall flat growth, sometimes with undulating retinal thickening. Overlying extensive vitreous tumor seeds (31, 91%) and vitreous hemorrhage (8, 24%) were noted. Calcification was present on ultrasonography (27/34, 79%) and computed tomography (8/9, 89%). Enucleation was performed for all 34 eyes, and there were no cases of metastases at 47 months follow-up., Conclusions: Diffuse infiltrating retinoblastoma can masquerade as uveitis or unexplained hyphema or keratic precipitates. Suspicion for retinoblastoma is important., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

Objective: The purpose of this paper is to classify glial tumors observed in the canine retina and optic nerve, describe the histopathological features and provide prognostic information on these neoplasms., Methods: The database of the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) was searched to collect canine glioma cases. Clinical and follow-up information was gathered from submission forms and an extensive follow-up survey. Slides were reviewed to describe the histopathological characteristics of the neoplasm and classify them. Immunohistochemistry for Glial Fibrillary Acidic Protein (GFAP) was performed in all cases., Results: 18 canine glioma cases were found in the COPLOW database. There was no breed or gender predilection. The mean age was 9.33 +/- 3.67 years. Follow-up information was available for 12 dogs, 8 of which were dead at the time of most recent contact, with a survival time ranging from 0 days (globes received after euthanasia) up to 20 months post-enucleation. In 6 of the 8 dogs that had died during this stud), tumor extended to the margin where the optic nerve had been sectioned. Light microscopic examination of the optic nerve of the affected eyes of four dogs that were still alive during this study revealed no tumor at this surgical margin. One neoplasm was classified as low-grade astrocytoma, 5 tumors as medium-grade astrocytoma, 11 tumors as high grade-astrocytoma and 1 tumor as oligodendroglioma. GFAP was positive in all but two tumors., Conclusion: Retinal and optic nerve gliomas may be considered as differential diagnoses of intraocular and orbital masses. The metastatic potential appears to be low, but ascending invasion into the ventral aspect of the brain is possible.

Background: Retinoblastomas are the most common malignant intraocular tumor of childhood. We describe the survival outcomes and prognostic factors of patients with a retinoblastoma receiving primary treatment at our hospital over the last 20 years., Methods: A retrospective series study of 30 retinoblastoma cases treated from January 1, 1987 to August 31, 2006 was conducted from a review of medical records and histopathological sections. Variables, including age at onset, laterality, treatment modalities, treatment delay, and optic nerve invasion, were analyzed to elucidate the prognostic factors associated with cumulative survival., Results: Most of the cases had an advanced retinoblastoma, and 23 patients received enucleation treatment. The average period of delay for treatment was 5.37 months after discovery of the disease. The overall cumulative survival rate was 83.08%. Patients with optic nerve invasion had a significantly lower survival rate (60.0%) than those without optic nerve involvement (94.75%). Treatment delay in excess of 6 months was correlated with tumor invasion of the optic nerve., Conclusions: Tumor invasion of the optic nerve is the most significant prognostic factor for surviving a retinoblastoma. Delayed treatment increases the risk of optic nerve invasion. Parental awareness of both the risk of this consequence and the significance of early treatment is vital to achieving improved survival rates.

Objective: To report the efficacy of iodine I 125 plaque radiotherapy for the treatment of vasoproliferative tumors (VPTs) of the ocular fundus., Methods: The clinical features and outcomes of patients with VPTs who underwent iodine I 125 plaque radiotherapy were evaluated. Univariate and multivariate logistic regression analyses were performed to assess the effect of preoperative findings on visual acuity and complications. Kaplan-Meier survival estimates for the probability of adverse outcomes were performed., Results: Of the 30 eyes treated, 17 (57%) had primary and 13 (43%) had secondary VPTs. The median tumor base was 8.6 mm (range, 3.5-18.0 mm) and median tumor thickness was 3.7 mm (range, 2.5-6.3 mm). Exudative retinal detachment was present in 23 eyes (77%). Tumor regression was observed in 29 of 30 eyes (97%) and retinal detachment completely resolved in 15 of 23 eyes (65%). Visual acuity improved or remained stable in 22 eyes (73%). The only factor predictive of visual improvement was the classification of primary VPT (relative risk, 19; 95% confidence interval, 2-185; P = .01). Kaplan-Meier estimates of radiation complications at 5 years predicted cataract in (48%), transient vitreous hemorrhage in (16%), and neovascular glaucoma in (8%) of eyes. No patient developed radiation maculopathy or papillopathy., Conclusions: Iodine I 125 plaque radiotherapy is an effective method of treating larger (>2.5-mm thickness) VPTs with extensive exudative retinal detachment.

Purpose: To evaluate the outcome of patients with retinoblastoma and postlaminar optic nerve invasion (PLONI)., Design: Retrospective interventional case series., Participants: Sixty-one consecutive patients included in 3 successive protocols were analyzed., Methods: Pathologic review was done in each case. Patients were stratified into 2 risk groups: the high-risk group included those with concomitant full choroidal and/or scleral invasion and were given adjuvant chemotherapy. Those without these features were considered low risk and chemotherapy was withheld after 1994., Main Outcome Measures: Extraocular relapse and survival according to stratification., Results: The probability of event-free survival (pEFS) was 0.91 and the probability of overall survival (pOS) was 0.94 at 5 years. Patients in the high-risk group (n = 22) had pEFS of 0.86. Three had extraocular relapse (involving the central nervous system; all died of disease). Microscopic scleral invasion was associated to extraocular relapse (P = 0.05). Lower risk patients (n = 39) had a pEFS of 0.94 and pOS of 1. Eighteen received postenucleation chemotherapy and none relapsed. Twenty-one received no adjuvant therapy and 2 had a systemic relapse but were successfully retrieved. Relapsing patients had a higher ratio of affected optic nerve (>25% of it overall length; P = 0.02)., Conclusions: Patients with PLONI have an excellent outcome with current therapy. Risk stratification according to the presence of concomitant choroidal and/or scleral invasion may help in the decision of giving adjuvant therapy.

Context: Retinoblastoma is the most common malignant intraocular tumor in children. It has been shown that adjuvant therapy following enucleation in patients with high-risk histopathologic features significantly decreases the mortality. We describe the association of extensive necrosis of tumor and intraocular structures with 2 of the major risk factors: optic nerve invasion and choroidal invasion. This may alert the pathologist who makes the observation of extensive necrosis to carefully search for histologic features associated with adverse outcome., Objective: To determine whether extensively necrotic retinoblastoma is associated with high-risk histologic prognostic factors for metastatic disease and patient survival., Design: Retrospective case series. Forty-three eyes of 43 patients with retinoblastoma who underwent enucleation between 1990 and 2001 were evaluated. Medical records, histopathology specimens, pathology reports, and clinical photographs were reviewed. Tumors were designated as exhibiting extensive necrosis if more than 95% of tumor cells and intraocular tissues were necrotic. The main outcome measure was the association of extensive tumor necrosis with 3 high-risk histopathologic features: extraocular extension, optic nerve invasion, or choroidal invasion. Metastatic disease, patient survival, and associations with pathologic findings were also analyzed., Results: Optic nerve head invasion (P < .001), post-lamina-cribrosal invasion (P < .001), and choroidal invasion by tumor (P = .004) were observed more frequently in eyes with extensive necrosis compared with eyes without extensive necrosis. Two of the 11 patients with extensively necrotic intraocular retinoblastoma died from metastatic disease (P = .06). None of the 32 patients without extensive necrosis developed metastatic disease or died., Conclusions: Extensive ocular tissue and tumor necrosis is associated with histologic high-risk prognostic factors for tumor metastasis and mortality.

Purpose: To evaluate the clinical features, treatment, and prognosis in patients with metastatic retinoblastoma., Design: Retrospective interventional case series., Participants: Eighteen consecutive patients with metastatic retinoblastoma who were diagnosed and managed at the Oncology Service of Ankara University, Turkey, between January 1999 and January 2005., Methods: All patients underwent magnetic resonance imaging (MRI) of the orbit and brain, lumbar puncture, bone marrow aspiration, and bone scintigraphy for metastatic evaluation. Histopathologic confirmation of retinoblastoma via enucleation, exenteration, or orbital biopsy was obtained in each patient. The status of extraocular spread (optic nerve, extrascleral extension, or both) was assessed based on histopathologic or MRI results. Systemic treatment for metastatic retinoblastoma consisted of chemotherapy and radiotherapy (craniospinal, orbital, or both), if necessary., Main Outcome Measures: Status of extraocular spread, site of metastasis, and survival from metastatic retinoblastoma., Results: At presentation, the mean patient age was 45 months (range, 13-86). Ten patients had unilateral retinoblastoma, 7 had bilateral retinoblastoma, and 1 had trilateral retinoblastoma. All patients with metastatic retinoblastoma had histopathologic or MRI evidence of unilateral extraocular disease characterized by optic nerve involvement, extrascleral extension, or both. Nine of 18 patients experienced central nervous system (CNS) involvement, 5 patients had distant and CNS metastasis, and 4 patients had distant metastasis only. Fourteen patients underwent craniospinal irradiation and 12 had orbital irradiation. At a mean follow-up of 24 months (range, 4-62), all patients with CNS and concurrent distant and CNS metastasis were deceased. Four patients who had distant metastasis only were alive at a follow-up ranging from 9 to 62 months., Conclusions: The prognosis for metastatic retinoblastoma is dismal and the presence of CNS involvement may portend an even worse outcome.

Based on 2283 cases of retinoblastoma diagnosed in children aged 0-14 years, incidence and survival in Europe during the period 1978-1997 are described. Data were provided to the Automated Childhood Cancer Information System (ACCIS) from 60 paediatric and general cancer registries. During 1988-1997, the cumulative incidence of retinoblastoma in the ACCIS regions was found to be between 44.2 and 67.9 per million births. The highest incidence was seen in the first year of life. The age-standardised (World standard) incidence rate for the age-range 0-14 years was 4.1 per million. Approximately one-third of cases had bilateral tumours. Overall incidence increased over the period 1978-1997 by 1% per year, as derived from a model adjusted for sex, age group and type of registry (general or paediatric). The 5-year survival rate improved from 89% to 95% during the period covered by the study. This improvement was seen in both unilateral and bilateral cases but was significant only for the unilateral tumours. Survival was lower in the East region, although smaller differences were also observed between the other four regions (British Isles, North, South and West). Availability and quality of registration data on retinoblastoma need to be improved for effective evaluation of incidence and survival.

Background: In this study, the authors aim to describe the survival and clinical characteristics of 141 retinoblastoma cases treated at Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey, between 1981 and 2004., Method: The authors retrospectively analyzed the clinical records of 141 children (177 eyes) diagnosed with retinoblastoma and treated between 1981 and 2004. Information on gender, laterality, age at diagnosis, presenting signs, spread of tumor, treatment modality, survival rate, and family history were collected., Results: A total of 105 cases (74.5%) were unilateral and 36 cases (25.5%) were bilateral. The mean age overall at the time of diagnosis was 25 months; in unilateral cases, 29 months; and in bilateral cases, 16 months. The most common presenting signs were leukocoria (116 cases, 82%), strabismus (14 cases, 10%) and proptosis (11 cases, 8%). A total of 28 cases had orbital extension, nine patients had central nervous system invasion, and five cases exhibited bone marrow involvement. In total, 16 patients (11%) had a family history of retinoblastoma. One case developed a secondary neoplasm. The 3 year cumulative survival rate of 141 patients was 89.69% (unilateral, 90.74%; bilateral 87.35% P = 0.9371, P > 0.05, log rank test)., Conclusion: The study's survival rate was similar to developed countries. The success in higher survival rates is based on the authors multidisciplinary team approach done by the same group and the support of the authors' clinic and government in sponsoring the medical insurance of all patients.

A significant risk of lung cancer was identified among hereditary, but not nonhereditary, retinoblastoma (Rb) patients. Tobacco use was investigated to determine whether differences in smoking prevalence might explain the lung cancer excess and to characterize smoking patterns in adult survivors of Rb. Subjects were 441 hereditary and 395 nonhereditary 1-year survivors of Rb, age >or=18 years, who responded to a telephone survey about current health behavior, including tobacco use. Response rates were 76% for hereditary and 73% for nonhereditary survivors. We compared patterns and predictors of current tobacco use among hereditary and nonhereditary survivors with other childhood cancer survivor studies and the U.S. population. Hereditary Rb survivors currently smoke cigarettes significantly less frequently than nonhereditary survivors (16. 8% versus 24.3%), although among current smokers, age at smoking initiation (17 years old) and average cigarettes (1.5 packs) smoked daily are similar. Predictors of current and ever cigarette smoking include nonhereditary Rb, older age, being female, less education, and use of other tobacco products. Rb survivors smoke cigarettes significantly less than the U.S. population (rate ratio, 0.63; 95% confidence interval, 0.5-0.8 for males; rate ratio, 0.75; 95% confidence interval, 0.6-0.9 for females), but Rb survivors have comparable smoking rates with other childhood cancer survivors. Smoking did not account for the increased risk of lung cancer among hereditary Rb patients, and this may point to an enhanced sensitivity to the carcinogenic effects of tobacco. Adult survivors of Rb should be encouraged to stop smoking.

To evaluate the efficacy of conservative management of intraocular retinoblastoma with chemoreduction combined with local therapy with or without plaque radiation in the preservation of the eye, and avoidance of external beam radiation therapy (EBRT) (success rate). From 1995 to 2000, 84 newly diagnosed patients with intraocular retinoblastoma were admitted to the Pediatric Department of the Hospital do Cancer A.C. Camargo, São Paulo, Brazil. All children were treated with 2 to 6 cycles of chemotherapy (carboplatin, vincristine, and etoposide) plus local therapy (cryotherapy, laser photocoagulation, and thermotherapy), or plaque radiation therapy during and/or after the chemotherapy. The Mann-Whitney test was used to compare means of quantitative variables. The chi test or the Fisher exact test were employed to verify the association between the outcome and the independent variables. For all tests alpha=5% was adopted. Success rate was higher for patients with bilateral tumors (54%) than for children with unilateral tumors (19%) (P=0.003). For patients with Reese-Ellsworth stages I, II, and III, no statistically significant differences in the success rates were noted in the group of unilateral (50%) and bilateral tumors (79.1%) (P=0.179). Among children with Reese-Ellsworth stages IV and V, the success rate was significantly higher for patients with bilateral tumors (40.7%) than for those with unilateral (0%) (P=0.012). Chemoreduction combined with local therapy, with or without plaque radiotherapy, is efficacious in avoiding enucleation and the use of external beam radiation therapy for children with intraocular retinoblastoma.

Background: The prognosis of intraocular lymphoma (IOL) is poor, and the optimal treatment has yet to be defined. This study assesses the clinical characteristics and outcome of patients with IOL diagnosed and treated in the new millennium., Methods: Patient data in this retrospective multicentre study were compiled by standardised questionnaires sent to seven university ophthalmology departments. All cases diagnosed with primary and secondary IOL in the past 5 years not associated with HIV infection were included., Results: Twenty-two patients, 11 men and women; median age 64 (range 38-83) years, median Karnofsky performance status 90% (range 50-100%), were included. Nineteen patients had primary IOL (PIOL): 13 a newly diagnosed disease and six an ocular relapse of primary central nervous system lymphoma (PCNSL). Three patients had secondary IOL. First-line treatment for IOL included systemic chemotherapy in 13 cases, ocular radiation in six and intraocular chemotherapy in three. Complete remission was achieved in 14/20 evaluable patients, partial remission in five and stable disease in one. All patients treated with ifosfamide (IFO) or trofosfamide (TRO) (n=8) responded. Median progression-free survival (PFS) and overall survival were 10 (range 1+ to 44.5+) and 22.5 (range 1+ to 49+) months, respectively. Patients with newly diagnosed PIOL and ocular relapse of PCNSL had a median PFS of 10 (range 1+ to 44.5+) and 6 (range 2 to 6+) months, respectively. Median PFS was 12 (range 3+ to 22.5+) months after systemic and 5.5 (range 1+ to 44.5+) months after local first-line therapy., Conclusions: The prognosis of PIOL is similar to that of PCNSL without ocular involvement. Systemic therapy possibly prolongs PFS as compared with local management of (P)IOL. The high response rate to monotherapy with IFO and TRO is promising.

Purpose: The mortality rate of patients with retinoblastoma still varies in developing countries, and data for Asia and Taiwan are relatively scarce. In this retrospective study, we aimed to describe the survival characteristics and prognostic factors of 54 retinoblastoma cases diagnosed at the Taipei Veterans General Hospital between 1982 and 2004., Methods: From medical records, we retrospectively analyzed the data of 54 consecutive children diagnosed in our hospital between 1982 and 2004 as having retinoblastoma. Data on sex, laterality, age at diagnosis, presenting signs, family history, duration of symptoms, lag time for treatment, spread of tumor, treatment mode, and survival time were collected., Results: Seventy-five percent of the cases were unilateral and 25% of the cases were bilateral. The mean patient age at the time of diagnosis was 26.3 months. The mean duration of symptoms was 2.96 months. After diagnosis, the mean lag time before treatment was 2.59 months. The most common presenting signs were leukocoria (71.4%), red, painful, or tearing eye (18.4%), strabismus (14.3%), and blurred vision (14.3%). Only 3 of 52 cases (5.8%) were familial. The most common sites of extraocular invasion included the central nervous system (seven cases) and the orbit (seven cases). In 13.7% of the cases, parents had refused the treatment suggested by the doctors. None of the patients developed a secondary neoplasm. The 5-year overall survival rate was 80.9% (unilateral, 88.1%; bilateral, 64.3%). The survival rate of patients with an interval between onset and treatment of <5 months was 90.9%, and that for an interval of >5 months was 60.9%. The survival rate of those with a lag time of <2.5 months was 90.0%, and that of those with one of >2.5 months was 31.3%. The survival rate of patients with intraocular and extraocular disease was 96.9% and 39.2%, respectively. Extraocular disease was an independent factor indicating a poor prognosis, determined by multivariate analysis., Conclusions: The mortality rate of patients with retinoblastoma is higher in Taiwan than in developed countries. The proportion of patients' parents refusing or delaying treatment in Taiwan is high. The factors for a poor prognosis were an interval between onset and treatment of >5 months, a lag time before treatment of >2.5 months, and extraocular disease. The duration of symptoms was not a prognostic factor. The only independent factor indicating a poor prognosis was extraocular disease.

Purpose: To evaluate the response/recurrence rate and the outcome in intraocular retinoblastoma treated with chemoreduction and focal therapy, the authors performed a retrospective review of their patients., Methods: The series included 46 newly diagnosed patients with unilateral or bilateral intraocular retinoblastoma (58 eyes) receiving carboplatin/etoposide chemotherapy associated with focal therapy (laser or cryotherapy). The mean follow-up was 53 months (range 11-125)., Results: Fifty-one eyes (88%) presented with complete response after four to eight courses of chemotherapy combined with focal treatment. The response rate was 100% in group 1, 94% in group 2, 100% in group 3, 83% in group 4, and 70% in group 5 (5 vs. 1-4, P < 0.03; 5-4 vs. 1-3, P < 0.025). Twenty-nine eyes (57%) relapsed after a mean of 7 months (range 2-36). The relapse rate was 30% in group 1, 27.% in group 2, 67% in group 3, 80% in group 4, and 100% in group 5 (5 vs. 1-4, P < 0.001; 4-5 vs. 1-3, P < 0.001). Seven of 18 cases achieved a second complete response with further conservative treatment (total courses 8-14). Twenty-nine eyes (50%) were treated without external-beam radiotherapy or enucleation: 90% in group 1, 69% in group 2, 67% in group 3, 33% in group 4, and 6% in group 5 (5 vs. 1-4, P < 0.01; 5-4 vs. 1-3, P < 0.001). Ten eyes (17%) required external-beam radiotherapy and 21 eyes (36%) enucleation. The ocular salvage rate was 67%., Conclusions: Although all groups of patients with intraocular retinoblastoma responded to carboplatin/etoposide chemotherapy associated with focal therapy, all the cases in group 5 relapsed. This approach is questionable in group 5, in which could be justified to delay aggressive treatment in a very young child.

Objective: To investigate the effectiveness of the vitamin D analogues 1,25-(OH)(2)-16-ene-23-yne vitamin D(3) (16,23-D(3)) and 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)) in inhibiting retinoblastoma growth in large tumors in a xenograft model and with prolonged use in a transgenic model., Methods: For the large-tumor study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model was used. Subcutaneous tumors were allowed to grow to an average volume of 1600 mm(3). Systemic treatment with 1 of the vitamin D analogues or with vehicle (control groups) was carried out for 5 weeks. For the long-term study, transgenic beta-luteinizing hormone-large T antigen (LHbeta-Tag) mice were systemically treated with 1 of the 2 compounds or vehicle (control groups) for up to 15 weeks. Tumor size and signs of toxicity were assessed., Results: In the large-tumor study, tumor volume ratios for the 1alpha-OH-D(2) and 16,23-D(3) groups were significantly lower than those for controls (P<.002). No significant differences in tumor volume were seen between the 1alpha-OH-D(2) and 16,23-D(3) groups (P =.15). In the long-term study, the 1alpha-OH-D(2) group showed significantly smaller tumor size compared with its control (P<.001). No significant difference was seen between the 16,23-D(3) group and its control. Some toxic effects related to hypercalcemia were seen in both studies., Conclusions: In athymic mice in the large-tumor study, both 1alpha-OH-D(2) and 16,23-D(3) were effective in inhibiting tumor growth compared with controls. In the long-term study, 1alpha-OH-D(2) inhibited tumor growth but 16,23-D(3) did not. Effective doses of both compounds caused hypercalcemia and a significant increase in mortality. Clinical Relevance Use of 1alpha-OH-D(2) inhibited tumor growth in large tumors and with long-term treatment compared with controls. Because of hypercalcemia-related toxic effects seen in the present experiments, in clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that lower serum calcium levels or use of relatively lower doses or skipped doses. The ideal alternative solution would be to identify vitamin D analogues that retain the antineoplastic action without the calcemic activity.

Objective: To describe patient and ocular outcomes following initial treatment with external beam radiotherapy (EBT) in eyes with Reese-Ellsworth group Vb retinoblastoma., Methods: Retrospective case series (from January 1, 1979, to February 28, 2002). The Kaplan-Meier method was used to analyze survival (ocular and patient) and incidence (second cancer) data., Results: Two hundred forty-three patients with 1 or more Reese-Ellsworth group Vb eyes were identified. Of 284 group Vb eyes, 63 (22.2%) initially received EBT, vs 172 (60.6%) that were initially enucleated. Of the 63 radiated group Vb eyes, 31 (49.2%) had no further tumor growth, 26 (41.3%) developed a recurrence, and 8 (12.7%) developed a new tumor. Of the 63 radiated group Vb eyes, 33 (52.4%) developed ocular complications. The ocular survival rate of radiated group Vb eyes was 81.4% at 1 year and 53.4% at 10 years. Twenty-eight radiated group Vb eyes survived to the last follow-up with visual acuity information. Thirteen patients developed second cancers, 11 in the field of radiation. The probability of developing a second cancer following initial EBT for group Vb disease in patients with bilateral disease was 29.7% by 10 years after diagnosis. Survival from second cancers in patients with bilateral disease initially receiving EBT for group Vb disease was 93.6% at 5 years and 52.6% at 18(1/4) years. No patient with unilateral disease developed a second cancer. Deaths due to metastatic retinoblastoma were uncommon., Conclusions: To our knowledge, this is the first study focusing exclusively on group Vb eyes treated initially with EBT, most of which were salvaged with vision. Outcome data provided herein are clinically relevant when choosing treatment options for advanced intraocular retinoblastoma.

Background: Retinoblastoma (RB) is a relatively uncommon tumour in childhood. The incidence of retinoblastoma in Mexico is probably higher than the incidence reported worldwide, however there is not enough information about the characteristics of this illness in Mexico. This report aims to present the results of a multicentre clinical survey of RB in Mexico., Methods: A retrospective study was carried out on all RB cases treated in 16 institutions during the last six years. The variables analysed were age at diagnosis, sex, affected eyes, treatment modalities, and pathological staging. Overall survival was obtained., Results: The authors analysed 500 cases; age range was 0-182 months. There were 364 unilateral cases (72.8%). Enucleation was performed in 84.9% of the patients. The St Jude's staging was: 7.4% stage I, 52.8% stage II, 18.0% stage III, 11.4% stage IV, 7.2% not evaluated, and 3.2% missing data. Chemotherapy was used in 74.4% of the patients. Disease free survival was 89% at 73 months follow up., Conclusions: The paper presents a great number of cases and pioneers multicentre studies in paediatric ophthalmology and oncology in this country. Given the great number of patients in advanced stages and the variability on treatment schemes, it is evident that it is mandatory to work in a cooperative group and develop a national early detection programme as well as a treatment protocol which include all specialists involved in the care of patients with RB.

Background: The purpose of this study was to report our experience using episcleral plaque brachytherapy (EPBRT) to treat retinoblastoma and to demonstrate its applicability in multimodality treatment., Procedure: We treated 26 tumors in 25 eyes from a group of 21 children with unilateral (n = 4) or bilateral (n = 17) retinoblastoma. The group comprised 8 girls and 13 boys; the median age was 25 months (range: 2-64 months) at the time of EPBRT. Iodine-125 ((125)I) was used for all applications. The median dose was 44 Gy (range: 35-47.6 Gy). EPBRT was administered primarily at the time of relapse after primary chemotherapy or radiation therapy., Results: For eyes treated with EPBRT, the eye preservation rate was 15/25 with a median follow-up of 47 months (range: 2-198 months); the lesion control rate was 25/26 with a median follow-up of 13 months (range: 1-140 months). The median time to additional whole-eye treatment after EPBRT was 12 months (range: 2-105 months)., Conclusions: Similar to previously reported series, EPBRT shows a high rate of successful tumor control as a primary treatment for retinoblastoma, as well as a secondary therapy at the time of relapse. EPBRT also allows for a clinically significant delay in the time to additional measures for the affected eye. Therefore, EPBRT should be considered as a form of local ophthalmic therapy that avoids or delays the use of external-beam radiotherapy, especially for patients primarily treated with chemotherapy who might require consolidation therapy., (Copyright 2004 Wiley-Liss, Inc.)

Retinoblastoma is usually curable in developed countries. The morbidity and mortality of patients with hereditary retinoblastoma is still threatened by the occurrence of secondary tumours. Between 1971 and 1988, 427 patients with retinoblastoma were treated in the ophthalmologic, paediatric and radiotherapy departments of the Institut Curie. In this study, we report the clinical and therapeutic features and the outcome of 25 patients treated for a second malignant neoplasm, diagnosed between 1997 and 1999 at the Institut Curie. The median time interval between the diagnosis of retinoblastoma and SMN was 11.2 years (range 3.8-20.6 years). Histopathological diagnoses included: 12 osteosarcomas, 12 soft tissue sarcomas and, 1 malignant oligodendroglioma. The second malignant neoplasm was located inside the radiation field in 21 cases and outside in 4. Twenty three patients received pre-operative chemotherapy. Surgery was performed in 16 patients. Post-operative chemotherapy was administered in 12 patients and external beam radiotherapy was used in 2 patients. Response to treatment was evaluable in 24 patients: complete remissions were observed in 14/24, partial remissions in 2/24 and progressive disease in 8/24. Nineteen patients died. Six are still alive, with 4 in complete remission (median follow-up 8.8 years; range 5.8-13.9 years). Despite aggressive therapy, the prognosis of patients with second malignant neoplasm occurring after retinoblastoma is very poor. It is important to provide information to retinoblastoma patients regarding the risk of a second tumour as this may facilitate an early tumour detection.

Objective: To evaluate the occurrence of new retinoblastomas in patients treated with 6 cycles of chemoreduction., Design: Prospective nonrandomized single-center case series., Setting: Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia., Participants: A total of 162 eyes of 106 patients with retinoblastoma treated with 6 cycles of chemoreduction between January 1, 1995, and May 31, 2002., Intervention: All patients received intravenous chemoreduction with vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor., Main Outcome Measure: Development of new intraretinal retinoblastoma during or after treatment with chemoreduction. Recurrent subretinal tumor seeds or vitreous seeds were excluded from this analysis, and only primary new intraretinal tumors were included., Results: Of 28 patients with unilateral retinoblastoma, new intraretinal tumor development was found during or after chemoreduction in 2 (9%) of the 23 patients with sporadic disease and 4 (80%) of the 5 patients with familial disease. The new tumor was located in the macula in none, between the macula and equator in 7 (54%), and between the equator and ora serrata in 6 (46%). Of the 78 patients with bilateral retinoblastoma, new tumor development was found during or after chemoreduction in 11 (19%) of the 57 patients with sporadic disease and 8 (38%) of the 21 patients with familial disease. The new tumor was macula in 2 (4%), between the macula and equator in 30 (55%), and between the equator and ora serrata in 23 (42%). Overall, according to Kaplan-Meier analysis, new tumor development occurred in 23% of patients by 1-year follow-up and 24% by 5-year follow-up. By multivariate analysis, the most important risk factors for the development of new tumors was younger age at presentation (median age, 2 months with new tumor vs 9 months without new tumor) and family history of retinoblastoma (12 [48%] of patients with new tumor vs 14 [17%] without new tumor)., Conclusions: Children with retinoblastoma treated with chemoreduction should be followed for new intraretinal tumor development, as it peaks at a mean interval of 5 months after initiation of chemoreduction and affects 24% of patients by 5 years of follow-up. New tumors are most commonly found in those who develop disease as young infants and those with a family history of retinoblastoma.