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.

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.

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.

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.

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.

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.

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.

Chemoreduction of Orbital Recurrence of Uveal Melanoma by Intra-Arterial Melphalan.

BACKGROUND/AIMS: The treatment of orbital melanoma poses a management challenge. This case explores the delivery of high-dose melphalan to an orbital recurrence of uveal melanoma via intra-arterial delivery of melphalan to the orbit. A 62-year-old man developed recurrent orbital disease 7 months after enucleation for a large uveal melanoma. He received 6 monthly intra-arterial infusions of melphalan to the orbit, ranging in dose from 20 to 30 mg per infusion. Following the last infusion, mild temporary erythema was noted on the forehead along the distribution of the supratrochlear artery. The orbital recurrence was reduced in size by 66% in the longest dimension as measured by magnetic resonance imaging (MRI). However, 9 months following intra-arterial melphalan, tumor regrowth was detected on MRI, and additional treatment options were pursued. CONCLUSION: This case demonstrates that intra-arterial melphalan can result in nonsustained tumor regression of recurrent orbital uveal melanoma. It suggests that local delivery of high-dose melphalan may be helpful as a neoadjuvant treatment for uveal melanoma, and future studies will be useful to confirm the value of this approach in additional cases of recurrent and possibly in primary uveal melanoma.

Association of electroretinography with visual outcomes after ophthalmic artery chemosurgery for retinoblastoma in ICRb D and E eyes.

IMPORTANCE: Predictions of visual outcomes are useful in clinical and family decisions regarding treatment for retinoblastoma. Very little has been published on the association of post-treatment visual acuity with pre-treatment electroretinography (ERG), which can be performed on infants too young to reliably quantify visual acuity. OBJECTIVE: To report associations of pre-treatment ERG with post-treatment visual acuity in eyes with advanced retinoblastoma treated with ophthalmic artery chemosurgery (OAC). DESIGN: Retrospective case-control study of eyes treated from 2006 through 2017, with mean follow-up of 51 months (range 2.3-150 months). SETTING: Single large academic center. PARTICIPANTS: Group D and E eyes treated with OAC at Memorial Sloan Kettering Cancer Center with recorded visual acuity and ERG (30Hz flicker). MAIN OUTCOME AND MEASURE: Snellen visual acuity (uncorrected) compared to initial 30Hz flicker ERG. RESULTS: This study included 157 Group D and E eyes. Results of the Jonckheere-Terpstra test for trend were statistically significant and indicated that eyes with lower pre-treatment ERG readings tended to have more visual impairment post-treatment. Among eyes with initial ERG 75+ µV, 11 of 32 eyes (34%) had visual acuity 20/40 or better. Among eyes with ERG 0 µV, 44 of 46 (96%) had visual acuity of 20/200 or worse. CONCLUSIONS AND RELEVANCE: Eyes with advanced intraocular retinoblastoma treated with OAC can achieve excellent visual acuity, but poor ERG at initial visit is associated with poor visual acuity after treatment in the majority of eyes. Expectations regarding visual potential may influence decisions about treatment.

Impaired drainage of vein of Labbé following venous sinus stenting for idiopathic intracranial hypertension.

PURPOSE: The impact of venous sinus stenting (VSS) on vein of Labbé (VOL) drainage is poorly understood. The purpose of the study is to examine the incidence and potential high risk factors of impaired VOL drainage among idiopathic intracranial hypertension (IIH) patients following VSS. MATERIALS AND METHODS: Institutional review board approved prospective evaluation of all IIH patients who underwent VSS over a 5 year period (January 2012 to December 2017) at Weill Cornell Medical Center constituted the study population. Patient demographics, procedural details (laterality of stenting, balloon angioplasty, number of stents, and stent diameters), morphology of the VOL and changes in the flow in the VOL, type of sinus stenosis, and transverse sinus symmetry were evaluated. We used χ2 analysis to evaluate impaired VOL drainage against other variables. Statistical significance was set at 0.05. RESULTS: 70 consecutive patients (67 women, 3 men) with a mean age of 31±9.8 years underwent VSS. Stenosis was extrinsic in 63% (n=44) and intrinsic in 37% (n=26) of patients. Impaired drainage of the VOL was detected in 9/70 (13%) patients. Ipsilateral VOL was recognized as dominant in 20% (n=14), co-dominant in 51% (n=36), and non-dominant in 29% (n=20) of patients. Impaired VOL drainage was significantly associated with ipsilateral VOL dominance (P=0.001) and stent diameter of ≥9 mm (P=0.042). All patients demonstrated widely patent VOL on follow-up contrast enhanced MR venography at 3 months and 24 months. CONCLUSION: Impaired drainage of the ipsilateral VOL is a potential consequence of VSS with 13% incidence, and has significant association with ipsilateral superficial cortical venous drainage via dominant VOL and stent diameter of ≥9 mm. CLINICAL TRIAL REGISTRATION: NCT01407809.

Stent-assisted coil embolization of anterior communicating artery aneurysms using the LVIS Jr stent.

BACKGROUND AND PURPOSE: This retrospective study evaluates the safety and mid-term and long-term effectiveness of stent-assisted coil embolization of anterior communicating artery (Acomm) aneurysms treated with the LVIS Jr stent. MATERIALS AND METHODS: All patients treated with the LVIS Jr stent for Acomm aneurysms between June 2015 and March 2018 were included in the analysis. Details of the procedure's periprocedural adverse events, immediate aneurysm occlusion rates, and clinical and angiographic follow-up assessment were collected. RESULTS: A total of 25 patients with 25 aneurysms were included. Eighteen aneurysms were found incidentally. Seven patients presented with seven ruptured aneurysms: Six were remotely ruptured and one acutely ruptured. Twenty-four patients were treated successfully and one technical failure is reported. The parent arteries measured 1.4 mm to 2.9 mm in diameter (mean, 2.3 mm). Intraprocedural thromboembolic complications occurred in two patients (8%) and an intraoperative aneurysm rupture in one patient (4%). Immediate complete aneurysm occlusion was noted in 18 out of 25 patients (72%). Clinical follow-up ranged from three months to 36 months (mean, 15.8 months) and the imaging follow-up ranged from two to 35 months (mean, 14.2 months). Complete aneurysm occlusion was achieved in 14 out of 20 patients (70%) at last angiographic follow-up. Of the two patients with in-stent thrombosis, one patient had an acutely ruptured aneurysm and the other patient was treated with an LVIS Jr stent in a Y configuration. Neurological morbidity and mortality rate were 0%. CONCLUSIONS: Complex, wide-necked Acomm aneurysms can be effectively treated with stent-assisted embolization using LVIS Jr stents.