Incidence and Risk Factors for Neutropenia After Intra-Arterial Chemotherapy for Retinoblastoma.

Importance: Intra-arterial chemotherapy (IAC) has quickly gained popularity as a mainstay of treatment for retinoblastoma. Intra-arterial chemotherapy has been described as having several advantages over systemic chemotherapy, including reducing systemic toxicity and neutropenia; however, studies on the risk of neutropenia after IAC remain limited. Objective: To estimate the incidence of neutropenia after IAC, as well as identify risk factors associated with the development of neutropenia. Design, Setting, and Participants: This case series included pediatric patients with unilateral or bilateral retinoblastoma who were treated with IAC at a single quaternary care center from July 13, 2013, to January 6, 2023. Exposure: All patients were treated with IAC and underwent multiple IAC cycles depending on treatment response. The primary chemotherapy agent used was melphalan, but topotecan or carboplatin could be used along with melphalan. Melphalan doses were kept to 0.4 mg/kg or less per cycle. After each IAC cycle, complete blood cell counts were obtained within 10 to 12 days and repeated until the absolute neutrophil count (ANC) was greater than or equal to 1000/µL. Main Outcomes and Measures: The primary outcome was the minimum ANC after each IAC cycle. The secondary outcome was the development of severe (grade 3 or 4) neutropenia (ANC <1000/µL). Regression analyses were used to identify associations between variables and outcomes. Receiver operating characteristic curves were used to calculate threshold dose for each chemotherapy agent potentially associated with the development of severe neutropenia. Results: A total of 64 eyes of 49 patients (mean [SD] age, 1.7 [1.2] years; 25 females [51.0%]) with retinoblastoma were treated with 171 cycles of IAC. The mean (SD) nadir ANC was 1325.3 (890.7)/µL and occurred a median (IQR) of 10 (10-14) days (range, 6-28 days) after IAC administration. The frequency distribution of post-IAC neutropenia grades 0, 1, 2, 3, 4, and missing was 31 (18.1% of cycles), 25 (14.6%), 40 (23.4%), 37 (21.6%), 26 (15.2%), and 12 (7.0%), respectively. Factors weakly correlated with a lower ANC were higher melphalan dose (ß = -2356 [95% CI, -4120.6 to -611.2]; adjusted R2 = 0.251; P = .01) and higher topotecan dose (ß = -4056 [95% CI, -7003.6 to -1344.5]; adjusted R2 = 0.251; P = .006). Conclusions and Relevance: In this case series of patients with retinoblastoma, the incidence of severe neutropenia after IAC was nearly 40%, which is higher than previously reported. Extended laboratory monitoring may aid in capturing previously overlooked cases of neutropenia. Topotecan may be associated with the development of neutropenia; limiting topotecan doses, especially in the setting of a high melphalan dose, may be beneficial in reducing the risk of neutropenia.

The association between maternal nutrient intake during pregnancy and the risk of sporadic unilateral retinoblastoma among offspring.

Previous studies have associated maternal diet during pregnancy with the development of sporadic unilateral retinoblastoma (RB), but few studies have focused on the role of individual nutrients. The aim of this study is to investigate the association between maternal nutrient intake during pregnancy and the development of sporadic unilateral RB in the offspring. A modified food frequency questionnaire, with additional questions on supplement use, was completed via a phone interview. Cases were recruited from hospitals and controls were comprised of friends and relatives of the patient without a history of cancer. Overall, 168 sporadic unilateral RB cases and 145 controls were included in case-control study. We performed logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI), adjusting for child's age, child's sex, parental race/ethnicity, maternal education, total calorie intake during pregnancy, maternal age at birth, maternal smoking during pregnancy, pre-pregnancy body mass index, maternal weight gain during pregnancy, paternal age at birth, and maternal multivitamin use in the year before pregnancy. In the adjusted model, the interquartile (IQR) increase in vitamin A intake, which was measured in retinol activity equivalent (RAE; OR: 0.64, 95 % CI: 0.46-0.90), and vitamin D intake (OR: 0.62, 95 % CI: 0.42-0.91) significantly reduced the risk of sporadic unilateral RB. These findings suggest that a higher intake of vitamins A and D can be a protective factor for sporadic unilateral RB. Further analyses in consideration of multi-exposures such as parental occupational exposures are warranted to discover the complex etiology of sporadic unilateral RB. In addition, the role of nutritional epigenetics for how maternal nutrient intake influences the risk of sporadic unilateral RB in the offspring still needs to be explored.

Sunlight exposure in infancy decreases risk of sporadic retinoblastoma, extent of intraocular disease.

BACKGROUND: Prior ecologic studies suggest that UV exposure through sunlight to the retina might contribute to increased retinoblastoma incidence. AIMS: Our study objectives were (1) to examine the relationship between exposure to sunlight during postnatal retinal development (prior to diagnosis of sporadic disease) and the risk of retinoblastoma, and (2) to examine the relationship between sun exposure during postnatal retinal development, and the extent of disease among children with unilateral and bilateral retinoblastoma. METHODS AND RESULTS: We interviewed 511 mothers in the EpiRbMx case-control study about their child's exposure to sunlight during postnatal retinal cell division by examining three time periods prior to Rtb diagnosis coinciding with developmental stages in which outdoor activities vary. Weekly sun exposure was compared by age period, between unilateral (n = 259), bilateral (n = 120), and control (n = 132) children, accounting for two factors affecting UV exposure: residential elevation and reported use of coverings to shield eyes. For cases, association between sunlight exposure and clinical stage was examined by laterality at each age period. After adjusting for maternal education and elevation, sun exposure was lower in cases than controls in all three age periods especially during the first 6 months, and in children 12-23 months whose mothers did not cover their eyes when outdoors. In children diagnosed after 12 months of age, sun exposure during the second year of life (age 12-23 months) appeared inversely correlated (r = -0.25) with more advanced intraocular disease in bilateral Rtb children after adjusting for maternal education, residential elevation, and age of diagnosis (p < .09) consistent with effects of Vitamin D exposure on intraocular spread in earlier transgenic murine models of retinoblastoma, and suggesting potential chemopreventive strategies. CONCLUSION: Sun exposure in early childhood is protective for retinoblastoma and may decrease degree of intraocular spread in children with bilateral Rtb.

Genotype-phenotype correlation in von Hippel-Lindau disease.

BACKGROUND/AIMS: Retinal haemangioblastomas (RH) remain a major cause of visual impairment in patients with von Hippel-Lindau (VHL) disease. Identification of genotype-phenotype correlation is an important prerequisite for better management, treatment and prognosis. METHODS: Retrospective, single-centre cohort study of 200 VHL patients. Genetic data and date of onset of RH, central nervous system haemangioblastomas (CNSH), pheochromocytoma/paraganglioma (PPGL), clear cell renal cell carcinoma (ccRCC) and pancreatic neuroendocrine neoplasm (PNEN) were collected. The number and locations of RH were recorded. RESULTS: The first clinical finding occurred at an age of 26 ± 14 years (y) [mean ± SD]. In 91 ± 3% (95% CI 88-94) of the patients, at least one RH occur until the age of 60y. A total of 42 different rare VHL gene variants in 166 patients were detected. A higher age-related incidence of RH, CNSH, ccRCC and PNEN was detected in patients with a truncating variant (TV) compared to patients with a single amino-acid substitution/deletion (AASD) (all p < 0.01), while it is reverse for PPGL (p < 0.01). Patients with a TV showed 0.10 ± 0.15 RH per y during their lifetime compared to 0.05 ± 0.07 in patients with AASD (p < 0.02). The median enucleation/phthisis-free survival time in patients with a TV was 56y (95% CI 50-62) compared to 78y (95% CI 75-81) in patients with AASD (p < 0.02). CONCLUSION: Compared to patients with AASD, patients with a TV develop RH, CNSH, ccRCC and PNEN earlier. They experience a higher number of RH and bear a higher risk of enucleation/phthisis. Thus, patients with a TV might be considered for a more intensive ophthalmological monitoring.

Medical radiation exposure and risk of sporadic retinoblastoma.

BACKGROUND: While there is evidence that parental exposure to medical radiation is associated with increased risk of sporadic bilateral retinoblastoma in offspring, this association has not been confirmed. Additionally, the relationship between paternal and maternal exposures and sporadic unilateral retinoblastoma has not been fully investigated. PROCEDURE: Data were obtained from two large multicenter case-control studies of retinoblastoma. For the paternal analyses, 268 bilateral cases, 155 unilateral cases, and 358 controls were included. For the maternal analyses, 298 bilateral cases, 184 unilateral cases, and 404 controls were included. Logistical regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) to evaluate the associations between parental exposures to medical radiation and sporadic retinoblastoma, while adjusting for potential confounders. RESULTS: Paternal exposure to medical radiation was not significantly associated with sporadic bilateral retinoblastoma in offspring. However, increasing paternal exposure to gonadal radiation was associated with increased risk of unilateral retinoblastoma (P-trend = .03). Maternal history of upper and lower gastrointestinal (GI) series was associated with bilateral retinoblastoma (OR = 1.9, 95% CI: 1.1-3.2 and OR = 6.9, 95% CI: 2.9-16.4, respectively). However, there was no association between maternal exposure to medical radiation and unilateral retinoblastoma in offspring. CONCLUSION: Our investigation adds to the evidence that medical radiation exposure in fathers as well as mothers prior to pregnancy may increase the risk of germline alterations leading to the development of retinoblastoma in their offspring. However, our findings could point to a more complex etiological framework for this important pediatric malignancy.

Von Hippel-Lindau Syndrome Phenotype With Prominent Vitreoretinal Neovascularization Treated With Early PPV: A Case Series and Literature Review.

BACKGROUND AND OBJECTIVE: To describe a case series of three patients in one family with Von Hippel-Lindau (VHL) disease who presented with vitreoretinal neovascularization and resulting tractional retinal detachments (TRDs). This vitreoretinal phenotype of VHL may benefit from early surgical intervention. PATIENTS AND METHODS: Descriptive case series of three patients in one family with VHL disease. A review of the literature regarding surgical intervention for VHL was performed. RESULTS: All three patients developed prominent intravitreal neovascularization with fibrovascular growth within the vitreous secondary to a retinal capillary hemangioma. Two subjects with intravitreal neovascularization were treated with laser and cryotherapy but eventually developed a TRD. The final vision in these two patients was light perception and 20/300. The eye that was preemptively treated with vitrectomy to remove the vitreous sustaining the neovascularization had visual acuity of 20/50 after surgery. CONCLUSION: Intravitreal neovascularization with fibrovascular proliferation may be an indication for vitrectomy prior to the development of retinal detachment. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:109-115.].

Development of Vitreoretinal Lymphoma in a Patient with Sarcoid Uveitis.

PURPOSE: The purpose of this article is to report the first case of primary vitreoretinal lymphoma in a patient with sarcoid uveitis. MATERIAL AND METHODS: A 63-year-old woman with biopsy-proven sarcoid uveitis diagnosed 7 years ago was presented for a 6-month history of bilateral intermediate uveitis and gait disturbance with cerebral magnetic resonance imaging suggestive of neurosarcoidosis. Because of corticoids resistance, a vitrectomy and a cerebral biopsy were performed. The final diagnosis was primary central nervous system diffuse lymphoma. Patient died despite the chemotherapy with an initial improvement of visual and neurological features. CONCLUSION: Ophthalmologists should know that patient followed up with sarcoid uveitis can develop a primary vitreoretinal diffuse large B-cell lymphoma.

VASOPROLIFERATIVE TUMORS IN INTERMEDIATE UVEITIS.

PURPOSE: To describe patients with intermediate uveitis complicated by vasoproliferative tumors (VPTs). METHODS: Data were collected at seven Uveitis/Ocular Oncology centers on demographic, ophthalmic findings at baseline and at follow-up, and on imaging. The therapeutic intervention, final visual acuity, and duration of follow-up were recorded. RESULTS: A total of 36 eyes from 34 patients (12 men, 22 women; mean age 35.3 ± 14.2 years) were included in this study. Visual acuity at presentation ranged from 20/40 to counting fingers. At the time of VPT diagnosis, intermediate uveitis was active in all eyes. The mean VPT thickness was 3.06 ± 0.86 mm. Local treatment to the VPT was provide in 22 eyes (61.1%) and no local treatment to the VPT in 14 eyes (38.9%). After the VPT was detected, systemic or local treatment for the inflammation was initiated and on follow-up FAs 94.4% of the eyes showed resolution of the vascular leakage. During follow-up of 35.8 months, the 22 VPTs treated locally had a reduction in the tumor thickness to 1.25 mm, whereas the 14 VPTs untreated remained stable (final mean tumor thickness 2.65 mm). CONCLUSION: The presence of active intermediate uveitis accompanied by VPTs suggests the need for an aggressive uveitis treatment.

INTRAVITREAL INJECTION OF PROPRANOLOL FOR THE TREATMENT OF RETINAL CAPILLARY HEMANGIOMA IN A CASE OF VON HIPPEL-LINDAU.

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of intravitreal propranolol for the management of retinal capillary hemangioma in a patient with Von Hippel-Lindau. METHODS: Two intravitreal injections of 50 µg/0.05 mL propranolol were administered 6 weeks apart in the left eye of a 26-year-old patient with bilateral multiple retinal capillary hemangiomas. Safety and response to therapy were evaluated using electroretinogram, fluorescein angiography, and measurement of visual acuity. Laser photocoagulation was performed in the right eye. RESULTS: One month after the second intravitreal injection of propranolol, fluorescein leakage decreased from the tumors located on the optic nerve head and in the inferonasal retinal periphery. Reduction of the retinal capillary hemangioma vascularity and enhancement of its fibrosis associated with the attenuation of the feeder vessel were also observed. Ophthalmic examination showed no adverse effect except for a mild transient vitreous haziness after each injection. Electroretinogram performed 4 weeks after the first injection revealed no retinal toxicity. CONCLUSION: Intravitreal propranolol showed a therapeutic effect on retinal capillary hemangioma with no short-term adverse effects except a mild transient inflammatory response in a patient with Von Hippel-Lindau.

VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects.

PURPOSE: To provide an update summarizing the biologic pathways governing von Hippel-Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. METHODS: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel-Lindau, von Hippel-Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. RESULTS: von Hippel-Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. CONCLUSION: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

The incidence of consecutive manifestations in Von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an autosomal dominant rare tumor syndrome characterized by high penetrance. VHL mutation carriers develop numerous manifestations in multiple organs during life. The natural course of development of new and growth of existing VHL-related manifestations is still unclear. In this study we aimed to gain insight into the development of subsequent manifestations in VHL disease. We retrospectively scored each new VHL-related manifestation as detected by standard follow-up (retina, central nervous system, kidneys and pancreas, excluding adrenal and endolymfatic sac manifestations) in 75 VHL mutation carriers. The Kaplan-Meier method was used to plot the cumulative proportions of all consecutive manifestations in each organ against age. The cumulative average number of manifestations in all organs during life was calculated by summating these cumulative proportions. Poisson model parameters were used to calculate average time to the detection of consecutive VHL manifestations in each organ. Consecutive VHL-related kidney and retina manifestations during life occur linearly according to Poisson distribution model. The total number of VHL manifestations rises linearly, with an average of seven VHL-related lesions at age 60 years. The incidence of consecutive VHL-related manifestations is constant during life in VHL mutation carriers. Our data is consistent with the notion that somatic inactivation of the remaining allele (Knudson's "two-hit" hypothesis) is the determining factor in developing new VHL-related manifestations.

The Relationship Between Vasoproliferative Tumor and Uveitis in a Multiple Sclerosis Patient: A Case Report and Review of the Literature

Vasoproliferative retinal tumor (VPRT) is a rare, benign lesion with a variable clinical course depending on the individual. Favorable outcomes are obtained with early diagnosis and treatment of patients with VPRT. In this case report, we present a case of concomitant VPRT and multiple sclerosis along with our management of uveitis and secondary glaucoma that presumably developed following cryotherapy for VPRT.

Coats disease associated with vasoproliferative tumor treated with cryotherapy and intravitreal injections of triamcinolone / Doença de Coats associada a tumor vasoproliferativo tratada com crioterapia e injeções intravítreas de triancinolona

Abstract Report of a case of Coats disease associated with retinal vasoproliferative tumor in a young female patient with two peripheral vascularized tumors and lipid exudation involving the macula and peripapillary region with serous retinal detachment areas and pre-papillary fibrous proliferation. The proposed and performed treatment was the intravitreal injection of triamcinolone acetonide to decrease the tumor exudation, followed by photocoagulation of the peripheral areas of telangiectasia without subretinal fluid and cryotherapy of the tumors. Despite that this is a rare and difficult to treat combination, in this case report, success was obtained in receding the tumor masses and reapplying the retina, leading to anatomic and visual stabilization.

Resumo Relato de um caso de Doença de Coats associada a tumor vasoproliferativo de retina em uma paciente jovem com duas tumorações vascularizadas periféricas e exsudação lipídica acometendo mácula e região peripapilar com áreas de descolamento de retina seroso e proliferação fibrosa pré-papilar. O tratamento proposto e realizado foi a injeção intra-vítrea de triancinolona para diminuir a exsudação do tumor, seguida de fotocoagulação periférica das áreas de telangiectasia sem fluido subretiniano e criocoagulação dos tumores. Apesar de se tratar de uma associação rara e de difícil tratamento, neste relato de caso, obteve-se êxito em regredir as massas tumorais e reaplicar a retina, levando à estabilização anatômica e visual.

EARLY DETECTION OF RETINAL HEMANGIOBLASTOMAS IN VON HIPPEL-LINDAU DISEASE USING ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY.

PURPOSE: To study the use of ultra-widefield fluorescein angiography (UWF FA) in the detection and management of retinal capillary hemangioblastomas in patients with von Hippel-Lindau disease. METHODS: This is a retrospective study of patients with von Hippel-Lindau disease who underwent UWF FA using the Optos camera at a single center from June 2009 to May 2015. The clinical use of UWF FA was reviewed, and the number of hemangioblastomas identified on UWF FA was compared with ophthalmoscopy and a simulated seven standard field (7SF) FA montage. RESULTS: Twenty eyes of 10 patients were identified. Only 33% of lesions seen on UWF FA were also found on ophthalmoscopy, and 88% of lesions visualized on UWF FA were located outside the 7SF overlay. In 5 eyes that had gaze steering, 18% of lesions could be visualized only on gaze-steered images. For the 14 eyes with data available, 6 had procedures recommended and 8 eyes observed based on data from UWF FA. One of 20 eyes had a lesion on ophthalmoscopy that was missed by imaging. CONCLUSION: Ultra-widefield FA using the Optos camera is helpful for the evaluation and management of patients with von Hippel-Lindau disease. The UWF FA with gaze steering appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography.

Mir-138-5p acts as a tumor suppressor by targeting pyruvate dehydrogenase kinase 1 in human retinoblastoma.

OBJECTIVE: MicroRNAs have caught more attention for their role in tumor progression. Retinoblastoma (RB) is one of these ordinary malignant tumors. This study aims to identify whether mir-138-5p can regulate the development of RB, and find out its potential mechanism. MATERIALS AND METHODS: Mir-138-5p expression in RB cells was monitored by RT-qPCR. Besides, the role of mir-138-5p in RB development was explored through function experiments in vitro. The potential mechanism was further explored by RT-qPCR, luciferase assay, and Western blot assay. RESULTS: In our investigation, mir-138-5p was lower-expressed in RB cells than that in retinal pigment epithelial cells. Moreover, overexpression of mir-138-5p repressed cell viability, migration and invasion, and induced apoptosis of RB cells, while downregulated mir-138-5p increased cell viability, migration and invasion, and reduced apoptosis of RB cells. Furthermore, pyruvate dehydrogenase kinase 1 (PDK1) could be downregulated via overexpression of mir-138-5p, while PDK1 was upregulated via knockdown of mir-138-5p. CONCLUSIONS: Our results suggested that mir-138-5p could repress the development of RB via suppressing PDK1, which may offer a new vision for interpreting the mechanism of RB tumorigenesis.

Retinal meteor.

We describe a case of a 65-year old man diagnosed with retinal vasoproliferative tumour secondary to posterior uveitis. The fluorescein angiography shows an interesting meteor-like leak emanating from the tumour and rising towards the superior retina in the later frames of the angiogram. Pictorially, we call it the "Retinal Meteor" and also describe the possible mechanism for this pattern of leakage.

Posterior Pole and Peripheral Retinal Fibrovascular Proliferation in von Hippel Lindau Disease.

PURPOSE: To report the occurrence of fibrovascular proliferation (FVP) in the retina in von Hippel-lindau (VHl) patients and its association with prior treatment. DESIGN: A retrospective study. METHODS: A retrospective study of 101 VHL patients. Fundus photos were available for 28 patients. FVP was classified into peripheral and posterior pole. RESULTS: All 28 patients had retinal capillary hemangioblastomas (RCH) in 1 or both eyes; 15 patients were found to have FVP (group A), whereas 13 patients did not (group B). Mean age of patients in group A was 35 ± 11.3 years and 36.6 ± 13.8 in group B (P = 0.74). In group A, 27 eyes had RCH; 21 (77.77%) had FVP. In group B, 19 eyes had RCH. The number of treated eyes was significantly higher in group A (81.48%) than group B (42.1%) (P = 0.007). In group A, FVP was noted in the posterior pole in 9 eyes, in the periphery in 5 eyes, and 7 eyes developed both posterior pole and peripheral FVP. CONCLUSIONS: FVP can occur in the peripheral retina and in the posterior pole. There is a significant association between prior treatment of RCH and the occurrence of FVP.