bluuebunny/crossref_metadata_2025_split huggingface dataset:
BSCI-12. Inhibition of melanoma brain metastasis by targeting miR-146a
Authors: Wang Jiwei , Rigg Emma , Lunavat Taral R , Zhou Wenjing , Feng Zichao , Hoang Tuyen , Bjerkvig Rolf , Thorsen Frits 
Published: August 2021

Abstract

Background
Melanoma has the highest propensity of any cancer to metastasize to the brain, with late-stage patients developing brain metastasis (MBM) in 40% of cases. Survival of patients with MBM is around 8 months with current therapies, illustrating the need for new treatments. MBM development is likely caused by molecular interactions between tumor cells and the brain, constituting the brain metastatic niche. miRNAs delivered by exosomes released by the primary tumor cells may play a role in niche establishment, yet the mechanisms are poorly understood.
Here, the aim was to identify miRNAs released by exosomes from melanomas, which may be important in niche establishment and MBM progression.

Materials and Methods
miRNAs from exosomes collected from human astrocytes, melanocytes, and MBM cell lines were profiled to determine differential expression. Functional in vitro validation was performed by cell growth and migration assays, cytokine arrays, qPCR and Western blots. Functional in vivo studies were performed after miR knockdown in MBM cell lines. An in silico docking study was performed to determine drugs that potentially inhibit transcription of miR-146a to impede MBM development.

Results
miR-146a was the most upregulated miRNA in exosomes from MBM cells and was highly expressed in human and animal MBM samples. miR-146a mimics activated human astrocytes, shown by increased proliferation and migration, elevated expression of GFAP in vitro and in mouse brain tumor samples, and increased cytokine production. In animal studies, knockdown of miR-146a in MBM cells injected intracardially into mice reduced BM burden and increased animal survival. Based on the docking studies, deserpidine was found to be an effective inhibitor of MBM growth in vitro and in vivo.

Conclusions
MiR-146a may play an important role in MBM development, and deserpidine is a promising candidate for clinical use.
BSCI-14. tGLI1 is an actionable therapeutic target in breast cancer brain metastases
Authors: Doheny Daniel , Manore Sara , Wong Grace , Zhu Dongqin , Sirkisoon Sherona , Rimkus Tadas , Anguelov Marlyn , Aguayo Noah , Regua Angelina , Cox Anderson O’Brian , Furdui Cristina , Thomas Alexandra , Masters Adrianna Henson , Strowd Roy , Lo Hui-Wen 
Published: August 2021

Abstract
Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive a median of 14.1 months following diagnosis. Cancer stem cells are thought to be one of the driving forces behind distant metastasis, treatment resistance, and late-stage recurrence. Despite advances made in understanding breast cancer stem cells (BCSC), it remains challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. The hedgehog-smoothened pathway is an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting smoothened have demonstrated limited clinical efficacy in breast cancer. Truncated glioma-associated oncogene homolog 1 (tGLI1) was discovered in our laboratory as an alternative GLI1 splice variant that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. Our laboratory recently reported that tGLI1 promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64–78, 2020). tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. This study aimed to determine if tGLI1 can be therapeutically targeted. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, and novel derivatives specifically inhibit tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Mechanistic studies suggest that KCZ-dependent cell kill is, in part, mediated through downregulation of tGLI1 target genes OCT4, Nanog, and VEGFA. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier (BBB) and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis demonstrates ketoconazole crosses the blood-tumor barrier and that tGLI1 expression correlates with tGLI1 signaling in resected samples. Collectively, these data establish tGLI1 as an actionable target for BCBM.
BSCI-19. Therapeutic intervention of lung-, breast-, and melanoma-brain metastasis
Authors: Kieliszek Agata , Bassey-Archibong Blessing , Venugopal Chitra , Singh Sheila 
Published: August 2021

Abstract

Background
The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumours. BM predominantly originate from primary lung, breast, and melanoma tumours with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM.

Methods
Using a large in-house biobank of patient-derived BM cell lines, the Singh Lab has generated murine orthotopic patient-derived xenograft models of BM and captured a “premetastatic” population of BM cells that have just seeded the brains of mice before forming clinically detectable tumours: a cell population that is impossible to detect in human patients but represents a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable tumours.

Results
RNA sequencing of pre-metastatic BM cells from all three primary tumour models with subsequent Connectivity Map analysis identified a lead compound that exhibits selective anti-BM activity in vitro. Preliminary in vivo work has shown that this lead compound reduces the tumor burden of treated mice compared to vehicle control while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BM phenotype.

Conclusion
Therapeutic targeting of premetastatic BM cells could prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients.
LMD-06. A NSCLC patient with leptomeningeal metastasis harboring rare EGFR mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report
Authors: Wang Hui , Shan Changguo , Hong Weiping , Wen Lei , Lai Mingyao , Cai Linbo 
Published: August 2021

Abstract
Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, He developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript’s submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patients with LM carrying EGFR G719S and L861Q. Aslo, it is recommended to consider performing leptomeningeal biopsy for precision treatment in NSCLC paiernts with leptomeningeal metastasis.
LMD-08. Precision medicine for Leptomeningeal Carcinomatosis: a case report
Authors: Sinicrope Kaylyn , Sturgeon Emily , Coombs Lennea , Ghiassi Mahan , Sun David , Rocca Renato La , Spalding Aaron 
Published: August 2021

Abstract
Leptomeningeal disease (LMD) is an aggressive late-stage event in cancer. It is rare in gynecological malignancies. We present a case of a patient diagnosed with cervical adenocarcinoma grade III, stage Ib1 who developed LMD treated with immunotherapy based on modern molecular medicine.
The patient is 61-year-old female diagnosed with locally advanced cervical adenocarcinoma in November of 2017 and was rendered without evidence of disease after combined chemotherapy and pelvic irradiation. One year after initial treatment, she was found to have a solitary right cerebellar lesion on MRI for which she underwent gross total resection followed by stereotactic radiosurgery to the resection cavity. The pathology of the lesion was consistent with metastatic carcinoma of cervical primary. Next generation sequencing was performed on the brain metastasis tissue and was notable for a high tumor mutational burden (tTMB-high). One year after surgery she developed left arm weakness, and vertical diplopia. She underwent MRI of the brain and spine that demonstrated new nodular enhancement within the folia of the vermis and multi-level leptomeningeal enhancement in the cervical spine, consistent with LMD. She was treated for LMD with radiation to the whole brain and cervical spine. Radiation was followed with single-agent Pembrolizumab due to the reported response in cancer patients with tTMB-high status to immunotherapy. She is currently 6 months from her initial LMD diagnosis and is clinically stable with radiographic improvement.
This case presents an extremely rare complication of cervical cancer. It also highlights a unique treatment option for patients with LMD found to have tTMB-high status. Immunotherapy is of particular interest in cases of cervical adenocarcinoma as this cancer commonly has moderately-high TMB. Several studies have investigated the response of leptomeningeal disease to immunotherapy with variable results, though none have evaluated the response of tumors with tTMB-high.
LMD-15. Beyond cytologY - A single institution experience using CNSideTM for diagnosing and monitoring treatment response in Non-Small Cell Lung Cancer patients with Leptomeningeal Carcinomatosis (LMC)
Authors: Akerley Wallace , Puri Sonam , Chalmers Anna , Blouw Barbara , Boorgula Smitha , Schultz Robbie , Fisher Deanna , Dugan Michael , Mayer Julie 
Published: August 2021

Abstract

Introduction
Leptomeningeal Carcinomatosis (LMC) occurs in 3–9% of Non-Small Cell Lung Cancer (NSCLC) patients. Diagnosis of LMC includes clinical evaluation, imaging, and cytology. These have modest sensitivity and are inadequate for monitoring treatment response. Biocept’s CNSideTM is a proprietary assay utilizing a 10-antibody capture cocktail with microfluidic chamber that quantitatively detects tumor cells in the cerebrospinal fluid (CSF). Switch BlockerTM is a proprietary single gene assay that detects actionable mutations in the CSF. We describe a retrospective single institution experience using these assays in NSCLC patients with confirmed LMC or suspected LMC, treated between 2017 and 2021.

Methods
For fresh samples, CNSide and cytology were used to detect tumor cells, NGS and Switch Blocker was used to detect actionable mutations. Frozen samples were analyzed by NGS and/or Switch Blocker assays.

Results
CSF was collected from 30 samples (16 unique patients), of which frozen (8 unique patients) and fresh samples (8 unique patients; 5 with and 3 without LMC). CNSide detected tumor cells in 100% samples (10/10) vs cytology in 40% samples (4/10). Of those without LMC, neither CNSide nor cytology identified tumor cells. In patients with serial samples, CNSide tracked the clinical course. Analysis of frozen CSF by NGS identified mutations including EGFR in six (6), ALK in three (3) and BRAF in one (1) patient, which correlated with the primary tumor. The median survival from diagnosis of LMC for those with frozen samples was 71.6 weeks.

Conclusion
We demonstrate that 1) survival of patients with LMC can be prolonged, especially when an actionable target is identified, 2) CNSide has greater sensitivity in detecting LMC than cytology, and 3) quantitative monitoring of CSF tumor cells can be used to guide initial and subsequent therapies. Larger clinical trials are needed to better establish the utility of CNSide in managing LMC.
LMD-20. Immune Suppressive Macrophages and Signal Transducer and Activator of Transcription 3 (STAT3) Expression are common in Melanoma Leptomeningeal Disease
Authors: Najem Hinda , Marisetty Anantha , Horbinski Craig , Burks Jared , Heimberger Amy B 
Published: August 2021

Abstract
Leptomeningeal disease (LMD) in melanoma patients is associated with significant neurological impairments and has a dismal outcome with a median survival of 1.8 months. Despite the therapeutic benefit of targeted therapies and immunotherapies for most kinds of Stage IV melanoma, patients with LMD do not typically benefit. A deeper understanding of the tumor microenvironment (TME) of LMD may provide more appropriate therapeutic selection. A retrospective analysis of subjects who underwent surgical resection with LMD (n=8) were profiled with seven color multiplex to evaluate the expression of the global immune suppressive hub - the signal transducer and activator of transcription 3 (STAT3) and for the presence of CD3 T cells, CD68+ monocytes, CD163 immune suppressive macrophages, CD11c+ antigen presenting cells (APCs) in association with the melanoma tumor marker S100B and DAPI for cellular nuclear identification. High-resolution cellular imaging and quantification was conducted using the Akoya Vectra Polaris. CD163+ macrophage is the most frequent immune cell population in the LMD TME. Occasional CD3+ T cells and CD11c+ APC are also identified, although the latter has concurrent expression of CD163. STAT3 nuclear localization is heterogeneously expressed in the various immune cell populations. Occasional immune cluster interactions can be seen in the tumor stroma and the tumor edge. In conclusion, the TME of LMD is largely devoid of CD3+ T cells, but is enriched for immune suppression and innate immunity.
LMD-22. Clinicopathological spectrum of leptomeningeal metastases: A 3 year retrospective study
Authors: Pahwa Saloni , Sharma Anila , Kamboj Meenakshi , Mehta Anurag 
Published: August 2021

Abstract

Objectives
Cytological examination of cerebrospinal fluid is a widely used cost effective, simple procedure and a reliable routine diagnostic test. CSF cytology helps in detection of inflammatory diseases of the CNS, diagnosis of subarachnoid haemorrhage and the identification of malignant cells in metastatic or rarely primary CNS malignancies.Leptomeningeal metastases (LM) is estimated to occur in 5% of all patients with cancer. It has a higher propensity to occur in solid tumours compared to haematological malignancies.In view of poor prognosis, early diagnosis may aid in appropriate tumour staging and aggressive therapeutic intervention.

Methods
All the samples of CSF received in the Department of Laboratory for cytological examination and reported as ‘positive for malignant cells’ during the year January 2018 to December 2020were included in the study. All the cases were routinely evaluated on Neubauer’s chamber, direct smear and a cytospin preparation stained using MGG stain. The clinical records and any further ancillary testing performed were retrospectively analysed.

Results
87cases with LM were identified over 3 year duration. Mean age of presentation was 43 years. Metastatic solid malignancies (56%) had a higher incidence of leptomeningeal metastases compared to haematolymphoid malignancies (40%) and CNS medulloblastomas(2%). Most common solid tumour with involvement of CSF was adenocarcinoma lung (51%) followed by breast carcinoma (37%). Of all the cases of adenocarcinoma lung with LM, EGFR mutant NSCLC were 40% while 8% showed ALK gene rearrangement. Amongst the haematological malignancies, acute leukaemia’s constituted 67% of cases while systemic NHLs were 34%. Most of the cases (97%) presented with neurological symptoms during the course of treatment while 3 cases (3%) showed LM at the time of first presentation.

Conclusions
With appropriate clinicoradiological correlation, CSF cytology remains the gold standard for identification of malignant cells in cases with already known primary tumour (leptomeningeal dissemination of the disease). In this study, clinical features of both solid and haematolymphoid malignancies were evaluated. The group of solid malignancies included adenocarcinomas lung, breast, gastrointestinal tract and renal cell carcinoma. With the availability of EGFR TKIs and ALK inhibitors, overall survival of the patients may be prolonged with therapeutic interventions despite limited CSF and CNS penetration of these drugs.
OTHR-02. Engineered “of the shelf” allogeneic cellular therapies for metastatic brain tumors
Authors: Shah Khalid , Kitamura Yohei , Du Wanlu , Kanaya Nobu 
Published: August 2021

Abstract
Brain metastatic patients have multiple metastatic lesions or diagnostically challenging asymptomatic lesions, making surgery an inadequate therapeutic option. Given the challenges related to systemic delivery of a majority of therapeutic agents across the BBB, engineered cell based therapies offer an excellent platform to target metastatic tumors in the brain. We have established the use tumor cell surface receptor targeted allogeneic “off the shelf” gene engineered cellular therapies and developed two different approaches to treat brain metastases. In one approach, we have armed allogenic stem cells (SC) with oncolytic herpes virus (oHSV) variants and tested them in different mouse models of brain metastatic (BM) tumor derived from brain seeking metastatic melanoma tumor cells from patients. We show that intracarotid artery administration of SC-oHSV effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor bearing mice. We also show that a combination of SC-oHSV and PD-L1 blockade increases IFNγ-producing CD8+ tumor-infiltrating T lymphocytes and results in a profound extension of the median survival in syngeneic brain metastatic melanoma mouse models. In another approach, we have explored the versatility of cell mediated bi-functional EGFR and DR4/5-targeted treatment in basal like breast cancer (BLBC) mouse models featuring different patterns of brain metastasis. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL releasing allogeneic SCs alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. These findings provide a clinically applicable therapeutic platform to target disseminated metastatic lesions in the brain and define a new paradigm for treatment of brain metastases.
OTHR-04. Gynecological Malignancies With Metastasis To The Central Nervous System: A Case Series and Systematic Review of the Literature
Authors: Sajjad Azeem , Adesina Adeleso , Halkiadakis Penelope , Murphy Kelsey , Mulligan Kathleen , Labak Collin , Wijesekera Olindi , Hodges Tiffany 
Published: August 2021

Abstract

Introduction
Gynecologic malignancies are an increasingly common proportion of central nervous system metastatic disease. As genetic sequencing technology improves and becomes more accessible, mutations associated with CNS metastasis are easier to elucidate. The aims of this case series and systematic literature review are to describe the patient population with CNS metastatic disease from a gynecologic primary, and to investigate why the proportion of CNS metastasis from gynecologic malignancies is increasing. Ultimately, we hope to improve understanding of this subset of metastatic CNS malignancies and improve management strategies.

Methods
A literature review of articles describing patients from 1990–2020 who were diagnosed with CNS metastasis from a known gynecologic primary malignancy was performed. Demographics, cancer type, mutation characteristics, management for metastatic disease, progression free survival, number of CNS metastases, and location of metastatic disease were assessed. Inclusion criteria were age&gt;18 years, diagnosis of primary ovarian, uterine, or cervical cancer with confirmed metastatic disease to the CNS, including brain parenchyma, leptomeninges, or intradural spinal cord or dural metastases. Exclusion criteria included pediatric population and bony metastases (e.g., bony spine metastases without evidence of meningeal/parenchymal invasion).

Results
Our review showed that patients with gynecological metastasis to the CNS generally have worse outcomes regarding overall survival, progression free survival, and quality of life than patients without CNS metastasis.

Discussion
Our results infer that the reported increase in incidence of CNS metastasis from gynecologic malignancies is a reflection of improvement of detection given advances in technology, improved patient follow up, and increased overall survival of patients with gynecologic malignancies. Further characterization of mutations from gynecologic malignancies associated with brain metastasis could result in development of more treatment options for patients in the future and help determine factors that contribute to developing metastasis to the CNS of various degrees, thus, potentially inform treatment strategies.