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Primary orbital retinoblastoma, optic nerve extension. Axial computed tomography scan showing optic nerve extension of retinoblastoma in the left eye as indicated by gross thickening of the optic nerve up to the orbital apex
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Orbital extension is a major cause of death in children with retinoblastoma in the developing countries. Delayed detection and inappropriate management contribute to poor outcome. Conventional treatment including primary orbital exenteration or chemotherapy or radiotherapy alone result in mortality as high as 70%. The recent understanding on the ro...
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Background: Households affected by HIV/AIDS are at an increased risk for food insecurity and malnutrition. Poor nutrition contributes to more than a third of all deaths associated with infectious diseases among children under 5 years of age in developing countries
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... This is followed by EBRT and 12 additional cycles of chemotherapy. 148 The appropriate treatment of retinoblastoma is complex (Fig. 5). Given that each case presents its own set of unique challenges, it is imperative that treatment strategies are meticulously customized to account for specific disease manifestations, resource availability, as well as regional cultural norms and traditions. ...
... Identifying early signs of RB like leukocoria, 4 signaled by an absent red reflex in childhood, and offering rapid intervention can help confer an improved prognosis. Late signs of the disease include manifestations of orbital extension, 5 such as proptosis and iris neovascularization. Tumors have a poorer prognosis when identified at this stage. ...
Retinoblastoma (RB) is a rare malignant tumor that arises in the developing retina in one or both eyes of children. Pathogenic variants of the RB1 tumor suppressor gene drive the majority of germline and sporadic RB tumors. Considering the risk of tumor spread, the biopsy of RB tumor tissue is contraindicated. Advancement of chemotherapy has led to preservation of more eye globes. However, this has reduced access to tumor material from enucleation specimens. Recently, liquid biopsy of aqueous humor (AH) has advanced the RB tumor- or eye-specific genetic analysis. In particular, nucleic acid analysis of AH demonstrates the genomic copy number profiles and RB1 pathogenic variants akin to that of enucleated RB eye tissue. This advance reduces the previous limitation that genetic assessment of the primary tumor could be done only after enucleation of the eye. Additionally, nucleic acid evaluation of AH allows the exploration of the genomic landscape of RB tumors at diagnosis and during and after treatment. This review explores how AH sampling and AH nucleic acid analysis in RB patients assist in diagnosis, prognosis, and comprehending the pathophysiology of RB, which will ultimately benefit individualized treatment decisions to carefully manage this ocular cancer in children.
... Scleral invasion was seen in 7.7% (n=6) cases, which was in keeping with other studies, such as that in Argentina with 8.8% and Pakistan with 7% [17]. Orbital extension was seen in 16.7% (n=13) cases, which is comparable to 18% in an Indian study [20]. This is due to the advanced stages of the tumours in developing countries. ...
Background: Retinoblastoma (RB) is a malignant tumour that develops from the immature cells of the retina. It is the most frequent type of paediatric intraocular cancer and is curable. Clinical and histological findings after enucleation of the affected eye dictate not only the patient's secondary care but also their prognosis. We assessed the clinical and histopathologic predictors of survival among children with RB from two tertiary health facilities in Uganda.
Methods: This retrospective research utilized archived formalin fixed and paraffin-embedded blocks of eye specimens enucleated between 2014 and 2016 at Mbarara University of Science and Technology (MUST) Pathology Department and Ruharo Eye Centre (REC) in Mbarara, Uganda. The specimens were then processed and stained with haematoxylin and eosin. The confirmation of RB was made to include the histologic stage and features of the tumor. Biographic data of the patients and clinical features, such as leukocoria, proptosis, phthisis, staphyloma and buphthalmos, were retrieved from the records.
Results: Males (55.1%, n=43) dominated the study population (N=78). The median age was 31 months. The most common clinical sign was leukocoria (69.2%, n=52), and the most predominant histopathological stage was stage 1 (41%, n=32). Optic nerve (ON) invasion was seen in 38.5% (n=30), choroidal invasion in 29.5% (n=23), scleral invasion in 7.7% (n=6) and orbital extension in 16.7% (n=13) of the cases. Flexner-Wintersteiner rosettes were seen in 34.6% (n=27). Necrosis was a prominent feature (71.8%, n=56). The two-year survival was estimated to be 61.5% (n=48). Leukocoria (risk ratio (RR) 1.1), female gender (RR 1.4), intralaminar ON invasion (RR 7.6) and a lack of orbital extension (RR 7) were significant predictors of survival.
Conclusion: Leukocoria and proptosis are noticeable clinical signs of RB. Most patients present while in stage one although stage four presentation is also common. Leukocoria, ON invasion, orbital extension and gender are significant factors predictive of survival in patients with RB.
... Scleral invasion was seen in 7.7% cases which was in keeping with other studies such as that of Argentina at 8.8%, and 7% of Pakistan [30,31]. Orbital extension was seen in 16.7% which is comparable to 18% in Indian study [32]. This is due to the advanced stages of the tumours in developing countries. ...
... The presence of orbital invasion was associated with a 10-27 times higher risk of systemic metastasis as compared to cases without orbital invasion. This is in agreement with studies done in USA and in India [32,42]. ...
BACKGROUND: Retinoblastoma is a malignant tumour that develops from the immature cells of the retina. It is the most frequent type of paediatric intraocular cancer and is curable. Clinical and histological findings after enucleation of the affected eye dictate not only the patient's secondary care but also their prognosis. We assessed the clinical and histopathologic predictors of survival among children with retinoblastoma from two tertiary health facilities in Uganda. METHODS: This retrospective research utilized archived formalin fixed & paraffin embedded blocks of eye specimens enucleated between 2014 to 2016 at Mbarara University, pathology department and Ruharo Eye Centre. The specimens were then processed and stained with haematoxylin and eosin. The confirmation of retinoblastoma was made to include histologic stage and features of the tumor. Biographic data of the patients and the clinical features such as leukocoria, proptosis, phthisis, staphyloma, buphthalmos were retrieved from the records.RESULTS: Males (55.1%) dominated the study population (N=78). The median age was 31 months. The commonest clinical sign was leukocoria (69.2%) and the most abundant histopathological stage was stage 1 (41%). Optic nerve invasion 39.5%, choroidal invasion 29.5%, scleral invasion 7.7% and orbital extension 16.7% were seen. Flexner-Wintersteiner rosettes were seen in 24.6%. Necrosis was a prominent feature (71.2%). The two-year survival was estimated to be 62%. Leukocoria (RR 1.1), female gender (RR 1.4), intralaminar optic nerve invasion (RR 7.6) and a lack of orbital extension (RR- 7) were significant predictors of survival.CONCLUSION: Leukocoria and proptosis are noticeable clinical signs of retinoblastoma. Most patients present while in stage one although stage four presentation is also common. Leukocoria, optic nerve invasion, orbital extension, and gender are significant factors predictive of survival in patients with retinoblastoma.
... 5,6,12 In low-and middle-income countries, mortality rates of these patients may be as high as 50 to 90% although some promising results were published for patients with extraocular disease limited to the orbit and/or preauricular nodes. 1,2,5,7,8,[26][27][28] On the other hand, metastatic patients with orbital disease usually present with a poor clinical status and rapid deterioration making it essential to provide treatments that exert a fast response and prevent local relapse. Thus intensive multimodal treatments are used showing important benefits compared to historical cohorts in terms of overall survival. ...
Purpose:
Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term toxicity (including death). We studied orbital and systemic exposure of topotecan in the swine model after ophthalmic artery chemosurgery (OAC) and intravenous (IV) delivery.
Methods:
Landrace pigs (n = 3) underwent 30-minute OAC of topotecan (4 mg), and samples were serially obtained from the femoral artery and from a microdialysis probe inserted into the lateral rectus muscle sheath of the infused eye as a surrogate of the orbital irrigation. Animals were recovered, and, after a wash-out period, plasma and microdialysate samples from the contralateral eye were collected after a 30-minute IV infusion of topotecan (4 mg). Samples were quantified by high-performance liquid chromatography, and population pharmacokinetic analysis was conducted using MonolixSuite.
Results:
After OAC, median topotecan exposure in the orbit was 5624 ng × h/mL (range 3922-12531) compared to 23 ng × h/mL (range 18-75) after IV infusion. Thus, topotecan exposure in the orbit was 218-fold (range 75-540) higher after OAC than after IV infusion despite comparable systemic exposure (AUCpl) between routes (AUCpl, OAC: 141 ng × h/mL [127-191] versus AUCpl, IV: 139 ng × h/mL [126-186]). OAC was more selective to target the orbit because the median (range) orbital-to-plasma exposure ratio was 44 (28-65) after OAC compared to 0.18 (0.13-0.40) after IV infusion.
Conclusions:
OAC of topotecan resulted in higher orbital exposure than after IV infusion and was a more selective route for local drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy.
... Poor vision, strabismus, a white hue, and pain with tenderness in the eye are common clinical findings at the time of presentation [3,4]. Compared to patients without orbital invasion, the frequency of orbital invasion is linked to a 10-to 27-fold higher risk of metastasis [5,6]. Optic nerve invasion with or without the involvement of a resection margin, choroidal invasion, and enucleation of an affected eye more than 120 days after initial diagnosis have all been demonstrated to be independently linked with the emergence of metastases [7]. ...
Retinoblastoma makes up about 3% of all childhood malignancies. The frequency of metastatic retinoblastoma ranges from 4.8 to 11%. Assessing the bone marrow status of newly diagnosed patients is crucial because of the advantages of autologous bone marrow transplants for high-risk patients. This study aimed to determine the utility of bone marrow examination in cases of retinoblastoma and its correlation with hematological findings. This retrospective study was conducted at the Department of Pathology, King George’s Medical University, Lucknow, India. A total of 34 cases of retinoblastoma with bone marrow examination were included in the study. Bone marrow infiltration was present in 17.65% (6/34) cases of retinoblastoma. Bone marrow aspirate myelogram showed that marrow metastasis in retinoblastoma was significantly linked with a reduced percentage of total myeloid cells (p=0.001) and segmented cells (p=0.006). The present study demonstrated that 15% (3/20) of retinoblastoma patients previously classified as nonmetastatic before bone marrow examination (stages I to III based on histology, imaging, and bone scan) had bone marrow metastases following bone marrow examination and were upgraded to stage IV. To conclude, a diligent and exhaustive search for metastatic cells in bone marrow is advised if the myelogram shows a reduced percentage of total myeloid and segmented cells. All stage II and stage III cases of retinoblastoma must undergo bone marrow examination for early metastasis detection, as it may result in an upgrade to stage IV disease, impacting the prognosis and necessitating distinct treatment modalities.
... The occurrence of advanced IORB is more common in LMICs due to limited awareness and delayed diagnosis. Table 4. [5][6][7]11,[15][16][17][18] As is apparent, the prevailing evidence is largely from single-arm or retrospective studies. It prompted us to study a head-to-head compar- However, the significance of this finding remains elusive, especially as it failed to translate to a superior globe or vision salvage (p = .58). ...
Background: Access to intra-arterial chemotherapy for retinoblastoma in low- and
middle-income countries (LMICs) is limited. There is a need to optimize the efficacy of systemic chemotherapy for advanced intraocular retinoblastoma, particularly
in LMICs. The aim was to compare the efficacy of standard versus higher dose
carboplatin-based intravenous chemotherapy for group D and E retinoblastoma.
Methods: The single-center, single-blinded, randomized study was conducted during
2019–2021. Patients with newly diagnosed group D or E retinoblastoma were randomized to receive vincristine, etoposide, and standard versus higher dose (<36 months:
18.6 vs. 28 mg/kg; ≥36 months: 560 vs. 840 mg/m2) carboplatin. Examination under
anesthesia and ultrasonography was performed at diagnosis and following three cycles
of chemotherapy. Group E eyes with poor likelihood of globe/vision salvage at diagnosis
were excluded.
Results: Thirty-two eyes of 30 patients were analyzed: 17 group D and 15 group E eyes.
The tumor response to chemotherapy with regards to regression pattern (p = .72),
tumor shrinkage (diameter: p = .11, height: p = .96), subretinal seeds (p = .91), and vitreous seeds (p = .9) were comparable between the two treatment arms. The globe salvage
(group D [82% vs. 67%; p = .58]; group E [12.5% vs. 29%; p = .57]) and salvage of meaningful vision (group D [100% vs. 75%; p = .13]; group E [100% vs. 50%; p = .48]) were
comparable between standard and higher dose arms. No excess treatment-related
toxicity was observed in the higher dose arm.
Conclusions: Higher dose carboplatin-based intravenous chemotherapy did not result
in superior globe or vision salvage in group D or E retinoblastoma.
... Managing intraocular Rb tumors via efficient diagnoses, genetic screening, and clinical procedures [1,2] help to achieve excellent survival rates worldwide. However, metastatic retinoblastoma is still a major concern in many countries [3][4][5]. Rb tumors that grow rapidly have sufficient feeder arteries and drainage veins and are characterized by the presence of a multifocal yellowish-white tumor mass with floating subretinal or vitreous cancer seeds [6]. If neglected or untreated, advanced Rb tumors demonstrate massive choroidal invasion [7] and metastatic spread, primarily through the optic nerve [8] and sclera [9], to regional lymph nodes, the central nervous system (CNS), and bone marrow [10], causing a potent threat not only to vision but to the life of the child. ...
Summary: Our study identified the differential expression and potential effects of microRNAs in retinoblastoma vs. pediatric retina and advanced vs. non-advanced tumors. We provide evidence of the epithelial-mesenchymal transition (EMT) and chemoresistance programs in advanced tumors, which were potentially attributed to miR-181a-5p. We analyzed the differential expression of relevant EMT-and chemoresistance-related proteins in advanced vs. non-advanced tumors and chemotherapy-adapted Y79 cells to assess whether EMT and chemoresistance mechanisms were linked. We further examined the possible role of TGFβ as a potential regulator of such differences and highlighted the role of miR-181a-5p in EMT-and chemoresistance-related gene expression and drug sensitivity. Abstract: Advanced retinoblastoma (Rb) tumors display high metastatic spread to distant tissues, causing a potent threat to vision and life. Through transcriptomic profiling, we discovered key up-regulated genes that belonged to the epithelial-mesenchymal transition (EMT) and chemotherapy resistance pathways in advanced Rb tumors. Through in vitro models, we further showed that Rb null tumor cells under prolonged chemo drug exposure, acquires a metastasis-like phenotype through the EMT program mediated by ZEB1 and SNAI2 and these cells further acquires chemo-therapeutic resistance through cathepsin-Land MDR1-mediated drug efflux mechanisms. Using a miRNA microarray, we identified miR-181a-5p as being significantly reduced in advanced Rb tumors , which was associated with an altered EMT and drug-resistance genes. We showed that enhancing miR-181a-5p levels in Rb null chemo-resistant sublines reduced the ZEB1 and SNAI2 levels and halted the mesenchymal transition switch, further reducing the drug resistance. We thus identified miR-181a-5p as a therapeutically exploitable target for EMT-triggered drug-resistant cancers that halted their invasion and migration and sensitized them to low-dose chemotherapy drugs.
... Managing intraocular Rb tumors via efficient diagnoses, genetic screening, and clinical procedures [1,2] help to achieve excellent survival rates worldwide. However, metastatic retinoblastoma is still a major concern in many countries [3][4][5]. Rb tumors that grow rapidly have sufficient feeder arteries and drainage veins and are characterized by the presence of a multifocal yellowish-white tumor mass with floating subretinal or vitreous cancer seeds [6]. If neglected or untreated, advanced Rb tumors demonstrate massive choroidal invasion [7] and metastatic spread, primarily through the optic nerve [8] and sclera [9], to regional lymph nodes, the central nervous system (CNS), and bone marrow [10], causing a potent threat not only to vision but to the life of the child. ...
Advanced retinoblastoma (Rb) tumors can infiltrate distant tissues and cause a potent threat to vision and life. Through transcriptomic profiling, we discovered key epithelial to mesenchymal transition (EMT) and chemotherapy resistance genes at higher expression levels in advanced Rb tumors. Rb-/- tumor cells acquire metastasis-like phenotype through the EMT program that critically contributes to chemoresistance. We demonstrate that prolonged chemo-drug exposure in Rb cells elicits an EMT program through ZEB1 and SNAI2 that further acquires therapeutic resistance through cathepsin L and MDR1 mediated drug efflux mechanisms. Further, 16 significantly differentially expressed miRNAs were identified in patient tumors, of which miR-181a-5p was significantly reduced in advanced Rb tumors and associated with altered EMT and drug resistance genes. Enhancing miR-181a-5p levels in Rb-/- cells and Rb-/- chemo-resistant sublines controls EMT transcription factors ZEB1 and SNAI2 and halts the transition switch, thereby reversing drug resistance. We thus identify miR-181a-5p as a potential therapeutic target for EMT triggered drug-resistant cancers that can halt their invasion and sensitize them to low dose chemotherapy drugs.
Graphical Abstract
... A case report on the successful use of intravitreous chemotherapy in a Filipino patient has also been published and another case series is on the way. 15 Without data on treatment and outcomes, it is also difficult to identify treatment failures and to try new protocols to address them. 15 Having data on treatment and outcomes can also invite research collaborations from international groups such as the American Joint Committee on Cancer Ophthalmic Oncology Task Force. ...
... 15 Without data on treatment and outcomes, it is also difficult to identify treatment failures and to try new protocols to address them. 15 Having data on treatment and outcomes can also invite research collaborations from international groups such as the American Joint Committee on Cancer Ophthalmic Oncology Task Force. 16 The COVID-19 pandemic provided researchers globally extra time to conduct studies, COVID-19-related or otherwise, and publish them. ...
Retinoblastoma has an estimated worldwide incidence of 1 in 16,000-18,000 births every year although it varies from region to region, with Asia having one of the highest incidence rates.1,2 The Philippines is listed as one of the six Asian countries that will be the source of 43% of the estimated world’s retinoblastoma cases in 2023.3 Local incidence was reported at 142 (128-157) per live births in 2013 and is expected to
increase to 152 (137-168) per live births in 2023.3,5
