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Introduction:Children with retinoblastoma have anesthesia for exams and treatment, but there is little information about how long treatment interventions (laser, cryotherapy, and intravitreal injections) add to routine exams under anesthesia (EUA). This information would be useful for planning operating room schedules, staff schedules, family expectations, and billing. Methods:A retrospective, single-center, Institutional Review Board (IRB) approved review of anesthesia duration for retinoblastoma children undergoing EUA with laser, cryotherapy, or intravitreal injections performed at MSK between January 2019 and November 2023. Results:Three hundred eight patients had 2,399 EUAs. The average EUA lasted 24.3 min (range 7–77 min) when no interventions were done. Laser photocoagulation added an average of 18.9 min (range 19–77 min), cryotherapy 26.1 min (range 27–75 min), and intravitreal injection 23.5 min (range 10–71 min) to the basic EUA time. Bilateral laser treatments took 8 min longer than unilateral treatments. Conclusion:EUAs for children with retinoblastoma can be performed relatively quickly. Interventions such as laser, cryotherapy, or intravitreal injections roughly double the time under anesthesia but in some cases can take much longer (>1 h).

IMPORTANCE: Plasma measurements of RB1 circulating tumor DNA (ctDNA) after completion of treatment may be associated with the development of metastases in patients with retinoblastoma. OBJECTIVE: To determine if the absence of previously detectable plasma ctDNA is associated with metastasis-free survival in patients with a minimum of 1 year follow-up after treatment of retinoblastoma. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted from June 2019 to September 2023. Patients with retinoblastoma who had measurable ctDNA levels at diagnosis and had repeated ctDNA measurements after ocular treatment (enucleation or intra-arterial chemotherapy) with a minimum of 1 year of follow-up (mean [SD], 28.2 [10.3] months) were included in the study. Patients were recruited from a single-center, tertiary cancer hospital. EXPOSURE: Memorial Sloan Kettering’s New York State–approved gene test, which interrogates 129 known cancer genes (called ACCESS), was performed on plasma samples before and after ocular treatments. All exons of the RB1 gene are included in the test and listed as ctDNA in this article. MAIN OUTCOMES AND MEASURES: Plasma ctDNA level before treatment, after completion of ocular treatment, and development or absence of metastases. RESULTS: A total of 24 patients (mean [SD] age, 20.7 [17.1] months; 15 female [62.5%]) were included in the study. None of the 23 patients who had a measurable ctDNA level and then no detectable ctDNA level after completion of ocular treatment developed metastases with a minimum of 1 year of follow-up. One patient had persistent measurable ctDNA after initial treatment and developed metastases. CONCLUSION AND RELEVANCE: Patients with retinoblastoma who had a measurable ctDNA level at diagnosis did not develop metastases if the plasma ctDNA level became unrecordable after ocular treatment; 1 patient who had persistent measurable ctDNA after treatment did develop metastasis.

Background/aimsOcular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and sites of disease.MethodsProspective registry-based study of predominantly adult histiocytosis patients at a single-institution tertiary referral centre. 180 eyes of 90 patients (46 males, 44 females) with histiocytosis (Erdheim-Chester disease 34, Rosai-Dorfman 20, xanthogranuloma 7, mixed histiocytosis 13, Langerhans cell histiocytosis (LCH) 15, ALK-positive histiocytosis 1). Ocular findings were categorised by the structure involved. Histiocytosis subtype, sites of disease and genetic status were correlated to ocular findings.ResultsOcular disease was present in more than half the histiocytosis patient cohort and occurred with other disease sites. Ocular findings were statistically significantly different across histiocytic subtypes with LCH subtypes having the lowest proportion of ocular findings (7%) and all other subtypes having rates of ocular findings which were five times that of patients with LCH (p=0.0009). Of patients with ocular findings, 41% of patients reported ocular symptoms and were significantly more in the group with ocular disease present versus those patients without ocular involvement. The presence of ocular findings was not statistically different by BRAFV600E, MAP2K1or RASisoform mutational status.ConclusionsOcular disease is a common feature of histiocytosis with significant visual symptomatology and occurrence in tandem with multisystem sites. Ocular findings vary by histiocytic subtype. The mutational profile of the cohort reflects known mutations in this clinical population, with no specific driver mutation associated with ocular disease.

Introduction:Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension. Case Presentations:In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients’ IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy. Discussion/Conclusion:This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors.

BackgroundRetinoblastoma (Rb) is the most common primary ocular malignancy of childhood. Left untreated, it is 100% fatal and carries a substantial risk of impaired vision and removal of one or both eyes. Intra-arterial chemotherapy (IAC) has become a pillar in the treatment paradigm for Rb that allows for better eye salvage and vision preservation without compromising survival. We describe the evolution of our technique over 15 years.MethodsA retrospective chart review was conducted of 571 patients (697 eyes) and 2391 successful IAC sessions over 15 years. This cohort was separated into three 5-year periods (P1, P2, P3) to assess trends in IAC catheterization technique, complications, and drug delivery.ResultsFrom a total of 2402 attempted IAC sessions, there were 2391 successful IAC deliveries, consistent with a 99.5% success rate. The rate of successful super-selective catheterizations over the three periods ranged from 80% in P1 to 84.9% in P2 and 89.2% in P3. Catheterization-related complication rates were 0.7% in P1, 1.1% in P2, and 0.6% in P3. Chemotherapeutics used included combinations of melphalan, topotecan and carboplatin. The rate of patients receiving triple therapy among all groups was 128 (21%) in P1, 487 (41.9%) in P2, and 413 (66.7%) in P3.ConclusionsThe overall rate of successful catheterization and IAC started high and has improved over 15 years, and catheterization-related complications are rare. There has been a significant trend towards triple chemotherapy over time.

Introduction:Many cancers have derangement of the mitogen-activated pathway kinase (MAPK), making this pathway blockade a therapeutic target. However, inhibitors of MAPK can result in adverse effects including retinopathy. This study compares clinical and morphological characteristics of serous retinal disturbances in patients taking agents with variable inhibition of MAPK: either direct interference of mitogen-activated protein kinase kinase (MEK) or extracellular signal-regulated kinase (ERK) inhibitors or with indirect inhibition via interference with FGFR signaling. Methods:This retrospective observational study of prospectively collected pooled data is from a single tertiary oncology referral center. Of 339 patients receiving MAPK inhibitors (171, 107, and 61 on FGFR, MEK, and ERK inhibitors, respectively) for treatment of metastatic cancer, this study included 128 eyes of 65 patients with evidence of retinopathy confirmed by optical coherence tomography (OCT). The main outcome was characteristics of treatment-emergent choroid/retinal OCT abnormalities as compared to baseline OCT. Results:In all patients on one of three drug classes (FGFRi, MEKi, ERKi), the retinopathy manifested as subretinal fluid foci that were bilateral, fovea involving, and reversible without intervention. There were notable differences between the three classes of drugs: the proportion of patients with retinopathy, number of fluid foci per eye, proportion of eyes with intraretinal edema, and the proportion of symptomatic patients was least for the upstream target (FGFR inhibitors) and greatest for the downstream targets (MEK or ERK inhibitors). Conclusion:This study shows MAPK pathway inhibitors may cause subretinal fluid foci with unique clinical and morphological characteristics depending on the target (FGFR, MEK, or ERK) implicated. Retinopathy is more common, more symptomatic, and more severe (more fluid foci, more expansive fluid configurations) the further downstream the MAPK pathway is inhibited.

Objectives: The COVID-19 Healthcare Personnel Study is a longitudinal survey to assess the changing impact of the COVID-19 pandemic on the New York State health care workforce. We analyzed results from a follow-up survey of physicians, nurse practitioners, and physician assistants on the availability of equipment and personnel, work conditions, physical and mental health of participants, and impact of the pandemic on commitment to their profession.Methods: We conducted an online survey of all licensed New York State physicians, nurse practitioners, and physician assistants in April 2020 (N = 2105) and a follow-up survey in February 2021 (N = 978). We analyzed changes in item responses from baseline to follow-up. We calculated survey-adjusted paired ttests and odds ratios (ORs) using survey-adjusted generalized linear models controlling for age, sex, region of practice, and hospital versus non–hospital-based practice.Results: Twenty percent of respondents expressed continuing concern about personnel shortages at both baseline and follow-up. Respondents reported working approximately 5 more hours on average during a 2-week period at follow-up compared with baseline (78.1 vs 72.6 hours; P= .008). For 20.4% (95% CI, 17.2%-23.5%) of respondents, mental health issues had become persistent. More than one-third (35.6%; 95% CI, 31.9%-39.4%) of respondents reported that they thought about leaving their profession more often than once per month. The association between persistent mental and behavioral health issues and contemplating leaving one’s profession was significant (OR = 2.7; 95% CI, 1.8-4.1; P< .001).Conclusions: Interventions such as decreasing the number of hours worked, ensuring health care professionals do not work directly with patients while ill, and addressing shortages of personal protective equipment can help address concerns of the health care workforce.

Long-term individual recovery from a catastrophic event involves the restoration of critical lifelines such as housing and employment as well as social and emotional well-being, particularly for displaced and highly traumatized populations. One strategy for measuring recovery over time involves a longitudinal observational cohort. This analysis examines the cost and effort involved in developing and maintaining a longitudinal cohort. The Gulf Coast Child and Family Health Study recruited 1,079 randomly sampled individuals in Louisiana and Mississippi within months after Hurricane Katrina and followed them for 13 years. Participants in the study were interviewed in person five times over the study period. Despite the challenges involved in maintaining a transient and economically vulnerable study cohort, 80.4 percent of all eligible participants were surveyed at the fifth time point, over a decade after the event. At each round of data collection, the refusal rate ranged from less than 1 percent to 3.3 percent. Reasons for non-participation included institutional inaccessibility for those who were incarcerated, in treatment programs, or in nursing homes. Physical and mental health issues which precluded participation included cognitive decline and significant loss of function. Other participants were lost to follow-up or death. At the final round of face-to-face interviewing in 2018, the average field cost per survey was $353.27, not including a respondent incentive of $50, and required an average of 15.74 hours per case to complete. This report describes the strategies employed to maintain such a long-term disaster cohort.

This article uses longitudinal data from the Gulf Coast Child and Family Health Study to examine the impact of residential mobility on the long-term mental health trajectories of individuals displaced or severely impacted by Hurricane Katrina. Analyses begin with a descriptive understanding of residential mobility post-Katrina, including an explanation of who moved and how often in the 13 years after the storm, and determine which social groups were more likely to experience residential mobility than others. Secondly, it builds on these descriptive results by examining how residential mobility can influence the mental health of disaster survivors over time. Lastly, analyses determine how residential mobility rates differ depending on various social characteristics, and how such relationships influence mental health recovery. Results demonstrate that there is a statistically significant relationship between high rates of residential mobility and mental health recovery, and that particular social characteristics increase the risk for high residential mobility.

Background/aimsUveal lymphoid hyperplasia (formerly benign reactive hyperplasia of the choroid) spans histopatholological characteristics ranging from reactive hyperplasia to low-grade lymphoid neoplasm. There is strong evidence that other low-grade lymphoid neoplasms, particularly of gastric derivations, respond to oral antibiotics. Here, we explore that response of uveal lymphoid hyperplasia to treatment with only oral antibiotics and steroids.MethodsFour eyes of three patients with clinically diagnosed uveal lymphoid hyperplasia were treated with a course of oral antibiotics and steroids. The main outcome was clinical response of choroidal infiltrate by optical coherence tomography (OCT) measurements of choroidal thickness and visual acuity. Secondary outcome measure included local and systemic recurrence. Clinical response was evaluated by clinical exam, fundus photography, ultrasound and OCT.ResultsAll 4 eyes displayed a clinical response at a median 2 weeks after starting oral antibiotics and steroid course. The choroidal infiltration regressed as evidenced by: decrease of choroidal thickness by a median of 421 nm, myopic shift in refractive error by a median of 0.50 Diopters, and improved vision by a median of 1.5 Snellen lines. At a median of 51-month follow-up, all four eyes had a sustained complete response and no patient has developed systemic disease to date.ConclusionsIn this small cohort of patients with uveal lymphoid hyperplasia, measurable and sustained clinical responses were observed with antibiotics/steroids, without systemic recurrence. This suggests combination antibiotic/steroid therapy is a reasonable treatment for select cases of uveal lymphoid hyperplasia, and may avoid the need for systemic chemotherapy/monoclonal antibody and/or external beam irradiation.

Background Subsequent malignant neoplasms are a major cause of premature death in survivors of hereditary retinoblastoma. Radiotherapy further increases the risk of death. Mortality information is limited among long-term survivors who were irradiated for hereditary retinoblastoma. Methods We examined cause-specific mortality among 1854 retinoblastoma survivors who were diagnosed from January 1, 1914, through December 31, 1996, at two US institutions. Standardized mortality ratios (SMRs) were calculated by use of US mortality data to estimate expected numbers of deaths. The relative rates (RRs) of mortality due to subsequent malignant neoplasms associated with multiple risk factors were evaluated with Poisson regression models. Cumulative mortality from subsequent malignant neoplasms was calculated by treating other causes of death as competing risks. Results A total of 151 deaths due to subsequent malignant neoplasms occurred among 1092 hereditary retinoblastoma survivors (SMR = 35, 95% confidence interval [CI] = 30 to 41) compared with 12 deaths among 762 nonhereditary retinoblastoma survivors (SMR = 2.5, 95% CI = 1.3 to 4.4). In this extended follow-up of retinoblastoma survivors, we found no evidence of excess mortality from non-neoplastic causes compared with the general population. However, excess mortality from subsequent malignant neoplasms (particularly sarcomas, melanomas, and cancers of the brain and other parts of the nervous system) among hereditary retinoblastoma survivors extended beyond 40 years after retinoblastoma diagnosis. The additional 13 years of follow-up since our last mortality study revealed a previously unreported increased risk of death due to cancers of the corpus uteri (primarily sarcomas) and confirmed the previously reported elevated risk of death from lung cancer among hereditary retinoblastoma survivors. Among hereditary and nonhereditary retinoblastoma survivors, the relative rates of mortality from subsequent malignant neoplasm were higher in those who had been treated with radiotherapy than in those who had not. Cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 25.5% (95% Cl = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors. Conclusions The temporal patterns of site-specific excess risks of subsequent malignant neoplasms in retinoblastoma survivors should inform screening programs designed for the early detection and treatment of subsequent malignant neoplasms.

•Health care workers of racial/ethnic minorities experienced greater personal protective equipment (PPE) shortages.•They were also more likely to report reusing disposable PPE in an unsafe manner.•These disparities persisted even after improvement in PPE supplies.

Background Survivors of hereditary retinoblastoma have an increased risk for second malignancies, especially soft tissue sarcomas. However, the risks of individual histologic subtypes of soft tissue sarcomas have not been evaluated. Methods We estimated the risk for six subtypes of soft tissue sarcomas (fibrosarcoma, liposarcoma, histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and others) in a cohort of 963 one-year survivors of hereditary retinoblastoma among patients diagnosed at two US institutions from 1914 through 1984. We calculated standardized incidence ratios (SIRs) for specific subtypes of soft tissue sarcomas by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results database. We also calculated the cumulative risk for all soft tissue sarcomas combined. Results We observed 69 soft tissue sarcomas in 68 patients with hereditary retinoblastoma. Risks were elevated for soft tissue sarcomas overall (SIR = 184, 95% confidence interval [CI] = 143 to 233) and for individual subtypes. Leiomyosarcoma was the most frequent subtype (SIR = 390, 95% CI = 247 to 585), with 78% of leiomyosarcomas diagnosed 30 or more years after the retinoblastoma diagnosis (SIR = 435, 95% CI = 258 to 687). Among patients treated with radiotherapy for retinoblastoma, we found statistically significantly increased risks of soft tissue sarcomas in the field of radiation. Irradiated patients also had increased risks of soft tissue sarcomas, especially leiomyosarcomas, outside the field of radiation, and risks of soft tissue sarcomas were increased in nonirradiated patients as well, indicating a genetic predisposition to soft tissue sarcomas independent of radiation. The cumulative risk for any soft tissue sarcoma 50 years after radiotherapy for retinoblastoma was 13.1% (95% CI = 9.7% to 17.0%). Conclusion Long-term follow-up of a cohort of survivors of hereditary retinoblastoma revealed a statistically significant excess of leiomyosarcoma and other soft tissue sarcomas that persists decades after the retinoblastoma diagnosis. Retinoblastoma survivors should undergo regular medical surveillance for sarcomas in their adult years.

This paper considers the use of discrete Hopfield neural networks for solving school timetabling problems. Two alternative formulations are provided for the problem: a standard Hopfield-Tank approach, and a more compact formulation which allows the Hopfield network to be competitive with swapping heuristics. It is demonstrated how these formulations can lead to different results. The Hopfield network dynamics are also modified to allow it to be competitive with other metaheuristics by incorporating controlled stochasticities. These modifications do not complicate the algorithm, making it possible to implement our Hopfield network in hardware. The neural network results are evaluated on benchmark data sets and are compared with results obtained using greedy search, simulated annealing and tabu search. Keywords: Hopfield neural networks; Timetabling; Combinatorial optimisation; Simulated annealing; Tabu search

Supplemental Digital Content is available in the text.Detectable metastasis at the time of initial diagnosis of uveal melanoma (UM) is rare. The purpose of this investigation was to evaluate the characteristics and outcomes in patients with metastatic UM (MUM) at initial diagnosis. An institutional review board-approved retrospective case series analysis was performed in 21 patients that presented for management of MUM at initial diagnosis. Patient, tumor and treatment parameters were recorded, and ophthalmic symptoms, metastasis response and overall survival were assessed. Among 21 patients, median tumor diameter was 18 mm (range, 9.1–35 mm), with 76% classified as a Collaborative Ocular Melanoma Study (COMS) large size. Sites of metastasis included liver (95%), bone (29%) and lung (29%), among others, and were confirmed by biopsy in 95% of patients studied. Symptomatic primary tumors were present in 81%, causing pain (24%) or vision loss (57%). Primary tumor therapy (PTT) was provided upfront for 52% of patients with enucleation (24%) and brachytherapy (29%). Eye pain developed 3–6 months after diagnosis in four of 10 patients who did not receive upfront PTT, whereas it did not occur in any of the 11 patients who received upfront PTT (P= 0.04). PTT palliated pain in all cases. The median overall survival was 11.9 months (range, 2.5–21.1 months). Patients presenting with MUM at initial diagnosis have high-risk tumors and experience survival like patients who develop metastases metachronously. PTT is not associated with survival but may mitigate ophthalmic symptoms, especially in patients with large tumors at risk for causing symptoms.

Objectives: To identify patients with retinoblastoma whose conditions were diagnosed at the age of 1 month or younger and to describe their clinical features (including ocular and patient survival) and the development of second nonocular tumors. Materials and Methods: A retrospective study of 1831 patients. The cumulative incidence of second cancer development was analyzed using the Kaplan-Meier method. Results: Forty-six patients were identified as having a diagnosis of retinoblastoma at the age of 1 month or younger (mean age, 18.5 days). Family history (31 patients [67%]) exceeded leukocoria (6 patients [13%]) as the most common reason for detection. Twenty-six (56%) of the 46 patients were seen with unilateral retinoblastoma, with 22 ultimately developing cancer in the fellow eye. At the initial diagnosis, 81 (85%) of the 95 tumors were detected in zones 1 and 2. Eighty-two (93%) of the 88 subsequent tumors were located in zones 2 and 3. In the 26 patients who had unilateral retinoblastoma, 16 of the initially affected eyes and 21 of the fellow eyes were salvaged. In the 19 (44%) of 20 patients who were seen initially with bilateral retinoblastomas, 31 (82%) of the 38 eyes were salvaged. The mean follow-up was 10.9 years. The incidence of second nonocular cancers reached 54% by 23.7 years for the patients who received radiation therapy, while the incidence was 0% for the patients who did not. Four(8.7%) of the 46 patients developed metastatic disease and died; 3 of these patients had documented metastases in the first month of life (one at birth). Conclusions: The most common manifesting sign of children diagnosed as having retinoblastoma in the first month of life is family history. Eyes with Reese-Ellsworth group I retinoblastomas were the most common. In patients with bilateral and unilateral retinoblastoma, new (subsequent) ocular tumors developed in a centrifugal pattern. Despite an early diagnosis, patients' eyes came to enucleation, and metastatic disease and death occurred from ocular metastases. In patients who received radiation therapy, the probability of developing second nonocular cancer is 54% by 23.7 years; no second cancers developed in patients who did not receive radiation therapy. Arch Ophthalmol. 2002;120:738-742

BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Accounting for discrepancies in large scientific codes, a tedious but necessary task for developers, is automated through use of the Guard relative debugger. Large scientific codes are constantly evolving. Refinements […]

IMPORTANCE: Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor–associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy. OBJECTIVE: To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021. MAIN OUTCOMES AND MEASURES: Characteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution. RESULTS: A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor–associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was −0.1 (−0.2 to −0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (−0.03 to 0). No patient discontinued drug therapy on account of their retinopathy. CONCLUSIONS AND RELEVANCE: FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.

Background: Children diagnosed with retinoblastoma, a rare cancer of the eye, tend to develop and die of second primary cancers in childhood and adolescence, but few investigations have followed patients into adulthood. Retinoblastoma is frequently caused by inherited mutations of the RB1 tumor suppressor gene. Most patients with germline (hereditary) mutations have bilateral disease. Purpose: We sought to quantify the mortality from second malignancies among long-term survivors of retinoblastoma and to identify factors that predispose to these deaths. Methods: A retrospective cohort study examined mortality among 1603 patients enrolled at 1 year after diagnosis of retinoblastoma during the period 1914-1984. Data on demography, family history, and retinoblastoma treatment were collected by medical chart review and questionnaire interview. Number of deaths, by cause, was compared with the corresponding expected figure based on U.S. mortality data for the general population for 1925-1990. Results: Follow-up was complete for 1458 patients (91%) for a median of 17 years after retinoblastoma diagnosis. A total of 305 deaths occurred, 167 of them from retinoblastoma. There were 96 deaths from second primary tumors (relative risk [RR] = 30), 21 from other known causes (RR = 1.0), and 21 from ill-defined or unknown causes. Statistically significant excess mortality was found for second primary cancers of bone, connective tissue, and malignant melanoma and benign and malignant neoplasms of brain and meninges. Among 919 children with bilateral retinoblastoma, 90 deaths from second primary tumors occurred (RR = 60). Deaths from second tumors were more frequent among females (RR = 39) than males (RR = 22) (P = .007). The cumulative probability of death from second primary neoplasms was 26 % at 40 years after bilateral retinoblastoma diagnosis, and additional cancer deaths occurred thereafter. Radiotherapy for retinoblastoma further increased the risk of mortality from second neoplasms. An excess of mortality from a second cancer, not seen in prior studies, was found among the 684 children with unilateral disease (RR = 3.1; 95 % confidence interval = 1.0-7.3). Conclusions: These findings implicate germinal mutations in the retinoblastoma gene in second cancer mortality. Radiotherapy treatment for retinoblastoma appears to further enhance the inborn susceptibility to development of a second cancer. Implications: Patients with retinoblastoma, particularly bilateral retinoblastoma, should have careful follow-up, and interventions should be developed to reduce mortality from a second cancer. [J Natl Cancer Inst 85:1121-1128, 1993]

Big data and advanced computational methods are increasingly being used to inform decision making in social policy globally. As a result, there is a pressing need to identify best practice digital infrastructure design that allows policymakers and social sciences researchers to access, manipulate and use big data soundly and ethically, while identifying and resolving issues that can lead to unintended consequences and adverse social policy outcomes. However, building such digital infrastructure continues to be a technical challenge for users of big social and administrative data. This paper presents a model to evaluate and design best practice infrastructure for the use of big data in social policy. Our model identifies key technical infrastructure considerations for six stages of a data analysis pipeline, namely (1) data storage, (2) data integration, (3) data access, (4) data analysis, (5) data interpretation and (6) data operationalisation. We demonstrate the model via two applications: the E‐Verify online employment rights system and the Australian COVIDSafe app. The model provides a high‐level guide for social policymakers and researchers to consider systematically the relevant technical considerations when designing or upgrading digital infrastructure that uses analytical tools and big datasets from multiple sources.

Purpose:This study evaluates and characterizes the choroid underlying congenital hypertrophy of the retinal pigment epithelium (CHRPE). Methods:Retrospective observational study of CHRPE at least 2 mm in diameter. Choroidal vascular architecture was qualitatively examined. Choroidal thickness was measured by 2 independent observers using enhanced depth imaging spectral domain optical coherence tomography. Results:Forty-six eyes of 46 patients with CHRPE were included. Thirty-two lesions had imaging sufficient for analysis. Haller’s layer was healthy in 18 (56%), thin in 13 (41%), and absent in 1 (2%). Sattler’s layer was atrophic in 30 (94%), and choriocapillaris was atrophic in 31 (97%). CHRPE with thinned Haller’s layer had significantly larger diameter. The mean sub-CHRPE choroidal thickness was 82.4 ± 7.9 µm, compared to a thickness of 148.4 ± 9.6 µm in the normal adjacent choroid (p< 0.0001). Mean retinal thickness overlying the CHRPE was 77.3 ± 4.3 µm, compared to a retinal thickness of 137.8 ± 2.9 µm overlying the normal adjacent choroid (p< 0.0001). Sub-CHRPE choroidal thickness was a mean of 56.2 ± 3.1% of the adjacent normal choroidal thickness. Conclusion:The underlying choroid CHRPE is thinner than the adjacent normal choroid. All layers of the choroid can be thin with a preference of the inner Sattler’s and choriocapillaris layers.

Background:Patients with uveal melanoma (UM) are known to have quality of life (QOL) issues after treatment, but QOL concerns after initial diagnosis are ill-defined. Objectives:We studied the QOL concerns of patients with UM after initial diagnosis to identify factors associated with QOL. Method:Between September 2011 and May 2016, UM planning to undergo radiotherapy completed the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ)-C30, as well as the Ophthalmic Oncology module, QLQ-OPT30. Demographic, ophthalmic, and tumor related characteristics were recorded. The primary outcome was the QOL score and fraction of patients reporting any or severe symptoms. A multiple stepwise regression model investigated the association of demographic, ophthalmic, and tumor characteristics with QOL. Results:QOL concerns were assessed in 201 subjects. The majority (51/60) of QOL items had a high response rate (≥90%), and internal consistency on scales (median Cronbach α = 0.85) with the most common severe QOL concern being worry about disease recurrence (41%). The most common ophthalmic symptoms reported were vision impairment (81%) and ocular irritation (66%). Multivariable regression modeling demonstrated several significant associations. Conclusions:Severe worry about UM recurrence, ocular irritation, and vision impairment was reported by many patients. Clinicians should be aware of these concerns and implement management strategies.

Background:Central retinal vein occlusion (CRVO) is a visually threatening event that has rarely been observed in patients taking MEK1/2 inhibitors and that may necessitate permanent discontinuation of a potentially efficacious therapy. We investigated the clinical characteristics of CRVO in patients on mitogen-activated protein kinase kinase (MEK) inhibition to better understand their predisposing factors and clinical course. Case Series:This was a single-center, retrospective cohort study (between December 2006 and September 2018). Three of 546 patients enrolled in 46 prospective trials involving treatment with MEK inhibitors at Memorial Sloan Kettering Cancer Center were identified as having CRVO. Clinical examination and course, multimodal ophthalmic imaging, and serum laboratory results (including homocysteine levels and genetic variants of methylene tetrahydrofolate reductase [MTHFR]) were reviewed for the 3 affected patients. All 3 patients with MEK inhibitor-associated CRVO had elevated serum homocysteine and gene variants of MTHFR (1 homozygous for A1298C, 1 heterozygous for A1298C, and 1 homozygous for C677T). Following intravitreous injections of anti-VEGF and discontinuation of drug, all patients regained vision to their baseline. Discussion:MEK inhibitor-associated CRVO is a rare event which can exhibit visual recovery after drug cessation and intravitreous anti-VEGF injections. In this cohort, it was associated with hyperhomocysteinemia and genetic mutations in MTHFR, suggesting a potential role for hyperhomocysteinemia screening prior to initiation of MEK inhibitor therapy.

Background:Dilating eye drops are routinely used in pediatric retinoblastoma patients during anesthetized ophthalmologic exams. Information on the systemic effects of ocular mydriatics, especially in anesthetized pediatric patients, is limited. Objective:The primary aim of this study was to analyze hemodynamic changes during mydriatic eye drop administration in anesthetized pediatric patients. Methods:A retrospective chart review was performed for pediatric retinoblastoma patients who underwent MRI with anesthesia. Baseline blood pressure (BP) and heart rate (HR) were charted for each patient at induction. HR and mean arterial pressure (MAP) measurements were recorded at 5, 10, 15, 30, and 45 min after eye drop administration. Secondarily, we included data from 15 patients who received dilating eye drops while under sevoflurane general anesthetic. All patients were dilated with phenylephrine 2.5 or 10% (depending on age) and tropicamide 1%. Results:The final analysis included 176 anesthesia encounters. The results demonstrate no statistically significant deviation of more than 20% from baseline for either HR or MAP. Additionally, we did not detect any difference between patients who were anesthetized with propofol versus sevoflurane. Conclusions:We did not observe significant hemodynamic instability with administration of dilating eye drops during propofol anesthesia.

Supplemental Digital Content is available in the text.We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (>1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.

Magnetic resonance imaging (MRI) has been used for baseline brain imaging and afterward as a screening tool for trilateral retinoblastoma (TRB), but there is no consensus on timing or frequency of screening worldwide. In this study, a cohort of hereditary retinoblastoma patients at increased risk for TRB was identified and the usefulness of aggressive neuroimaging was examined.

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1Rand rearrangements in RETand ALKthat conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.

PURPOSE: To report a case of orbital foreign body granuloma formation, mimicking tumor recurrence, secondary to the use of Avitene after enucleation for intraocular retinoblastoma. METHODS: Eight months after undergoing enucleation for retinoblastoma, a 21- month-old boy underwent a biopsy of an orbital mass. RESULTS: Histopathologic examination of the orbital biopsy specimen disclosed a proliferative granulomatous foreign body reaction surrounding multiple foci of a coarse fibrillar intercellular substance consistent with Avitene. No retinoblastoma cells were present. CONCLUSION: A foreign body reaction should be included in the differential diagnosis of orbital mass lesions after surgery in which Avitene is used.