How Much Time Do Focal Treatments for Retinoblastoma Add to Anesthetic Exposure?

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).

Hearing Evaluations in Children With Retinoblastoma Treated With Intra-arterial Carboplatin Chemotherapy: A Single Institution Review.

PURPOSE: To determine whether the administration of intra-arterial carboplatin affected the hearing of children with retinoblastoma. METHODS: Children with retinoblastoma who were treated with intra-arterial carboplatin chemotherapy were included. Hearing tests before chemotherapy including tympanometry, distortion product otoacoustic emissions, and audiogram (if achievable) were performed and repeated 3 to 9 months after concluding intra-arterial therapy. The study was approved by the institutional review board. Patients were identified from the retinoblastoma clinic when the treatment plan included intra-arterial carboplatin chemotherapy. Children were excluded if they had previous intra-arterial carboplatin or preexisting hearing loss but were included if they had systemic carboplatin and dosing was available. Tympanometry was performed to rule out inner ear fluid. All examinations were performed by a certified audiologist with the same equipment, calibrated regularly by a certified technician. RESULTS: Twenty-two children (32 eyes) were evaluable. Because most children are diagnosed at a young age and are unable to participate in an audiogram, distortion product otoacoustic emission measurement was the primary measurement. No child displayed hearing loss. CONCLUSIONS: Intra-arterial chemotherapy with carboplatin did not cause ototoxicity in any child by distortion product otoacoustic emission measurement in contrast to systemic chemotherapy where ototoxicity is common. Distortion product otoacoustic emission levels were essentially unchanged from before to after intra-arterial chemotherapy in children with retinoblastoma. These findings suggest that intra-arterial carboplatin does not affect outer hair cell function, and distortion product otoacoustic emission tests can provide useful information when monitoring children at risk of developing carboplatin ototoxicity. [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XXX-XXX.].

Craniospinal irradiation and/or intraventricular radioimmunotherapy after high-dose chemotherapy and autologous stem cell rescue in patients with CNS retinoblastoma-Safety and outcomes.

BACKGROUND: The prognosis for patients with central nervous system (CNS) retinoblastoma (RB) (trilateral or stage 4b metastatic RB) treated with high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT) remains poor. The impact of irradiation when administered as part of upfront therapy post HDC-ASCT on treatment outcomes and survival is unknown. METHODS: We performed a retrospective review of all patients with CNS RB (seven stage 4b, eight trilateral, one pineal lesion belonging to methylation group RB) who underwent induction chemotherapy with an intent to proceed to HDC-ASCT at two institutions. RESULTS: Twelve of 16 patients (n = 75%) achieved an objective response to induction chemotherapy, while four patients had progressive/refractory disease; two patients responded to subsequent therapy and proceeded to ASCT, and two patients did not. Seven of 14 patients who underwent HDC-ASCT, received radiotherapy as part of upfront therapy post HDC-ASCT in the form of craniospinal irradiation (CSI) (n = 3), intraventricular radioimmunotherapy (n = 3), or both CSI and intraventricular radioimmunotherapy (n = 1). The Kaplan-Meier estimate of overall survival for these patients was 62.5% at 5 years; no patients developed second malignant neoplasms within the radiation fields. For the seven patients who did not receive radiotherapy, the overall survival was 28.6% at 5 years. CONCLUSIONS: CSI (23.4 Gy) alone or in conjunction with intraventricular RIT may have clinical utility in eliminating persistent MRD post HDC-ASCT, contributing to improved disease-free survival in patients with CNS RB. This treatment strategy merits evaluation in a prospective, multicenter clinical trial for patients with CNS metastatic RB.

Improved method of dilating pupils for ophthalmic exams under anesthesia (faster and easier).

Objective: The pupils of children with retinoblastoma are routinely dilated pre-procedure with Tropicamide and Phenylephrine. Despite that, the pupil constricts once general anesthesia begins. The aim of this study is to see if adding Ketorolac to the regular dilating drops given pre-procedure shortens the length of anesthesia. Methods: Retrospective comparison of time under anesthesia for two groups of retinoblastoma children receiving anesthesia for examination under anesthesia: one group (January 1, 2019 to October 1, 2022) had been dilated with Tropicamide 1% and Phenylephrine 2.5% while the second group (October 2, 2022 to July 1, 2023) was dilated with a combination drop using those drugs with topical Ketorolac 0.5% and Proparacaine 0.5%. Results: Average anesthesia time for patients who received the older two-drug combination was 25 minutes vs. 16 minutes (36% reduction in exposure time) for those who received the newer four-drug combination (9 minutes less anesthesia) (P < 0.001). Conclusions: The use of a combined dilating drop that incorporated Tropicamide 1%, Phenylephrine 2.5%, Proparacaine 0.5% and Ketorolac 0.5% significantly shortened the time for exams under anesthesia for children with retinoblastoma because the pupil remained dilated after anesthesia induction with Sevoflurane. Using this combined drop, children will receive 5-10 hours less anesthesia during their treatment for retinoblastoma and staff will have more than 150 hours of fewer exposure to anesthetic gasses. In addition, far fewer drops are necessary pre-anesthesia, minimizing trauma to the children and families.

Accuracy and Completeness of Large Language Models About Antibody-Drug Conjugates and Associated Ocular Adverse Effects.

PURPOSE: The purpose of this study was to assess the accuracy and completeness of 3 large language models (LLMs) to generate information about antibody-drug conjugate (ADC)-associated ocular toxicities. METHODS: There were 22 questions about ADCs, tisotumab vedotin, and mirvetuximab soravtansine that were developed and input into ChatGPT 4.0, Bard, and LLaMa. Answers were rated by 4 ocular toxicity experts using standardized 6-point Likert scales on accuracy and completeness. ANOVA tests were conducted for comparison between the 3 subgroups, followed by pairwise t-tests. Interrater variability was assessed with Fleiss kappa tests. RESULTS: The mean accuracy score was 4.62 (SD 0.89) for ChatGPT, 4.77 (SD 0.90) for Bard, and 4.41 (SD 1.09) for LLaMA. Both ChatGPT (P = 0.03) and Bard (P = 0.003) scored significantly better for accuracy when compared with LLaMA. The mean completeness score was 4.43 (SD 0.91) for ChatGPT, 4.57 (SD 0.93) for Bard, and 4.42 (SD 0.99) for LLaMA. There were no significant differences in completeness scores between groups. Fleiss kappa assessment for interrater variability was good (0.74) for accuracy and fair (0.31) for completeness. CONCLUSIONS: All 3 LLMs had relatively high accuracy and completeness ratings, showing LLMs are able to provide sufficient answers for niche topics of ophthalmology. Our results indicate that ChatGPT and Bard may be slightly better at providing more accurate answers than LLaMA. As further research and treatment plans are developed for ADC-associated ocular toxicities, these LLMs should be reassessed to see if they provide complete and accurate answers that remain in line with current medical knowledge.

RB1 circulating-tumor DNA in the blood of Retinoblastoma patients increases in untreated patients.

PURPOSE: Circulating tumor DNA (ctDNA) in plasma has been identified in many cancers, including retinoblastoma at diagnosis. We have previously shown that with treatment (enucleation or ophthalmic artery chemosurgery (OAC)) all ctDNA disappears; and if there is persistent plasma ctDNA after treatment metastases develop. The purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with retinoblastoma who have delayed treatment. METHODS: Circulating tumor DNA RB1 was detected and VAF was measured at diagnosis and again prior to any intervention at some time later ranging from 2 to 28 days. RESULTS: Four patients with five ctDNA RB1 mutations were detected at diagnosis and VAF was increased on re-evaluation of the same RB1 mutations in ctDNA. CONCLUSION: In this small cohort, every patient (4) and every RB1 mutation (5) plasma level VAF% increased when measured at two time periods before treatment was instituted suggesting that growing tumors demonstrate increasing plasma ctDNA.

Plasma-Derived Cell-Free DNA for the Diagnosis of Ocular-Involving Histiocytosis.

Purpose: Circulating tumor DNA (ctDNA) is released into the plasma by many cancers and offers clinical applications including noninvasive diagnostics. Histiocytosis results from myelogenous clonal expansion of histiocytes, predominantly driven by mutations in the mitogen-activated protein kinase pathway that are potentially detectable by ctDNA-based sequencing assays. However, ocular-involving histiocytosis is often a diagnostic challenge leading to delayed diagnosis and the need for invasive biopsy of sensitive ocular structures. The purpose of this study is to determine whether sequencing of plasma-derived ctDNA can noninvasively diagnose ocular-involving histiocytosis. Design: Single tertiary cancer referral center. Participants: Twenty-four adult patients with ocular-involving histiocytosis and ctDNA sequencing. Methods: Circulating tumor DNA was analyzed (via digital droplet polymerase chain reaction for BRAF V600E, and/or next-generation sequencing) and variant allele frequency was measured at initial presentation to our center. Patient demographics, clinical characteristics, and oncogenic mutations identified from tumor-based sequencing were recorded. Main Outcome Measures: Plasma-derived ctDNA detectability of pertinent driver mutations of histiocytosis. Results: At the initial presentation of 14 patients with ocular-involving histiocytosis, sequencing of plasma-derived ctDNA detected driver mutations for histiocytosis (BRAF V600E [10], KRAS [2], ARAF [1], and concurrent MAP2K1/KRAS [1]). Mutations found in circulating cell-free DNA were 100% concordant in 11 of 11 patients with mutations identified by solid tumor sequencing. Of 10 patients without driver mutation detected in ctDNA, 3 patients had alterations (CBL mutation or kinase fusion) not captured in the ctDNA sequencing assay, 3 were wildtype even by tumor sequencing; in 4 patients, tumor-based sequencing identified mutations (BRAF [2], MAP2K1 [2]) not detected in ctDNA. Detectable mutations in ctDNA were significantly more likely in patients with uveal infiltration (P = 0.036). Conclusions: In this cohort, plasma-derived ctDNA was detectable and diagnostic in the majority of patients with ocular-involving histiocytosis. This suggests that if ocular histiocytosis is suspected (particularly if involving the uvea), noninvasive plasma-derived ctDNA analysis is a helpful diagnostic tool that may obviate the need to invasively biopsy sensitive ocular structures. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ocular side effects of anticancer agents used in the treatment of gynecologic cancers.

The treatment landscape of gynecologic cancers has expanded in recent years to include targeted and immune-based therapies. These therapies often have ocular side effects not seen with conventional chemotherapies, some of which can cause significant visual impairment if not recognized in a timely fashion. Clinicians must know how to appropriately identify, mitigate, and treat these ocular adverse events. Management often involves working with an interdisciplinary team of eye specialists, and it is important to know when to refer patients for specialized care. Proactive identification of eye specialists, especially in rural and community settings where access to care can be limited, may be necessary. Here, we discuss the management of common ocular toxicities seen with novel anticancer agents used to treat gynecologic cancers.

A Phase II Study Assessing Long-term Response to Ibrutinib Monotherapy in Recurrent or Refractory CNS Lymphoma.

PURPOSE: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. RESULTS: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. CONCLUSIONS: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.

MEK Inhibitor-Associated Ocular Hypertension.

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.

Ocular findings in patients with histiocytosis and association with clinical and molecular features.

BACKGROUND/AIMS: Ocular 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. METHODS: Prospective 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. RESULTS: Ocular 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, MAP2K1 or RAS isoform mutational status. CONCLUSIONS: Ocular 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.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Nanocapsules Comprised of Purified Protein: Construction and Applications in Vaccine Research.

Nanoparticles show great promise as a platform for developing vaccines for the prevention of infectious disease. We have been investigating a method whereby nanocapsules can be formulated from protein, such that the final capsules contain only the cross-linked protein itself. Such nanocapsules are made using a silica templating system and can be customised in terms of size and porosity. Here we compare the construction and characteristics of nanocapsules from four different proteins: one a model protein (ovalbumin) and three from infectious disease pathogens, namely the influenza virus, Helicobacter pylori and HIV. Two of the nanocapsules were assessed further. We confirm that nanocapsules constructed from the urease A subunit of H. pylori can reduce subsequent infection in a vaccinated mouse model. Further, we show that capsules constructed from the HIV gp120 protein can be taken up by dendritic cells in tissue culture and can be recognised by antibodies raised against the virus. These results point to the utility of this method in constructing protein-only nanocapsules from proteins of varying sizes and isoelectric points.

Clearance of plasma cell free DNA in metastatic uveal melanoma with radiographic response to immune checkpoint inhibitors.

Purpose: To report a case of metastatic uveal melanoma treated with immune checkpoint inhibition in which serial circulating tumor DNA (ctDNA) was assessed throughout treatment. Observations: A 33-year-old man was diagnosed with metastatic uveal melanoma and initially had progression of disease following hepatic embolization and nivolumab/ipilimumab. At the time, plasma ctDNA GNA11 and SF3B1 were measurable and repeat ctDNA showed increased variant allele frequency following further progression of disease on vorinostat. Following additional nivolumab/ipilimumab, radiographic response was noted and repeat ctDNA became undetectable and remained so at 27 months follow up. Conclusions and importance: Clearance of cell free DNA in metastatic uveal melanoma may be associated with radiographic response to immune checkpoint inhibitors.

Circulating Tumor DNA Posttreatment Measurements and Clinical Correlates in Retinoblastoma.

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.

Solid Lipid Nanoparticles Delivering a DNA Vaccine Encoding Helicobacter pylori Urease A Subunit: Immune Analyses before and after a Mouse Model of Infection.

In this study, novel solid lipid particles containing the adjuvant lipid monophosphoryl lipid A (termed 'SLN-A') were synthesised. The SLN-A particles were able to efficiently bind and form complexes with a DNA vaccine encoding the urease alpha subunit of Helicobacter pylori. The resultant nanoparticles were termed lipoplex-A. In a mouse model of H. pylori infection, the lipoplex-A nanoparticles were used to immunise mice, and the resultant immune responses were analysed. It was found that the lipoplex-A vaccine was able to induce high levels of antigen-specific antibodies and an influx of gastric CD4+ T cells in vaccinated mice. In particular, a prime with lipoplex-A and a boost with soluble UreA protein induced significantly high levels of the IgG1 antibody, whereas two doses of lipoplex-A induced high levels of the IgG2c antibody. In this study, lipoplex-A vaccination did not lead to a significant reduction in H. pylori colonisation in a challenge model; however, these results point to the utility of the system for delivering DNA vaccine-encoded antigens to induce immune responses and suggest the ability to tailor those responses.