Spatiotemporal Patterns of Tumor Occurrence in Children with Intraocular Retinoblastoma.
ABSTRACT: To accurately map the retinal area covered by tumor in a prospectively enrolled cohort of children diagnosed with retinoblastoma.Orbital MRI in 106 consecutive retinoblastoma patients (44 bilateral) was analyzed. For MRI-visible tumors, the polar angle and angle of eccentricity of points defining tumor perimeter on the retina were determined by triangulation from images in three orthogonal planes. The centroid of the mapped area was calculated to approximate tumor origin, and the location and cumulative tumor burden were analyzed in relation to mutation type (germline vs. somatic), tumor area, and patient age at diagnosis. Location of small tumors undetected by MRI was approximated with fundoscopic images.Mapping was successful for 129 tumors in 91 eyes from 67 patients (39 bilateral, 43 germline mutation). Cumulative tumor burden was highest within the macula and posterior pole and was asymmetrically higher within the inferonasal periphery. Tumor incidence was lowest in the superotemporal periphery. Tumor location varied with age at diagnosis in a complex pattern. Tumor location was concentrated in the macula and superonasal periphery in patients <5.6 months, in the inferotemporal quadrant of the posterior pole in patients 5.6-8.8 months, in the inferonasal quadrant in patients 8.8-13.2 months, and in the nasal and superotemporal periphery in patients >13.2 months. The distribution of MRI-invisible tumors was consistent with the asymmetry of mapped tumors.MRI-based mapping revealed a previously unrecognized pattern of retinoblastoma localization that evolves with age at diagnosis. The structured spatiotemporal distribution of tumors may provide valuable clues about cellular or molecular events associated with tumorigenesis in the developing retina.
Project description:To investigate anterior scleral thickness in a cohort of healthy subjects using enhanced depth imaging anterior segment optical coherence tomography.Observational case series. The mean scleral thickness in the inferonasal, inferotemporal, superotemporal, and superonasal quadrant was measured 2 mm from the scleral spur on optical coherence tomography in healthy volunteers.Fifty-three eyes of 53 Caucasian patients (25 male and 28 female) with an average age of 48.6 years (range: 18 to 92 years) were analysed. The mean scleral thickness was 571 ?m (SD 84 ?m) in the inferonasal quadrant, 511 ?m (SD 80 ?m) in the inferotemporal quadrant, 475 (SD 81 ?m) in the superotemporal, and 463 (SD 64 ?m) in the superonasal quadrant. The mean scleral thickness was significantly different between quadrants (p?<?0.0001, repeated measures one-way ANOVA). The association between average scleral thickness and age was statistically significant (p?<?0.0001, Pearson r?=?0.704).Enhanced depth imaging optical coherence tomography revealed the detailed anatomy of the anterior sclera and enabled non-invasive measurements of scleral thickness in a non-contact approach. The anterior scleral thickness varies significantly between quadrants, resembling the spiral of Tillaux. An association of increasing scleral thickness with age was found.
Project description:PURPOSE:To visualize and quantify conventional outflow directly in its anatomic location. METHODS:We obtained fluorescein canalograms in six porcine whole eyes and six porcine anterior segment cultures. Eyes were perfused with a constant pressure of 15 mmHg using media containing 0.017 mg/ml fluorescein. Flow patterns were visualized using a stereo dissecting microscope equipped for fluorescent imaging. Images were captured every 30 seconds for 20 minutes for time lapse analysis. Anterior chamber cultures were imaged again on day three of culture. Canalograms were first analyzed for filling time per quadrant. We then wrote a program to automatically compute focal flow fits for each macropixel and to detect convergent perilimbal flow patterns with macropixels grouped into 3 equal-radial width rings around the cornea. A generalized additive model was used to determine fluorescence changes of individual macropixels. RESULTS:The resulting imaging algorithm deployed 1024 macropixels that were fit to determine maximum intensity and time to fill. These individual fits highlighted the focal flow function. In whole eyes, significantly faster flow was seen in the inferonasal (IN) and superonasal (SN) quadrants compared to the superotemporal (ST) and inferotemporal (IT) ones (p<0.05). In anterior chamber cultures, reduced flow on day 1 increased in all quadrants on day 3 except in IT (p<0.05). Perilimbal ring analysis uncovered convergent perilimbal flow. CONCLUSIONS:An algorithm was developed that analyzes regional and circumferential outflow patterns. This algorithm found flow patterns that changed over time and differ in whole eyes and anterior segment cultures.
Project description:PURPOSE:To evaluate the relationship between injection site and pain severity following intravitreal injection of bevacizumab (IVB). DESIGN:Prospective, randomized, four-armed, clinical trial. METHODS:The present study was a prospective, randomized, four-armed clinical trial, which included 1004 eyes from 1004 patients. Patients receiving IVB were randomly assigned into four groups: superotemporal (ST); superonasal (SN); inferotemporal (IT); and inferonasal (IN) injections. The visual analog scale (VAS) was used to assess pain. Primary study variables were the relationship between pain severity and injection site, number of previous injections, age, sex, and indication for injection. Secondary variables included best-corrected visual acuity (BCVA) and central macular thickness (CMT) changes 1 month post IVB. RESULTS:Overall mean pain score was 2.86?±?2.2. Indications for injection were diabetic macular edema (84.1%), neovascular age-related macular degeneration (7.7%), and macular edema secondary to retinal vein occlusion (8.2%). The mean VAS scores in the SN, IN, ST, and IT groups were 1.5?±?1.7, 3?±?2.3, 4?±?2, and 3?±?2.1, respectively. Pain severity was significantly correlated with injection site (p?<?0.001) and sex (p?<?0.001); females showed higher pain scores. A negative correlation existed between pain score and number of previous injections (p?=?0.03). Pain severity was not associated with age (p?=?0.659), lens status (p?=?0.478), vitreous reflux (p?=?0.648), or indication for injection (p?=?0.390). No significant complications were observed. CONCLUSIONS:ST quadrant was the most painful and SN quadrant was the least painful sites for IVB. Pain severity score was significantly associated with injection site, number of injections, and sex.
Project description:Recently introduced microincisional glaucoma surgeries that enhance conventional outflow offer a favorable risk profile over traditional surgeries, but can be unpredictable. Two paramount challenges are the lack of an adequate training model for angle surgeries and the absence of an intraoperative quantification of surgical success. To address both, we developed an ex vivo training system and a differential, quantitative canalography method that uses slope-adjusted fluorescence intensities of two different chromophores to avoid quenching. We assessed outflow enhancement by trabecular micro-bypass (TMB) implantation or by ab interno trabeculectomy (AIT). In this porcine model, TMB resulted in an insignificant (p?>?0.05) outflow increase of 13?±?5%, 14?±?8%, 9?±?3%, and 24?±?9% in the inferonasal, superonasal, superotemporal, and inferotemporal quadrant, respectively. AIT caused a 100?±?50% (p?=?0.002), 75?±?28% (p?=?0.002), 19?±?8%, and 40?±?21% increase in those quadrants. The direct gonioscopy and tactile feedback provided a surgical experience that was very similar to that in human patients. Despite the more narrow and discontinuous circumferential drainage elements in the pig with potential for underperformance or partial stent obstruction, unequivocal patterns of focal outflow enhancement by TMB were seen in this training model. AIT achieved extensive access to outflow pathways beyond the surgical site itself.
Project description:Purpose:This study assessed physician-investigator experience with suprachoroidal (SC) injections, an investigational therapeutic administration technique using a 900 or 1100 µm microneedle to inject drugs into the SC space. Methods:Datasets from six clinical trials across three diseases (noninfectious uveitis; diabetic macula edema, and retinal vein occlusion) were assessed. In addition to a user survey, retrospective correlations were performed between procedural variables (needle length), and demographics, and ocular characteristics. Results:In the user survey, 84% (31/37) of physician-investigators did not perceive the SC injections to be meaningfully more challenging than other ocular injections. For the correlation analysis, the 900 µm needle was used for 71% (412/581) of baseline injections, and switching to the longer needle occured in the remaining 29% of baseline injections. No statistical correlations were found between needle lengths and age, race, disorder, refraction, visual acuity, intraocular pressure, retinal central subfield thickness, or lens status. Patient gender and needle length were statistically associated, with 76% (210/275) versus 66% (202/306) of injections administered with 900 µm needles for female and male gender, respectively. Injection quadrant correlated to needle length with 78% (214/275) of superotemporal quadrant injections administered with 900 µm needles, compared with 65% (73/113) of inferotemporal quadrant injections. Conclusions:Both the user survey and the correlation analysis demonstrated that SC injection is well accepted by physician-investigators, and the two needle lengths accommodate a wide range of anatomic and demographic variables. Translational Relevance:These results, along with the presented ex-vivo endoscopic imaging, suggest that SC injection could be readily adopted in clinical practice for targeted compartmentalized delivery of ocular therapeutics.
Project description:Purpose:To quantitatively demonstrate asymmetric choroidal outflow in pachychoroid (central serous chorioretinopathy [CSC]/pachychoroid pigment epitheliopathy [PPE]) eyes using mid-phase, ultra-widefield indocyanine green angiography (UWF ICGA) images. Methods:Eyes with a clinical diagnosis of CSC/PPE were imaged with multimodal imaging including UWF ICGA (Optos California). Quadrant brightness was measured by manually segmenting based on vortex vein location, calculating the brightness "max-min" value to assess nonuniformity between quadrants, and comparing between CSC/PPE and control eyes. A multivariate linear regression was performed to determine, across individual eyes, which specific quadrants have the greatest brightness in pachychoroid eyes, after taking into account patient-eye-specific variability. Results:Thirty-three eyes (18 patients) with CSC/PPE along with 16 eyes of 9 controls had a mean age of 51.94 ± 9.72 vs. 53.78 ± 17.92 years (P = 0.731), respectively. Max-min analysis showed significantly increased likelihood of nonuniform drainage between vortex veins in both CSC/PPE and control eyes. Multivariate linear regression in control eyes showed that on average, the inferotemporal quadrant was significantly brighter than the superonasal quadrant (9.72 units, P < 0.001). Among CSC/PPE eyes, adjusting for the preferential, nonuniform drainage in control eyes, the inferonasal and inferotemporal quadrants in CSC/PPE eyes remained significantly brighter than the reference quadrant by 5.36 units (P = 0.034) and 7.51 units (P = 0.008), respectively. Conclusions:Asymmetric choroidal venous outflow occurs in both control and CSC/PPE eyes based on UWF ICGA quantitative brightness levels in each quadrant. Increased brightness levels along inferior quadrants in mid-phase ICGA images suggest venous outflow congestion among eyes with CSC or PPE.
Project description:To investigate the relationship between mammographic density measured in four quadrants of a breast with the location of the occurred cancer.One hundred and ten women diagnosed with unilateral breast cancer that could be determined in one specific breast quadrant were retrospectively studied. Women with previous cancer/breast surgery were excluded. The craniocaudal (CC) and mediolateral oblique (MLO) mammography of the contralateral normal breast were used to separate a breast into 4 quadrants: Upper-Outer (UO), Upper-Inner (UI), Lower-Outer (LO), and Lower-Inner (LI). The breast area (BA), dense area (DA), and percent density (PD) in each quadrant were measured by using the fuzzy-C-means segmentation. The BA, DA, and PD were compared between patients who had cancer occurring in different quadrants.The upper-outer quadrant had the highest BA (37 ± 15 cm2) and DA (7.1 ± 2.9 cm2), with PD = 20.0 ± 5.8%. The order of BA and DA in the 4 separated quadrants were: UO > UI > LO > LI, and almost all pair-wise comparisons showed significant differences. For tumor location, 67 women (60.9%) had tumor in UO, 16 (14.5%) in UI, 7 (6.4%) in LO, and 20 (18.2%) in LI quadrant, respectively. The estimated odds and the 95% confidence limits of tumor development in the UO, UI, LO and LI quadrants were 1.56 (1.06, 2.29), 0.17 (0.10, 0.29), 0.07 (0.03, 0.15), and 0.22 (0.14, 0.36), respectively. In these 4 groups of women, the order of quadrant BA and DA were all the same (UO > UI > LO > LI), and there was no significant difference in BA, DA or PD among them (all p > 0.05).Breast cancer was most likely to occur in the UO quadrant, which was also the quadrant with highest BA and DA; but for women with tumors in other quadrants, the density in that quadrant was not the highest. Therefore, there was no direct association between quadrant density and tumor occurrence.
Project description:To investigate the safety and potential efficacy of ranibizumab for prevention of radiation complications in patients treated with proton irradiation for choroidal melanoma.Forty patients with tumors located within 2 disc diameters of the optic nerve and/or macula were enrolled in this open-label study. Participants received ranibizumab 0.5 mg or 1.0 mg at tumor localization and every 2 months thereafter for the study duration of 24 months. The incidence of adverse events, visual acuity, and other measures of ocular morbidity related to radiation complications were assessed. Historical controls with similar follow-up meeting the eligibility criteria for tumor size, location, and baseline visual acuity were assembled for comparison.Fifteen patients with large tumors and 25 patients with small/medium tumors were enrolled. Thirty-two patients completed the month 24 visit. No serious ocular or systemic adverse events related to ranibizumab were observed. At 24 months, the proportion of patients with visual acuity ? 20/200 was 30/31 (97%) in the study group versus 92/205 (45%) in historical controls (P < .001). The proportion of patients with visual acuity ?20/40 was 24/31 (77%) in the study group versus 46/205 (22%) in controls at 24 months (P<.001). Clinical evidence of radiation maculopathy at month 24 was seen in 8/24 (33%) patients with small/medium tumors versus 42/62 (68%) of controls (P = .004). Three patients with large tumors developed metastases.In this small pilot study, prophylactic ranibizumab appears generally safe in patients treated with proton irradiation for choroidal melanoma. High rates of visual acuity retention were observed through 2 years.
Project description:This case report presents an incidental finding of a rectal GIST (gastrointestinal stromal tumor) presenting as a submucosal calculus, not previously reported. A 53-year-old man without a significant medical history presented with abdominal pain in the left lower quadrant, and with constipation. Upon rectal examination, a hard submucosal swelling was palpated 4 cm from the anus, at 3 o'clock, in the left rectum wall. X-ray photos, computerized tomography (CT)-scan and a magnetic resonance imaging (MRI) scan clearly showed a calculus. Excision revealed a turnip-like lesion, 3.1 x 2.3 x 1.8 cm. Analysis showed it was a rectal GIST, a rare mesenchymal tumor of the gastrointestinal tract, which expressed CD117 (or c-kit, a marker of kit-receptor tyrosine kinase) and CD34. Calcification is not a usual clinicopathological feature of GISTs [1-3], and although a number of rectal GISTs have been reported [4-9], we have found no cases so far of rectal GIST presenting as a submucosal calculus. In general, GISTs are rare mesenchymal tumors of the gastrointestinal tract (nerve tissue, smooth muscle). Histology and immunohistochemistry discriminate gastrointestinal stromal tumors from leiomyomas and neurinomas. The most important location is the stomach; the rectal location is rare. Usually, the classic signs of malignancy such as cellular invasion and metastasis are missing. A set of histologic criteria stratifies GIST for risk of malignant behavior such as mitotic activity and tumor size, cellular pleomorphism, developmental stage of the cell and quantity of cytoplasma [7,13]. Tumors with a high mitotic activity and size above 5 cm are considered malignant. Recent pharmacological advances such as tyrosine kinase inhibitors have determined c-kit (i.e., CD117) as the most important marker, amongst others. C-kit positive tumors respond extremely well to chemotherapy with Imatinib (Glivec, Gleevec) [10-12].
Project description:The human retinal pigment epithelium (RPE) is reportedly 3% bi-nucleated. The importance to human vision of multi-nucleated (MN)-RPE cells could be clarified with more data about their distribution in central retina.Nineteen human RPE-flatmounts (9 ? 51 years, 10 > 80 years) were imaged at 12 locations: 3 eccentricities (fovea, perifovea, near periphery) in 4 quadrants (superior, inferior, temporal, nasal). Image stacks of lipofuscin-attributable autofluorescence and phalloidin labeled F-actin cytoskeleton were obtained using a confocal fluorescence microscope. Nuclei were devoid of autofluorescence and were marked using morphometric software. Cell areas were approximated by Voronoi regions. Mean number of nuclei per cell among eccentricity/quadrant groups and by age were compared using Poisson and binominal regression models.A total of 11,403 RPE cells at 200 locations were analyzed: 94.66% mono-, 5.31% bi-, 0.02% tri-nucleate, and 0.01% with 5 nuclei. Age had no effect on number of nuclei. There were significant regional differences: highest frequencies of MN-cells were found at the perifovea (9.9%) and near periphery (6.8%). The fovea lacked MN-cells almost entirely. The nasal quadrant had significantly more MN-cells compared to other quadrants, at all eccentricities.This study demonstrates MN-RPE cells in human macula. MN-cells may arise due to endoreplication, cell fusion, or incomplete cell division. The topography of MN-RPE cells follows the topography of photoreceptors; with near-absence at the fovea (cones only) and high frequency at perifovea (highest rod density). This distribution might reflect specific requirements of retinal metabolism or other mechanisms addressable in further studies.