Correlation of gene expression with magnetic resonance imaging features of retinoblastoma: a multi-center radiogenomics validation study.

OBJECTIVES: To validate associations between MRI features and gene expression profiles in retinoblastoma, thereby evaluating the repeatability of radiogenomics in retinoblastoma. METHODS: In this retrospective multicenter cohort study, retinoblastoma patients with gene expression data and MRI were included. MRI features (scored blinded for clinical data) and matched genome-wide gene expression data were used to perform radiogenomic analysis. Expression data from each center were first separately processed and analyzed. The end product normalized expression values from different sites were subsequently merged by their Z-score to permit cross-sites validation analysis. The MRI features were non-parametrically correlated with expression of photoreceptorness (radiogenomic analysis), a gene expression signature informing on disease progression. Outcomes were compared to outcomes in a previous described cohort. RESULTS: Thirty-six retinoblastoma patients were included, 15 were female (42%), and mean age was 24 (SD 18) months. Similar to the prior evaluation, this validation study showed that low photoreceptorness gene expression was associated with advanced stage imaging features. Validated imaging features associated with low photoreceptorness were multifocality, a tumor encompassing the entire retina or entire globe, and a diffuse growth pattern (all p < 0.05). There were a number of radiogenomic associations that were also not validated. CONCLUSIONS: A part of the radiogenomic associations could not be validated, underlining the importance of validation studies. Nevertheless, cross-center validation of imaging features associated with photoreceptorness gene expression highlighted the capability radiogenomics to non-invasively inform on molecular subtypes in retinoblastoma. CLINICAL RELEVANCE STATEMENT: Radiogenomics may serve as a surrogate for molecular subtyping based on histopathology material in an era of eye-sparing retinoblastoma treatment strategies. KEY POINTS: • Since retinoblastoma is increasingly treated using eye-sparing methods, MRI features informing on molecular subtypes that do not rely on histopathology material are important. • A part of the associations between retinoblastoma MRI features and gene expression profiles (radiogenomics) were validated. • Radiogenomics could be a non-invasive technique providing information on the molecular make-up of retinoblastoma.

Determining Asymmetry Thresholds in Anophthalmia/Microphthalmia Using a Three-dimensional Animated Model.

PURPOSE: Congenital microphthalmia and anophthalmia are rare development disorders with underdevelopment of the orbital region, resulting in asymmetry of the face. No clear guidelines exist to determine when these deviations are acceptable. METHODS: The face of a healthy 6-year-old child was three-dimensionally scanned. On this scan, we modeled various incremental degrees of facial asymmetries using three-dimensional modeling software. We modeled for smaller palpebral fissures, sunken eyes, and downward displacement of the eye. We also tested whether adjusting the vertical palpebral fissure height in relation to the horizontal palpebral fissure width affected perception. A total of 22 videos were created in which the model turned the head horizontally and vertically. We created a questionnaire asking raters how acceptable the face is, on a linear scale from 0 to 10. RESULTS: Results showed a correlation between the degree of asymmetry and the acceptability score of the raters. Enophthalmos of ≥6 mm, palpebral fissure width ≤79% compared with the other eye, and 2 mm or more downward displacement of the eye resulted in a significant different acceptability score. The desire for correction was strongly increased when these thresholds were exceeded. Adjusting the vertical palpebral fissure height to the horizontal palpebral fissure width resulted in a worse acceptability score. CONCLUSION: A unilateral sunken eye (enophthalmos) of 6 mm or more, asymmetric horizontal palpebral fissure length of ≤79%, and a lower position of one eye of more than 2 mm resulted in unacceptable judgment. These data can be used to evaluate treatment outcome in children treated for congenital microphthalmia and anophthalmia.

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.

Optic nerve thickening on high-spatial-resolution MRI predicts early-stage postlaminar optic nerve invasion in retinoblastoma.

OBJECTIVES: To assess the diagnostic accuracy of nerve thickening on MRI to predict early-stage postlaminar optic nerve invasion (PLONI) in retinoblastoma. Furthermore, this study aimed to incorporate measurements into a multiparametric model for radiological determination of PLONI. METHODS: In this retrospective multicenter case-control study, high-spatial-resolution 3D T2-weighted MR images were used to measure the distal optic nerve. Histopathology was the reference standard for PLONI. Two neuroradiologists independently measured the optic nerve width, height, and surface at 0, 3, and 5 mm from the most distal part of the optic nerve. Subsequently, PLONI was scored on contrast-enhanced T1-weighted and 3D T2-weighted images, blinded for clinical data. Optic nerve measurements with the highest diagnostic accuracy for PLONI were incorporated into a prediction model for radiological determination of PLONI. RESULTS: One hundred twenty-four retinoblastoma patients (median age, 22 months [range, 0-113], 58 female) were included, resulting in 25 retinoblastoma eyes with histopathologically proven PLONI and 206 without PLONI. ROC analysis of axial optic nerve width measured at 0 mm yielded the best area under the curve of 0.88 (95% confidence interval: 0.79, 0.96; p < 0.001). The optimal width cutoff was ≥ 2.215 mm, with a sensitivity of 84% (95% CI: 64, 95%) and specificity of 83% (95% CI: 75, 89%) for detecting PLONI. Combining width measurements with the suspicion of PLONI on MRI sequences resulted in a prediction model with an improved sensitivity and specificity of respectively up to 88% and 92%. CONCLUSION: Postlaminar optic nerve thickening can predict early-stage postlaminar optic nerve invasion in retinoblastoma. CLINICAL RELEVANCE STATEMENT: This study provides an additional tool for clinicians to help determine postlaminar optic nerve invasion, which is a risk factor for developing metastatic disease in retinoblastoma patients. KEY POINTS: • The diagnostic accuracy of contrast-enhanced MRI for detecting postlaminar optic nerve invasion is limited in retinoblastoma patients. • Optic nerve thickening can predict postlaminar optic nerve invasion. • A prediction model combining MRI features has a high sensitivity and specificity for detecting postlaminar optic nerve invasion.

Magnetic Resonance Imaging Can Reliably Differentiate Optic Nerve Inflammation from Tumor Invasion in Retinoblastoma with Orbital Cellulitis.

PURPOSE: To investigate the prevalence and magnetic resonance imaging (MRI) phenotype of retinoblastoma-associated orbital cellulitis. Additionally, this study aimed to identify postlaminar optic nerve enhancement (PLONE) patterns differentiating between inflammation and tumor invasion. DESIGN: A monocenter cohort study assessed the prevalence of orbital cellulitis features on MRI in retinoblastoma patients. A multicenter case-control study compared MRI features of the retinoblastoma-associated orbital cellulitis cases with retinoblastoma controls. PARTICIPANTS: A consecutive retinoblastoma patient cohort of 236 patients (311 eyes) was retrospectively investigated. Subsequently, 30 retinoblastoma cases with orbital cellulitis were compared with 30 matched retinoblastoma controls without cellulitis. METHODS: In the cohort study, retinoblastoma MRI scans were scored on presence of inflammatory features. In the case-control study, MRI scans were scored on intraocular features and PLONE patterns. Postlaminar enhancement patterns were compared with histopathologic assessment of postlaminar tumor invasion. Interreader agreement was assessed, and exact tests with Bonferroni correction were adopted for statistical comparisons. MAIN OUTCOME MEASURES: Prevalence of retinoblastoma-associated orbital cellulitis on MRI was calculated. Frequency of intraocular MRI features was compared between cases and controls. Sensitivity and specificity of postlaminar optic nerve patterns for detection of postlaminar tumor invasion were assessed. RESULTS: The MRI prevalence of retinoblastoma-associated orbital cellulitis was 6.8% (16/236). Retinoblastoma with orbital cellulitis showed significantly more tumor necrosis, uveal abnormalities (inflammation, hemorrhage, and necrosis), lens luxation (all P < 0.001), and a larger eye size (P = 0.012). The inflammatory pattern of optic nerve enhancement (strong enhancement similar to adjacent choroid) was solely found in orbital cellulitis cases, of which none (0/16) showed tumor invasion on histopathology. Invasive pattern enhancement was found in both cases and controls, of which 50% (5/10) showed tumor invasion on histopathology. Considering these different enhancement patterns suggestive for either inflammation or tumor invasion increased specificity for detection of postlaminar tumor invasion in orbital cellulitis cases from 32% (95% confidence interval [CI], 16-52) to 89% (95% CI, 72-98). CONCLUSIONS: Retinoblastoma cases presenting with orbital cellulitis show MRI findings of a larger eye size, extensive tumor necrosis, uveal abnormalities, and lens luxation. Magnetic resonance imaging contrast-enhancement patterns within the postlaminar optic nerve can differentiate between tumor invasion and inflammatory changes.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

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

Screening for Pineal Trilateral Retinoblastoma Revisited: A Meta-analysis.

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

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma.

PURPOSE: To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. DESIGN: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. PARTICIPANTS: Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. METHODS: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. MAIN OUTCOME MEASURES: Diagnosis and mortality from subsequent neoplasm. RESULTS: Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. CONCLUSIONS: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Determinants of health-related quality of life proxy rating disagreement between caregivers of children with cancer.

PURPOSE: Proxy reports of health-related quality of life (HRQoL) are commonly used in pediatric oncology. However, it is not known if caregivers' reports differ. This study therefore aims to compare paternal and maternal proxy reports, and explore determinants of couple disagreement (sociodemographic and medical characteristics, and parental QoL and distress). METHODS: Both parents completed the PedsQL generic (child's HRQoL), Short Form-12 (own QoL) and Distress Thermometer for Parents. To assess agreement in child HRQoL, intra-class correlation coefficients (ICCs) were calculated. Differences between fathers/mothers were assessed with paired t tests. Systematic disagreement patterns were visualized with Bland-Altman plots. Characteristics of parental couples with a mean proxy difference in the highest quartile (highest proxy score minus lowest proxy score) were explored with multiple logistic regression analysis. RESULTS: Parents of 120 children with cancer (87% post-treatment, mean age 11.0 ± 5.7 years) participated. No significant differences were found between paternal and maternal proxy scores, and agreement was good on all scales (ICCs 0.65-0.83). Bland-Altman plots revealed no systematic disagreement patterns, but there was a wide range in magnitude of the differences, and differences went in both directions. Couples with a mean proxy difference (irrespective of which direction) in the highest quartile (± 20 points) were more likely to have a child in active treatment, with retinoblastoma or relapsed disease, and to diverge in their own QoL. CONCLUSIONS: If proxy reports of only one parent are available, clinicians may reasonably assume that paternal and maternal reports are interchangeable. However, if in doubt, respondent's sex is not of major importance, but clinicians should be aware of patient's and family's characteristics.

Gender-specific differences in parental health-related quality of life in childhood cancer.

BACKGROUND: Parents of children with cancer are at risk for impaired health-related quality of life (HRQoL). Most prior research has focused on the HRQoL of mothers. The aim of this study is to describe HRQoL in mothers and fathers, and determine the influence of sociodemographic, medical, and psychosocial factors. PROCEDURE: In a cross-sectional study, both parents completed questionnaires on sociodemographics, distress, and HRQoL. Parental HRQoL was compared to healthy population values. Differences between mothers and fathers were evaluated with multilevel analysis. Gender-specific HRQoL determinants were assessed via multiple linear regression analysis. RESULTS: Parents (202 mothers, 150 fathers; comprising 121 couples) of 231 children with different cancer diagnoses (mean time since diagnosis 3.3 ± 1.4 years, 90% posttreatment) participated. Compared to healthy women and men, mothers and fathers reported significantly impaired HRQoL on the following domains: cognitive functioning, sleep, daily activities, and vitality (Cohen's d = 0.3-0.9). Additionally, maternal HRQoL was reduced on the domains gross motor functioning, pain, social functioning, sexuality, and depressive emotions. Mothers scored worse than fathers on six of 12 domains. Risk factors for adverse outcomes in both parents were higher distress, emotional and parenting problems, little social support, medication use, and active treatment of the child. Other determinants in mothers were non-Dutch background and unemployment, while lower HRQoL in fathers was predicted by their child's diagnosis type, shorter time since diagnosis, and treatment intensity. CONCLUSION: These outcomes illustrate the need for family-centered care. Future interventions aimed at improving parental functioning should take into account gender-specific differences in HRQoL to reach optimal efficacy.

MR Imaging Features of Retinoblastoma: Association with Gene Expression Profiles.

Purpose To identify associations between magnetic resonance (MR) imaging features and gene expression in retinoblastoma. Materials and Methods A retinoblastoma MR imaging atlas was validated by using anonymized MR images from referral centers in Essen, Germany, and Paris, France. Images were from 39 patients with retinoblastoma (16 male and 18 female patients [the sex in five patients was unknown]; age range, 5-90 months; inclusion criterion: pretreatment MR imaging). This atlas was used to compare MR imaging features with genome-wide messenger RNA (mRNA) expression data from 60 consecutive patients obtained from 1995 to 2012 (35 male patients [58%]; age range, 2-69 months; inclusion criteria: pretreatment MR imaging, genome-wide mRNA expression data available). Imaging pathway associations were analyzed by means of gene enrichment. In addition, imaging features were compared with a predefined gene expression signature of photoreceptorness. Statistical analysis was performed with generalized linear modeling of radiology traits on normalized log2-transformed expression values. P values were corrected for multiple hypothesis testing. Results Radiogenomic analysis revealed 1336 differentially expressed genes for qualitative imaging features (threshold P = .05 after multiple hypothesis correction). Loss of photoreceptorness gene expression correlated with advanced stage imaging features, including multiple lesions (P = .03) and greater eye size (P < .001). The number of lesions on MR images was associated with expression of MYCN (P = .04). A newly defined radiophenotype of diffuse-growing, plaque-shaped, multifocal tumors displayed overexpression of SERTAD3 (P = .003, P = .049, and P = .06, respectively), a protein that stimulates cell growth by activating the E2F network. Conclusion Radiogenomic biomarkers can potentially help predict molecular features, such as photoreceptorness loss, that indicate tumor progression. Results imply a possible role for radiogenomics in future staging and treatment decision making in retinoblastoma.

9.4T and 17.6T MRI of Retinoblastoma: Ex Vivo evaluation of microstructural anatomy and disease extent compared with histopathology.

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

An Individualized 3-Dimensional Designed and Printed Conformer After Dermis Fat Grafting for Complex Sockets.

PURPOSE: To introduce a novel technique to design individually customized conformers for postenucleation sockets with dermis fat implants. METHODS: We use a 3-dimensional scan of the frontal face/orbit and eyelid contour to design an individualized conformer. This polymethylmetacrylate printed conformer is adapted to patients' socket, palpebral fissures, horizontal eyelid aperture, curvature of the eyelids, and mean diameter of patients' contralateral eye. Sutures through holes in the inferior part of the conformer and in the extension can be placed to fixate the conformer and anchor fornix deepening sutures. RESULTS: A correct fitting conformer can be printed and attached to the socket and eyelids. The shape of this conformer can be used subsequently postsurgically to design the ocular prosthesis. CONCLUSION: Presurgical planning is important to anticipate for a functional socket to adequately fit an artificial eye. The presented technique using 3-dimensional imaging, designing, and printing promises to prevent conformer extrusion and forniceal shortening.

Genomic landscape of retinoblastoma in Rb-/- p130-/- mice resembles human retinoblastoma.

Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb-/- p107-/- retinoblastomas, somatic copy number alterations (SCNAs) like Mdm2 amplification or Cdkn2a deletion targeting the p53-pathway occur, which is uncommon for human retinoblastoma. In our study, we determined SCNAs in retinoblastomas developing in Rb-/- p130-/- mice and compared this to murine Rb-/- p107-/- tumors and human tumors. Chimeric mice were made by injection of 129/Ola-derived Rb-/- p130-/- embryonic stem cells into wild type C57BL/6 blastocysts. SCNAs of retinoblastoma samples were determined by low-coverage (∼0.5×) whole genome sequencing. In Rb-/- p130-/- tumors, SCNAs included gain of chromosomes 1 (3/23 tumors), 8 (1/23 tumors), 10 (1/23 tumors), 11 (2/23 tumors), and 12 (4/23 tumors), which could be mapped to frequently altered chromosomes in human retinoblastomas. While the altered chromosomes in Rb-/- p130-/- tumors were similar to those in Rb-/- p107-/- tumors, the alteration frequencies were much lower in Rb-/- p130-/- tumors. Most of the Rb-/- p130-/- tumors (16/23 tumors, 70%) were devoid of SCNAs, in strong contrast to Rb-/- p107-/- tumors, which were never (0/15 tumors) SCNA-devoid. Similarly, to human retinoblastoma, increased age at diagnosis significantly correlated with increased SCNA frequencies. Additionally, focal loss of Cdh11 was observed in one Rb-/- p130-/- tumor, which enforces studies in human retinoblastoma that identified CDH11 as a retinoblastoma suppressor. Moreover, based on a comparison of genes altered in human and murine retinoblastoma, we suggest exploring the role of HMGA1 and SRSF3 in retinoblastoma development. © 2016 Wiley Periodicals, Inc.

Altered eigenvector centrality is related to local resting-state network functional connectivity in patients with longstanding type 1 diabetes mellitus.

INTRODUCTION: Longstanding type 1 diabetes (T1DM) is associated with microangiopathy and poorer cognition. In the brain, T1DM is related to increased functional resting-state network (RSN) connectivity in patients without, which was decreased in patients with clinically evident microangiopathy. Subcortical structure seems affected in both patient groups. How these localized alterations affect the hierarchy of the functional network in T1DM is unknown. Eigenvector centrality mapping (ECM) and degree centrality are graph theoretical methods that allow determining the relative importance (ECM) and connectedness (degree centrality) of regions within the whole-brain network hierarchy. METHODS: Therefore, ECM and degree centrality of resting-state functional MRI-scans were compared between 51 patients with, 53 patients without proliferative retinopathy, and 49 controls, and associated with RSN connectivity, subcortical gray matter volume, and cognition. RESULTS: In all patients versus controls, ECM and degree centrality were lower in the bilateral thalamus and the dorsal striatum, with lowest values in patients without proliferative retinopathy (PFWE < 0.05). Increased ECM in this group versus patients with proliferative retinopathy was seen in the bilateral lateral occipital cortex, and in the right cuneus and occipital fusiform gyrus versus controls (PFWE < 0.05). In all patients, ECM and degree centrality were related to altered visual, sensorimotor, and auditory and language RSN connectivity (PFWE < 0.05), but not to subcortical gray matter volume or cognition (PFDR > 0.05). CONCLUSION: The findings suggested reorganization of the hierarchy of the cortical connectivity network in patients without proliferative retinopathy, which is lost with disease progression. Centrality seems sensitive to capture early T1DM-related functional connectivity alterations, but not disease progression. Hum Brain Mapp 38:3623-3636, 2017. © 2017 Wiley Periodicals, Inc.

A Novel Method to Measure Artificial Eye Motility.

PURPOSE: To measure objectively, reproducibly, and noninvasively artificial eye motility, a fundamental aspect in the (cosmetic) outcome of enucleation. METHOD: A gaze- and pupil-tracking system, the "iView X," was implemented to measure horizontal eye motility. The system, with adjusted software, was tested with patients wearing 1 prosthetic eye after enucleation for retinoblastoma. Measurements were repeated 5 times in every patient and analyses were performed twice by 2 independent observers. Reproducibility was tested via linear mixed models. After the implementation of the method, more data were obtained, including more patients with a history of enucleation for the treatment of retinoblastoma for eye tracker measurement, and differences in motility percentages between implant types and sizes were analyzed via Mann-Whitney U tests. RESULTS: The intraclass correlation coefficient of the interobserver variable in the patient test group (n = 27, 6-53 years) was 0.98 and 0.96 for measurement of left gaze and right gaze, respectively. Intraobserver variation was <0.001. In the total of 58 included patients for comparative analysis, mean difference of prosthesis motility compared with the contralateral eye in abduction was 57.1% (range 3.2-91.5%); in adduction 65.8% (range 24.0-92.0%). No statistical differences were found between the different implant types and sizes. CONCLUSION: Motility measurements of the prosthetic eye in comparison to the contralateral eye using the iView X system are reproducible and reliable. This is, to the authors' knowledge, the first easy applicable, noninvasive, reproducible, and commercially available instrument to evaluate prosthesis motility. With the adjusted software program (freely available on request), a similar objective measurement can be performed worldwide. The implant size or type did not influence the outcome of the motility measurement; this finding deserves additional study.

Disrupted subject-specific gray matter network properties and cognitive dysfunction in type 1 diabetes patients with and without proliferative retinopathy.

INTRODUCTION: Type 1 diabetes mellitus (T1DM) patients, especially with concomitant microvascular disease, such as proliferative retinopathy, have an increased risk of cognitive deficits. Local cortical gray matter volume reductions only partially explain these cognitive dysfunctions, possibly because volume reductions do not take into account the complex connectivity structure of the brain. This study aimed to identify gray matter network alterations in relation to cognition in T1DM. METHODS: We investigated if subject-specific structural gray matter network properties, constructed from T1-weighted MRI scans, were different between T1DM patients with (n = 51) and without (n = 53) proliferative retinopathy versus controls (n = 49), and were associated to cognitive decrements and fractional anisotropy, as measured by voxel-based TBSS. Global normalized and local (45 bilateral anatomical regions) clustering coefficient and path length were assessed. These network properties measure how the organization of connections in a network differs from that of randomly connected networks. RESULTS: Global gray matter network topology was more randomly organized in both T1DM patient groups versus controls, with the largest effects seen in patients with proliferative retinopathy. Lower local path length values were widely distributed throughout the brain. Lower local clustering was observed in the middle frontal, postcentral, and occipital areas. Complex network topology explained up to 20% of the variance of cognitive decrements, beyond other predictors. Exploratory analyses showed that lower fractional anisotropy was associated with a more random gray matter network organization. CONCLUSION: T1DM and proliferative retinopathy affect cortical network organization that may consequently contribute to clinically relevant changes in cognitive functioning in these patients.

Diagnostic Accuracy of Intraocular Tumor Size Measured with MR Imaging in the Prediction of Postlaminar Optic Nerve Invasion and Massive Choroidal Invasion of Retinoblastoma.

Purpose To assess the correlation of intraocular retinoblastoma tumor size measured with magnetic resonance (MR) imaging in the prediction of histopathologically determined metastatic risk factors (postlaminar optic nerve invasion and massive choroidal invasion). Materials and Methods The ethics committee approved this retrospective multicenter study with a waiver of informed consent. The study population included 370 consecutive patients with retinoblastoma (375 eyes) who underwent baseline MR imaging, followed by primary enucleation from 1993 through 2014. Tumor sizes (maximum diameter and volume) were measured independently by two observers and correlated with histopathologic risk factors. Receiver operating characteristic curves were used to analyze the diagnostic accuracy of tumor size, and areas under the curve were calculated. Logistic regression analysis was performed to evaluate potential confounders. Results Receiver operating characteristic analysis of volume and diameter, respectively, yielded areas under the curve of 0.77 (95% confidence interval [CI]: 0.70, 0.85; P < .0001) and 0.78 (95% CI: 0.71, 0.85; P < .0001) for postlaminar optic nerve invasion (n = 375) and 0.67 (95% CI: 0.57, 0.77; P = .0020) and 0.70 (95% CI: 0.59, 0.80; P = .0004) for massive choroidal tumor invasion (n = 219). For the detection of co-occurring massive choroidal invasion and postlaminar optic nerve invasion (n = 219), volume and diameter showed areas under the curve of 0.81 (95% CI: 0.70, 0.91; P = .0032) and 0.83 (95% CI: 0.73, 0.93; P = .0016), respectively. Conclusion Intraocular tumor size shows a strong association with postlaminar optic nerve invasion and a moderate association with massive choroidal invasion. These findings provide diagnostic accuracy measures at different size cutoff levels, which could potentially be useful in a clinical setting, especially within the scope of the increasing use of eye-salvage treatment strategies. (©) RSNA, 2015 Online supplemental material is available for this article.

Subgenual Cingulate Cortex Functional Connectivity in Relation to Depressive Symptoms and Cognitive Functioning in Type 1 Diabetes Mellitus Patients.

OBJECTIVES: Patients with Type 1 diabetes mellitus (T1DM) are at an increased risk for major depression, but its underlying mechanisms are still poorly understood. In nondiabetic participants, mood disturbances are related to altered subgenual cingulate cortex (SGC) resting-state functional connectivity. We tested for SGC connectivity alterations in T1DM, whether these alterations were related to depressive symptoms, and if depressive symptoms were associated with cognition. METHODS: A bilateral SGC seed-based resting-state functional magnetic resonance imaging analysis was performed in 104 T1DM patients and 49 controls without known psychiatric diagnosis or treatment. Depressive symptoms were self-reported using the Center for Epidemiological Studies Depression scale. Cognition was assessed with a battery of standardized tests. RESULTS: In patients versus controls, SGC to right inferior frontal gyrus and frontal pole connectivity was decreased (52 voxels, z valuepeak = 3.56, pcluster-FWE = .002), whereas SGC to bilateral precuneus (33 voxels, z valuepeak = 3.34, pcluster-FWE = .04) and left inferior parietal lobule (50 voxels, z valuepeak = 3.50, pcluster-FWE = .003) connectivity was increased. In all participants, increased depressive symptoms was related to lower SGC to inferior frontal gyrus and frontal pole connectivity (ß = -0.156, p = .053), and poorer general cognitive ability (ß = -0.194, p = .023), information processing speed (ß = -0.222, p = .008), and motor speed (ß = -0.180, p = .035). CONCLUSIONS: T1DM patients showed a pattern of SGC connectivity that is characterized by lower executive control and higher default mode network connectivity. Depressive symptoms are partially related to these alterations and seem to exacerbate T1DM-related cognitive dysfunction. Future studies should detail the effect of diagnosed major depressive disorder in this population and establish what alterations are diabetes specific.

Retinal blood flow is increased in type 1 diabetes mellitus patients with advanced stages of retinopathy.

BACKGROUND: Diabetic retinopathy (DRP) is a common microvascular complication seen in patients with type 1 diabetes mellitus (T1DM). The effects of T1DM and concomitant (proliferative) DRP on retinal blood flow are currently unclear. Therefore, we measured retinal vascular blood flow in T1DM patients with and without DRP and non-diabetic controls. We further assessed the acute effects of panretinal photocoagulation on retinal microvascular bloodflow in eight patients with diabetes. METHODS: Thirty-three T1DM patients with proliferative DRP, previously treated with panretinal photocoagulation (pDRP), 11 T1DM patients with untreated non-proliferative retinopathy (npDRP) and 32 T1DM patients without DRP (nDRP) were compared with 44 non-diabetic gender-matched controls. Using scanning laser Doppler flowmetry (HRF, Heidelberg) blood flow in the retinal microvasculature was measured temporal and nasal of the optic disc and averaged into one flow value per eye. The right eye was used as a default for further analyses. Eight patients with novel proliferative retinopathy (4 T1DM and 4 with type 2 diabetes) were measured before and several months after photocoagulation. Between-group differences in retinal blood flow were assessed using ANOVA corrected for multiple comparisons (Bonferroni). RESULTS: Retinal blood flow was higher in the treated pDRP compared with the nDRP group and controls (all P Bonferroni < 0.01). Furthermore, there was a positive linear trend for blood flow with lowest blood flow in the control group and highest in the pDRP group (P-for-trend < 0.01). In the eight patients with novel proliferative retinopathy, blood flow did not significantly change before and after panretinal photocoagulation (P > 0.05). Using regression analysis, no variables were found as predictors of retinal blood flow. CONCLUSIONS: In comparison with controls and nDRP patients, retinal blood flow significantly increased in the pDRP group, which previously underwent photocoagulation treatment, but not in the npDRP patients. These changes may be a consequence of a failing vascular autoregulation in advanced diabetic retinopathy.