Managing the consequences of aggressive conservative treatment for refractory retinoblastoma with vitreous seeding

A 4 year-old girl with bilateral, non-familial retinoblastoma (RB) was referred to our care after primary enucleation OS and active tumor OD refractory to multiple therapies (intravenous chemotherapy, laser/cryotherapy, and I-125 plaque radiotherapy). Vitreous seeding OD, initially controlled by several sessions of Ophthalmic Artery Infusion Chemotherapy (OAIC) and periocular chemotherapy, recurred shortly thereafter. The patient underwent intravitreal (IVit) Melphalan injections achieving tumor control despite the concurrent development of keratopathy, pupillary synechiae, cataract, and necrosis of the inferior fornix and the adjacent orbital fat, all secondary to the treatments administered. Repeated amniotic membrane implants and tarsorrhaphy were performed to alleviate the symptoms. Despite being tumor free for 6 months, a poor fundus view and treatment-related complications prompted us to consider enucleation, but parents declined. Following recent negative magnetic resonance imaging (MRI), her cataract was removed. She was then found to have tumor recurrence. Her eye was enucleated 12 months ago and she recovered well from the surgery. As ocular oncology embarks in eye-preserving treatments for retinoblastoma, it is important to address the cumulative effects and associated impact of such treatments and the possibility of failure

The antinucleon-nucleon interaction at low energy : annihilation dynamics

The general properties of antiproton-proton annihilation at rest are presented, with special focus on the two-meson final states. The data exhibit remarkable dynamical selection rules : some allowed annihilation modes are suppressed by one order of magnitude with respect to modes of comparable phase-space. Various phenomenological analyses are reviewed, based on microscopic quark dynamics or symmetry considerations. The role of initial- and final-state interaction is also examined.Comment: 128 pages, 49 tables, 27 figure

Comparison of Alternative Tumor Size Classifications for Posterior Uveal Melanomas

PURPOSE. Determine which posterior uveal melanoma (PUM) size classification with three categories has the best prognostic discrimination. METHODS. Single-institution study of 424 consecutive patients with PUM. The tumor's largest basal diameter (LBD), smallest basal diameter (SBD), and thickness (TH) were estimated by fundus mapping and ultrasonography. Tumors were assigned to "small,'' "medium,'' or "large'' size categories defined by 11 different classifications (Linear LBD, Rectangular LBD 3 TH, Cubic LBD 3 SBD 3 TH, Warren Original, Warren Modified, Augsburger, COMS Original, COMS Revised, TNM 2002, and modified TNM 2010 classification [a, b]). Prognostic significance of classifications was evaluated by Kaplan-Meier event curves with computation of log rank test for trend statistic. RESULTS. In six classification systems (Warren Original, Warren Modified, COMS Revised, TNM 2002, TNM 2010a, TNM 2010b) >50% of tumors fell within one subgroup. In the Warren Original classification <5% of tumors fell within one subgroup. Separation of Kaplan-Meier curves among three size categories was judged "excellent'' in four classifications (Linear LBD, Cubic Volume, TNM 2010a, and TNM 2010b) and "very poor'' in the Warren Original. Linear LBD classification was associated with highest log rank statistic value. TNM 2010a, TNM 2010b, TNM 2002, Augsburger, and Cubic Volume classifications were also determined to be quite good. CONCLUSIONS. Linear LBD classification was the best three-size category discriminator among low-, intermediate-, and high-risk subgroups. Considering our findings, it seems possible that the arduous work required to apply complex classifications, especially for three-category systems, for PUM may not be justified in routine clinical practice

Indications for Fine Needle Aspiration Biopsy of Posterior Segment Intraocular Tumors

PURPOSE: To define 4 indication categories of fine needle aspiration biopsies (FNABs) of solid intraocular tumors and describe the differences among the patients, tumors, and results of biopsy in these 4 indication categories. METHODS: Retrospective descriptive analysis of 880 FNABs of a solid intraocular tumor of the posterior ocular segment performed by in the authors' ocular oncology practice during the period July 1980 through July 2014. RESULTS: FNABs were performed as a separate procedure in 372 cases (42.3%), at plaque implantation in 279 (31.7%), post-enucleation in 225 (25.6%), and postresection/pre-laser in 4 (0.4%). FNABs were categorized as diagnostic in 292 (33.2%), confirmatory in 121 (13.8%), investigational in 187 (21.3%), and prognostic in 280 (31.8%). Prior to the biopsy, all patients who underwent diagnostic FNAB had a tumor of uncertain pathologic type, while all patients who underwent confirmatory FNAB had a clinically diagnosed malignant intraocular neoplasm. In contrast, all patients who underwent a prognostic FNAB had an unequivocal primary posterior uveal melanoma clinically, while patients who underwent an investigational biopsy all had an unequivocal or probable malignant intraocular tumor of a specific type. Most diagnostic FNABs were performed transvitreously (n = 255, 87.3%) compared to prognostic FNABs (n = 143, 51.1%) (P < .001). Overall, 733 FNABs (83.3%) yielded a sufficient specimen for cytologic diagnosis. Diagnostic and confirmatory FNABs were the most likely to yield an insufficient aspirate (28.4% and 20.7%, respectively), while investigational and prognostic FNABs were most likely to yield sufficient specimens (94.7% and 90.0%, respectively) (P < .001). Mean post-FNAB follow-up of the entire group was 62.7 months (standard deviation [SD] = 59.8, 95% confidence interval [CI] = 58.7-66.6). Mean posttreat ment follow-up or total follow-up of untreated patients was 53.7 months (SD = 58.7, 95% CI = 49.8-57.6). CONCLUSIONS: Because of the substantial differences shown among FNAB cases performed for different indications, it seems appropriate to report results of FNAB or other biopsy methods according to the category (indication) of the biopsy. (C) 2019 Elsevier Inc. All rights reserved

Relationship Between Rate of Posterior Uveal Melanoma Flattening Following Plaque Radiotherapy and Gene Expression Profile Class of Tumor Cells

PURPOSE. To evaluate the relationship between rate of flattening of posterior uveal melanomas (PUMs) over the first 6 months following I-125 plaque radiotherapy and gene expression profile (GEP) class of tumor cells obtained by fine needle aspiration biopsy (FNAB) prior to treatment. METHODS. Retrospective analysis of relationship between GEP of PUM cells obtained by FNAB at or prior to treatment and rate of tumor flattening following I-125 plaque radiotherapy. Impact of initial tumor thickness was minimized by pairing cases so baseline tumor thickness in subgroups was matched to within +/- 0.5 mm. Paired t-testing compared mean tumor thickness in GEP subgroups at 3- and 6-months post treatment assessments. RESULTS. Our initial group consisted of 269 patients. Seventy-seven tumors (28.6%) were GEP class 2. Twenty-seven of these were treated by I-125 plaque radiotherapy post-FNAB and returned for post treatment evaluations at 3 and 6 months. A matched GEP class 1 tumor was identified for 25 class 2 cases. Matched tumor pairs ranged in thickness from 2.5 to 11.5 mm at baseline. Mean tumor thickness at baseline in the GEP 1 subgroup was 5.8 and 5.9 mm in the GEP 2 subgroup. Three-months post plaque, mean tumor thickness was 4.5 mm in class 1 cases and 4.6 mm in class 2 cases (paired t = 0.31, P = 0.76). The 6-month post-plaque, mean tumor thickness was 4.0 mm in each subgroup (paired t = 0.25, P = 0.81). CONCLUSIONS. Our study showed a lack of association between the GEP class and the rate of flattening of posterior uveal melanomas following I-125 plaque radiotherapy of PUMs

Independent Prognostic Significance of Gene Expression Profile Class and Largest Basal Diameter of Posterior Uveal Melanomas

To determine whether any conventional clinical prognostic factors for metastasis from uveal melanoma retain prognostic significance in multivariate models incorporating gene expression profile (GEP) class of the tumor cells. Prospective, interventional case series with a prognostic model. Single-institution study of GEP testing and other conventional prognostic factors for metastasis and metastatic death in 299 patients with posterior uveal melanoma evaluated by fine-needle aspiration biopsy (FNAB) at the time of or shortly prior to initial treatment. Univariate prognostic significance of all evaluated potential prognostic variables (patient age, largest linear basal diameter of tumor [LBD], tumor thickness, intraocular location of tumor, melanoma cytomorphologic subtype, and GEP class) was performed by comparison of Kaplan-Meier event rate curves and univariate Cox proportional hazards modeling. Multivariate prognostic significance of combinations of significant prognostic factors identified by univariate analysis was performed using step-up and step-down Cox proportional hazards modeling. GEP class was the strongest prognostic factor for metastatic death in this series. However, tumor LBD, tumor thickness, and intraocular tumor location also proved to be significant individual prognostic factors in this study. On multivariate analysis, a 2-term model that incorporated GEP class and largest basal diameter was associated with strong independent significance of each of the factors. Although GEP test is the most robust prognostic indicator in uveal melanoma and early studies of mostly larger tumors found that no clinicopathologic factors had significant prognostic value independent of GEP, our single-center study, which included a substantial proportion of smaller tumors, showed that both GEP and LBD of the tumor are independent prognostic factors for metastasis and metastatic death in multivariate analysis

Sufficiency of FNAB aspirates of posterior uveal melanoma for cytologic versus GEP classification in 159 patients, and relative prognostic significance of these classifications

To determine the relative sufficiency of paired aspirates of posterior uveal melanomas obtained by FNAB for cytopathology and GEP, and their prognostic significance for predicting death from metastasis. Prospective non-randomized IRB-approved single-center longitudinal clinical study of 159 patients with posterior uveal melanoma sampled by FNAB in at least two tumor sites between 09/2007 and 12/2010. Cases were analyzed with regard to sufficiency of the obtained aspirates for cytopathologic classification and GEP classification. Statistical strength of associations between variables and GEP class was computed using Chi-square test. Cumulative actuarial survival curves of subgroups of these patients based on their cytopathologic versus GEP-assigned categories were computed by the Kaplan-Meier method. The endpoint for this survival analysis was death from metastatic uveal melanoma. FNAB aspirates were insufficient for cytopathologic classification in 34 of 159 cases (21.9 %). In contrast, FNAB aspirates were insufficient for GEP classification in only one of 159 cases (0.6 %). This difference is statistically significant (P < 0.001). Six of 34 tumors (17.6 %) that yielded an insufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2, while 43 of 125 tumors (34.7 %) that yielded a sufficient aspirate for cytopathologic diagnosis were categorized as GEP class 2. To date, 14 of the 49 patients with a GEP class 2 tumor (28.6 %) but only five of the 109 patients with a GEP class 1 tumor (5.6 %) have developed metastasis. Fifteen of 125 patients (12 %) whose tumors yielded sufficient aspirates for cytopathologic classification but only four of 34 patients (11.8 %) whose tumors yielded insufficient aspirates for cytopathologic classification developed metastasis. The median post-biopsy follow-up time for surviving patients in this series was 32.5 months. Cumulative actuarial 5-year probability of death from metastasis 14.1 % for those with an insufficient aspirate for cytopathologic classification versus 22.4 % for those with a sufficient aspirate for cytopathologic classification (log rank P = 0.68). In contrast, the cumulative actuarial 5-year probability of metastatic death was 8.0 % for those with an insufficient/unsatisfactory aspirate for GEP classification or GEP class 1 tumor, versus 45.0 % for those with a GEP class 2 tumor (log rank P = 0.005). This study confirmed that GEP classification of posterior uveal melanoma cells obtained by FNAB is feasible in almost all cases, including most in which FNAB yields an insufficient aspirate for cytodiagnosis. The study also confirmed that GEP classification is substantially better than cytologic classification for predicting subsequent metastasis and metastatic death