Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse

Background The blood-cerebrospinal fluid (CSF) barrier (BCSFB) is critically important to the pathophysiology of the central nervous system (CNS). However, this barrier prevents the safe transmission of beneficial drugs from the blood to the CSF and thus the spinal cord and brain, limiting their effectiveness in treating a variety of CNS diseases. Methods This study demonstrates a method on SD rats for reversible and site-specific opening of the BCSFB via a noninvasive, low-energy focused shockwave (FSW) pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg), posing a low risk of injury. Results By opening the BCSFB, the concentrations of certain CNS-impermeable indicators (70 kDa Evans blue and 500 kDa FITC-dextran) and drugs (penicillin G, doxorubicin, and bevacizumab) could be significantly elevated in the CSF around both the brain and the spinal cord. Moreover, glioblastoma model rats treated by doxorubicin with this FSW-induced BCSFB (FSW-BCSFB) opening technique also survived significantly longer than untreated controls. Conclusion This is the first study to demonstrate and validate a method for noninvasively and selectively opening the BCSFB to enhance drug delivery into CSF circulation. Potential applications may include treatments for neurodegenerative diseases, CNS infections, brain tumors, and leptomeningeal carcinomatosis.

Clinical Trial Eligibility Criteria and Recently Approved Cancer Therapies for Patients With Brain Metastases

Brain metastases cause significant morbidity and mortality in patients with advanced cancer. In the era of precision oncology and immunotherapy, there are rapidly evolving systemic treatment options. These novel therapies may have variable intracranial efficacy, and patients with brain metastases remain a population of special interest. Typically, only patients with stable, asymptomatic and/or treated brain metastases are enrolled in clinical trials, or may be excluded altogether, particularly in the setting of leptomeningeal carcinomatosis. Consequently, this leads to significant concerns on the external validity of clinical trial evidence to real-world clinical practice. Here we describe the current trends in cancer clinical trial eligibility for patients with brain metastases in both early and late phase trials, with a focus on targeted and immunotherapies. We evaluate recent newly FDA approved therapies and the clinical trial evidence base leading to approval. This includes analysis of inclusion and exclusion criteria, requirements for baseline screening for brain metastases, surveillance cerebral imaging and incorporation of trial endpoints for patients with brain metastases. Finally, the use of alternative sources of data such as real-world evidence with registries and collaborative studies will be discussed.

Multifocal spinal glioblastoma and leptomeningeal carcinomatosis in an elderly male with hydrocephalus and myelopathy

Background: Primary spinal glioblastoma multiforme with multifocal leptomeningeal enhancement is rarely diagnosed or documented. We describe a rare case of multifocal spinal isocitrate dehydrogenase (IDH) wild type glioblastoma with leptomeningeal carcinomatosis in an elderly male presenting with a chronic subdural hematoma, progressive myelopathy, and communicating hydrocephalus. Case Description: A 77-year-old male with a medical history of an acoustic schwannoma, anterior cranial fossa meningioma, and immune thrombocytopenic purpura presented with right-sided weakness after repeated falls. Magnetic resonance imaging of the brain and spine demonstrated a left-sided subdural hematoma, leptomeningeal enhancement of the brain and skull base, ventricles, and the cranial nerves, and along with florid enhancement of the leptomeninges from the cervicomedullary junction to the cauda equina. Most pertinent was focal thickening of the leptomeninges at T1 and T6 with mass effect on the spinal cord. A T6 laminectomy with excisional biopsy of the lesion was planned and completed. Findings were significant for glioblastoma the World Health Organization Grade IV IDH 1 wild type of the thoracic spinal cord. Subsequently, his mental status declined, and he developed progressive hydrocephalus which required cerebrospinal fluid diversion. Unfortunately, the patient had minimal improvement in his neurological exam and unfortunately died 2 months later. Conclusion: In a review of the limited literature describing similar cases of primary spinal glioblastoma, the prognosis of this aggressive tumor remains unfavorable, despite aggressive treatment options. The purpose of this report is to increase awareness of this rare condition as a potential differential diagnosis in patients presenting with multifocal invasive spinal lesions.

Successful Remedy With Osimertinib in a Patient of Thr790Met-positive Non-small Cell Lung Cancer With Leptomeningeal Carcinomatosis and Resistant to Gefitinib

Patients of non-small cell lung cancer (NSCLC) with activated EGFR mutations is more apt to develop leptomeningeal metastasis (LM) than the other types of lung cancers [1]. Examination of circulating tumor DNA (ctDNA) in cell-free cerebrospinal fluid (CSF) has been shown to be useful in detecting the genomic mutations of tumors in central nervous system (CNS) and has also been used to monitor tumor progression and evaluate the response to treatments [2]. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is considered to be a recent standardized treatment for EGFR Thr790Met-mutant NSCLC because of its good efficacy in both systemic and CNS metastasis [3].

CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

INNV-01. THE CASE OF LEPTOMENINGEAL CARCINOMATOSIS RELATED HYDROCEPHALUS MANAGED WITH SYSTEMIC AND INTRATHECAL CHEMOTHERAPY

INTRODUCTION Leptomeningeal carcinomatosis (LC) is an end-stage sequela of metastatic cancer that commonly leads to severe neurological symptoms due to hydrocephalus and commonly treated with surgery or radiation. As these procedures are invasive and have associated risks, chemotherapy could be a great alternative. We report a case of a hydrocephalus related to LC in a patient with Stage IV breast cancer that resolved after the administration of HD-MTX and intrathecal cytarabine. CASE A 64-year-old right-handed woman with Stage IV ER positive, PR positive, HER2 negative invasive lobular carcinoma of the left breast on chemotherapy with palbociclib and alpelisib who presented with mild occipital headaches, diplopia and imbalance. Imaging revealed an extensive abnormal leptomeningeal enhancement withing the posterior fossa compatible with leptomeningeal carcinomatosis. CSF cytology was consistent with metastatic adenocarcinoma. Liquid biopsy detected circulating tumor cells. During the admission for the cycle 1 of systemic chemotherapy with HD-MTX and intrathecal cytarabine, neurological status deteriorated as she became stuporous due to the newly developed moderate obstructive and communicating hydrocephalus. Surgical innervation was considered but given her response to serial Ommaya taps and dexamethasone, we proceeded with observation. Symptomatic improvement was noted within few days and confirmed on imaging showing the resolution of previously seen hydrocephalus. DISCUSSION This case highlights the role of non-invasive combination of systemic and intrathecal chemotherapy in patients with LC-related hydrocephalus aimed to preserve patient’s quality of life. No relevant disclosures.

Unilateral Oculomotor Nerve Palsy Associated with Leptomeningeal Carcinomatosis and Intracranial Hypertension

Meningeal carcinomatosis is caused by cancer cells invading the meninges and can cause cranial nerve palsies or intracranial hypertension. Intracranial hypertension can present various symptoms such as headache, visual loss, diplopia and may rarely include unilateral cranial nerve palsy. We report a 57-year-old female with leptomeningeal carcinomatosis and intracranial hypertension who presented as unilateral oculomotor nerve palsy.