Ommaya Reservoir Research Articles

EXTH-01. INTRATHECAL DELIVERY OF DENDRITIC CELL VACCINE ERADICATES TUMOR GROWTH AND PROTECTS AGAINST LEPTOMENINGEAL DISEASE RE-INOCULATION IN HER2+ AND TRIPLE NEGATIVE BREAST CANCER LMD XENOGRAFT MODELS

Abstract BACKGROUND Leptomeningeal disease (LMD) occurs in approximately 5% of patients with breast cancer and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in breast cancer patients. In pre-clinical and clinical trials, the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ breast cancer patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in breast cancer-associated LMD immunocompetent animal models. METHODS Luciferase-labeled HER2+ TUBO breast cancer cells were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir in patients) for the IT administration of DCVs into the CSF. RESULTS AND DISCUSSION breast cancer-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p< 0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ breast cancer-LMD and 28% in triple negative breast cancer-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found evidence of CD4+ and CD8+ T-cells infiltration, and robust IFN-g and IL18 response upon DCV treatment. CONCLUSIONS Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in breast cancer patients with LMD.

Ommaya Reservoir and the External Ventricular Drainage

Childhood hydrocephalus is a highly diverse disease caused by various factors, and most surgical treatments are performed during infancy. Despite the diversity of hydrocephalus pathologies, treatment options are limited. It is difficult for pediatric neurosurgeons to select and perform appropriate surgical procedures for neonates and infants. Treatment options for hydrocephalus are broadly divided into permanent and temporary. Permanent treatments include cerebrospinal fluid shunt and endoscopic third ventriculostomy; temporary treatment entails cerebrospinal fluid drainage using lumbar puncture and intermittent cerebrospinal fluid drainage with an Ommaya reservoir, ventricular drainage, and ventriculosubgaleal shunt. This article describes in detail Ommaya reservoir placement and ventricular drainage as representative procedures for temporarily treating hydrocephalus.

346P The safety and efficacy of intrathecal chemotherapy with pemetrexed via the Ommaya reservoir for leptomeningeal metastases from lung adenocarcinoma: A prospective study

In this prospective clinical study, we aimed to evaluate the efficacy and toxicities of intrathecal chemotherapy (IC) with pemetrexed via the Ommaya reservoir in lung adenocarcinoma (LUAD) with refractory leptomeningeal metastases (LM).

Traumatic Subdural Hygroma Due to Injury of an Ommaya Reservoir: A Case Report

A 68-year-old male patient was transferred to the emergency department after a passerby found him lying on the road with a bicycle. He had been diagnosed with neurolymphomatosis in 2006 and had an Ommaya reservoir targeted to the right lateral ventricle via the right Kocher’s point for chemotherapy. His initial mental status was stuporous. Brain computed tomography (CT) showed multiple traumatic injuries. Seven days after admission, bilateral subdural hygroma (SDG) developed. We performed CT cisternography. The contrast was directly injected into the Ommaya reservoir and CT images were obtained. On cisternography, contrast leakage points were identified from the Ommaya reservoir. The patient underwent surgery for Ommaya reservoir removal and occlusion of the permanent tract of the Ommaya reservoir. This case shows a rare etiology of traumatic SDG and demonstrates the usefulness of CT cisternography to determine cerebrospinal fluid leakage from an implant.

Glioma Espionage From Longitudinal CSF Proteomics

Abstract AIMS Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. METHOD Global proteomic analysis of CSF was performed on the Somalogic platform – an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples. RESULTS Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden. CONCLUSION Our data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal access to gliomas via Ommaya reservoirs.

Multidisciplinary management of patients with non-small cell lung cancer with leptomeningeal metastasis in the tyrosine kinase inhibitor era.

Leptomeningeal metastasis (LM) is a challenging scenario in non-small cell lung cancer (NSCLC). Considering that outcomes of treatment modalities stratified by LM chronological patterns related to brain metastasis (BM) are lacking, the aim of this study was to evaluate outcomes and explore prognostic factors. The authors retrospectively collected data of patients with NSCLC undergoing Ommaya reservoir implantation, ventriculoperitoneal shunt implantation, or lumboperitoneal shunt implantation. Based on radiographic findings and time from diagnosis of NSCLC to LM, the authors divided them into subtypes of LM as follows: LM without BM; LM concurrent with BM; or LM after BM. The Kaplan-Meier method was applied to analyze overall survival (OS) and multivariate Cox regression for prognostic factors. Sixty-one patients with LM were included, with a median OS of 8.1 (range 0.2-70.0) months. Forty-three (70.5%) patients had EGFR-mutant disease. Forty-two (68.9%) patients had 19-del or L858R mutation, and one (1.6%) patient had G719A mutation. Fifty-seven (93.4%) patients had hydrocephalus. Twenty-one (34.4%) patients received whole-brain radiotherapy before LM diagnosis, 3 (4.9%) patients underwent operation for BMs before LM diagnosis, and 42 (68.9%) patients received EGFR tyrosine kinase inhibitor (TKI) therapy before LM diagnosis. Eleven patients were treated with chemotherapy, 10 patients were treated with TKIs, and 32 patients were treated with chemotherapy combined with TKIs before LM diagnosis. Patients with LM after BM had lower Karnofsky Performance Status (KPS) scores (KPS score 50) than did those with LM without BM (KPS score 80) or LM concurrent with BM (KPS score 70; p = 0.003). More patients with LM after BM received intrathecal methotrexate than in the other subgroups (p < 0.001). The median OS was significantly shorter in the LM after BM than in the concurrent LM and BM and the LM without BM subgroups (5.4 vs 5.5 vs 11.6 months; p = 0.019). Cox regression revealed that a KPS score ≥ 70 (HR 0.51; p = 0.027) and shunt implantation (HR 0.41; p = 0.032) were favorable prognostic factors. Patients with NSCLC who had LM without BM had better survival outcomes (11.6 months) compared with those who had LM after BM or concurrent LM and BM. Aggressive shunt implantation may be favored for LM.

P06.05.A Repeated intracranial administration of ipilimumab and nivolumab in patients with recurrent glioblastoma (rGB): A multi-cohort adaptive phase I clinical trial

Abstract Background Perioperative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with IV NIVO was shown to be feasible, safe and associated with an encouraging survival benefit (Duerinck et al. JITC 2021). In subsequent cohorts, combination of iCE administration with biweekly intracavitary (iCA, via an Ommaya reservoir) administration of increasing doses of IPI and NIVO was investigated. Methods Three cohorts were defined according to resectability and postoperative treatment schedule. Patients (pts) in cohort-A and -C underwent a maximal safe resection, pts in cohort-B stereotactic biopsy only. All pts received iCE administration of 10 mg NIVO and 5 mg IPI at the end of the surgical intervention, after which an OR was implanted and an additional 10mg of NIVO and IPI (1, 5 or 10 mg) was administered iCA in cohort-C. All pts received biweekly postoperative NIVO 10 mg IV and iCA administrations of NIVO (3 dose levels were investigated in cohorts-A and -B: 1, 5, or 10 mg) for up to a maximum of 24w postoperatively. In cohort-C, 10 mg of NIVO was complemented with IPI (1, 5, or 10 mg). NGS and RNA gene expression profiling was performed on all tissue samples. Results In total, 44 pts were included (A: n= 16, B: n= 16, C: n= 12 recruitment ongoing). All pts in cohort-A and -B are off study treatment. All pts received the predefined dose of iCE IPI/NIVO and at least one administration of the predefined iCA dose. AE were infrequent and mostly not immune-related. Most common AE were fatigue(n=37), headache(n=25), confusion(n=18) and postoperative fever(n=15). Bacterial colonization of the Ommaya port occurred in 6 pts, subacute neurological deterioration requiring corticosteroids in 8 pts. There were no grade 5 AEs. Median PFS was 13w for cohort-A, 5w in cohort-B and 13w in cohort-C. Median OS is 43weeks in A, 29w in B and is not yet reached in cohort-C after median follow-up of 23w. OS did not differ significantly between study cohorts. OS of pts who underwent surgical resection (cohorts-A and -C) compared favorably to a historical cohort of 469 Belgian patients with rGB (treated in three prospective phase II clinical trials and a large multicenter early acces program for bevacizumab). Conclusions iCE followed by repeated iCA administrations of increasing doses of NIVO with/without IPI in rGB is feasible and safe without dose limiting AEs. A potential survival benefit seems restricted to pts amenable to surgical resection.

OS11.4.A Intrathecal delivery of dendritic cell vaccine eradicates tumor growth and protects against leptomeningeal disease re-inoculation in immunocompetent HER2+ and triple negative breast cancer leptomeningeal disease xenograft models

Abstract Background Leptomeningeal disease (LMD) occurs in ~5% of patients with breast cancer (BC) and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in BC patients. In pre-clinical and clinical trials the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ BC patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in BC-LMD immunocompetent animal models. Material and Methods Luciferase-labeled HER2+ TUBO BCs were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir clinically in patients) for the IT administration of DCVs into the cerebral spinal fluid (CSF). Results BC-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p&amp;lt;0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ BC-LMD and 28% in triple negative breast cancer-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found evidence of CD4+ and CD8+ T-cells infiltration, and robust IFN-gamma and IL18 response upon DCV treatment. Conclusion Our preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in BC patients with LMD.

OS01.6.A Through the Looking Glass: CSF Proteomics for Glioma Monitoring and Response Assessment

Abstract Background The development of novel glioma therapies necessitates rapid, longitudinal, and individualized feedback from each patient's tumor. Due in part to the relative inaccessibility of dynamic gliomas, little information is available regarding mechanisms of in situ therapeutic response and resistance which may be needed to iteratively develop candidate therapies and combinations thereof. To address this challenge, we are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. Material and Methods Global proteomic analysis of CSF was performed on the Somalogic platform -- an aptamer-based technology for highly sensitive and specific analyses of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria: 1) decrease with lower tumor burden as defined by tumor resection, and 2) increase with greater tumor burden as defined by recurrence in individual paired patient samples. Results Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. When queried in an independent validation cohort, the HGG proteomic signature was consistently enriched across 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. In two patients for whom CSF was available prior to and immediately after resections, proteins in the HGG signature decreased as indicated by a lower tumor burden. Interestingly, the glioma CSF proteomic signature was highly enriched for blood-associated proteins (as defined by two paired sets of CSF samples with low vs. high hemoglobin), despite these patients' samples containing little-to-no hemoglobin proteins. Conclusion Global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas has the promise to yield biomarkers which may be used to gain insights regarding glioma biology, tumor burden, and evolution throughout a patient's disease and treatment course.

Role of Ommaya Reservoir Placement in Hydrocephalus Management following Aneurysmal Subarachnoid Hemorrhage, an Initial Experience

Abstract Introduction Weaning from external ventricular drainage (EVD) of cerebrospinal fluid (CSF) in hydrocephalus induced by aneurismal subarachnoid hemorrhage (SAH) had been proposed either through the rapid, gradual or intermittent approaches. There are no uniform guidelines for it. Given this, we planned to study the comparative outcome between EVD drainage with intermittent clamping versus EDV followed by Ommaya reservoir. Material and Methods The present retrograde observational study was conducted from July 2018 to March 2021 in the department of neurosurgery with 67 patients who developed hydrocephalus following SAH after aneurysm rupture. We divided the patients into two groups. Group 1 had only EVD placed for CSF drainage with intermittent clamping before the placement of the ventriculoperitoneal (VP) shunt, and, in group 2, an Ommaya reservoir was placed after EVD before the shunt. Result There were 38 patients in group 1 and 29 in group 2. They were age-matched, with a mild male predominance in group 1. Shunt dependency was significantly reduced in group 2 patients (p = 0.011), along with reduced length of stay in ICU (p = 0,001) and length of stay in Hospital (p = 0.019). We found improved Glasgow outcome score in group 2 patients (p = 0.006) together with reduced incidence of infarct (p = 0.0095). Conclusion We may infer from the present study that continuous drainage through EVD, initially, in hydrocephalus induced by SAH following aneurysm rupture, increases cerebral perfusion pressure (CPP) and decreases intracranial pressure (ICP) leading to decreased infarct rate and intermittent drainage through Ommaya following EVD reservoir, decreases shunt dependency, reduces ICU and hospital stay, with improved Glasgow outcome score on follow-up, but these findings need to be validated in a prospective randomized control trial.

Phase I/II trial of local interstitial chemotherapy with arsenic trioxide in patients with newly diagnosed glioma

BackgroundGlioma is the most common primary brain tumor in adults with poor prognosis. The glioma patients benefit from STUPP strategy, including maximum and safe resection and adjuvant radiotherapy and chemotherapy. Arsenic trioxide could inhibit various tumors. However, it is a challenge to evaluate the efficiency and safety of srsenic trioxide in glioma patients.ObjectiveThe arsenic trioxide has the potent therapeutic effect on glioma. However, the safety and efficacy of local interstitial chemotherapy with arsenic trioxide in newly diagnosed glioma patients is unclear.MethodsAll patients received partial or complete tumor resection and intraoperative implantation of Ommaya reservoirs followed by standard radiotherapy. Arsenic trioxide with the starting dose 0.3 mg was administered via an Ommaya reservoir catheter inserted into the tumor cavity for 5 consecutive days every 3 months for a total of eight cycles unless tumor progression or excessive toxicity was observed.ResultsNo hematological or grade 4 non-hematological toxicity was observed in any patient during arsenic trioxide treatment. The maximum tolerated dose of 1.5 mg of arsenic trioxide was safe and well tolerated. The median overall survival for WHO grade 3 glioma was 33.6 months, and for glioblastoma was 13.9 months. The median progression-free survival for WHO grade 2 glioma was 40.3 months, for grade 3 glioma was 21.5 months, and for glioblastoma was 9.5 months.ConclusionThese results suggest that arsenic trioxide is safe and well tolerated with local delivery into the tumor cavity of the brain, and the dose recommended for a phase II trial is 1.5 mg.

Intrathecal therapy for the management of leptomeningeal metastatic disease: a scoping review of the current literature and ongoing clinical trials.

Leptomeningeal metastatic disease (LMD) from advanced malignancies has poor prognoses and limited treatments. Intrathecal therapy (ITT) protocols are available, showing variable outcomes. We reviewed the therapeutic and toxicity profiles of ITT in LMD. PubMed, EMBASE, Web-of-Science, and Scopus were searched following the PRISMA-ScR guidelines to include studies reporting ITT for LMD. gov and Cochrane were searched to identify ongoing clinical trials. We included 27 published studies encompassing 2161 patients and 4 ongoing trials. LMD originated from brain metastases (85.5%), lymphomas (5.4%), high-grade gliomas (4.6%), medulloblastomas (2.3%), and leukemias (2.1%). LMD was mostly diagnosed with the co-presence of neurological-related symptoms and positive imaging and/or cerebrospinal fluid cytology (60.8%). The most common ITT agents were methotrexate (35.9%), cytarabine (21.9%), and thiotepa (8.2%), standalone or combined. Patients received a median of 6.5 ITT cycles (range, 1.0-71.0) via intraventricular (58.8%) or lumbar intrathecal (41.2%) routes. The Ommaya reservoir was implanted in 38.5% cases. Concurrent systemic chemotherapy (45.2%) and/or radiotherapy (30.6%) were used. After 1-3 cycles, 44.7% patients had improved clinical status and 29.9% converted into negative cerebrospinal fluid cytology. The most common ITT-related severe adverse events were neutropenia (6.5%), meningitis (5.2%) and encephalopathy (4.5%). Median freedom from progression was 2.4months (range, 0.1-59.5) and median overall survival 5.5months (range, 0.1-148.0). Current ITT protocols are variable but effective and well-tolerated in LMD. Ongoing trials are investigating dose-limiting toxicity profiles and long-term overall survival. Future studies should analyze the therapeutic and safety profiles of ITT compared to newer systemic therapies.

LOCL-04 SAFETY AND FEASIBILITY OF RHENIUM-186 NANOLIPOSOME (186RNL) IN LEPTOMENINGEAL METASTASES [LM] PHASE 1/2A DOSE ESCALATION TRIAL

BACKGROUNDLM is a devastating subarachnoid (SA) complication most commonly from breast, lung, melanoma, and gastrointestinal malignancies affecting 110,000 in the USA. Common therapies are radiation and SA/IV chemotherapy. Without treatment, survival is short with limited treatment options and better options urgently needed. 186RNL emits beta particles (with gamma-rays) with low dose rate and high radiation density. We report first results of the enrolling ReSPECT-LM phase 1/2a 186RNL-LM dose escalation trial. MATERIAL AND METHODSPreclinical syngeneic rat model animals were 186RNLtreated at day15 with intraventricular186RNL(0.689 mCi) providing mean CSF-radiation absorbed dose=1,136 ±226Gy. 50% control animals[unloaded liposomes] and 100%186RNL treated animals were alive at 14days. At 4 weeks, 75% control animals and 37.5% treated animals had died. Based on this preclinical data and 186RNL recurrent glioma human experience, a phase I/2a dose escalation ReSPECT-LM Trial was initiated to characterize safety/tolerability of a single intrathecal(IT) 186RNL administration. Following, to identify maximum tolerated/feasible doses, 186RNL anti-tumor activity as a single agent in LM patients (breast and NSCLC), characterize 186RNL pK & dosimetry via Ommaya delivery, determine the overall response rate (ORR) for 186RNL treated patients based on CSF/radiographic findings, and describe survival distribution. RESULTSReSPECT-LM is enrolling and 1st patient dosed (6.6 mCi186RNL, 5ml) via Ommaya reservoir. The dose was well-tolerated with no complaints/AEs as of Day 28 following treatment. Imaging and CSF tumor cell assays at pre &post-dose were performed. 186RNL gamma imaging confirmed rapid, complete and durable SA dose distribution through168hours. Pre-dose CSF tumor cell count was 70.77 cells/ml and following treatment, 39.79 cells/ml at 24, and ~6 cells/ml at both 48 &168hours. CONCLUSION186RNL’s unique formulation and characteristics may have promise for LM patients. An update of the ReSPECT-LM clinical trial will be provided.

BSCI-10 TAPPING INTO GLIOMAS’ SECRETS: CSF PROTEOMICS FOR BIOMARKER DISCOVERY, GLIOMA MONITORING, AND THERAPEUTIC RESPONSE ASSESSMENT

Abstract INTRODUCTION Rapid, detailed feedback is needed to understand the individualized biological impacts of novel glioma therapies. We are performing glioma biomarker discovery by serial cerebrospinal fluid (CSF) sampling from Ommaya reservoirs to determine how the CSF proteome can reveal early longitudinal intelligence regarding glioma status, biology, and therapeutic response. METHODS Global proteomic analysis of CSF was performed on the Somalogic platform − an aptamer-based technology for highly sensitive and specific analysis of over 7,000 proteins. Discovery analysis comprised of the top-500 ranked proteins in CSF from seven patients with high-grade gliomas (HGG) versus non-glioma controls. The top-500 HGG proteins were then preliminarily filtered to include only proteins that met two additional criteria of decrease with resection and increase with recurrence in individual paired patient samples. RESULTS Proteomic enrichment analysis revealed a conserved HGG CSF proteomic signature defined by 79 proteins, including ones known to be over-expressed in solid tumor malignancies, such as retinoblastoma binding protein 4, heat shock protein 90, and sorcin. The HGG proteomic signature was consistently enriched in an independent validation cohort consisting of 13 gliomas diverse in primary versus recurrent status, subtype, and grade, when compared to control CSF samples. Encouragingly, proteins in the HGG signature decreased in the two patients for whom CSF was collected prior to and after resection (both at POD16 and POD18) with decreased tumor burden. CONCLUSION Our preliminary data demonstrate the ability to gain detailed, individualized insights regarding glioma biology, tumor burden, and evolution through global CSF proteomics acquired from longitudinal neurosurgical access to unique gliomas.

BSCI-01 INTRATHECAL DELIVERY OF DENDRITIC CELL VACCINE ERADICATES TUMOR GROWTH AND PROTECTS AGAINST LEPTOMENINGEAL DISEASE (LMD) RE-INOCULATION IN IMMUNOCOMPETENT HER2+ AND TRIPLE NEGATIVE BREAST CANCER (TNBC) LMD XENOGRAFT MODELS

BACKGROUNDLMD occurs in ~5% of patients with breast cancer (BC) and has a median survival of 2-4 months. We found a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune responses in BC patients. In pre-clinical and clinical trials the administration of class II HER2 peptide-pulsed dendritic cell vaccine (HER2-DCV) partially restores anti-HER2 Th1 immune responses with pathologic complete responses in HER2+ BC patients. Here, we examined the intrathecal (IT) delivery of HER2/HER3-DCV in BC-LMD immunocompetent animal models.MATERIALS AND METHODSLuciferase-labeled HER2+ TUBO BCs were injected into the cisterna magna of BALB/c mice to produce LMD. We used our Murine Ommaya (mimics an Ommaya reservoir clinically in patients) for the IT administration of DCVs into the cerebral spinal fluid (CSF).RESULTS AND DISCUSSIONBC-LMD mice were randomized into following groups: 1) HER2-DCV IT 2) HER3-DCV IT 3) HER2/HER3-DCV IT. The median survival of untreated (control) group was 15 days. All groups given DCV IT prolonged survival (p<0.001). Interestingly, HER2-/HER3-DCV IT was able to rescue disease mice (71% in HER2+ BC-LMD and 28% in TNBC-LMD) and showed complete tumor regression. Some surviving mice were immune to subsequent tumor rechallenge. In mice CSF, we found the presence of CD4+ and CD8+ T-cells, and robust IFN-gamma and IL18 response upon DCV treatment. Collectively, this suggests IT delivery of DCV elicits immune response in CSF targeting LMD.CONCLUSIONOur preclinical data supported a clinical trial (submitted) of the IT delivery of DCV in BC patients with LMD.

Preservation of endocrine function after Ommaya reservoir insertion in children with cystic craniopharyngioma.

Children with craniopharyngiomas (CP) can experience significant morbidities caused by extensive surgery and/or radiation. Ommaya reservoir insertion (ORI) into cystic CP represents a minimally invasive approach allowing immediate decompression and aims to avoid additional injuries. The purpose of this study was to determine the surgical outcome and relevance of upfront ORI (± intracystic treatment) for preservation of endocrine function. We performed a retrospective chart review of children with CP treated at the Hospital for Sick Children between 01/01/2000 and 15/01/2020. Endocrine function was reviewed at the time of initial surgery and throughout follow-up. New endocrinological deficits related to the index procedure were defined as immediate failure (IF), whereas postoperative duration of endocrinological stability(ES) wasanalyzed using the Kaplan-Meier method. The rate of IF and ES was compared between the treatment groups. Seventy-nine patients were included and had a median age of 8.3years (range 2.1-18.0years); 31 were males. Fifty-three patients with upfront surgical treatment, including 29 ORI and 24 gross total or partial resections had sufficient endocrinological follow-up data. Endocrine dysfunction occurring immediately after the index procedure (IF)was observed in 15 patients (62.5%) in the resection group compared to two patients (6.8%) in the ORI group, odds ratio: 0.05 (CI: 0.01-0.26, p < 0.0001). Excluding those with immediate endocrinologicaldeficits, mean ES after ORI was 19.4months (CI: 11.6-34.2), compared to 13.4months (CI:10.6-NA) after surgical resection. Endocrine function was preserved in patients with upfront ORI (± intracystic treatment), which was confirmed as a minimally invasive procedure with an overall low morbidity profile.

Intrathecal methotrexate in combination with systemic chemotherapy in glioblastoma patients with leptomeningeal dissemination: A retrospective analysis.

BACKGROUNDGlioblastoma (GBM) is one of the most common and aggressive primary malignant brain tumors with severe symptoms and a poor prognosis. Leptomeningeal dissemination (LMD) is a serious complication of GBM that often results in dire outcomes. There is currently no effective treatment.AIMTo estimate the clinical outcomes of combination therapy in GBM patients with LMDMETHODSA retrospective analysis was conducted using data collected from GBM patients diagnosed with LMD from January 2012 to December 2019 at our institution. All these patients had received at least one cycle of a combination therapy consisting of intrathecal methotrexate (MTX) and systemic chemotherapy. Clinical and pathological data were analyzed to explore the outcome of GBM patients with LMD and to determine the most effective treatment.RESULTSTwenty-six patients were enrolled in this study. The median time from GBM diagnosis to LMD development was 9.3 mo (range: 2-59 mo). The median overall survival of LMD patients from diagnosis to after receiving systemic chemotherapy in combination with intrathecal MTX was 10.5 mo (range: 2-59 mo). In the Cox univariate analysis, gross resection of tumor (P = 0.022), Karnofsky performance status (KPS) > 60 (P = 0.002), and Ommaya reservoir implant (P < 0.001) were correlated with survival. Multivariate analysis showed that KPS > 60 (P = 0.037) and Ommaya reservoir implant (P = 0.014) were positive factors correlated with survival. Myelotoxicity and gastrointestinal reactions were the common toxicities of this combination therapy. According to Common Terminology Criteria of Adverse Events 4.03, most of the patients presented with toxicity less than grade 3.CONCLUSIONIntrathecal MTX administration combined with systemic chemotherapy is a potentially effective treatment for patients with GBM and LMD, with mild treatment-related side effects.

Complications Associated With Ventriculoperitoneal Shunt Surgery for Normal Pressure Hydrocephalus Using Stereotactic Navigation and Abdominal Laparoscopy: A Single-Institution Case Series.

Normal pressure hydrocephalus (NPH) is characterized by cerebral ventriculomegaly and the triad of magnetic gait, urinary incontinence, and cognitive impairment. Treatment includes ventriculoperitoneal (VP) shunt surgery. To evaluate complication rates in a cohort of patients undergoing VP shunt surgery with stereotactic proximal catheter navigation and laparoscopic distal catheter placement. This study was a retrospective consecutive cohort analysis of 117 patients with NPH undergoing VP shunt placement using both stereotactic navigation and laparoscopy from 2015 to 2020. Patients with obstructive hydrocephalus and those with central nervous system infection, intraventricular hemorrhage, Ommaya reservoirs, or undergoing shunt revision at initial encounter were excluded. Variables included demographics and comorbidities, NPH symptoms, operative details, radiographic outcomes, and rates of complications, readmissions, and reoperations within 1, 3, and 12 months. Impact of demographics and comorbidities on complication rates was assessed using Fisher exact tests. Zero patients required reoperation within 30 days. One intracranial hemorrhage was detected on immediate postoperative head computed tomography. Four patients ultimately required revision: 2 for catheter repositioning to alleviate abdominal pain, 1 ligation for a colectomy, and 1 removal for shunt infection. Patients with cardiac or other neurological comorbidities had higher rates of readmission and complications. Systemic complications totaled 12% in the first 30 days. The combination of intraoperative stereotactic navigation and laparoscopic assistance leads to low rates of serious complications and reoperations for VP shunt implantation in patients with NPH. These changes to surgical technique are easy to implement and may reduce the risk for this common operation.

DDEL-05. Intraventricular therapy with topotecan is feasible and safe: Experience in 50 pediatric patients with various malignant brain tumors

BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (>1 and <2 years 0.25mg, >2 and <3 years 0.32mg). RESULTS: In total, 1168 doses of topotecan (1-87/patient, mean 23, median 18) were administered at our department. Treatment was given over a period of 0-65 months (mean and median 33 months). Intraventricular treatment with topotecan was generally well tolerated. Two patients reported side effects. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after intraventricular administration of topotecan, another girl with recurrent medulloblastoma reported fatigue. CONCLUSION: Intraventricular therapy with topotecan is feasible and generally well tolerated. Topotecan can be an important addition for patients with recurrent malignant brain tumors to increase cytotoxic drug concentrations in CSF.

DDEL-03. The use of programmable valves as a vehicle for intrathecal chemotherapy delivery in infants with CNS tumors and hydrocephalus.

INTRODUCTION: Current chemotherapy protocols for treatment of embryonal brain tumors in infants recommend administration of intrathecal chemotherapy either by a lumbar tap or via an Ommaya reservoir. Children with concurrent hydrocephalus and shunts may have sub-therapeutic levels of chemotherapy in the CSF due to constant CSF drainage to extra-CNS compartments. We present our experience in delivery of chemotherapy to young children via programmable valves. RESULTS: A retrospective analysis of infants with CNS malignancies and hydrocephalus treated with a shunt and a programmable valve (CERTAS™ Plus Programmable Valves - Integra Life Sciences) was conducted. Five infants 1.1-3 years of age (mean 2) were included. Pathologies included atypical teratoid rhabdoid tumor (ATRT N=2), medulloblastoma (N=2), and metastatic rhabdomyosarcoma(N=1). Intrathecal injections were conducted in an outpatient setting unless hospitalization was required for other reasons. Only one child required sedation due to noncompliance. A total of 61 chemotherapeutic administrations were performed directly through the valve while set on an extremely high opening pressure for several hours( 35 with hydrocortisone and cytarabine, 26 with topotecan). There were no infections, leaks or major complications. One child required a wound revision due to exposure of the proximal catheter related to extremely thin skin, one child developed somnolence and fever which were not related to a shunt malfunction or infection, and one child had clinical and radiological shunt over-drainage solved by increasing of valve settings. CONCLUSIONS: Programmable ventriculoperitoneal valves appear to a safe method for delivery of chemotherapy in infants with malignant CNS tumors .This technique may potentially have an added value for children with concurrent shunts, and may also obviate the need for an additional ventricular access device .