MRI Features for Identifying MYCN-amplified RB1 Wild-type Retinoblastoma.

Background MYCN-amplified RB1 wild-type (MYCNARB1+/+) retinoblastoma is a rare but clinically important subtype of retinoblastoma due to its aggressive character and relative resistance to typical therapeutic approaches. Because biopsy is not indicated in retinoblastoma, specific MRI features might be valuable to identify children with this genetic subtype. Purpose To define the MRI phenotype of MYCNARB1+/+ retinoblastoma and evaluate the ability of qualitative MRI features to help identify this specific genetic subtype. Materials and Methods In this retrospective, multicenter, case-control study, MRI scans in children with MYCNARB1+/+ retinoblastoma and age-matched children with RB1-/- subtype retinoblastoma were included (case-control ratio, 1:4; scans acquired from June 2001 to February 2021; scans collected from May 2018 to October 2021). Patients with histopathologically confirmed unilateral retinoblastoma, genetic testing (RB1/MYCN status), and MRI scans were included. Associations between radiologist-scored imaging features and diagnosis were assessed with the Fisher exact test or Fisher-Freeman-Halton test, and Bonferroni-corrected P values were calculated. Results A total of 110 patients from 10 retinoblastoma referral centers were included: 22 children with MYCNARB1+/+ retinoblastoma and 88 control children with RB1-/- retinoblastoma. Children in the MYCNARB1+/+ group had a median age of 7.0 months (IQR, 5.0-9.0 months) (13 boys), while children in the RB1-/- group had a median age of 9.0 months (IQR, 4.6-13.4 months) (46 boys). MYCNARB1+/+ retinoblastomas were typically peripherally located (in 10 of 17 children; specificity, 97%; P < .001) and exhibited plaque or pleomorphic shape (in 20 of 22 children; specificity, 51%; P = .011) with irregular margins (in 16 of 22 children; specificity, 70%; P = .008) and extensive retina folding with vitreous enclosure (specificity, 94%; P < .001). MYCNARB1+/+ retinoblastomas showed peritumoral hemorrhage (in 17 of 21 children; specificity, 88%; P < .001), subretinal hemorrhage with a fluid-fluid level (in eight of 22 children; specificity, 95%; P = .005), and strong anterior chamber enhancement (in 13 of 21 children; specificity, 80%; P = .008). Conclusion MYCNARB1+/+ retinoblastomas show distinct MRI features that could enable early identification of these tumors. This may improve patient selection for tailored treatment in the future. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rollins in this issue.

Orbital cellulitis with panophthalmitis and scleral necrosis - a case report.

BACKGROUND: Orbital cellulitis is common in young children and is often secondary to coexisting sinus disease. Coexisting orbital cellulitis and panophthalmitis is a rare clinical event and usually occurs secondary to trauma or from an endogenous source. CASE PRESENTATION: A febrile 2-year-old male presented with periorbital inflammation and exudative retinal detachment. Imaging showed acute sinusitis and extensive orbital cellulitis. Because of progressive scleral thinning, the patient underwent enucleation. CONCLUSION: We present a case of concurrent orbital cellulitis, panophthalmitis, and scleral necrosis in an immunocompetent pediatric patient. Timely intervention is important to prevent life threatening complications with the rare occurrence of coexistent orbital cellulitis and panophthalmitis.

Blue nevi of the palpebral conjunctiva: report of 2 cases and review of literature.

PURPOSE: To describe two patients with blue nevi of the palpebral conjunctiva and to review the existing literature on common and cellular blue nevi of the conjunctiva. METHODS: Report of two cases and literature review. RESULTS: We present two cases of blue nevi in the palpebral conjunctiva: an atypical cellular blue nevus of the left upper eyelid and a common blue nevus around the lacrimal punctum of the left lower eyelid. Both patients underwent full thickness eyelid excision with wide margins. There was no tumor recurrence at 11 and 4 months postoperatively. CONCLUSIONS: Blue nevi are a group of melanocytic tumors that rarely involve the ocular adnexa. They may arise in the palpebral conjunctiva and should be considered in the differential diagnosis of pigmented lesions in this location as they can mimic melanoma.

Structural Differences in Meibum From Teenagers Without and With Dry Eye and Allogeneic Hematologic Stem Cell Transplantations.

Although dry eye occurs mostly in adults, dry eye may be induced in teens receiving allogeneic hematologic stem cell transplantations (AHSCT). Changes in meibum composition and structure has been associated with dry eye. The structure of meibum from teens with dye eye or teens with dry eye and AHSCT has not been studied, so in this study, we compared the structure of meibum from teens receiving AHSCT that had a dry eye with meibum from teens without AHSCT and without dry eye symptoms.

Sphenoid Dysplasia: A Rare Presentation of Infantile Myofibroma.

The authors report a case of isolated congenital orbital myofibroma causing sphenoid dysplasia and presenting as global restriction of extraocular motility and ptosis in a neonate. Sphenoid wing dysplasia is most commonly associated neurofibromatosis 1 but this patient had no evidence of neurofibromatosis on clinical examination and genetic testing. Congenital orbital myofibroma can have secondary effects on bone and likely the lesion was present early in development leading to aplasia of the sphenoid bone. To the best of the authors' knowledge, this is the first reported case of sphenoid wing aplasia secondary to congenital orbital myofibroma independent of neurofibromatosis 1.

Insights into Tear Film Stability from Babies and Young Adults: A Study of Human Meibum Lipid Conformation and Rheology.

Babies have the most stable tears and people with dry eye have the least stable tears. Meibum may contribute to tear film stability, so in this study, the hydrocarbon chain conformation and rheology of meibum from babies was studied for the first time. Infrared spectroscopy was used to measure lipid phase transitions. Rheology was measured using Langmuir film technology. Meibum from 25 donors 1 to 13 years old was compared with meibum from 18 donors 13 to 25 years old. The phase transition temperature and lipid order (stiffness) increased with increasing age from 1 to 25 years. The increase in meibum lipid order from 1 to 25 years of age may contribute to the instability of the tear film with age and contribute to films with a higher reciprocal compressibility modulus that are not as compressible and not as viscoelastic. Changes in the lipid phase transition parameters of meibum lipid with dry eye are an exacerbation of the changes observed with age. The lower reciprocal compressibility moduli of meibum films from children and babies compared with meibum from adults reiterates higher stability in their films which spread better, resist deformation, and facilitates their ability to be quickly restored after blinking.

Effects of Lipid Saturation on the Surface Properties of Human Meibum Films.

Elevated levels of acyl chain saturation of meibomian lipids are associated with vastly different effects: from enhanced tear film (TF) stability in infants to shortened TF breakup time in meibomian gland disease patients. Thus it is important to study the effect of saturation on the surface properties of human meibum (MGS). Therefore, MGS films (1, 2, 3, 4, 5, 10, 25, 50, 67, and 100% saturation) were spread at the air/water interface of a Langmuir surface balance. The layers' capability to reorganize during dynamic area changes was accessed via the surface pressure (π)-area (A) compression isotherms and step/relaxation dilatational rheology studies. Film structure was monitored with Brewster angle microscopy. The raise in the % (at ≥10%) of saturation resulted in the formation of stiffer, thicker, and more elastic films at π ≥ 12 mN/m with the effects being proportional to the saturation level. At the same time, at low (≤10 mN/m) π the raise in saturation resulted in altered spreading and heterogeneous structure of MGS layers. The strong impact of saturation on MGS surface properties correlates with our recent spectroscopy study, which demonstrated that saturation induced increase of MGS acyl chain order, phase transition temperature, and cooperativity.

High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome.

BACKGROUND: Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous whole-exome sequencing study using DNA derived from peripheral blood identified mosaic mutations in DICER1 in two children with overgrowth and developmental delay as well as more typical phenotypes of germline DICER1 mutation. However, very-low-frequency mosaicism is difficult to detect, and thus, causal mutations can go unnoticed. Highly sensitive, cost-effective approaches are needed to molecularly diagnose these persons. We studied four children with multiple primary tumours known to be associated with the DICER1 syndrome, but in whom germline DICER1 mutations were not detected by conventional mutation detection techniques. METHODS AND RESULTS: We observed the same missense mutation within the DICER1 RNase IIIb domain in multiple tumours from different sites in each patient, raising suspicion of somatic mosaicism. We implemented three different targeted-capture technologies, including the novel HaloPlex(HS) (Agilent Technologies), followed by deep sequencing, and confirmed that the identified mutations are mosaic in origin in three patients, detectable in 0.24-31% of sequencing reads in constitutional DNA. The mosaic origin of patient 4's mutation remains to be unequivocally established. We also discovered likely pathogenic second somatic mutations or loss of heterozygosity (LOH) in tumours from all four patients. CONCLUSIONS: Mosaic DICER1 mutations are an important cause of the DICER1 syndrome in patients with severe phenotypes and often appear to be accompanied by second somatic truncating mutations or LOH in the associated tumours. Furthermore, the molecular barcode-containing HaloPlex(HS) provides the sensitivity required for detection of such low-level mosaic mutations and could have general applicability.

Human Meibum Age, Lipid-Lipid Interactions and Lipid Saturation in Meibum from Infants.

Tear stability decreases with increasing age and the same signs of instability are exacerbated with dry eye. Meibum lipid compositional changes with age provide insights into the biomolecules responsible for tear film instability. Meibum was collected from 69 normal donors ranging in age from 0.6 to 68 years of age. Infrared spectroscopy was used to measure meibum lipid phase transition parameters. Nuclear magnetic resonance spectroscopy was used to measure lipid saturation. Increasing human meibum lipid hydrocarbon chain unsaturation with age was related to a decrease in hydrocarbon chain order, cooperativity, and in the phase transition temperature. The change in these parameters was most dramatic between 1 and 20 years of age. Meibum was catalytically saturated to determine the effect of saturation on meibum lipid phase transition parameters. Hydrocarbon chain saturation was directly related to lipid order, phase transition temperature, cooperativity, changes in enthalpy and entropy, and could account for the changes in the lipid phase transition parameters observed with age. Unsaturation could contribute to decreased tear film stability with age.

Utility of Head CT Scan for Acute Inpatient Delirium.

 Delirium is a common occurrence in hospitalized patients, especially in the geriatric age group. Data was retrospectively reviewed for patients who developed delirium during hospitalization. Acute intracranial changes on imaging were noted only in four patients (11%) and all had preimaging clinical symptoms and signs, which warranted imaging. Imaging should be considered only in the presence of head injury, fall, history of anticoagulation, focal neurological signs, fever, and raised intracranial pressure. Development of more clear guidelines will result in decreased ordering of unnecessary neuroimaging, substantial cost savings, and less radiation exposure for patients.

Microvascular flow ultrasound imaging for retinoblastoma.

PURPOSE: To present the results of a pilot study of microvascular flow imaging (MFI) in characterizing tumor vasculature of retinoblastoma. METHODS: The medical records of consecutive patients with retinoblastoma presenting at our institution between July 2019 and June 2022 that were imaged using MFI were reviewed retroactively. Each patient underwent diagnostic evaluation according to standard of care by examination under anesthesia with fluorescein angiography and ocular ultrasound imaging, including color Doppler and MFI. RESULTS: Thirteen eyes of 10 patients with retinoblastoma were included. MFI showed a prominent feeder vessel in 8 eyes, basket vasculature in 6 eyes and tumor bed vascularity in 10 eyes. MFI showed a more extensive vascular branching pattern that was not visible on color Doppler and fluorescein angiography in all eyes. CONCLUSIONS: MFI of retinoblastoma patients could add information about tumor vascularity not detectable by color Doppler or fluorescein angiography. Further study is needed to determine whether this information could be used to predict prognosis for ocular salvage and tumor response to treatment.

Three-Dimensional Ultrasound Imaging of Retinoblastoma and Its Correlation With Pathology.

BACKGROUND AND OBJECTIVE: Monitoring the response of retinoblastoma to globe-salvaging therapies is based on subjective assessments of changes determined by fundoscopy, ultrasound, and optical coherence tomography. Advances in organ-preserving therapies have increased the need for objective, quantitative estimates of tumor response to treatment. Primary tumor volume is a metric that can be objectively determined as a surrogate measure of treatment response. PATIENTS AND METHODS: We evaluated the correlation of objective, quantitative estimates of tumor volume made with two-dimensional (2D) and three-dimensional (3D) ultrasound with gold standard pathological tumor volumes derived by analysis of enucleation specimens. RESULTS: Twelve eyes in 12 patients undergoing primary enucleation were evaluated by 2D and 3D ultrasound during ophthalmic examination under anesthesia prior to enucleation. 2D- and 3D-ultra-sound measurements of tumor volume were both strongly correlated with pathological estimates of tumor volume (r = 0.69, P = 0.018; and r = 0.66, P = 0.027, respectively). CONCLUSIONS: 2D- and 3D-ultrasound measurements of retinoblastoma primary tumor volume are highly correlated with pathological estimates. 3D measurements are easy to perform with volumetric probes and consider the irregular morphology of the tumor. Further study should be undertaken to evaluate the performance of these metrics as surrogate markers of tumor response to treatment. [Ophthalmic Surg Lasers Imaging Retina 2024;55:136-140.].

Amniotic Membrane Augmentation for Enucleation After Chemotherapy in Retinoblastoma.

PURPOSE: To describe amniotic membrane augmentation for enucleation after chemotherapy in retinoblastoma. METHODS: This was a retrospective study of patients with retinoblastoma who underwent enucleation. The study also evaluated the utility of amniotic membrane grafting in enucleation after chemotherapy in eyes with retinoblastoma. RESULTS: In this study, 110 eyes of 107 patients were analyzed, and 49 patients had previous systemic chemotherapy, 13 eyes had previous intra-arterial chemotherapy, and 7 eyes had external beam radiation. Amniotic graft was used in 8 eyes (5 following IAC, 2 following systemic chemotherapy, and 1 after both). After IAC, 3 of 7 eyes without amniotic graft had implant exposure compared to 0 of 6 eyes with amniotic graft (P = .05). Pathological examination of the conjunctiva after intra-arterial chemotherapy showed goblet cell hypoplasia that hinders wound healing. CONCLUSIONS: Amniotic membrane augmentation improves wound integrity in patients with retinoblastoma, especially following intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XXX-XXX.].

Prenatal Diagnosis of Retinoblastomas: A Scoping Review.

Purpose: The objective of this review is to explore the prenatal diagnosis of retinoblastoma and the recommended screening practices. Patients and Methods: An electronic literature search on prenatal diagnosis of retinoblastoma was conducted on the PubMed database. Publications within the last 20 years that matched the inclusion criteria were selected. The literature search included the following keywords: retinoblastoma, prenatal, diagnosis, screening, and associated synonyms to increase search sensitivity. Nine studies were included for investigation and extracted to identify prenatal diagnostic and screening techniques for retinoblastoma, their associated impact, and the target population that should receive prenatal screening for retinoblastoma. Results: Familial retinoblastoma has an autosomal inheritance pattern and 90% penetrance. Therefore, future parents with a family history of retinoblastoma are strongly advised to get tested for retinoblastoma (Rb) gene mutations; if one of the parents is positive for a mutated allele of the RB1 gene, there is a 45% chance that their child will inherit a mutated allele of the retinoblastoma gene, rendering the allele non-functional in all of the cells of the individual and predisposing the child to a higher risk of developing retinoblastoma as well as other secondary cancers. Thus, prenatal screening and diagnosis of retinoblastoma is crucial for early diagnosis and optimal treatment. Conclusion: Prenatal testing for retinoblastoma in high-risk families is important for everyone in the family. For the parents, prenatal screening has been shown to improve their family planning decisions and psychological well-being as they can mentally prepare beforehand and make informed decisions. More importantly, these practices have shown to yield better treatment and vision outcomes in the newborn.

Efficacy of a prolonged stability melphalan formulation for intra-arterial treatment of retinoblastoma.

BACKGROUND: Melphalan, which is poorly soluble at room temperature, is widely used for the treatment of retinoblastoma by selective ophthalmic artery infusion. Evomela, a propylene glycol-free formulation of melphalan with improved solubility and stability, has recently been used as an alternative.To compare the safety and efficacy of Evomela with standard-formulation melphalan (SFM) in the treatment of retinoblastoma by selective ophthalmic artery infusion. METHODS: We performed a retrospective case-control study of patients with retinoblastoma undergoing selective ophthalmic artery infusion with SFM or Evomela at a single institution. Cycle-specific percent tumor regression (CSPTR) was estimated by comparing photos obtained during pretreatment examination under anesthesia (EUA) with those obtained during post-treatment EUA 3-4 weeks later. CSPTR, ocular salvage rates, complication rates, operation times (unadjusted and adjusted for difficulty of ophthalmic artery catheterization), and intraprocedural dose expiration rates were compared between Evomela- and SFM-treated groups. Univariate and multivariate analyses were performed. RESULTS: Ninety-seven operations (melphalan: 45; Evomela: 52) for 23 patients with 27 retinoblastomas were studied. The ocular salvage rate was 79% in the SFM-treated group and 69% in the Evomela-treated group. Multivariate regression controlling for tumor grade, patient age, and treatment history revealed no significant differences in ocular salvage rate, CSPTR, complication rates, or operation times. Although the dose expiration rate was higher for the SFM-treated group, the difference was not statistically significant. Notably, there were no ocular or cerebral ischemic complications. CONCLUSION: Evomela has non-inferior safety and efficacy relative to SFM when used for the treatment of retinoblastoma by selective ophthalmic artery infusion.

Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group.

BACKGROUND: Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. RESULTS: Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSIONS: Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Resection of intraocular tumors (partial lamellar sclerouvectomy) in the pediatric age group.

PURPOSE: To describe the outcome of intraocular tumor resection by partial lamellar sclerouvectomy (PLSU) in the pediatric age group. DESIGN: Retrospective, interventional case series. PARTICIPANTS: We included 37 patients who underwent PLSU for intraocular tumors under age 21 years. METHODS: Medical records were reviewed for clinical, operative, and histopathologic features. MAIN OUTCOME MEASURES: Globe salvage, visual acuity, surgical side effects, tumor control, and tumor-related metastasis and death. RESULTS: The mean patient age was 9 years (median, 10; range, 0.25-17) and there were 22 (59%) females and 15 (41%) males. The tumor involved mainly the iris (n = 27; 73%), ciliary body (n = 7; 19%), or choroid (n = 3; 8%). The mean tumor basal dimension was 7 mm (median, 6; range, 3-15) and thickness was 3.6 mm (median, 3; range, 0.2-9.6). The histopathologic diagnosis was melanoma (n = 19; 51%), cyst (n = 5; 14%), medulloepithelioma (n = 4; 10%), melanocytoma (n = 3; 8%), lacrimal gland choristoma (n = 2; 5%), gliosis (n = 1; 3%), nevus (n = 1; 3%), hemorrhage (n = 1; 3%), and leiomyoma (n = 1; 3%). Intraoperative adverse effects included vitreous loss in 19 (51%) and hyphema in 4 (11%). Postoperative side effects included early transient hyphema in 9 (24%) and late cataract in 12 (32%). Local tumor recurrence was detected in 5 cases (13%) at mean interval of 28 months, including melanoma (n = 3) and medulloepithelioma (n = 2). Enucleation was necessary in 9 (24%) cases for recurrence in 3 (8%), prophylactic in eyes with high-grade malignancy in 5 (13%), and for blind painful eye in 1 (3%). Of the 28 salvaged eyes, final visual acuity was ≥ 20/40 in 18 (64%), 20/50 to 20/100 in 5 (18%), and <20/200 in 5 (18%). There were no cases of metastasis or death at a mean of 51 months of follow-up. CONCLUSIONS: A surgically challenging procedure, PLSU can achieve control of selected intraocular tumors. Medulloepithelioma responds poorly to local resection and in most cases enucleation is required. If the globe is salvaged, visual acuity is ≥ 20/40 in 64% of children. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.