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).

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.

What have we learnt about intraarterial chemotherapy (Ophthalmic Artery Chemosurgery) for retinoblastoma in the past 18 years? The third A. Linn Murphree Lecture.

Intraarterial chemotherapy (Ophthalmic Artery Chemosurgery/OAC) for retinoblastoma has transformed management of retinoblastoma worldwide since Pierre Gobin MD and I introduced it in 2006. Case reports, institutional series, meta-analyses, and randomized trials have validated its effectiveness and safety. It allows more eyes to be saved (at Memorial Sloan Kettering Cancer Center (MSKCC) as a result, we have gone from removing 96% of retinoblastoma eyes that presented with leukocoria (comparable to modern day International Classification "D" and "E" eyes) to saving 95% of these eyes with primary OAC management allows the majority of advanced intraocular eyes to be salvaged (both "D" and "E" eyes) prior to the chemoreduction era to saving 95% of these eyes with primary OAC management. OAC attains cures faster than intravenous protocols, has fewer systemic side effects, and is overall cheaper than intravenous approaches (because of the absence of side effects which are the main driver of cost in pediatric oncology). Unlike systemic chemotherapy no ports are needed (and no removal of ports for life threatening infections), it does not alter the immune system (so children can be immunized), it does not affect patient growth (and children who had received systemic chemotherapy catch up in growth during OAC), it does not affect hearing (which systemic Carboplatin does-especially in children <6 months of age), it eliminates the second cancers caused by radiation and systemic chemotherapy and does not compromise survival with all series showing patient survival >98%.

The Impact of Li Fraumeni and Germline Retinoblastoma Mutations on Leiomyosarcoma Initiation, Outcomes and Genetic Testing Recommendations.

PURPOSE: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous, occurring mostly in sporadic but also syndromic settings. The role of pathogenic germline variants (PGV) as LMS drivers and impact on outcome remain uncertain. EXPERIMENTAL DESIGN: We perform a comprehensive clinicopathologic and molecular analysis using a tumor-normal DNA next-generation sequencing assay (MSK-IMPACT) of germline-associated LMS compared to sporadic LMS. RESULTS: Among 285 LMS [120 soft tissue LMS (STLMS), 165 uterine (ULMS)] with germline testing, 78 (27%, 43 STLMS, 35 ULMS) cases harbored PGV: 35/78 (45%) of PGV carriers showing biallelic inactivation of the corresponding gene in the tumor (26 STLMS, 9 ULMS). The most frequent germline predispositions were TP53 (Li-Fraumeni syndrome) (17 patients, 16 in STLMS) and RB1 (retinoblastoma) (13 patients, 11 in STLMS). Germline TP53 and somatic RB1 alterations often co-occurred in the tumor, and vice versa. Other biallelically inactivated PGV were enriched in DNA damage repair-related genes: CHEK2, MSH2, MSH6, RAD51D, BRCA2 and FANCA. Monoallelic PGV were mostly in ULMS and associated with co-occurring TP53 and RB1 somatic alterations. STLMS patients with biallelic but not monoallelic PGV were significantly younger than sporadic STLMS patients (median ages 38 vs 52 vs 58 years). No differences in disease-specific or progression-free survival were observed in germline-associated vs sporadic LMS, regardless of biallelic status. CONCLUSIONS: While ULMS patients had a relatively low proportion of PGV, a high percentage of STLMS patients with PGV had tumor biallelic status, indicating that PGV drive tumorigenesis in these individuals. These findings have significant implications for genetic testing recommendations.

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.

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.

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.

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.

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.

Advancements in super-selective catheterization and drug selection for intra-arterial chemotherapy for retinoblastoma: a 15-year evolution.

BACKGROUND: Retinoblastoma (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. METHODS: A 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. RESULTS: From 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. CONCLUSIONS: The 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.

Plasma Circulating Tumor DNA to Assist in the Diagnose of Unknown Primary Malignancy Underlying Choroidal Metastases.

PURPOSE: Management of suspected choroidal metastases requires diagnostic imaging and an invasive, sometimes intraocular, biopsy to determine the primary malignancy. This multistep process takes time which may impact morbidity and mortality. METHODS: Retrospective review of one case. RESULTS: A 56-year-old woman presented with bilateral amelanotic choroidal masses suspicious for metastases of unknown origin. Plasma circulating tumor DNA revealed EGFR, PTEN, SMAD4, a profile consistent with non-small cell lung cancer. Subsequent radiographic imaging and scapular biopsy revealed lung adenocarcinoma and genetic profile concordant with the liquid biopsy. Patient was started on EGFR-inhibitor, Osimertinib1, with measurable systemic and ocular response. CONCLUSION: Plasma circulating tumor DNA revealed the genetic profile of the primary malignancy underlying choroidal metastases of unknown origin; aiding in the prompt diagnosis and detecting the driver mutation which guided management with targeted therapy.

Establishment and Comprehensive Characterization of a Novel Preclinical Platform of Metastatic Retinoblastoma for Therapeutic Developments.

Purpose: Although there have been improvements in the management of metastatic retinoblastoma, most patients do not survive, and all patients suffer from multiple short- and long-term treatment toxicities. Reliable and informative models to assist clinicians are needed. Thus we developed and comprehensively characterized a novel preclinical platform of primary cell cultures and xenograft models of metastatic retinoblastoma to provide insights into the molecular biology underlying metastases and to perform drug screening for the identification of hit candidates with the highest potential for clinical translation. Methods: Orbital tumor, bone marrow, cerebrospinal fluid, and lymph node tumor infiltration specimens were obtained from seven patients with metastatic retinoblastoma at diagnosis, disease progression, or relapse. Tumor specimens were engrafted in immunodeficient animals, and primary cell lines were established. Genomic, immunohistochemical/immunocytochemical, and pharmacological analysis were performed. Results: We successfully established five primary cell lines: two derived from leptomeningeal, two from orbital, and one from lymph node tumor dissemination. After the intravitreal or intraventricular inoculation of these cells, we established cell-derived xenograft models. Both primary cell lines and xenografts accurately retained the histological and genomic features of the tumors from which they were derived and faithfully recapitulated the dissemination patterns and pharmacological sensitivity observed in the matched patients. Conclusions: Ours is an innovative and thoroughly characterized preclinical platform of metastatic retinoblastoma developed for the understanding of tumor biology of this highly aggressive tumor and has the potential to identify drug candidates to treat patients who currently lack effective treatment options.

Pharmacokinetics of Orbital Topotecan After Ophthalmic Artery Chemosurgery and Intravenous Infusion in the Swine Model.

Purpose: Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term toxicity (including death). We studied orbital and systemic exposure of topotecan in the swine model after ophthalmic artery chemosurgery (OAC) and intravenous (IV) delivery. Methods: Landrace pigs (n = 3) underwent 30-minute OAC of topotecan (4 mg), and samples were serially obtained from the femoral artery and from a microdialysis probe inserted into the lateral rectus muscle sheath of the infused eye as a surrogate of the orbital irrigation. Animals were recovered, and, after a wash-out period, plasma and microdialysate samples from the contralateral eye were collected after a 30-minute IV infusion of topotecan (4 mg). Samples were quantified by high-performance liquid chromatography, and population pharmacokinetic analysis was conducted using MonolixSuite. Results: After OAC, median topotecan exposure in the orbit was 5624 ng × h/mL (range 3922-12531) compared to 23 ng × h/mL (range 18-75) after IV infusion. Thus, topotecan exposure in the orbit was 218-fold (range 75-540) higher after OAC than after IV infusion despite comparable systemic exposure (AUCpl) between routes (AUCpl, OAC: 141 ng × h/mL [127-191] versus AUCpl, IV: 139 ng × h/mL [126-186]). OAC was more selective to target the orbit because the median (range) orbital-to-plasma exposure ratio was 44 (28-65) after OAC compared to 0.18 (0.13-0.40) after IV infusion. Conclusions: OAC of topotecan resulted in higher orbital exposure than after IV infusion and was a more selective route for local drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy.

Localized Recurrence of Multiple Myeloma in the Lacrimal Gland.

The authors report the case of a multiple myeloma recurrence isolated to the lacrimal gland. The patient is a 54-year-old man with a medical history of IgA kappa multiple myeloma status post multiple lines of chemotherapy and stem cell transplantation (×2) who was presumed to be without evidence of disease. Six years following the transplant, he presented with a lacrimal gland tumor with a biopsy consistent with multiple myeloma. Systemic disease evaluation at that time, including positron emission tomography scan, bone marrow biopsy, and serum analysis, were negative. To the best of the authors' knowledge, no prior reports exist describing an isolated lacrimal gland recurrence of multiple myeloma with ultrasound and MRI imaging.