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Purpose To determine prospectively the efficacy and to assess potential side effects of melphalan selective ophthalmic artery chemotherapy (SOAC) as first-line treatment for unilateral retinoblastoma. Design Phase 2 nonrandomized, prospective study. Participants Patients with unilateral retinoblastoma group B, C, or D of the International Classification for Intraocular Retinoblastoma (IRC). Group D eyes with massive vitreous seeding were not eligible. Methods Melphalan SOAC associated with diode laser thermotherapy, cryotherapy, or both at 4-week intervals (3–6 cycles). For persistent vitreous seeding, intravitreal melphalan chemotherapy also was used. Main Outcome Measures The primary outcome was globe preservation rate. Secondary outcomes were tumor relapse rate, occurrence of ocular or systemic adverse events, and measurement of the dose area product (DAP). Results Between 2012 and 2017, 39 patients (39 eyes) with unilateral retinoblastoma were included prospectively. Three included patients did not receive SOAC (2 catheterization failures and 1 case of viral syndrome) and were considered failures. At diagnosis, IRC groups for the 36 treated patients were: B, n = 4 (11%); C, n = 13 (36%); and D, n = 19 (53%); median age was 21.5 months (range, 3.2–61.6 months). Median number of SOAC cycles was 3.9 (range, 1–6 cycles), and median melphalan dose was 4.9 mg/procedure. The median DAP was 1.24 Gy.cm2/procedure. Median follow-up was 63 months (range, 34–93 months). SOAC was associated with local treatments for 31 patients (86%): diode laser thermotherapy for all of them and cryotherapy or intravitreal chemotherapy for 10 (32%) and 9 patients (25%), respectively. SOAC treatment was interrupted in 5 patients because of severe ophthalmic (ptosis, n = 2; retinal ischemia, n = 2) or systemic (hypotension, n = 1) adverse events. At the cutoff date analysis, all patients were alive without metastasis. The 18-month eye preservation rate was 80% (range, 68.6%–94.6%). After a follow-up of at least 30 months, the ocular preservation rate was 69% (n = 24 preservations). Conclusions This first prospective trial demonstrated that SOAC with melphalan alone as first-line treatment for retinoblastoma is efficient and well tolerated with no metastatic events, although ocular ischemic complications were observed.

The management of retinoblastoma is complex. With increasing treatment modalities and increasing experience with each treatment modality, the globe salvage rates have drastically improved with time. Aqueous seeding in an eye with retinoblastoma is classified as group E based on International Classification of Intraocular Retinoblastoma, and most group E eyes were enucleated a decade earlier. Newer modalities of treatment have improved the globe salvage rates in group E eyes including those with aqueous seeding. Various globe salvage treatment modalities attempted for the management of aqueous seeds include external beam radiotherapy, plaque radiotherapy, intra-arterial chemotherapy, periocular chemotherapy, intravitreal chemotherapy and intracameral chemotherapy. Of all treatment modalities, intracameral chemotherapy holds promise for the management of aqueous seeds in selected patients, but it should be done with the utmost care by a trained ocular oncologist. Enucleation is still the preferred modality of treatment for eyes with advanced retinoblastoma and anterior segment invasion. This review focuses on the current evidence on aqueous seeding, highlighting the pathogenesis, classification, clinical presentation, treatment and outcomes.

PurposeTo explore the risk factors for ophthalmic artery (OA) stenosis and occlusion after intra-arterial chemotherapy (IAC) with selective ophthalmic artery catheterisation (OAC) in the treatment of retinoblastoma.DesignRetrospective, single centre case-control study.MethodsThe study was conducted including consecutive patients with unilateral or bilateral intraocular retinoblastoma undergoing IAC between June 2016 and June 2019 with a follow-up time of 4 years. Main outcomes are rate of IAC-induced OA occlusion and OA diameter.Results346 attempted OAC infusions were successful. The total incidence of OA occlusion was 15.89%. The occlusion and control groups were similar in patients’ age, sex and disease stage. Median OA diameter was 0.49 mm in those with OA occlusion, and 0.66 mm in those without occlusion. In the occlusion group, the OA diameter difference was significantly larger between the first IAC and the final IAC (0.22mm vs 0.12mm, p=0.001). In both groups, the median number of IAC treatments was 3. Multivariate Cox regression models included initial OA diameter (OR: 0.005, p=0.001), ratio of OA orifice diameter differences between first and last IAC to the initial OA orifice diameter (OR: 4.661, p=0.003), and number of IAC (OR: 1.538, p=0.042) as clinical features significantly associated with OA occlusion.ConclusionsThe OA diameter at first IAC treatment, the ratio of OA orifice diameter differences between first and last IAC to the initial OA orifice diameter and total number of IAC treatments may be three main clinical predictors for OA occlusion after IAC for retinoblastoma.

Background Retinoblastoma (RB) outcomes in Thailand are unfavorable compared to those of developed countries. This study aims to determine whether the clinical outcomes of patients with RB significantly improved after the implementation of new therapeutic approaches and which clinical factors affect survival and globe-saving outcomes. Methods The medical records of patients newly diagnosed with RB and treated at Siriraj Hospital between January 2005 and December 2018 were reviewed retrospectively. Clinical data, treatments, and outcomes were collected and analyzed. Results In 194 eyes (144 patients), leukocoria was the most common presenting feature (76.8%); 129 (66.5%) eyes were staged in group E of the International Classification of Intraocular Retinoblastoma. Of the 149 enucleated eyes, 35 had high-risk histopathological features, mostly choroidal invasion; 45 eyes (23.2%) could be salvaged. The 5-year overall survival rate was 90.3%, an improvement compared to the previous study. The 5-year enucleation-free survival rates of Groups A and B, C, D and E were 100%, 83.1%, 36.7% and 16.6% respectively. Factors associated with a lower survival rate were interval from symptom onset to diagnosis >3 months (hazard ratio (HR): 5.8: 95% confidence interval (CI): 1.637, 20.579) and buphthalmos (HR: 12.57: 95% CI: 3.936, 40.153). Factors associated with high-risk features were secondary glaucoma (HR: 11.016: 95% CI: 1.24, 98.10) and pseudohypopyon (HR: 14.110: 95% CI: 2.16, 92.05). Conclusions Survival rates and globe-saving rates appear to have improved; however, advanced-stage presentation remains the major hindrance. Further studies with a larger cohort and longer follow-up are warranted.

To analyze the risk factors and estimate the risk period for tumor recurrence in intraocular retinoblastoma (RB). Retrospective study of 60 RB patients. The mean age at presentation with RB was 16 months (median 11 months; range 1–84 months). Tumor was unilateral in 13 (22%) and bilateral in 47 (78%) patients. Of 83 eyes with intraocular RB, group B (n = 27; 33%) tumors were more common based on International Classification of Intraocular Retinoblastoma. All cases received intravenous chemotherapy as a primary treatment. Over a mean follow-up period of 57 months (median 38 months; range 12–185 months) post-primary treatment, 44 (73%) patients developed tumor recurrence. The mean interval between the completion of primary treatment and first tumor recurrence was 5 months (median 3 months; range 1–24 months). The total duration of treatment for complete tumor control including treatment of tumor recurrences was 20 months (median 19 months; 2–58 months). By multivariate analysis, the factors predictive of tumor recurrence were multiple tumors (p = 0.008) and retinal detachment (p = 0.003) at presentation. Kaplan–Meier estimate of tumor recurrence at 6 months, 1 year, 3 years, and 5 years was 20%, 31%, 68%, and 73%, respectively. There was no tumor recurrence beyond 5 years since primary treatment. Multiple tumors and retinal detachment at presentation are risk factors for tumor recurrence in RB. Close follow-up is mandatory for at least 5 years since the initiation of treatment for RB.

Purpose To review the occurrence of new solitary tumors during and after intravenous chemotherapy against retinoblastoma. Methods From 115 eyes of 78 patients with a diagnosis of intraocular retinoblastoma who underwent intravenous chemotherapy and focal treatment without prior treatment, patient demographics, age at diagnosis, laterality, classification (Reese-Ellsworth and International Classification of Retinoblastoma), and treatment options were recorded. In addition, the occurrence of small tumors during and after chemotherapy was documented with a detailed review of medical records and fundus photographs. Results Of a total of 115 eyes of 78 consecutive patients, new solitary tumors were observed in 50 eyes (50 / 115, 43%) of 40 patients (40 / 78, 51%). Multinominal logistic regression analyses showed that age at diagnosis (before 1 year) and vitreal seeding at diagnosis were linked to the development of isolated and miliary tumors, respectively. Kaplan-Meier analyses demonstrated that all small tumors developed with 20 months from the start of chemotherapy. Twenty-eight eyes (28 / 34, 82%) were salvaged with additional focal treatment in 34 eyes with isolated tumors. Conclusions Small tumors were observed during and after chemotherapy against retinoblastoma in patients who underwent intravenous chemotherapy and focal treatment. It is necessary to promptly identify and address small tumors for the preservation of eyeball and vision.

Purpose To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB). Design International, multicenter, registry-based retrospective case series. Participants A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Methods International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included. Main Outcome Measures Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC). Results Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2- and 5-year Kaplan–Meier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P Conclusions Multicenter, international, internet-based data sharing validated the 8th edition AJCC RB staging to predict globe-salvage in a large, heterogeneous, real-world patient population with RB.

PURPOSE: To analyse the prognostic factors for eye salvage for eyes with intra-ocular retinoblastoma (RB) that is resistant to systemic chemotherapy and focal therapy by external beam radiation therapy (EBRT). METHODS: A retrospective analysis of 28 eyes with intra-ocular RB that was resistant for systemic chemotherapy and focal consolidation therapy and received EBRT. Outcome measures included tumor stage at diagnosis, stage migration, type of tumor seeds, treatment modalities, eye globe salvage, metastasis, and survival. RESULTS: Most of the patients (83%) had bilateral RB, and 42% were females. All eyes were treated initially by combination of systemic chemotherapy and focal consolidation therapy. The dose of EBRT was 45 Gy. The mean follow-up was 6.5 years, and the overall eye globe salvage rate post EBRT was 46%: 67% (2/3) for group B, 71% (5/7) for group C, and 33% (6/18) for group D. Patient's gender, tumor site, laterality, and tumor stage at diagnosis were not significant prognostic factors (p> 0.05) for final outcome. The significant poor prognostic factors were tumor stage migration during systemic chemotherapy (p= 0.03) and presence of vitreous seeds at time of EBRT (p=0.001). Post EBRT complication rate was 68% (19/28) including; retinal detachment (3), vitreous hemorrhage (4), neovascular glaucoma (1), cataract (16), radiation retinopathy (2), and second malignancy (2). CONCLUSION: EBRT is an alternative for enucleation when RB is resistant to combined chemoreduction/focal consolidation therapy in absence in vitreous seeds. The known risks for EBRT are not justified for patients with unilateral RB and for those who have functional vision in the other eye.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy for retinoblastoma has dramatically altered the natural history of the disease. The remarkable outcomes associated with a high safety profile have pushed the envelope to offer treatment for patients weighing ≤10 kg. The purpose was to determine the efficacy and safety of IAC infusions performed in infants weighing ≤10 kg with intraocular retinoblastoma. MATERIALS AND METHODS: A retrospective chart review was performed for patients diagnosed with retinoblastoma and managed with intra-arterial chemotherapy. RESULTS: The total study cohort included 207 retinoblastoma tumors of 207 eyes in 196 consecutive patients who underwent 658 intra-arterial chemotherapy infusions overall. Of these, patient weights were [Formula: see text] 10 kg in 69 (35.2%) and >10 kg in 127 (64.8%) patients. Comparison (≤10 kg versus >10 kg) revealed that the total number of intra-arterial chemotherapy infusions was 222 versus 436. Periprocedural complications were not significantly different (2 [0.9%] versus 2 [0.5%]; P = .49). Cumulative radiation exposure per eye was significantly lower in infants weighing ≤10 kg (5.0 Gym(2) versus 7.7 Gym(2); P = .01). Patients weighing [Formula: see text] 10 kg had a greater frequency of complete tumor regression (82.6% versus 60.9%; P = .02). Mean fluoroscopy time was not significantly different (7.5 versus 7.2; P = .71). There was a significant difference in the frequency of enucleation (16 [21.6%] versus 52 [39.1%]; P = .01). Patients weighing [Formula: see text] 10 kg had greater number of aborted procedures (12 [5.4%] versus 7 [1.6%]; P = .01). On multivariate analysis, weight ≤10 kg was not an independent predictor of complications or procedure failure. CONCLUSIONS: Intra-arterial chemotherapy in patients weighing ≤10 kg is a safe and effective treatment.

OBJECTIVES To evaluate the long-term treatment outcomes in intraocular retinoblastoma (RB) including the associated factors for eventual treatment with external beam radiotherapy (EBRT) and enucleation as well as to analyse the risk factors for metastasis and death in extraocular RB. METHODS Retrospective analysis of 390 eyes from 256 (89.8%) intraocular RB and 29 (10.2%) extraocular RB cases diagnosed and treated between October 1998 and May 2018 at one of the largest tertiary care centers in Turkey. RESULTS Of 351 intraocular RB eyes, 53.3% had group D/E disease at presentation. 75 (21.4%) of 351 eyes underwent primary enucleation. Of the remaining 276 eyes undergoing eye-conserving treatments, 201 (72.8%) were salvaged. Most of these eyes were treated using intravenous chemotherapy and/or focal treatments [transpupillary thermotherapy (TTT) and cryotherapy] initially. EBRT was eventually required in 48 (17.4%) eyes and secondary enucleation in 75 (27.2%) eyes. At mean follow-ups of 76.7 and 39.7 months for intraocular and extraocular RB cohorts, respectively, 180 (46.2%) eyes underwent primary/secondary enucleation and exenteration. Overall, 13 cases developed metastasis and 9 died. Two patients with trilateral RB also expired. Multivariable risk factors for enucleation were the presence of vitreous seeds (p

Topic To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms. Clinical relevance Approximately 45% of patients with retinoblastoma—those with a germline RB1 pathogenic variant—are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued. Methods We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus. Results One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9–29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively. Conclusions Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low.

Purpose: To assess the efficacy and safety of pars plana vitrectomy (PPV) as a treatment for intraocular retinoblastoma (RB) patients. Methods: Twenty-eight RB patients who had PPV were recruited in this retrospective case study, using the digital wide-angle retinal imaging device to record and assess disease condition. Results: The mean value of follow-up time was 79.4 months from diagnosis and 73.1 months from PPV. Up to the end of the follow-up time after PPV, the 5-year survival rate was 96.4%. Ultimately, 35.7% patients underwent enucleation of the eyeball. Among patients with salvaged eyes, 50% had no light perception vision. During the postoperative follow-up time, 14.3% of patients required no further antitumor treatment, and the remaining patients still need to continue to receive systemic or local antitumor treatment, such as chemotherapy, arterial interventional therapy, laser treatment, cryotherapy, and so on. The complication after PPV include cataracts (46.4%), iris adhesion (7.1%), emulsification of the silicone oil (17.9%), band degeneration of the cornea (10.7%), glaucoma (3.6%), and retinal neovascularization (3.6%). Conclusion: According to our observations, we recommend that the utmost care should be taken when considering PPV for the treatment of activated RB. When weighing the risk of tumor recurrence and metastasis, PPV is not suitable for routine treatment. It is necessary to fully grasp the operative indications and strictly observe operation specifications, which includes close postoperative follow-up.

Simple Summary The role of organ-conserving surgery has not been explored in retinoblastoma as it has been in other cancers, such as breast cancer lumpectomy, partial nephrectomy for kidney cancer, and partial orchiectomy for testis cancer. This is largely accounted for by the high mortality of extraocular retinoblastoma compared to intraocular retinoblastoma, and fear of iatrogenic tumor spread with intraocular surgery. We propose the little-known word “tylectomy” (“tulos”, Greek for “lump”) to describe the surgical resection of retinoblastoma. Through review of consecutive patients treated by our team between 2012–2014, we compared survival of patients with eye salvage, including tylectomy, to those who had eye salvage without tylectomy or primary enucleation. We found that patients who had tylectomy had superior survival compared to those who had eye salvage without tylectomy (96% vs. 90%), and comparable survival to those with primary enucleation (96% vs. 95%). Our study supports tylectomy as a safe contribution to retinoblastoma management. Abstract Intraocular surgery is tabooed in retinoblastoma management, due to the concern of lethal extraocular spread. We reviewed the outcomes of consecutive children with intraocular retinoblastoma diagnosed at 29 Chinese centers between 2012–2014. We compared the outcomes of three categories of treatment: eye salvage including tylectomy (Group I), eye salvage without tylectomy (Group II), and primary enucleation (Group III). A total of 960 patients (1243 eyes) were diagnosed: 256 in Group I, 370 in Group II, and 293 in Group III; 41 patients abandoned treatment upfront. The estimated 5-year overall survivals (OS) were, for Group I, 94%, for Group II 89%, and for Group III 95%. The estimated 5-year disease-specific survivals (DSS) were, for Group I, 96%, for Group II 90%, and for Group III 95%. Patients in Group I had a significantly higher 5-year DSS than patients in Group II (p = 0.003) and not significantly different than patients in Group III (p = 0.367). Overall survival was not compromised by the inclusion of tylectomy in eye salvage therapy compared to eye salvage without tylectomy or primary enucleation. Disease-specific survival was better when tylectomy was included in eye salvage treatments. Tylectomy as part of multimodal treatment may contribute to the care of retinoblastoma patients with chemotherapy-resistant tumor, eyes with concomitant ocular complications, or at the risk of treatment abandonment.

Chemotherapy is now the primary treatment of retinoblastoma in eyes with visual potential or those that are considered not advanced for retinoblastoma. In addition to intravenous chemotherapy (IVC), drugs delivered via alternative routes such as intra-arterial and intravitreal administration have emerged as promising options for management of retinoblastoma. Various studies have shown excellent results in salvaging nearly 100% of groups A-C eyes; however, intra-arterial chemotherapy (IAC) seems to offer superior local control rates as compared with IVC for advanced intraocular retinoblastoma (groups D and E eyes). Intravitreal chemotherapy (IVitC), that delivers the highest concentration of drug in the vitreous cavity while minimizing systemic drug concentration, has emerged in recent years (2012) as an effective treatment for refractory or persistent vitreous seeding. The role of concomitant and subsequent therapies is an important consideration, particularly the use of IVitC in combination with IAC. As IVitC became acceptable during the era of IAC, most of the patients treated previously with IVC did not receive IVitC. Therefore, it is possible that some of the IVC failures could have been avoided with the use of IVitC. We provide our perspective of published data that seems to be skewed by evolving practice patterns that project enhanced efficacy of IAC when compared with historic control rates achieved with IVC. In absence of better-quality data or randomized controlled trials, it is hard to establish superiority of one treatment over the other.

Although intra-arterial chemotherapy (IAC) is commonly used for treating intraocular retinoblastoma, it is not a systemic therapy. We aimed to investigate whether the addition of intravenous chemotherapy (IVC) before IAC administration had any effects (whether beneficial or adverse) on patient outcomes. This multicenter retrospective cohort study included 213 patients with advanced intraocular retinoblastoma who received IVC plus IAC (n = 103) or IAC alone (n = 110) between April 2009 and January 2017. Eyes were grouped according to the International Intraocular Retinoblastoma Classification. Kaplan–Meier and Cox regression analyses were performed to compare survival outcomes between the two groups. Moreover, details regarding enucleation were recorded. The 3-year ocular survival rates were 62% in the IVC plus IAC group and 68% in the IAC group (hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.55–1.43, P = 0.61). Moreover, the corresponding 3-year overall survival rates were 97% and 93%, respectively (HR 1.56, 95% CI 0.41–5.90, P = 0.51), while the 3-year event-free survival rates were 76% and 72%, respectively (HR 0.96, 95% CI 0.56–1.65, P = 0.89). Within a 3-year follow-up period, IVC plus IAC produced no additional benefit over primary IAC for treating advanced intraocular retinoblastoma in terms of local tumor control and extending survival. Longer follow-up periods are required to assess long-term efficacy.

Retinoblastoma is one of the most common retinal tumors in young children. Current early diagnostic and treatment strategies focus on the possibility to implement eye-preserving therapies. The 5-year overall survival for children with retinoblastoma is now 100%. First-line eye removal is recommended in extensive intraocular seeding and poor visual prognosis. The volume of adjuvant therapy is based on the histological risk factors for disease progression. This paper discusses the algorithms to determine risk factors and further systemic treatment strategy in several large study groups. Eye and even vision preservation is now possible in at least 65–75% of retinoblastoma patients. The paper also describes in detail the methods of locally administering chemotherapy which are considered eye-preserving treatment options, i.e., selective intra-arterial chemotherapy and intravitreal chemotherapy. Various physical methods of eye-preserving treatment which underwent significant development over the past decade are highlighted. In conclusion, the authors emphasize that retinoblastoma survivors, their siblings and offspring should be carefully monitored.Keywords: children, retinoblastoma, enucleation, polychemotherapy, selective intra-arterial chemotherapy, intravitreal chemotherapy, laser photocoagulation, transpupillary thermotherapy, cryotherapy, brachytherapy, monitoring.For citation: Ivanova S.V., Kuleva S.A., Sadovnikova N.N. et al. Retinoblastoma. Part 2. Treatment strategies for intraocular retinoblastoma. Russian Journal of Clinical Ophthalmology. 2020;20(4):197–203. DOI: 10.32364/2311-7729-2020-20-4-197-203.

Background: Retinoblastoma often presents with advanced intraocular disease and despite conventional treatment with intravenous chemotherapy (IVC) and external beam radiation therapy, may still require enucleation.Aim of Study: To assess the efficacy of intra-arterial chemotherapy (IAC) in comparison with other modalities in the management of intraocular retinoblastoma.Material and Methods: Twenty one patients with thirty intra ocular retinoblastomas were included in the study from November 2013 to September 2016. Chemo reduction followed by adjuvant consolidative treatment has replaced external beam radiotherapy as the primary modality of treatment for intraocular retinoblastoma. Patients failed to respond ade-quately to a standard systemic chemotherapy (i.e., carboplatin, vincristine, and etoposide) with or without other local therapies, are referred for intra-arterial chemotherapy (IAC) to avoid enucleation. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy.Results: The current commonly used treatments for retin-oblastoma in our study were IVC and IAC, along with con-solidated therapy based on tumor staging. For international classification of retinoblastoma (ICRB) grading, we found a significantly higher success rates for RTB cases treated with IAC as primary or adjuvant therapy compared to other treat-ment modalities which achieved 90% versus 73.6% for globe salvage, 80% vs 52.6 % for solid tumor control, 75% vs 66.6% for subretinal seeds control, 66.7% vs 62.5% for vitreous seeds control respectively.Conclusion: IAC may be superior to IVC for the treatment of retinoblastoma, with a higher overall success rate and higher globe salvage especially in group D retinoblastoma that failed to respond to systemic chemotherapy and destined for enucleation.

Purpose To study the clinical presentation, treatment, and outcomes of patients with bilateral advanced intraocular retinoblastoma. Methods Retrospective case series of 72 patients. Results The mean age at presentation was 19 months. Leukocoria (n = 49, 68%) was the most common presenting complaint. The tumors were classified as groups D (n = 60, 42%) or E (n = 84, 58%) based on the Philadelphia version of International Classification of Retinoblastoma (ICRB); groups D (n = 84, 58%) or E (n = 60, 42%) based on Children's Hospital Los Angeles version of International Classification of Intraocular Retinoblastoma (ICIoR); T2 (n = 116, 81%) or T3 (n = 28, 19%) based on 8th edition American Joint Committee Classification (AJCC). Systemic chemotherapy (n = 138, 96%) was the most common primary treatment modality. The chance of globe salvage was higher for group D based on ICRB (83%; odds ratio (OR) 7.73; 95% confidence interval (CI) 3.45-17.33) or ICIoR (81%; OR 12.75; 95% CI 5.74-28.34) and T2b (73%; OR 5.19; 95% CI 2.51-10.73) based on AJCC. Over a mean follow-up period of 59 months, tumor recurrence was noted in 42 (29%) eyes and globe salvage was achieved in 83 (58%) eyes. Of the 50 eyes where vision was recorded, vision of 20/200 or better was achieved in 24 (48%) eyes. There were events of leukemia (n = 1, 1%), pinealoblastoma (n = 1, 1%), systemic metastasis (n = 3, 4%), and death (n = 4, 6%) during the follow-up period. Conclusion Multimodality treatment allows globe salvage (58%) and vision salvage (48%) in eyes with advanced group D and E intraocular retinoblastoma.

PURPOSE To evaluate the lenticular changes in advanced intraocular retinoblastoma (RB) and identify the risk factors for cataract in these eyes. METHODS Retrospective analysis of 48 primary enucleations. RESULTS All enucleated eyes were classified either as group D (n = 7; 15%) or group E (n = 41; 85%) tumors based on the International Classification of Intraocular Retinoblastoma. Of the 48 enucleated eyes with RB, cataract was noted clinically in only 5 (18%) cases, while histopathology revealed cataractous changes in 28 (58%) cases. Based on histopathology, the cataractous changes included anterior subcapsular cataract (n = 10; 36%), cortical cataract (n = 6; 21%), posterior subcapsular cataract (n = 10; 36%) and both anterior and posterior subcapsular cataract (n = 2; 7%). Based on multivariate logistic regression, only increased area of necrosis on histopathology was the significant (p = .009) factor predictive of cataractous changes in lens with an odds ratio of 1.08. CONCLUSION Eyes with advanced RB can harbor cataract in 58% cases, though most of these are subclinical. Clinically significant cataract may be evident in only 18% cases. Increased tumor necrosis is associated with the development of cataractous changes in RB cases.

Background and Purpose Intra-arterial chemotherapy (IAC) infusion for the treatment of intraocular retinoblastoma is an effective and relatively safe therapeutic option.1–3 However, one of the well described systemic complications following IAC is neutropenia.4 The purpose of this retrospective study is to examine the incidence of neutropenia over the course of treatment for each patient, and to further analyze if the incidence is affected by systemic chemotherapy or number of chemotherapeutic agents used for IAC. Methods We retrospectively identified 76 patients from a neurointerventional database spanning 10 years (March 2010 - August 2020) who underwent 214 cycles of IAC. Patient demographics, treatment course, angiographic technique as well as pre and post procedural complete blood counts were extracted from the medical record. Neutropenia, including all grades I-IV, is defined by an absolute neutrophil count (ANC) equal to or less than 1.5 x 10(9)/L. Eleven patients who did not obtain a post-procedural complete blood count during their treatment course were excluded. The presence of postprocedural neutropenia was further subdivided based on whether systemic intravenous chemotherapy was administered as well as according to the number of intra-arterial chemotherapeutic agents. Results The overall incidence of neutropenia was 62% in our total patient cohort. There was no statistically significant difference between the incidence of neutropenia in patients who did and did not receive systemic chemotherapy. The majority of patients received two chemotherapeutic agents (melphalan and topotecan), of which 58% and 54% of patients experienced neutropenia with and without systemic chemotherapy, respectively. The highest incidence of neutropenia was 100%, in five patients who received systemic chemotherapy and a three agent intra-arterial regimen (melphalan, topotecan, carboplatin). Conclusion Neutropenia is a systemic toxicity in more than half of patients who receive IAC infusion for intraocular retinoblastoma, and does not significantly differ in patients who do and do not receive systemic chemotherapy. References Ammanuel S, Alexander MD, Damato B, et al. Improved procedural safety following protocol changes for selective ophthalmic arterial infusion of chemotherapy for treatment of ocular retinoblastoma. Interv Neuroradiol. 2018;24(3):345–350. Yousef YA, Soliman SE, Astudillo PPP, et al. Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol. 2016;134(5):584–591. Monroy JE, Orbach DB, VanderVeen D. Complications of intra-arterial chemotherapy for retinoblastoma. Semin Ophthalmol. 2014;29(5–6):429–433. Dunkel IJ, Shi W, Salvaggio K, et al. Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular retinoblastoma. PLoS One. 2014;9(10):e108692. Disclosures A. Baker: None. S. Ammanuel: None. M. Caton: None. K. Narsinh: None. A. Ashfar: None. A. Banerjee: None. D. Cooke: None. C. Dowd: None. M. Amans: None. V. Halbach: None. R. Higashida: None. S. Hetts: None.

Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia Introduction Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Results Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers. Open access funding enabled and organized by Projekt DEAL.

Purpose Analysis of circulating tumor DNA (ctDNA) in the plasma of patients with retinoblastoma and simulating lesions. Design Retrospective cross-sectional study of the association of plasma ctDNA from retinoblastoma and simulating lesions with disease course. Participants Fifty-eight Memorial Sloan Kettering Cancer Center patients with retinoblastoma comprising 68 plasma ctDNA samples and 5 with retinoblastoma-simulating lesions. Methods The ctDNA analyzed with hybridization capture and next-generation sequencing in blood (plasma) of patients who had retinoblastoma or simulating lesions were evaluated for association with clinical course of the disease. Main Outcome Measures Presence or absence of molecular aberrations in the RB1 gene and correlations with clinical features. Results RB1 cell-free DNA (cfDNA) was detected in 16 of 19 patients with newly diagnosed, untreated intraocular retinoblastoma and in 3 of 3 patients with newly diagnosed, untreated metastatic disease. It was also present in 3 patients with recurrent intraocular disease before therapy, but was not present in patients with recurrent disease who received intra-arterial chemotherapy, nor in 21 patients who had undergone enucleation for unilateral disease. In 1 patient who had delayed treatment (insurance reasons) and showed rapid growth of the intraocular tumor, the variant allele frequency increased in 1 month from 0.34% to 2.48%. No RB1 mutations were detected in the cfDNA from plasma of patients with simulating lesions (3 with Coats disease and 1 with persistent fetal vasculature [PFV]). In 2 patients, we identified 2 independent RB1 mutations in plasma. Conclusions Mutations in RB1 were found in the cfDNA from blood of patients with newly diagnosed, untreated retinoblastoma and in patients who showed disease recurrence in the eye after prior treatment, but not in unilateral retinoblastoma after enucleation Levels of ctDNA increase in patients with progressive disease who did not receive any treatment. High plasma cfDNA levels were detected in patients with newly diagnosed metastatic disease, and these levels decreased after systemic chemotherapy was administered. Further validation is needed for measuring the somatic alterations in cfDNA from blood in retinoblastoma that could provide a promising method of monitoring patients in the future.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management. Fil: Aschero, María del Rosario. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Francis, Jasmine H.. Memorial Sloan-Kettering Cancer Center; Estados Unidos Fil: Ganiewich, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Gomez Gonzalez, Soledad. Hospital Sant Joan de Deu Barcelona; España Fil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ottaviani, Daniela. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Lemelle, Lauriane. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Mena, Marcela Daniela C. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Correa Llano, Genoveva. Hospital Sant Joan de Deu Barcelona; España Fil: Lamas, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Szijan, Irene. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina Fil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; España Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Doz, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Radvanyi, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados Unidos Fil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lavarino, Cinzia. Hospital Sant Joan de Deu Barcelona; España Fil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

BackgroundRetinoblastoma is the most common primary intraocular malignancy in children.ObjectiveTo determine the incidence of ophthalmic artery (OA) occlusion in patients treated with selective ophthalmic artery catheterization (OAC) for chemotherapy infusion for retinoblastoma. Also, to evaluate technical, anatomical, tumorous, and patient-related factors that are predictors of OA occlusion.MethodsA retrospective chart review was performed for patients diagnosed with intraocular retinoblastoma and managed with intra-arterial chemotherapy (IAC).ResultsThe total study cohort included 208 retinoblastoma tumors of 208 eyes in 197 consecutive patients who underwent 688 attempted IAC infusions overall with a total of 624 successful OAC infusions. The total incidence of ophthalmic artery thrombosis was 11.1% (23/208). The numbers of successful OAC procedures before diagnosing OA occlusion were one OAC in six cases (27.3%), two in seven cases (31.8%), three in four cases (18.2%), four in one case (4.5%), five in two cases (9.1%), and six in one case (4.5%).ConclusionsLocal factors relating to the chemotherapy and selective microcatheterization of the OA are essential factors in the development of OA thrombosis, as seen by the association of OA thrombosis with the frequency of IAC.

Purpose: To discuss the clinical presentation, management, and outcome of delayed metastasis in retinoblastoma (RB). Methods: Retrospective case series of three patients. Results: Mean age at diagnosis of RB was 29 months (median, 28 months; range, 11–48 months). All were males with non-familial bilateral intraocular RB. Primary treatment for RB included intravenous chemotherapy in all three cases. Secondary treatment included transpupillary thermotherapy/cryotherapy ( n = 6 eyes), periocular chemotherapy ( n = 2 eyes), intravitreal chemotherapy ( n = 1 eye), intra-arterial chemotherapy ( n = 1 eye), external beam radiotherapy (EBRT; n = 2 eyes), and enucleation ( n = 2 eyes). Primary tumor regression was achieved in all cases and remained status quo at the time of diagnosis of distant metastasis. Two patients developed bone metastasis (ulna; tibia) and one developed soft tissue metastasis (temporal fossa) over a mean follow-up period of 6 years (median, 7 years; range, 5–8 years) from diagnosis of RB. Mean age of detection of metastatic disease was 8 years (median, 8 years; range, 7–9 years). All the lesions were solitary and the diagnosis of metastatic retinoblastoma was confirmed by tissue biopsy. Metastatic disease was treated with surgical excision ( n = 1), chemotherapy ( n = 2), and EBRT ( n = 2). All patients are alive, with two patients free of disease over a mean follow-up period of 23 months (median, 23 months; range, 12–33 months); and 1 in remission 7 months after completion of EBRT. Conclusion: Long-term follow-up of RB cases is mandatory. In spite of intraocular tumor regression, metastasis can still occur many years after treatment of RB.

Purpose. To investigate the clinical presentations and outcomes of retinoblastoma in relation to the advent of new multimodal treatments in Thailand. Patients and Methods. Retrospective case series. We evaluated the clinical presentation, staging, details of treatment, and treatment outcomes of retinoblastoma patients who were treated at Ramathibodi Hospital, Bangkok, Thailand, between January 1, 2007, and December 31, 2018. The log-rank test was used to explore clinical characteristics and treatment modalities that affected globe salvage and survival curves. Results. This study included 124 eyes of 81 patients with retinoblastoma. Forty-three patients (53.1%) had bilateral retinoblastoma. The median age at diagnosis was 8 months (range, 1–48 months). Of 124 eyes, 9 eyes (7.3%) had extraocular retinoblastoma and 115 eyes (92.7%) had intraocular retinoblastoma, which were classified by the International Classification of Retinoblastoma (ICRB) as group A, 4 eyes (3.5%); group B, 19 eyes (16.5%); group C, 6 eyes (5.2%); group D, 31 eyes (27%); and group E, 56 eyes (47.8%). Treatment included systemic chemotherapy, intra-arterial chemotherapy, ruthenium-106 plaque brachytherapy, external beam radiation therapy, cryotherapy, transpupillary thermotherapy, subtenon chemotherapy, and intravitreal chemotherapy. At the median follow-up period of 38.4 months (range, 0.2–148.2 months), the overall globe salvage rate of intraocular retinoblastoma was 51.7%. For unilateral retinoblastoma, globe salvage rate was 37.5% (group B, 100%; group C, 100%; group D, 50%; and group E, 18.8%). For bilateral intraocular retinoblastoma, the globe salvage rate was 57.8% (group A, 100 %; group B, 94.4%; group C, 100%; group D, 64.7%; and group E, 28.2%). The overall survival rate was 93.8%. Conclusions. Recent advanced treatment modalities have improved the probability of globe salvage. However, enucleation remains an important life-saving intervention in many advanced cases.

Intra-arterial chemotherapy (IAC), also known as superselective ophthalmic artery chemotherapy or chemosurgery, is currently widely accepted as one of the primary treatment modalities for intraocular retinoblastoma worldwide. Following the introduction of the technique in 1998, IAC has evolved over the past decades to be safer and more effective. Accumulated evidence shows that IAC is more effective in providing eye salvage in group D and E retinoblastoma as compared to conventional systemic intravenous chemotherapy (IVC). In contrast to IVC, IAC has the added benefits of reduced overall treatment duration and minimal systemic toxicity. This review provides a comprehensive update on the history, technique, indications, contraindications, and outcome of IAC. We have also identified the strengths, weaknesses, opportunities and threats (SWOT analysis) of the technique in this review.

Importance: Retinoblastoma (Rb) is the most common primary malignant intraocular cancer in children. Systemic chemotherapy combined with local therapy is safe and effective for intraocular Rb. Objective: To summarize the short-term outcomes of patients with Rb to provide evidence for optimizing treatment protocols and improving therapeutic safety and efficacy. Methods: The clinical data of 356 patients (486 eyes) with intraocular Rb admitted to our center from December 2009 to April 2017 were retrospectively analyzed. The measures included drug toxicity, eye-preservation rate, and survival rate, with an emphasis on safety and short-term efficacy. The date of last follow-up was 30 November, 2017. Results: The patients comprised 226 unilateral Rb and 130 bilateral Rb. Enucleation before chemotherapy was performed in 72 patients. Among the 174 patients with unilateral Rb, enucleation after chemotherapy was performed in 80 patients (46.0%), and the eye was not enucleated in 89 (51.1%); 68 eyes were preserved (68/114, 59.6%) in Group D and 20 eyes (20/59, 33.8%) in Group E. Among the 220 eyes in patients with bilateral Rb, enucleation after chemotherapy was performed for 35 eyes; the eye-preservation rate was 91.7% in Group C, 79.1% in Group D, and 52.1% in Group E. All patients developed grade II to IV myelosuppression after chemotherapy, among whom 18 patients (5%) requiring transfusion. Fourteen patients (3.9%) died of intracranial metastasis following self-elected discontinuation of treatment (n = 7). Patients were followed up for a median of 47 (range, 1–96) months. The expected 5-year overall survival rate was 95.3% (96.7% for unilateral Rb and 92.9% for bilateral Rb, P = 0.074). Interpretation: The VEC (vincristine, etoposide, and carboplatin) regimen with local treatment was safe for intraocular Rb. Intracranial metastasis remains the most common cause of Rb-related death. Key words: Chemotherapy; Enucleation; Intraocular retinoblastoma; Local therapy

PURPOSE To identify the differences in the clinical and histopathologic features in eyes with advanced intraocular retinoblastoma in a developing country (India) versus a developed country (USA). METHODS Retrospective study. RESULTS Of 524 patients with retinoblastoma who underwent primary enucleation, 331 were from India, and 193 were from the USA. Asian Indians were older at presentation (35 months vs. 29 months; P = 0.02), had thicker tumors (13.8 mm vs. 12.4 mm; P = 0.0001) compared with Americans. High-risk intraocular retinoblastoma was more common in Asian Indians with a 2-fold greater risk compared with Americans (35% vs. 23%; odds ratio = 1.83; P = 0.003). Statistically significant differences in the histopathologic features (Asian Indians vs. Americans) included massive (≥3 mm) choroidal infiltration (17% vs. 6%; P = 0.0003) and optic nerve infiltration (48% vs. 15%; P = 0.0001). Asian Indians had a 5-fold greater risk of having optic nerve invasion (odds ratio = 5.45; P < 0.0001) and 3-fold greater risk of massive choroidal invasion (odds ratio = 2.80; P < 0.0001) compared with Americans. With appropriate use of adjuvant systemic chemotherapy, the difference in the rates of systemic metastasis (5% vs. 2%, P = 0.67) and related death in both countries (5% vs. 0%, P = 0.14) were not statistically significant. CONCLUSION High-risk intraocular retinoblastoma is more common in Asian Indians compared with Americans.

Introduction: Laser therapy is a cornerstone for control of intraocular retinoblastoma, after chemotherapy has brought the disease under initial control. Since first described over 6 decades ago, l...

Treatment of intraocular retinoblastoma is challenging. It requires a multidisciplinary personalized approach that includes focal treatments, chemotherapy, surgery and radiotherapy. Today, the focus of therapy has shifted to eye preservation with the major aim to save the child’s life and to preserve the eyeball as a functioning organ of vision with minimal complications. One of the most promising therapy approaches is selective intra-arterial chemotherapy (IAC), by which a cytostatic agent is given directly into the eye. This treatment modality has been shown to provide survival benefit and improvement of quality of life, reducing toxicity and minimizing side effects.

Orbital cellulitis associated with retinoblastoma is uncommon and is characterized by noninfectious inflammation of the periorbital structures. The underlying mechanism is thought to be necrosis of the intraocular tumor, leading to intraocular and periorbital inflammation. We report 2 retinoblastoma patients who presented with an orbital cellulitis-like picture and discuss clinical characteristics, histopathologic features, and treatment.

Background Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. Purpose To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. Study type Prospective case series. Population Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). Field strength/sequence In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. Assessment After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). Results Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 μm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 μm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. Data conclusion Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. Level of evidence 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.

The goal of this project was to demonstrate the feasibility of coupling the indirect ophthalmoscope laser delivery system with the 690 nm wavelength diode laser used to perform photodynamic therapy (PDT) in the treatment of retinoblastoma. For phase 1, a total of six pigmented rabbits were treated with the indirect laser delivery system. The laser source was provided by the Lumenis Opal 690 nm laser unit, delivered through a 810 nm Indirect ophthalmoscope headpiece and a hand-held 28-diopter indirect lens (1.0 mm spot size). Four rabbits received intravenous verteporfin at doses of 0.43 or 0.86 mg/kg, and two rabbits did not receive verteporfin (controls). A second phase of the study involved eight rabbits using a retinoblastoma xenograft to determine the effect of indirect PDT on subretinal tumors. For phase 1, a total of 20 laser treatments were performed in the right eyes of six rabbits. Laser power levels ranged between 40 and 150 mW/cm2 and treatment duration ranged between 1 and 3 min. In the four rabbits that received verteporfin, focal retinal scars were noted at 40 mW/cm2 and higher power levels. In the two control rabbits that did not receive verteporfin, thermal burns were confirmed at 75 mW/cm2 and higher power levels. Histopathology showed focal retino-choroidal scars at the site of PDT treatment, without evidence of generalized ocular damage. Using the retinoblastoma xenograft, the indirect PDT system was shown to cause areas of tumor necrosis on histopathology. The results of this pre-clinical study suggest verteporfin may be activated in the rabbit retina with the indirect delivery system and the 690 nm laser unit (i.e., Indirect PDT). Using verteporfin, treatment effects were observed at 40–50 mW/cm2 in the rabbit retina, while photocoagulation was achieved at 75 mW/cm2 and higher power levels. Fundoscopic and histopathologic examination of treated areas showed circumscribed areas of retinal damage and a lack of generalized ocular toxicity, suggesting that this modality may represent a safe and localized method for treating intraocular retinoblastoma.

Background Ophthalmic artery chemosurgery [OAC, intra-arterial chemotherapy (IAC)] was introduced in 2006 as treatment modality for intraocular retinoblastoma. The purpose of this commentary is to retrospectively review the incidence of metastatic deaths in retinoblastoma patients treated with OAC worldwide over a 10 year period. Retrospective data regarding metastatic deaths was collected from six international retinoblastoma centers (New York City USA, Philadelphia USA, Sao Paulo Brazil, Siena Italy, Lausanne Switzerland and Buenos Aires Argentina). All retinoblastoma patients from these centers (naive and recurrent, unilateral and bilateral) treated with OAC/IAC since 2006 have been included in this study. Data regarding number of patients, number of OAC/IAC infusions, number unilateral and bilateral, number treated for naive disease or salvage and number of metastatic deaths have been assessed. Over a 10-year period of time 1139 patients received OAC/IAC for 4396 infusions. At last follow-up there were only three metastatic deaths (all treated in Buenos Aires). Conclusion The current survey assessed the recorded risk of metastatic deaths in six retinoblastoma centers worldwide in children with retinoblastoma (unilateral or bilateral) treated with OAC/IAC as primary or secondary therapy. Overall, the observed risk for metastatic deaths from retinoblastoma was

To determine the diagnostic accuracy of conventional MRI in detecting tumour invasion of advanced intraocular retinoblastoma and to correlate ADC values with high-risk prognostic parameters. The sensitivities, specificities, positive predictive values (PPV), negative predictive values (NPV) and accuracies of MRI in detecting tumour-extent parameters of 63 retinoblastomas were determined. Furthermore, ADC values were correlated with high-risk prognostic parameters. MRI detected postlaminar optic nerve with a sensitivity of 73.3% (95% CI 44.9–92.2%) and a specificity of 89.6% (77.3–96.5%), while the specificity for choroidal invasion was only 31.8% (13.9-54.9%). Likewise, MRI failed to predicted early optic nerve invasion in terms of low sensitivity and PPV. In contrast, scleral and ciliary body invasion could be correctly excluded with high NPV. ADC values were significantly lower in patients with undifferentiated tumours, large tumour size, as with optic nerve and scleral invasion (all p

Purpose To report a patient who presented with a very late-onset new growth of intraocular retinoblastoma, which occurred 11 years after the initial combined treatment. Observations A 12-year-old monoophthalmic female patient presented with bilateral familial retinoblastoma showing new growth of intraocular tumor after 11 years of complete regression following combined local and systemic treatments. The new tumor growth was treated with diode laser transpupillary thermotherapy, ruthenium-106 plaque radiotherapy and adjuvant intravenous chemotherapy and the tumor regressed. Conclusions and importance Despite initial satisfactory treatment and complete regression of the tumor, very late-onset new growth of intraocular retinoblastoma can occur. Hence, life-long follow-up in all patients with retinoblastoma is warranted, given the risk for new tumor formation even later in life. To our knowledge, this is the first report of new growth of intraocular retinoblastoma after regression for more than a decade.

Background Conservative treatments of intraocular retinoblastoma often consist of chemotherapy and focal treatments. The protocols vary and currently may combine two or three drugs, with different number of cycles, associated to the ocular treatments. In case of macular/paramacular involvement, tumor location and retinal scars induced by focal treatments often have a major negative impact on final visual outcome. Methods This study aimed to include children affected by bilateral intraocular macular/paramacular retinoblastoma in a prospective phase II study. The protocol consisted of six cycles of a three-drug combination (vincristine, etoposide, carboplatin), and the addition of macula-sparing transpupillary thermotherapy (TTT) to the third cycle. The primary endpoint was the local control rate without external beam radiotherapy (EBR) and/or enucleation. Results Nineteen patients (26 eyes) were included from July 2004 to November 2009. Thirteen eyes belonged to group V of the Reese-Ellsworth classification and 10 to group D of the International Intraocular Retinoblastoma Classification. Macular/paramacular tumors were treated with chemotherapy alone in nine eyes, and with chemotherapy associated with macula-sparing TTT in 17 eyes. Four eyes experienced macular relapse. At a median follow up of 77 months, 23 eyes (88.5%) were saved without EBR, two were enucleated and one received EBR. The median visual acuity of the 24 saved eyes was 20/50. No severe adverse effect was observed. Conclusion Six cycles of a three-drug combination associated with macula-sparing TTT achieved good tumor control, improved eye preservation rates without EBR, and decreased macular damage, often providing satisfactory visual results with long-term follow up.

Objective Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively). Methods A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 μg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 μg. Results Overall, ERG decline (mean, 95% CI) for each injection was -5.58 μV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52). Conclusions and relevance No differences were found in retinal toxicity and ocular survival between 30 μg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.

Primary enucleation is a well-established method to achieve cure for advanced intraocular retinoblastoma. Recent treatment advances have induced a trend toward trial eye salvage using chemotherapy or other modalities. We investigated how pre-enucleation/postenucleation systemic chemotherapy and the resulting delayed enucleation affect patient survival after failed trial eye salvage.Multicenter, retrospective cohort study.Children with Group D and E retinoblastoma primarily or secondarily enucleated at 29 Chinese treatment centers.Data reviewed included clinical staging, time from diagnosis to enucleation, numbers of cycles of carboplatin, etoposide/teniposide and vincristine chemotherapy, disease-specific survival (DSS), histopathology, and follow-up.Primary outcome was DSS. Secondary outcome was histopathology of enucleated eyes.Primarily enucleated eyes had significantly shorter delay from diagnosis to enucleation than eyes treated with pre-enucleation chemotherapy (P0.001). Delay between diagnosis and enucleation3.5 months (Group D) and2 months (Group E) decreased survival (Group D: P = 0.018; Group E: P = 0.017). Compared with primarily enucleated children, children with 1 to 3 cycles of pre-enucleation chemotherapy for Group E eyes had no significant difference in survival (P = 0.74), but those who received ≥4 cycles had worse survival (P = 0.025). After pre-enucleation chemotherapy, more children with Group E (but not Group D) eyes had high-risk histopathology (pT3/pT4) (Group D: P = 0.076; Group E: P0.001) and worse survival than those primarily enucleated (P 0.001). Postenucleation chemotherapy improved survival of children with high-risk histopathology (pT3/pT4) (P = 0.001) but did not change survival of children with low-risk histopathology (pT1/pT2) (P = 0.52).We observed that pre-enucleation chemotherapy offered no survival benefit and timely enucleation minimized risk of metastatic death. Postenucleation chemotherapy improved survival of children with high-risk histopathology but was not useful for those with low-risk histopathology. These findings facilitate informed discussion on the risks and benefits of delayed enucleation, the use of systemic chemotherapy for trial salvage of eyes with advanced intraocular retinoblastoma, and the specific children who benefit from postenucleation chemotherapy.

Here we describe creation of a model of intraocular retinoblastoma on 4 mature immunodeficient BALB/c nude mice of both sexes. A suspension of the primary retinoblastoma culture was injected into each of the 8 eyes of the test animals. The injections were performed under the control of an operating microscope using insulin syringes with a diameter of 29G transsclerally into the subretinal space in a volume of 0.3 ml at a rate of 10,000 cells in 25 μl physiological saline. The culture of Rb10 cells derived from a patient with retinoblastoma passed 12 passages at the time of the experiments. After 9-week follow-up, a clinical (ophthalmoscopy) and instrumental (ultrasound) study was performed with visualization of the tumor mass on the fundus. After enucleation, a morphological study was performed. The retinoblastoma tumor nodes were identified in two eyes. The proposed model can be used for further research and for testing new chemotherapeutic drugs and treatment regimens for retinoblastoma.

PURPOSE: To determine the significance of large tumour size as a criteria for classifying advanced intraocular retinoblastoma, analysing rates of globe survival and high-risk (HE) histopathologic features. METHODS: Retrospective chart review of 212 eyes diagnosed with Group D (111 eyes) or Group E (101 eyes) retinoblastoma in at least one eye from January 1, 2006 to December 31, 2016 using the Los Angeles (LA) Classification System (no tumour size criteria for Group E). The 111 Group D tumours were then reclassified to Group E using 10, 12, 14, 16, 18 mm tumour size criteria, as determined by ultrasound or magnetic resonance imaging dimensions. RESULTS: For eyes in the original LA classification, 66.7% of Group D and 10.5% of Group E eyes undergoing globe preservation therapy avoided enucleation or radiotherapy (p < 0.0001; median follow-up of 33.0 months). In the LA classification, 8.5% of Group D and 26.3% of Group E enucleated globes had HE histopathologic features (p = 0.0065). When Group D eyes with tumours meeting the size criteria were reclassified to Group E, 65.7–74.4% of Group D and 16.1–36.7% of Group E eyes avoided enucleation or radiotherapy. Applying the tumour size criteria, 0–10.9% of Group D and 20.7–23.8% of Group E eyes had HE histopathologic features. CONCLUSION: Our retrospective analysis suggests that a large tumour size criteria for Group E retinoblastoma have no clinical basis, given that the LA classification system provided the greatest separation in globe salvage rates between Group D and E eyes. The LA classification system was also able to show a statistically significant difference in the rates of HE histopathologic features between Group D and E eyes. To avoid discrepancies in the literature, we recommend that centres use one uniform system for classifying advanced intraocular retinoblastoma.

Purpose Circulating tumor DNA (ctDNA) is released by many tumors into the plasma. Its analysis has minimal procedural risk and, in many cancers, has the potential for clinical applications. In retinoblastoma, the clinical correlations of ctDNA in eyes treated without enucleation have not been studied. This purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with unilateral retinoblastoma after intra-arterial chemotherapy (IAC) treatment. Variant allele frequency is a proxy for tumor fraction. Design Case series from a single tertiary cancer referral center. Participants Five patients with retinoblastoma with at least 1 measurable ctDNA plasma specimen both at the time of active intraocular retinoblastoma before IAC and after at least 1 IAC cycle. Methods Circulating tumor DNA RB1 was detected and VAF was measured before and after IAC treatment. Clinical correlations were made using clinical examination, fundus photography, ultrasound, and OCT. Main Outcome Measures Comparison of ctDNA RB1 VAF before and after IAC treatment for retinoblastoma and concordance of ctDNA RB1 detectability with activity of intraocular disease. Results Twenty-three ctDNA specimens were included from 5 patients. The 5 baseline RB1 VAFs ranged from 0.27% to 4.23%. In all patients, the subsequent post–intra-arterial RB1 VAF was lower than baseline (0.0%–0.17%). At 4 months (2 months after IAC completion), the ctDNA consistently was negative in the patients who demonstrated clinically inactive intraocular disease. Conclusions In this small cohort, a decremental decrease in ctDNA RB1 VAF was found after IAC, suggesting that relative VAF changes could be a biomarker of treatment response.

To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment.Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma.A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking.Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.

Aim: The aim of this study is to describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC) for intraocular retinoblastoma (RB). Materials and Methods: A retrospective, interventional series of 10 eyes with RB which underwent IAC using melphalan (5 mg/7.5 mg) and topotecan (1 mg), or melphalan (5 mg/7.5 mg) alone. Treatment outcomes were evaluated in terms of tumor control, vitreous seeds (VS) and subretinal seeds (SRS) control, and globe salvage rates. Results: Ten eyes of 10 patients underwent 38 IAC sessions (mean = 3.8; median = 4; range = 3–5 sessions). Following IAC, complete regression of main tumor was seen in 9 eyes (90%) and partial regression in 1 (10%). All four eyes with SRS showed complete regression (100%). Of 5 eyes with VS, 3 eyes (60%) showed complete regression, 1 eye (20%) showed relapse, while 1 eye (20%) showed no response. Globe salvage was achieved in 8 of 10 eyes (80%). Complications included transient ophthalmic artery narrowing (n = 2), branched retinal vein occlusion (n = 1), forehead skin pigmentation (n = 1), and vitreous hemorrhage (n = 2). There was no case of stroke, hemiplegia, metastasis, or death. Transient hematological changes included relative pancytopenia (n = 4), relative leukopenia (n = 5), and relative thrombocytopenia (n = 4). Mean follow-up was 26 months (median = 28, range = 13–36) from the initiation of first IAC. Conclusions: IAC is an effective therapy for globe preservation in eyes with intraocular RB, in the setting of a developing country like India. Larger studies with longer follow-up are required to validate these results.

Retinoblastoma is a highly malignant tumor of an eye, which is often detected at a far advanced stage in childhood. The most preferred treatment for such neoplasm is enucleation followed by placement of orbital implants. The affected child undergoes overwhelming psychological, social, emotional, and behavioral changes due to facial asymmetry resulting from enucleation. A team approach including pediatric ophthalmologist, psychologist, and a maxillofacial prosthodontist plays an important role in such cases helping such children in their reintegration in the society. This paper presents a case of a 4-year-old male patient who had undergone enucleation of his right eye due to intraocular retinoblastoma. The patient was rehabilitated cosmetically with precisely fabricated customized ocular prosthesis. An ocular prosthesis is a highly positive and noninvasive approach to improve the cosmetic appearance and psychological well-being of the patient.