Extraocular Spread Research Articles

A Case Series of Eye Removal Surgeries: Five Years of Experience at a Tertiary Eye Care Centre in Malaysia.

Eye removal surgeries, also called anophthalmic surgeries, are usually performed for a painful blinded eye due to various underlying causes. In this case review, we intended to study the indications, the types of anophthalmic surgeries, and post-operative complications related to eye removal surgeries. Five years of retrospective case review of surgical eye removals was conducted from 1st June 2018 to 31st May 2023 at Hospital Canselor Tuanku Muhriz (HCTM), University of Kebangsaan Malaysia (UKM). Medical record files were used to analyse the age, gender, affected eye, types of surgeries, and indications of the eye removal surgery. Fourteen eyes underwent anophthalmic surgeries inclusive of evisceration (78.57%, n = 11), enucleation (14.29%, n = 2), and exenteration (7.14%, n = 1). Among the evisceration group, 63.64% (n = 7) were due to endophthalmitis, 27.27% (n = 3) were due to ocular trauma, and 9.09% (n = 1) were done for a painful blind due to neovascular glaucoma. Two enucleation surgeries were performed for retinoblastoma and one exenteration for orbital metastatic malignancy. The preferred choice of anophthalmic surgery was in favour of evisceration, especially when the underlying causes were due to benign conditions. The most common indications of anophthalmic surgeries were endophthalmitis, trauma, and malignancies. Enucleationand exenterationwere performed mainly for the blinded eye due to the intraocular malignancies and malignancy with an extraocular spread. A fairly lesser number of anophthalmic surgeries over the five years could imply an improvement in the conservative management approach of a painful blinded eye.

Intraocular Surgery for Retinoblastoma: An Evaluation of Current Evidence

<b><i>Background:</i></b> Retinoblastoma (Rb) is the most common intraocular malignancy of childhood. The prognosis in Rb directly relates to the spread of disease beyond the eye, particularly to the central nervous system. Therefore, until the recent past, surgically entering an eye with active or recently active Rb was absolutely contraindicated in most centres around the world due to the risk of iatrogenic extraocular spread. <b><i>Summary:</i></b> In this review article, we explore the role of intraocular surgery in Rb. We describe the techniques which have been developed in order to safely deliver chemotherapeutic agents into the eye, both intravitreal and intracameral. We discuss the role of vitrectomy and endoresection for treatment of vitreous seeds and active retinal tumours. In the context of previously treated Rb, we outline various surgical interventions performed to improve visual outcomes or to manage the ocular sequelae of the disease. In particular, we review the various techniques used to maximise the safety of cataract, retinal and glaucoma surgery in children with a history of Rb. <b><i>Key Messages:</i></b> The role of intraocular surgery in Rb is now well established, particularly in the delivery of chemotherapeutic agents or in the presence of previously treated diseases. The role of intraocular surgery in eyes with active Rb is less well established and remains the subject of much debate. However, it is likely that with further development of safer surgical techniques, the indications and modalities will continue to broaden.

RETINOBLASTOMA IN AN OLDER CHILD: A CASE REPORT

Retinoblastoma is the most common intraocular malignancy of childhood. More than 90% of the patients are under 5-years old. It is uncommon in age above 5 years. In this study we report a case of retinoblastoma in a 9-year-old girl. She presented to our department with decreased vision in left eye noted for 6 days. Vision loss was non-progressive, associated with mild pain. Snellen’s acuity in the affected eye was light perception only. There were no signs of active inflammation in the anterior chamber. Anterior vitreous face demonstrated exuberant vitreous inflammation. A large, elevated, sessile lesion occupying the inferotemporal quadrant was seen just behind the lens with significant adjacent inflammation. Right eye examination was unremarkable. Ultrasound and Magnetic Resonance Imaging demonstrated retinoblastoma with no extra-ocular spread. Enucleation was done and biopsy of ocular tissue and bone marrow trephine biopsy was found normal. We conclude that any suspicious lesion in childhood must be evaluated for retinoblastoma. Even in older child the retinoblastoma may be localized and may have good visual prognosis.

Simultaneous Copy Number Alteration and Single-Nucleotide Variation Analysis in Matched Aqueous Humor and Tumor Samples in Children with Retinoblastoma.

Retinoblastoma (RB) is a childhood cancer that forms in the developing retina of young children; this tumor cannot be biopsied due to the risk of provoking extraocular tumor spread, which dramatically alters the treatment and survival of the patient. Recently, aqueous humor (AH), the clear fluid in the anterior chamber of the eye, has been developed as an organ-specific liquid biopsy for investigation of in vivo tumor-derived information found in the cell-free DNA (cfDNA) of the biofluid. However, identifying somatic genomic alterations, including both somatic copy number alterations (SCNAs) and single nucleotide variations (SNVs) of the RB1 gene, typically requires either: (1) two distinct experimental protocols-low-pass whole genome sequencing for SCNAs and targeted sequencing for SNVs-or (2) expensive deep whole genome or exome sequencing. To save time and cost, we applied a one-step targeted sequencing method to identify both SCNAs and RB1 SNVs in children with RB. High concordance (median = 96.2%) was observed in comparing SCNA calls derived from targeted sequencing to the traditional low-pass whole genome sequencing method. We further applied this method to investigate the degree of concordance of genomic alterations between paired tumor and AH samples from 11 RB eyes. We found 11/11 AH samples (100%) had SCNAs, and 10 of them (90.1%) with recurrent RB-SCNAs, while only nine out of 11 tumor samples (81.8%) had positive RB-SCNA signatures in both low-pass and targeted methods. Eight out of the nine (88.9%) detected SNVs were shared between AH and tumor samples. Ultimately, 11/11 cases have somatic alterations identified, including nine RB1 SNVs and 10 recurrent RB-SCNAs with four focal RB1 deletions and one MYCN gain. The results presented show the feasibility of utilizing one sequencing approach to obtain SCNA and targeted SNV data to capture a broad genomic scope of RB disease, which may ultimately expedite clinical intervention and be less expensive than other methods.

Seasonal Variation in the Diagnosis of Retinoblastoma

ABSTRACT Purpose To determine the seasonal variation in the diagnosis of retinoblastoma in a global sample of children and to investigate predictors of seasonal trends. Methods Data were collected through a global, multicenter, 1-year cross-sectional analysis that included all treatment- naïve retinoblastoma patients presenting to participating centers between January 1, 2017, and December 31, 2017. Due to variations in days per month, data were normalized to a 30-day/month calendar. Observed data were compared to a simulation study of expected results using a uniform distribution. Results Patient-level data were available for 4,351 children from 276 centers in 153 countries, of which 3,966 had a month of presentation recorded. There were relative peaks in disease presentation in January and July, with lower counts in November and December (p = .0015). No covariates were found to be significantly associated with the seasonal trend. Two covariates, patient age at presentation and extraocular tumor spread, showed a moderate association with month of presentation. Conclusion Our findings suggest seasonal trends in the presentation of retinoblastoma across the world. However, these trends do not appear to be related to income level of a country, climate, or other covariates. Any connection between seasonal variation of retinoblastoma presentation and retinoblastoma outcomes remains unclear or not present.

Extraocular retinoblastoma: literature review and clinical case (intracranial retinoblastoma involving the visual tracts)

Relevance. Retinoblastoma (RB) is the most common primary intraocular tumor in children. The incidence of RB ranges from 1:14,000 to 1:20,000 newborns. To date, the survival rates of patients with RB reach almost 100 % with timely and adequate diagnosis. Among childhood oncological diseases, RB accounts for 2.3–4.5 % and 85–90 % among intraocular tumors in children. According to the volume of tumor spread, intra- and extraocular forms of the disease are distinguished. Extraocular RB is the spread of the tumor beyond the eye with invasion of the orbital tissues, as well as the possible involvement of adjacent areas, including intracranial without and with regional and/or remote metastases. The main method of treatment of children with extraocular RB is neoadjuvant chemotherapy (CT) with planning of surgical intervention and adjuvant therapy. High-dose CT (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT), it allows to increase relapse-free survival in patients without metastatic lesions of the brain and spinal cord, but with their defeat, the prognosis of survival is extremely unfavorable, the nature of the disease is recurrent with 100 % lethality.Description of the clinical case. We report a case of bilateral RB: OD – with extraocular and intracranial spread of the tumor along the optic nerve with a lesion of the chiasm and a transition to the initial parts of the visual tracts. Secondary glaucoma. OS – with intraocular tumor growth in a 3-year-old child. After neoadjuvant chemotherapy, including intrathecal, a simultaneous two-stage operation was performed in the volume of bone-plastic (temporo-orbito-zygomatic) pterionic craniotomy on the right with prechiasmal resection of the right optic nerve and enucleation of the right eye. In the postoperative period, adjuvant chemotherapy was performed, followed by HDCT with auto-HSCT. Radiation therapy has become the final stage of treatment. Brachytherapy for OS tumor and remote radiotherapy for craniospinal region, right orbit, optic nerve stump with chiasm and pituitary pedicle were successively performed. After 14 months from the beginning of treatment and 5 months after its completion, a leptomeningeal relapse of the disease was detected.Conclusion. Rare observations of RB with damage to the visual tracts do not allow us to sufficiently study the features of the course of the tumor process, as well as to develop a single effective approach to antitumor treatment. Among the causes of mortality in patients with extraocular RB, the main one is metastasis, metastasis in the brain and spinal cord.

The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries

SummaryBackgroundRetinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival.MethodsWe did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models.FindingsThe cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope).InterpretationThis study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.FundingQueen Elizabeth Diamond Jubilee Trust.

Role of Fine Needle Aspiration Cytology (FNAC) in the Diagnosis of Adult-Onset Retinoblastoma: A Case Report

We report the role of fine needle aspiration cytology (FNAC) for suspected intraocular tumor in the case of a 25 year old man who presented with the chief complaint of a whitish reflex and painless diminution of vision in the right eye for 3 months. Examination revealed a large intraocular mass with overlying retinal detachment. B-scan ultrasonography revealed an intraocular mass with foci of intralesional calcification. Systemic workup was unremarkable. MRI of the brain and orbit ruled out extra ocular spread. Based on clinical suspicion of either amelanotic melanoma or adult-onset retinoblastoma, fine needle aspiration cytology (FNAC) was done which revealed retinoblastoma. The patient underwent primary enucleation of the right eye and histopathological analysis confirmed the diagnosis of retinoblastoma.

Extrascleral Extension from Choroidal Melanoma Diagnosed on Doppler Ultrasound

A 50-year-old woman was referred to our service with an amelanotic choroidal tumor in the right eye that we believed was a melanoma (Fig A). B-scan ultrasound suggested extraocular spread in the region of the inferior oblique muscle (Fig B). A Doppler scan showed that the tumor had blood flow (9.2 cm/s), distinguishing it from muscle (Fig C). Histology of the enucleated globe confirmed the diagnosis of choroidal melanoma with extrascleral extension (Fig D) (Magnified version of Fig A-D is available online at www.aaojournal.org).

Usefulness of Liquid Biopsy for Intraocular Malignancies

Retinoblastoma (RB) is the most common primary intraocular malignancy in children, whereas Uveal melanoma (UM) is the most common intraocular malignancy in adults [1,2]. Tissue biopsy is the standard gold technique for diagnosing the malignant neoplasm but an incisional tissue biopsy or fine needle aspiration biopsy (FNAB) is contraindicated for the intraocular malignancy [3]. Clinical diagnosis and imaging study are the only way to diagnose the intraocular malignancy due to the risk and fear of extraocular spread [4]. Recently, liquid biopsy has gained in popularity in the ophthalmic field. Liquid biopsy allows retinoblastoma diagnosis and a better understanding of the metastatic spread of uveal melanoma. Recently, the USA Food and Drug Administration (FDA) approved the make use of liquid biopsy (LB) as an appropriate diagnosis, prognosis, and also for monitoring tool in non-small cell lung carcinoma to keep away from invasive tissue biopsy in designated cases [5-7]. Liquid biopsy (LB) utilizes biofluid to evaluate for tumor-derived cells or cell-free DNA. LB is a relatively non-invasive technique rather than a tissue biopsy. In LB, material collected from multiple body fluids such as aqueous humor (AH), blood, cerebrospinal fluid, urine, and saliva for molecular diagnosis [8] and detecting of cancer biomarkers such as circulating tumor cells (CTC), tumor derived cell free DNA (ct-DNA), circulating tumor RNA (ct-RNA), microRNA (miRNA), tumorrelated exosomes (TREs), and extracellular vescicles (EVs) [7]. Aqueous humor samples for RB (Ocular LB) and Venous blood samples for UM (systemic LB) are utilizing for analyzing the molecular characteristics [8]. In others ophthalmic malignancies like conjunctival melanoma or squamous cell carcinoma, the role of LB is still not studied because tissue biopsy is routinely done for confirming the diagnosis and also for mutational status [9-11].

Gain of Chromosome 6p Correlates with Severe Anaplasia, Cellular Hyperchromasia, and Extraocular Spread of Retinoblastoma.

PurposeGain of chromosome 6p has been associated with poor ocular survival in retinoblastoma and histopathologic grading of anaplasia with increased risk of metastatic spread and death. This study examined the correlation between these factors and other chromosomal abnormalities as well as results of whole genome sequencing, digital morphometry, and progression-free survival.DesignRetrospective cohort study from 2 United States tertiary referral centers.ParticipantsForty-two children who had undergone enucleation for retinoblastoma from January 2000 through December 2017.MethodsStatus of chromosomes 6p, 1q, 9q, and 16q was evaluated with fluorescence in situ hybridization, the degree of anaplasia and presence of histologic high-risk features were assessed by ocular pathologists, digital morphometry was performed on scanned tumor slides, and whole genome sequencing was performed on a subset of tumors. Progression-free survival was defined as absence of distant or local metastases or tumor growth beyond the cut end of the optic nerve.Main Outcome MeasuresCorrelation between each of chromosomal abnormalities, anaplasia, morphometry and sequencing results, and survival.ResultsForty-one of 42 included patients underwent primary enucleation and 1 was treated first with intra-arterial chemotherapy. Seven tumors showed mild anaplasia, 19 showed moderate anaplasia, and 16 showed severe anaplasia. All tumors had gain of 1q, 18 tumors had gain of 6p, 6 tumors had gain of 9q, and 36 tumors had loss of 16q. Tumors with severe anaplasia were significantly more likely to harbor 6p gains than tumors with nonsevere anaplasia (P < 0.001). Further, the hematoxylin staining intensity was significantly greater and that of eosin staining significantly lower in tumors with severe anaplasia (P < 0.05). Neither severe anaplasia (P = 0.10) nor gain of 6p (P = 0.21) correlated with histologic high-risk features, and severe anaplasia did not correlate to RB1, CREBBP, NSD1, or BCOR mutations in a subset of 14 tumors (P > 0.5). Patients with gain of 6p showed significantly shorter progression-free survival (P = 0.03, Wilcoxon test).ConclusionsGain of chromosome 6p emerges as a strong prognostic biomarker in retinoblastoma because it correlates with severe anaplasia, quantifiable changes in tumor cell staining characteristics, and extraocular spread.

Tylectomy Safety in Salvage of Eyes with Retinoblastoma

Simple SummaryThe 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.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.

The Effects of Breastfeeding on Retinoblastoma Development: Results from an International Multicenter Retinoblastoma Survey.

Simple SummaryBreastfeeding has been shown to lower the risk of oncogenesis in many pediatric cancers, with longer periods of breastfeeding having the most protective effect. However, an association has not yet been determined for the consequence or benefit of breastfeeding in retinoblastoma (RB), the most common intraocular malignancy of childhood affecting 8000 children worldwide each year. Herein, we aimed to understand the role of breastfeeding in the severity of development of nonhereditary RB, specifically its relationship to age at diagnosis, ocular prognosis, and extraocular involvement. Our analysis of 344 patients indicated that neither breastfeeding nor formula feeding was associated with differences in age at diagnosis, ocular prognosis, or extraocular involvement. More research elucidating the factors affecting the development of RB is warranted both to understand the pathophysiology of tumor development and to develop clinical recommendations for preventive care.The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted.

Management of cataracts secondary to intravitreal chemotherapy injections for retinoblastoma seeding.

To report our experience in the management of cataracts presumably due to intravitreal chemotherapy administration in eyes with vitreous disease associated with retinoblastoma. This retrospective study consisted of a cohort of five eyes of five retinoblastoma patients who developed cataracts secondary to intravitreal chemotherapy administration and who then underwent cataract surgery. All patients underwent lensectomy and anterior vitrectomy with/without intraocular lens implantation via clear corneal approach. All cases were administered intraoperative intravitreal melphalan (35-40 mcg) and topotecan (10-20 mcg) at the end of cataract surgery as a preventive measure against retinoblastoma spread. Injections were repeated as needed in monthly follow-ups. Main outcome measures were enucleation rate and disease-free survival time. The age at surgery ranged between 5 and 10 years. Follow-up time varied from 12 to 16 months. Treatment-free period before surgery ranged between 3 and 20 months. Time from last injection to cataract detection was: 2, 2, 10, 6, and 7 months; and time from last injection to cataract surgery was: 8, 3, 20, 7, and 15 months in cases 1-5, respectively. None of the eyes required enucleation. Tumor control was achieved in all patients at the end of follow-up. Injection of melphalan and topotecan into anterior parts of the vitreous may lead to cataract formation. This can be safely managed with lensectomy and anterior vitrectomy and the use of intravitreal administration of melphalan and topotecan at the conclusion of the surgery as a precautionary measure against the potential risk of extraocular spread.

Pathologic evidence of retinoblastoma seeds supported by field emission scanning electron microscopy and Raman spectroscopy.

Purpose:The aim of this study was to examine the pathology of retinoblastoma (RB) seeds with supportive evidence by field emission scanning electron microscopy and Raman spectroscopy.Methods:This study was a laboratory-based observational study. Enucleated eyeballs received in the ocular pathology department of a tertiary eye care center in northeast India were included in the cohort after obtaining written informed consent during the surgery. The study was carried out for 6 years (2015–2020). Most of the eyeballs were Group-E RBs. Standard eyeballs sectioning were done by bread loaf techniques. Gross documentations included RB seeds seen in the smallest calotte done with utmost care. Seeds were documented also in permanent sections. Scanning electron microscopy and Raman spectroscopy were carried out in an index case.Results:Out of the total 59 cases, 35 RB cases had different seedings. The mean age at enucleation was 2.9 years. RB seeds were seen in vitreous (n = 19), subretinal plus vitreous (n = 7), anterior chamber (n = 1), over crystalline lens (n = 3), retinal surface (n = 1), retinal pigment epithelium (RPE; n = 2), subretinal (n = 1), calcified seeds (n = 2). Other characteristics were dusts (n = 7), clouds (n = 11), spheres (n = 4), and unspecified type (n = 13). Histopathological high-risk factors showed significant choroidal (n = 22) and optic nerve (n = 15) involvement. Few cases had extraocular spread. Undifferentiated tumor (n = 24) was seen with higher evidence of necrosis (n = 23). Raman spectra differentiated the seeds from the normal tissue on the basis of lipid and protein content.Conclusion:This study highlights the different types of RB seeds with high-risk factors. The morphology of those seeds showed the difference between vitreous and subretinal seeds under advanced microscopic observations.

International travel to obtain medical treatment for primary retinoblastoma: A global cohort study.

Early diagnosis and treatment of retinoblastoma (Rb), the most common intraocular malignancy, can save both the child's life and vision. However, access to services and hence chances for survival and preserving the eye and its vision vary widely across the globe. Some families have to, or make a choice to, leave their home country to seek planned medical treatment abroad. We aimed to investigate how frequently this cross-border travel occurs and the factors associated with it. A total of 278 Rb centres in 153 countries were recruited to participate in a global cross-sectional analysis of newly diagnosed Rb patients in 2017. Number and proportions of children who travelled from their home country for treatment were analysed by country, continent, socioeconomic stratum and clinical and demographic features. The cohort included 4351 new patients of whom 223 [5.1%, 95% confidence interval 4.5-5.8] were taken across country borders for planned medical treatment. Independently significant predictors of travelling across borders included: being from a country with a smaller population, being from a country classified as low socioeconomic status, having bilateral Rb and having intraocular disease without extraocular spread. The factors that determine international travel for Rb treatment are complex and deserve further investigation. We may need to rethink the way services are delivered in the light of the threat of severe curtailment of international travel from pandemics like corona virus disease 2019.

Interventions to improve early detection of childhood cancer in low- and middle-income countries: A systematic review.

Childhood cancer outcomes in low- and middle-income countries (LMICs) lag behind those in high-income countries (HICs), in part due to late presentation and diagnosis. Though several interventions targeting early detection of childhood cancer have been implemented in LMICs, little is known about their efficacy. We conducted a systematic review to identify studies describing such interventions. We searched multiple databases from inception to December 4, 2019. Studies were included if they reported on LMIC interventions focused on: (a) training of health care providers on early recognition of childhood cancer, or (ii) public awareness campaigns. We used preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines to conduct our review. The risk of bias in nonrandomized studies of interventions (ROBINS-I) checklist was used to assess quality of studies. Twelve studies met inclusion criteria (n=5 full text, n=7 abstract only). Five studies focused on retinoblastoma only, while the others focused on all types of childhood cancer. The majority studied multiple interventions of which early detection was one component, but reported overall outcomes. All identified studies used pre-post evaluative designs to measure efficacy. Five studies reported statistically significant results postintervention: decrease in extraocular spread of retinoblastoma, decrease in rates of refusal/abandonment of treatment, increase in number of new referrals, increase in knowledge, and an absolute increase in median 5-year survival. Other studies reported improvements without tests of statistical significance. Two studies reported no difference in survival postintervention. The ROBINS-I checklist indicated that all studies were at serious risk of bias. Though current evidence suggests that LMIC interventions targeting early detection of childhood cancer through health professional training and/or public awareness campaigns may be effective, this evidence is limited and of poor quality. Robust trials or quasi-experimental designs with long-term follow up are needed to identify the most effective interventions. Such studies will facilitate and inform the widespread uptake of early detection interventions across LMIC settings.

Recurrent retinoblastoma with intracranial extension post enucleation

Retinoblastoma amounts to be the most common intraocular childhood malignancy. More than 95% retinoblastoma are diagnosed before age five. Retinoblastoma may be sporadic or inherited. In both cases the tumor origin is biallelic mutation. Staging of retinoblastoma is based on intraocular location, extraocular & extraorbital spread, central nervous system involvement and systemic metastases. Diagnosis and management of retinoblastoma demands multidisciplinary approach, for which accurate imaging is indispensable. Concerns of the effects of radiation in retinoblastoma have led to a shift from radiation therapy to chemotherapy and locoregional treatment and magnetic resonance imaging becoming the standard imaging modality for diagnosis, staging and treatment monitoring. Keywords: Retinoblastoma, Retinoblastoma with Intracranial extension, Recurrent retinoblastoma.

Abstract B63: Survivorship, vision, and eye salvage following pars plana vitrectomy for residual active or recurrent retinoblastoma

Abstract Introduction: Intraocular surgery has long been taboo in the management of eyes with retinoblastoma due to concern of extraocular spread that carries poor survivorship. Pars plana vitrectomy (PPV) and tumor endoresection has recently emerged in China as an effective surgical treatment to salvage eyes with tumor resistant to chemotherapy, the current standard of care. To investigate the safety and efficacy of this novel treatment, we studied survivorship, visual acuity, and eye salvage rate of retinoblastoma children/eyes treated with PPV. Methods: Outcomes were reviewed for 227 children (247 eyes) treated with PPV and endoresection for residual active tumor or recurrent tumor following chemotherapy at 29 Chinese centers between 2013 and 2014. Results: At 5 years following PPV, 14 patients died, 8 related to the eye that had PPV. The 5-year overall survival rate following PPV was 93.7% (95% CI: 90.4% to 97.0%). The 5-year PPV eye-related survival rate (PPVSR) was 96.3% (95% CI: 93.8% to 98.9%). Children with PPV for residual active tumor had better survival than those with PPV for recurrent tumor (5-year PPVSR 98.1% vs. 91.4%, P = .021). Children with 1 to 3 cycles of neoadjuvant chemotherapy (intra-arterial or systemic chemotherapy) prior to PPV had similar survival to children with ≥4 cycles of chemotherapy (98.2% vs. 93.7%, P = .093). Children with adjuvant systemic chemotherapy following PPV had 100% (95% CI: 93.5% to 100%) 5-year PPVSR, not significantly higher than those without adjuvant chemotherapy (100% vs. 94.8%, P = .102). Of 94 eyes with partial or no retinectomy and documented visual acuity, the post-PPV visual acuity was 20/20-20/60 (23, 24%); 20/7-20/160 (6, 6%); 20/17-20/400 (9, 10%); counting fingers, hand motion, or light perception vision (42, 45%); and no light perception (NLP) (14, 15%). Complete retinectomy was performed on 93 of 247 (37.7%) eyes that, as expected, had NLP. The 5-year eye salvage rate following PPV was 80.7% (95% CI: 75.5% to 85.9%). PPV for residual active tumor and recurrent tumor had similar eye salvage rate (82.0% vs. 76.8%, P = .372). Eyes with International Intraocular Retinoblastoma Classification (IIRC) A, B, or C staging had better salvage rate than eyes with IIRC D or E staging (100.0% vs. 78.1%, P = .005). Eyes that received 1 to 3 cycles and ≥4 cycles of neoadjuvant chemotherapy had similar salvage rate (81.4% vs. 79.8%, P = .796). Conclusion: We observed that PPV salvaged 80.7% of eyes with residual active tumor after primary chemotherapy or recurrent tumor after remission. The 5-year eye-specific survival was 96.3%, comparable to survivorship using other treatment modalities. More cycles of neoadjuvant chemotherapy did not improve survivorship or eye salvage rate. In this cohort, all children with adjuvant chemotherapy following PPV survived at 5 years. PPV may be a game changer to improve health outcomes of patients with retinoblastoma, with the potential to become the new standard of care. Citation Format: Junyang Zhao, Zhao Xun Feng, Qiyan Li, Songyi Wu, Liwen Jin, Brenda L. Gallie. Survivorship, vision, and eye salvage following pars plana vitrectomy for residual active or recurrent retinoblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B63.

Proteomic Profiling of Retinoblastoma-Derived Exosomes Reveals Potential Biomarkers of Vitreous Seeding.

Retinoblastoma (RB) is the most common tumor of the eye in early childhood. Although recent advances in conservative treatment have greatly improved the visual outcome, local tumor control remains difficult in the presence of massive vitreous seeding. Traditional biopsy has long been considered unsafe in RB, due to the risk of extraocular spread. Thus, the identification of new biomarkers is crucial to design safer diagnostic and more effective therapeutic approaches. Exosomes, membrane-derived nanovesicles that are secreted abundantly by aggressive tumor cells and that can be isolated from several biological fluids, represent an interesting alternative for the detection of tumor-associated biomarkers. In this study, we defined the protein signature of exosomes released by RB tumors (RBT) and vitreous seeding (RBVS) primary cell lines by high resolution mass spectrometry. A total of 5666 proteins were identified. Among these, 5223 and 3637 were expressed in exosomes RBT and one RBVS group, respectively. Gene enrichment analysis of exclusively and differentially expressed proteins and network analysis identified in RBVS exosomes upregulated proteins specifically related to invasion and metastasis, such as proteins involved in extracellular matrix (ECM) remodeling and interaction, resistance to anoikis and the metabolism/catabolism of glucose and amino acids.