Targeted Neoadjuvant Intra-arterial Chemotherapy in Lacrimal Gland Adenoid Cystic Carcinoma: A Histological Correlation Using Apoptotic Tumor Markers.

Neoadjuvant intra-arterial cytoreductive chemotherapy is used for the treatment of lacrimal gland adenoid cystic carcinomas (ACC) to improve outcomes in this condition with an otherwise dismal prognosis. We share our experience in the management of an advanced case of ACC using a novel, highly targeted intra-arterial cytoreductive chemotherapy delivery technique involving both the internal and external carotid circulation, with an attempt to correlate the effect histologically. Refinement of the chemotherapy delivery using the tumor's vascular anatomy and appropriate blood vessel selection may lead to future globe sparing procedures without compromising survival.

Retinoblastoma management in 13q deletion syndrome patients using super-selective chemotherapies and other cancer-directed interventions.

BACKGROUND: This study aimed to identify best practices for treating 13q deletion syndrome (13q-) patients with retinoblastoma in the era of super-selective ophthalmic artery chemosurgery (OAC) and intravitreal injection therapy (IVIT). METHODS: Retrospective study of 21 eyes from 14 patients with retinoblastoma and 13q- who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between May 2006 and May 2020, with a mean follow up of 3.7 years. Ocular survival, patient survival, and treatment toxicities were assessed. RESULTS: Nine of the 12 eyes that underwent OAC/IVIT at MSKCC have been progression free for at least 1 year since their last treatments. Fifteen out of 26 OAC cycles resulted in grade 3-4 hematologic toxicity. There was one death from sepsis in the setting of intravenous chemotherapy (IVC) for metastatic disease that occurred after OAC/IVIT therapy. The 2-year Kaplan-Meier ocular survival estimate for the whole cohort was 75% and for the eyes that received OAC or IVIT at MSKCC 83%. For OAC hematologic toxicities, one platelet transfusion and two filgrastim doses were administered, and one patient was hospitalized for neutropenic fevers. CONCLUSIONS: The majority of 13q- eyes treated with OAC/IVIT-based regimens can be cured, and there were no deaths related to complications from OAC or IVIT. 13q- Patients did have increased risk of systemic treatment complications, even from super-selective chemotherapies. Despite these toxicities, only one patient developed febrile neutropenia, one patient required a blood product transfusion, and two patients received filgrastim for both OAC and IVC complications. PRÉCIS: Children with 13q deletion syndrome with retinoblastoma managed with intra-arterial and intravitreal chemotherapy have excellent patient and ocular survival with acceptable toxicity.

A systematic review of surgical treatments of idiopathic intracranial hypertension (IIH).

Idiopathic intracranial hypertension denotes raised intracranial pressure in the absence of an identifiable cause and presents with symptoms relating to elevated ICP, namely headaches and visual deterioration. Treatment of IIH aims at reducing intracranial pressure, relieving headache and salvaging patients' vision. Surgical interventions are recommended for medically refractory IIH and include CSF diversion techniques, optic nerve sheath fenestration, bariatric surgery and venous sinus stenting. Prospective studies on the surgical options for IIH are scant and no evidence-based guidelines for the surgical management of medically refractory IIH have been established. A search in Cochrane Library, MEDLINE and EMBASE from 1 January 1985 to 19 April 2019 for controlled or observational studies on the surgical treatment of IIH (defined in accordance with the modified Dandy or the modified Friedman criteria) in adults yielded 109 admissible studies. VSS improved papilledema, visual fields and headaches in 87.1%, 72.7% and 72.1% of the patients respectively, with a 2.3% severe complication rate and 11.3% failure rate. CSF diversion techniques diminished papilledema, visual field deterioration and headaches in 78.9%, 66.8% and 69.8% of the cases and are associated with a 9.4 severe complication rate and a 43.4% failure rate. ONSF ameliorated papilledema, visual field defects and headaches in 90.5, 65.2% and 49.3% of patients. Severe complication rate was 2.2% and failure rate was 9.4%. This is currently the largest systematic review for the available operative modalities for IIH. VSS provided the best results in headache resolution and visual outcomes, with low failure rates and a very favourable complication profile. In light of this, VSS ought to be regarded as the first-line surgical modality for the treatment of medically refractory IIH.

Retinoblastoma Vitreous Seed Clouds (Class 3): A Comparison of Treatment with Ophthalmic Artery Chemosurgery with or without Intravitreous and Periocular Chemotherapy.

PURPOSE: To compare the efficacy and toxicity of treating class 3 retinoblastoma vitreous seeds with ophthalmic artery chemosurgery (OAC) alone versus OAC with intravitreous chemotherapy. DESIGN: Retrospective cohort study. PARTICIPANTS: Forty eyes containing clouds (class 3 vitreous seeds) of 40 retinoblastoma patients (19 treated with OAC alone and 21 treated with OAC plus intravitreous and periocular chemotherapy). METHODS: Ocular survival, disease-free survival and time to regression of seeds were estimated with Kaplan-Meier estimates. Ocular toxicity was evaluated by clinical findings and electroretinography: 30-Hz flicker responses were compared at baseline and last follow-up visit. Continuous variables were compared with Student t test, and categorical variables were compared with the Fisher exact test. MAIN OUTCOME MEASURES: Ocular survival, disease-free survival, and time to regression of seeds. RESULTS: There were no disease- or treatment-related deaths and no patient demonstrated externalization of tumor or metastatic disease. There was no significant difference in the age, laterality, disease, or disease status (treatment naïve vs. previously treated) between the 2 groups. The time to regression of seeds was significantly shorter for eyes treated with OAC plus intravitreous chemotherapy (5.7 months) compared with eyes treated with OAC alone (14.6 months; P < 0.001). The 18-month Kaplan-Meier estimates of disease-free survival were significantly worse for the OAC alone group: 67.1% (95% confidence interval, 40.9%-83.6%) versus 94.1% (95% confidence interval, 65%-99.1%) for the OAC plus intravitreous chemotherapy group (P = 0.05). The 36-month Kaplan-Meier estimates of ocular survival were 83.3% (95% confidence interval, 56.7%-94.3%) for the OAC alone group and 100% for the OAC plus intravitreous chemotherapy group (P = 0.16). The mean change in electroretinography responses was not significantly different between groups, decreasing by 11 µV for the OAC alone group and 22 µV for the OAC plus intravitreous chemotherapy group (P = 0.4). CONCLUSIONS: Treating vitreous seed clouds with OAC and intravitreous and periocular chemotherapy, compared with OAC alone, resulted in a shorter time to regression and was associated with fewer recurrences requiring additional treatment and fewer enucleations. The toxicity to the retina does not seem to be significantly worse in the OAC plus intravitreous chemotherapy group.

Efficacy and toxicity of second-course ophthalmic artery chemosurgery for retinoblastoma.

OBJECTIVE: Assess the usefulness of second-course ophthalmic artery chemosurgery (OAC) for patients with intraocular retinoblastoma that recurred after prior OAC. This study evaluated the efficacy and toxicity of second-course OAC. DESIGN: Single-arm retrospective study of 29 eyes of 30 patients treated with second-course OAC at Memorial Sloan Kettering Cancer Center between May 2006 and July 2013, with a median follow-up of 25.9 months. PARTICIPANTS: Retinoblastoma patients who underwent a course of OAC, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently received additional OAC for recurrent tumor. METHODS: To determine efficacy, Kaplan-Meier survival estimates were generated and the Mantel-Cox test was used to compare curves. To determine toxicity, electroretinography (ERG) amplitudes were measured in response to 30-Hz photopic flicker stimulation before and after OAC treatment; systemic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). MAIN OUTCOME MEASURES: For efficacy, ocular progression-free survival, ocular event-free survival (e.g., enucleation, external-beam radiation, or intravitreal melphalan), and ocular survival. For toxicity, peak-to-peak comparisons between ERG studies before and after OAC treatment and CTCAE 4.0-graded systemic adverse events. RESULTS: Fifty percent of all recurrences were within 4.4 months and 90% were within 16 months of completion of the first course of OAC. The 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after second-course OAC were 82.8% (95% confidence interval [CI], 60.1%-93.2%), 57.3% (95% CI, 36.1%-73.7%), and 26.5% (95% CI, 11.0%-45.0%), respectively. All eyes without vitreous seeding were progression free, whereas eyes with vitreous seeding were associated significantly with worse ocular survival after second-course OAC (P = 0.03). After second-course OAC, 90% of eyes had stable or improved ERG responses. Of all evaluable cases, there was no increased risk of systemic toxicity during the second course compared with the initial course of OAC. CONCLUSIONS: Retinoblastoma eyes requiring second-course OAC after initial OAC treatment have good salvage rates, and the treatment has an acceptable ocular and systemic toxicity profile. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods because of progression of disease after second-line OAC, particularly if vitreous seeds are present at the time of initial OAC failure.

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.

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.

Ophthalmic artery chemosurgery for retinoblastoma prevents new intraocular tumors.

OBJECTIVE: To determine the incidence and timing of new intraocular tumor foci in genetic retinoblastoma cases after treatment with ophthalmic artery chemosurgery (OAC). DESIGN: Single-center retrospective review of all genetic retinoblastoma cases managed at Memorial Sloan-Kettering Cancer Center/Weil-Cornell Medical School since May 2006. PARTICIPANTS: Eighty-one patients (80 with bilateral disease and 1 with unilateral disease with a family history) with genetic retinoblastoma, with a total of 116 eyes treated with OAC since May 2006. METHODS: Retrospective, single-institution review of patients with bilateral retinoblastoma and unilateral retinoblastoma with a positive family history. New tumors were assessed by clinical notes, retinal drawings, and RetCam digital imaging (Clarity Medical Systems, Pleasanton, CA). MAIN OUTCOME MEASURES: New intraocular retinoblastoma tumors after treatment with OAC. RESULTS: Forty-one eyes were treated primarily with OAC (treatment-naïve group) and 75 eyes were treated with OAC after prior treatment with systemic chemotherapy, external beam radiation, or both and focal techniques. Of the 41 treatment-naïve eyes, a new intraocular tumor (one focus) subsequently developed in 1 eye. Of the 75 previously treated eyes, new tumors (single focus in each eye) subsequently developed in 6 eyes. CONCLUSIONS: Eyes receiving OAC demonstrate fewer new intraocular retinoblastomas after radiation or systemic chemotherapy than has been reported in the literature. This suggests that ophthalmoscopically undetectable tumors are present at the initial diagnosis and effectively are eliminated as a result of OAC.

Spinal dural arteriovenous fistulas: a review.

Spinal dural arteriovenous fistulas (SDAVF) are a rare pathologic entity with a diverse and often misleading clinical presentation. While digital subtraction spinal angiography remains the gold standard, recent advances in noninvasive vascular imaging have improved the diagnosis of SDAVF. As this condition can result in permanent spinal cord injury, all patients require treatment, which consists of surgical or endovascular occlusion of the fistula. Failure to recognize and treat SDAVF in a timely fashion can result in irreversible neurologic disability, including myelopathy, lower extremity weakness and bowel, bladder and sexual dysfunction. This article reviews the clinical features, pathogenesis, radiographic features and current treatment strategies for these complex lesions.

Persistence of retinal function after intravitreal melphalan injection for retinoblastoma.

BACKGROUND: The risk/benefit profile of intravitreal melphalan injection for treatment of active vitreous seeds in retinoblastoma remains uncertain. We report clinical and electroretinography results after 6 months of one patient who has shown a favorable initial clinical response to intravitreal melphalan injections for treatment of refractory vitreous seeds. METHODS: Clinical case report. PATIENT: The patient presented at age 17 months with bilateral retinoblastoma [OD: International Classification (ICRB) group E, Reese-Ellsworth (R-E) class Vb; OS: ICRB D, R-E Vb] with no known prior family history. The right eye was enucleated primarily. The patient received systemic chemotherapy and extensive local treatment to the left eye. Ten months later, she presented with recurrent disease, including fine, diffuse vitreous seeds. Tumor control was established with intra-arterial chemotherapy and local treatment. Subsequent recurrence was treated with further intra-arterial chemotherapy, local treatment, and plaque radiotherapy with iodine-125. Persistent free-floating spherical vitreous seeds were treated with 4 cycles of intravitreal melphalan injection via the pars plana, with doses of 30, 30, 30, and 20 µg. RESULTS: After 6 months of follow-up, the left eye remained free of active tumor. Visual acuity was 20/40. Photopic ERGs amplitudes were unchanged compared with those recorded prior to the intravitreal injection treatments. CONCLUSIONS: Intravitreal melphalan injection for refractory spherical vitreous seeds of retinoblastoma with favorable tumor response is compatible with good central visual acuity and preservation of retinal function as indicated by photopic ERG recordings.

Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model.

PURPOSE: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model. METHODS: 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry. RESULTS: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice. CONCLUSIONS: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.

Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment.

BACKGROUND: Superselective delivery of chemotherapy through the ophthalmic artery, i.e. ophthalmic artery chemosurgery, has been used for the treatment of advanced intraocular retinoblastoma. Herein, we evaluate the efficacy of ophthalmic artery chemosurgery for retinoblastoma associated with >50% retinal detachment. PROCEDURE: Retrospective review of 37 eyes of 34 retinoblastoma patients who had extensive (>50%) bullous non-rhegmatogenous retinal detachments and received ophthalmic artery chemosurgery either as primary treatment or as "salvage" treatment after failed multi-cycle intravenous chemotherapy and/or external beam radiation (mean follow-up, 21 months). Data on patient and ocular survival, complications of ophthalmic artery chemosurgery treatments, time course of retinal reattachment, and serial electroretinograms (ERG) were collected. RESULTS: A total of 134 ophthalmic artery chemosurgery injections were performed. All children survive. Five eyes (5/37; 14%) were enucleated for progression of disease. The Kaplan-Meier enucleation-free survival rate at 2 years was 87.9% (95% confidence interval, 76.5-99.3%). The retina reattached in 28 eyes (28/37; 76%) and the 30-Hz flicker ERGs improved by >25 µV in seven eyes (7/37; 19%), remained stable (change < 25 µV) in 26 eyes (26/37; 70%), and decreased by >25 µV in four eyes (4/37; 11%). The Kaplan-Meier retinal reattachment rate was 58% after 3 months and three ophthalmic artery chemosurgery infusions (95% confidence interval, 41.9-74.1%). CONCLUSIONS: Ophthalmic artery chemosurgery is effective in preventing enucleation, promoting retinal reattachment and preserving or improving retinal function in the majority of eyes with advanced retinoblastoma and >50% retinal detachment that would otherwise be considered for enucleation.

Biochemical measures of ovarian function in female survivors of retinoblastoma treated with intra-arterial melphalan: an initial report.

Since 2006, ophthalmic artery chemosurgery (OAC) has been used for ocular-sparing treatment of retinoblastoma. Systemic exposure to melphalan is known to cause ovarian dysfunction, but the effect of melphalan-based OAC has not yet been determined. Here, we assess biochemical and symptomatic measures of ovarian function in a cohort of pubertal female survivors of retinoblastoma treated with melphalan-based OAC. These 13 patients all had normal gonadotropins at a median age of 11.1 years, 9.6 years from the completion of therapy. None had symptoms of ovarian dysfunction. This study provides initial evidence that ovarian function remains intact after melphalan-based OAC.

Flow diversion for cerebral aneurysms.

The treatment of cerebral aneurysms includes open microsurgical options (e.g., clipping, trapping/bypass) and evolving endovascular techniques. Following the landmark trials that propelled endovascular treatment to the forefront, flow diversion has shown high aneurysm cure rates with minimal complications. Flow diversion stents are placed in the parent vessel, redirecting blood flow from the aneurysm, promoting reendothelization across the neck, and resulting in complete occlusion of the aneurysm. As a result, flow diversion has become increasingly used as the primary treatment for unruptured aneurysms; however, its applications are being pushed to new frontiers. Here, the authors present three cases showcasing the treatment of intracranial aneurysms with flow diversion. The video can be found here: https://stream.cadmore.media/r10.3171/2022.7.FOCVID2253.

Intraarterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: results of a phase I trial.

OBJECTIVE: Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population. METHODS: SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion. RESULTS: Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months). CONCLUSIONS: SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov).

Multiple pipeline embolization devices improves aneurysm occlusion without increasing morbidity: A single center experience of 140 cases.

INTRODUCTION: Rates of aneurysm occlusion with the pipeline embolization device (PED) has varied widely in the literature from 55.7% to 93.3% at 6 months, which may reflect a difference in technique including sizing and number of devices used. METHODS: 140 cases at our institution were retrospectively reviewed, and aneurysms treated with a single PED vs. multiple were compared. RESULTS: Complete aneurysm occlusion was achieved in 86.9% at 6 months, 91.8% at 1 year, and 97.6% at longest follow-up. Retreatment with an additional device was required in 7 (5.1%). Major and minor complication rate within 30 days was 1.4% and 5.0%, and at greater than 30 days was 0.8% and 3.1%. Patients treated with multiple PEDs had significantly higher rates of aneurysm occlusion at 6 months (92.9% vs. 75.6%, p = 0.017) and 12 months (98.4% vs. 81.1%, p = 0.014), with no difference in complications. The two groups were similar aside from a higher number of ophthalmic and paraophthalmic aneurysms treated with multiple PEDs (23.4% vs. 6.5%, p = 0.004; and 35.1% vs. 17.4%, p = 0.020), and more posterior communicating artery and recurrent aneurysms treated with a single PED (28.3% vs. 3.2%, p = 0.001; 23.9% vs. 8.5%, p = 0.031). The use of multiple PEDs was found to be an independent predictor of aneurysm occlusion in a multivariate analysis (p = 0.015). CONCLUSIONS: The use of multiple PEDs for intracranial aneurysms leads to significantly higher occlusion rates without added morbidity. This benefit is particularly appropriate for ophthalmic segment aneurysms, while more distal segments with eloquent perforating branches should be managed with caution.

RB1 Circulating Tumor DNA in the Blood of Patients with Unilateral Retinoblastoma: Before and after Intra-arterial Chemotherapy.

Purpose: Circulating tumor DNA (ctDNA) is released by many tumors into the plasma. Its analysis has minimal procedural risk and, in many cancers, has the potential for clinical applications. In retinoblastoma, the clinical correlations of ctDNA in eyes treated without enucleation have not been studied. This purpose of this study was to determine how the ctDNA RB1 variant allele frequency (VAF) changes in patients with unilateral retinoblastoma after intra-arterial chemotherapy (IAC) treatment. Variant allele frequency is a proxy for tumor fraction. Design: Case series from a single tertiary cancer referral center. Participants: Five patients with retinoblastoma with at least 1 measurable ctDNA plasma specimen both at the time of active intraocular retinoblastoma before IAC and after at least 1 IAC cycle. Methods: Circulating tumor DNA RB1 was detected and VAF was measured before and after IAC treatment. Clinical correlations were made using clinical examination, fundus photography, ultrasound, and OCT. Main Outcome Measures: Comparison of ctDNA RB1 VAF before and after IAC treatment for retinoblastoma and concordance of ctDNA RB1 detectability with activity of intraocular disease. Results: Twenty-three ctDNA specimens were included from 5 patients. The 5 baseline RB1 VAFs ranged from 0.27% to 4.23%. In all patients, the subsequent post-intra-arterial RB1 VAF was lower than baseline (0.0%-0.17%). At 4 months (2 months after IAC completion), the ctDNA consistently was negative in the patients who demonstrated clinically inactive intraocular disease. Conclusions: In this small cohort, a decremental decrease in ctDNA RB1 VAF was found after IAC, suggesting that relative VAF changes could be a biomarker of treatment response.

Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery).

PURPOSE: To report on our 3-year experience with the use of superselective ophthalmic artery infusion of chemotherapy as initial, primary treatment for intraocular retinoblastoma. DESIGN: Prospective, institutional review board-approved clinical trial. PARTICIPANTS: Twenty-eight eyes of 23 newly diagnosed retinoblastoma patients (Reese-Ellsworth [RE] group V, 25 eyes; RE IV, 1 eye; RE III, 1 eye; RE II, 1 eye), ages 3-88 months (mean, 22; median, 11) followed for 3-37 months (mean, 15; median, 14). METHODS: Cannulation of 1 or both ophthalmic arteries in young children with retinoblastoma was performed via the femoral artery under general anesthesia on an outpatient basis and chemotherapy (melphalan [n = 12], melphalan plus topotecan [n = 7], melphalan plus topotecan and carboplatin [n = 3], or melphalan plus carboplatin [n = 1]) infused. MAIN OUTCOME MEASURES: Patient survival, eye survival, systemic toxicity, complete blood counts, ophthalmic examination, retinal photography, and electroretinograms. RESULTS: We treated 23 newly diagnosed retinoblastoma patients initially with 75 separate intra-arterial chemotherapy infusions (range, 1-6 treatments; mean, 3.2) over a 3-year period. All children survived. Only 1 of the 28 eyes came to enucleation (for progressive disease). No eye was enucleated for ocular complications of the procedure and the only adverse ophthalmic findings were occasional transient lid edema, forehead hyperemia, and loss of nasal lashes. Kaplan-Meier enucleation free was 100% at 12 months and 89% at 2 years (95% confidence interval, 43%-98%). There were no deaths, strokes, or transfusions of any blood products; no effect on red cell count; 9 cycles of grade 3 and 1 cycle of grade 4 neutropenia; and no hospitalizations, episodes of fever/neutropenia, or complications at the site of femoral artery puncture. CONCLUSIONS: The ophthalmic artery(s) of children can safely be repeatedly canulated in very young children and high concentrations (but low doses) of chemotherapy infused on an outpatient basis. When used as initial therapy superselective chemotherapy delivered through the ophthalmic artery prevented enucleation, primary radiation or the use of systemic chemotherapy in 27 of 28 eyes.