bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-45. CUSTOMIZED LIPID NANOPARTICLES DELIVER NUCLEIC ACIDS TO IMMUNE CELLS IN BRAIN TUMORS
Authors: Grippin Adam , Wummer Brandon , Mendez-Gomez Hector , Wildes Tyler , Dyson Kyle , Dobson Jon , Mitchell Duane , Sayour Elias 
Published: December 2020

Abstract

BACKGROUND
Brain tumors are notoriously difficult to treat in part due to their isolation behind the blood brain barrier and their power to suppress antitumor immune responses. We have previously reported cationic liposome formulations capable of delivering immune modulatory nucleic acids to immune cells in various peripheral organs, but there is currently no reliable method to deliver nucleic acids into brain tumors without direct injection into the tumor site.

OBJECTIVE
Here, we report the development of a customized lipid nanoparticle to deliver immune modulatory nucleic acids to immune cells in brain tumors.

APPROACH
Cationic liposomes composed of varying lipid combinations were evaluated for their ability to deliver functional mRNA and siRNA to innate immune cells in vitro and in intracranial tumor models. Nucleic acids were labelled with Cy3 to monitor particle distribution in vivo.

RESULTS
Lipids composed of DOTAP and cholesterol selectively delivered mRNA and siRNA to intracranial GL261 and KR158b tumors. Interestingly, these particles selectively delivered these nucleic acids to CD45+ white blood cells with minimal delivery to CD45- tumor cells or normal brain tissue. Encapsulation of siRNA blocking programmed death ligand 1 (PDL1) significantly reduced PDL1 expression on innate immune cells in brain tumors, with the greatest effects on tumor-associated macrophages. Co-administration of systemic checkpoint blockade with intravenous administration of these lipid nanoparticles bearing PDL1 siRNA enabled systemic and intratumoral checkpoint blockade, leading to 37% long term survivorship in an otherwise fatal intracranial tumor model.

CONCLUSIONS
Our customized lipid nanoparticles enable potent intratumoral immune modulation via delivery of nucleic acids to immune cells in brain tumors.
IMMU-46. LINEAGE DEPLETED HEMATOPOIETIC STEM CELLS POTENTIATE IMMUNE CHECKPOINT RESPONSE TO ANTI-PD1 AND ANTI-CD276 IN MURINE GLIOMA
Authors: Larkin Trisha , Cruz Marjorie , Flores Catherine 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma multiforme (GBM) is a malignant brain tumor with rapid growth and infiltration, high treatment resistance, and dismal survival. Intratumoral heterogeneity and poor CNS penetration contribute to treatment resistance. Flores et al. demonstrated that hematopoietic stem cell transfer could reprogram gene expression within the tumor microenvironment, sensitizing glioma-bearing mice to treatment with immune checkpoint blockade. The objectives of this study are to expand on the role of HSCs in potentiating efficacy to immune checkpoint blockade with anti-PD1 and anti-CD276.

METHODS
KR158B murine glioma cells were implanted into the caudate nucleus of C57BL/6 mice. Hematopoietic stem cells were derived from naïve syngeneic mice and lineage depleted using the CliniMacs system. On Day 5, HSCs (105cells) were administered. Anti-CD276 and PD-1 monoclonal antibodies were administered every five days for a total of four dose administrations. Mice to allocated to no treatment, anti-CD276 only, or HSCs with or without PD1 and anti-CD276. Groups were followed for survival. Data was analyzed with GraphPad Prism.

RESULTS
The combination of lineage depleted HSCs + anti-CD276led to increased median survival when compared to the survival of mice treated with anti-CD276 monotherapy with the mice who received the combination surviving for a median of 62 days versus 36 days (p = 0.001, CI 0.204 to 1.655). The combination of HSCs + PD-1 therapy led to increased median survival of 60 days and long-term survivors, replicating prior findings from our group. Mice treated with HSC transfer, anti-B7-H3, and anti-PD-1 demonstrated a median survival of 76 days (p = 0.037).

CONCLUSION
We demonstrate a compounded survival effect when anti-B7-H3 and anti-PD1 were administered together with lineage depleted HSCs, suggesting an expanded avenue for overcoming treatment resistance. Future studies will be important to characterize the immune effects of combinatorial immune checkpoint administration with adjuvant HSC transfer.
IMMU-48. CD4+ T CELLS RESTRICT MEDULLOBLASTOMA GROWTH AND DISSEMINATION
Authors: Eisemann Tanja , Wechsler-Reya Robert 
Published: December 2020

Abstract
The immune system serves as a powerful defense not only against pathogens and parasites but also against neoplastic cells. Emerging immunotherapies that boost the activity of tumor-reactive immune cells or counteract immune suppressive mechanisms have shown promising effects in certain types of cancer. However, the success of immunotherapy for brain tumors has been limited, highlighting the need for a better understanding of the immune microenvironment in these tumors. Our previous studies have shown that T cells critically affect growth of the pediatric brain tumor medulloblastoma. In particular, depletion of CD4+ T cells results in more aggressive growth of medulloblastoma cells and allows these cells to metastasize to the spinal cord. The anti-tumoral effects of CD4+ T cells are not due to their function as helpers for CD8+ cytotoxic T cells, since CD8+ T cell depletion did not enhance tumor growth to the same extent as CD4+ T cell depletion. To test whether CD4+ T cells can recognize MHC class II molecules on tumor cells and attack these cells directly, we generated tumors from MHC class II knockout mice. Surprisingly, depletion of CD4+ cells in these animals still enhanced tumor growth and metastasis. These results suggest that CD4+ T cells regulate medulloblastoma growth and metastasis in a manner that is independent of CD8+ T cells and independent of MHC-II on tumor cells. Ongoing studies are aimed at elucidating the mechanisms by which CD4+ T cells regulate medulloblastoma growth, including the antigen-presenting cells that activate them and the effector cells responsible for killing tumor cells following their activation. These studies will advance our understanding of the immune microenvironment in medulloblastoma and allow us to design more effective therapies for controlling tumor growth and metastasis.
INNV-02. RADIOGRAPHIC CHARACTERISTICS AND STEROID USAGE IN LASER INTERSTITIAL THERMAL THERAPY VERSUS MEDICAL MANAGEMENT FOR BIOPSY-PROVEN RADIATION NECROSIS AFTER STEREOTACTIC RADIOSURGERY OF BRAIN METASTASES
Authors: Srinivasan Ethan , Sankey Eric , Grabowski Matthew , Griffin Andrew , Howell Elizabeth , Otvos Balint , Tsvankin Vadim , Atik Ahmet , Joshi Krishna , Barnett Gene , Fecci Peter , Mohammadi Alirezza 
Published: December 2020

Abstract

INTRODUCTION
Radiation necrosis (RN) occurs in 9–14% of patients after stereotactic radiosurgery (SRS) for brain metastases (BM). Medical management (MM) with steroids is a common first-line therapy, with variable response and numerous side effects, especially regarding immunotherapy. Laser interstitial thermal therapy (LITT) has been introduced as an efficacious, steroid-reducing alternative, however limited data exists comparing LITT to MM.

METHODS
Patients with biopsy-proven RN after SRS for BM who received LITT or MM at two academic centers were retrospectively reviewed. Treatment failure was defined as radiographic progression that necessitated a change in management. Measurements of total (TLV) and contrast-enhancing lesion volume (ceLV) were obtained from MRI by semi-automated analysis using the BrainLab iPlan Cranial 3.0 software.

RESULTS
Eighty-one patients were followed for 11.7 (4.3–27.0) months and 57 (70%) received LITT. Steroid cessation occurred at a median of 37 days post-LITT compared to 162 days after MM (p&lt; 0.01). Treatment failure occurred in 5% of LITT patients at 4.0 (3.2–4.8) months and 13% of MM patients at 4.4 (4.1–5.3) months (p &gt;0.05). Patients were 3.2 times more likely to be weaned off steroids when treated with LITT compared to MM (p&lt; 0.01), when controlled for age, pre-operative ceLV, and post-operative seizure on multivariate analysis. Both groups demonstrated decreasing TLV and ceLV between baseline and last follow-up MRI. At 6–9 months, the LITT cohort demonstrated a -59% change in ceLV compared to -7% with MM (p &gt;0.05). The LITT cohort demonstrated a significant decrease in ceLV between scans at 0–2 and 6–9 months (p&lt; 0.01). The MM group did not demonstrate a statistically significant decrease in ceLV until 12 months.

CONCLUSION
This study suggests that LITT for RN significantly reduces the time to steroid cessation, and earlier radiographic response to treatment by LITT. Large, prospective trials are needed to validate these findings.
INNV-03. EFFICACY AND LONG-TERM OUTCOMES IN THE MANAGEMENT OF LARGE BRAIN METASTASIS (≥ 4 CM3) USING 2-STAGED STEREOTACTIC RADIOSURGERY (2-SSRS): AN INTERNATIONAL STUDY
Authors: Hori Yusuke , Yomo Shoji , Wei Wei , Avecillas-Chasin Josue , Barnett Gene , Suh John , Chao Samuel , Murphy Erin , Mohammadi Alireza , Angelov Lilyana 
Published: December 2020

Abstract

INTRODUCTION
Stereotactic radiosurgery (SRS) for brain metastases results in time-to-local failure (TTLF) that significantly correlates with target volume and prescription dose. For large brain metastases (LBM), defined as ≥ 4 cm3, SRS monotherapy can result in &lt; 40% local control (LC) rates. To overcome the TTLF limitations in the management of LBM, 2-staged SRS (2-SSRS) has demonstrated 6-month LC rates of 85–90%. This international multi-institutional study represents the largest series of patients with LBM managed with 2-SSRS.

METHODS
181 patients with 218 LBM treated with 2-SSRS were retrospectively reviewed. Local failure (LF) was defined as ≥ 71.5% volumetric increase (equivalent to ≥ 20% increase in maximum diameter; RECIST criteria) from smallest volume date. Kaplan-Meier and log-rank tests were used to estimate and compare overall survival (OS) and TTLF; multivariable analysis was performed using Cox regression model.

RESULTS
Median age was 63 years (range: 29‒88), male sex was 50.3% with 34.8% of patients having non-small cell lung cancer. Median follow-up was 13.8 months (range:1.1‒49.4) and median OS was 14.6 months (95%CI: 12.6‒17.0). Median TTLF was 27.9 months (95%CI: 17.9‒NA) with a cumulative 6, 12 and 24-month LC of 91%, 81% and 71%, respectively. Using multivariable analysis, older age (≥ 65 years old; HR 1.58, 95%CI 1.06‒2.35, p=0.02) and larger total volume of concurrent small lesions (&gt; 3 cm3; HR 2.05, 95%CI 1.25‒3.39, p=0.005) negatively impacted OS while younger age (&lt; 65 years old; HR 2.60, 95%CI 1.26‒5.34, p=0.01) and RPA Class 3 (HR 3.10, 95%CI 1.26‒7.65, p=0.01) decreased TTLF. The number of concurrent LBM treated and total volume of the LBM were not significant factors.

CONCLUSIONS
This large multi-institutional dataset demonstrates excellent efficacy and long-term control of LBMs treated with 2-SSRS, which is independent of number or total volume of concurrent LBM.
INNV-20. ELEVATED INTRACRANIAL PRESSURE WITHOUT HYDROCEPHALUS IN PATIENTS WITH NEUROFIBROMATOSIS 2
Authors: Robell Lindsay , Harrison Rebecca , Sinicrope Kaylyn , Slopis John , McCutcheon Ian 
Published: December 2020

Abstract

BACKGROUND
Neurofibromatosis 2 is a tumor predisposition syndrome associated with multiple tumors of the central and peripheral nervous systems. Schwannomas and meningiomas are commonly observed. The occurrence of communicating hydrocephalus in this population has been observed clinically but not characterized in the literature.

METHODS
We present a retrospective case series of patients with NF2 and communicating hydrocephalus followed in the Neurofibromatosis clinic at MD Anderson Cancer Center.

RESULTS
We identified 11 patients in our Neurofibromatosis clinic with symptomatic elevation in intracranial pressure (ICP). All patients presented with worsening headaches, while six patients also presented with visual complaints leading to the diagnosis of elevated ICP. Dedicated venous imaging with either MRV or CTV was available for review in five patients. Occlusion or stenosis of the venous system (dural venous sinuses or internal jugular vein) was seen in nine patients. All patients had evidence of plaque-like meningiomas, and two patients had cervical schwannomas. Only one patient had radiographic evidence of obstructive hydrocephalus. All patients were treated for symptomatic elevated ICP with placement of a ventriculoperitoneal (VP) shunt. Three patients received acetazolamide prior to shunting, while one patient received acetazolamide after shunt placement. Seven (7/11) patients had documented improvement or resolution of headache after VP shunt placement. Two (2/6) patients had documented improvement or resolution of visual complaints.

CONCLUSIONS
We present 11 patients with NF2 who developed symptomatic elevation in ICP, ten patients without evidence of obstructive hydrocephalus and one with obstructive hydrocephalus. We hope to raise awareness of this clinical phenomena, previously uncharacterized in the literature. We propose a multifactorial mechanism involving plaque-like meningiomas, venous sinus stenosis, obstruction of cerebral venous outflow and cervical/jugular schwannomas in the development of symptomatic elevated ICP without evidence of obstructive hydrocephalus in patients with NF2.
INNV-27. BT-LIFE (BRAIN TUMOURS, LIFESTYLE INTERVENTIONS, AND FATIGUE EVALUATION): LESSONS LEARNED FROM RUNNING A NOVEL MULTI-SECTORAL RESEARCH TRIAL
Authors: G Rooney Alasdair , Hewins William , Walker Amie , Withington Lisa , Mackinnon Mairi , Robson Sara , Green Aimee , Anderson Garry , Bulbeck Helen , Torrens Claire , Emerson Julie , Dunlop Jo , Welsh Michelle , McEleney Tracy , Hopcroft Lisa , Wells Mary , McBain Catherine , Chalmers Anthony , Grant Robin 
Published: December 2020

Abstract

BACKGROUND
BT-LIFE is a multi-centre RCT of novel lifestyle coaching treatments for fatigued brain tumour patients. To our knowledge it is also the first example of ‘multi-sectoral research’ to combine healthcare, private, and charity sectors in this population. To maximise learning, the trial team devised a structured reflection opportunity to ask, “What went well and what would we do differently next time?”

METHOD
After trial closedown we convened a six-hour ‘focus group’ for management, principle investigators, research assistants, interventionists, qualitative researchers, trial statisticians, and the funder. Discussion was structured using a ‘timeline’ wall-chart which attendees freely populated with post-it notes summarising learning points from the trial. Minutes were taken in duplicate.

RESULTS
In total n=19 team members contributed. Many points were study-specific and will be used internally to plan a larger trial. Among points of wider interest, examples of success included: using regular teleconferences to co-ordinate a cohesive and highly collaborative team; obtaining secure nhs.net email addresses to facilitate multi-sectoral communication; and the clear value of employing one part-time research assistant per centre instead of relying on busy clinical staff to recruit. General future learning points included: speak to the prospective sponsor and ethical committees when writing the grant application to avoid pitfalls and facilitate faster opening if funding is secured; consider preceding emails with a phone call to ‘lay the ground’ in time-sensitive situations; identify staff training requirements as early as possible and cascade aggressively; and be sensitive to the fact that inter-sectoral attitudes and practices may vary widely and need actively monitored and managed. Therefore frequent and secure communication, pro-active problem-spotting, and inter-sectoral value alignment appear critical for success.

CONCLUSION
BT-LIFE provides many useful lessons for anyone interested in running multi-sectoral research.
NCMP-02. CEREBRAL SPINAL FLUID (CSF) PREDICTORS OF DEVELOPING DISSEMINATED NECROTIZING LEUKOENCEPHALOPATHY IN LEPTOMENINGEAL CARCINOMATOSIS (LMC): A SINGLE INSTITUTIONAL REVIEW
Authors: Yu Charles , Lin Irene , Leese Erika , Gatson Na Tosha 
Published: December 2020

Abstract

BACKGROUND
LMC is a rare complication of systemic cancer metastasis to the leptomeninges. Although first described in 1870 treatment options remain few for this rapidly fatal condition commonly excluded from clinical trials and disease site guideline updates. Whole brain radiation therapy (WBRT) and intrathecal (IT) chemotherapy are commonly employed and there is growing evidence for systemic therapies that cross the blood brain barrier. Disseminated necrotizing leukoencephalopathy (DNL) is a self-limited rare treatment-related radiographic finding variably associated with clinical decline and often misdiagnosed as progression or infection. DNL has been reported in patients exposed to IT chemotherapy and CNS irradiation. Our lab recently published improved LMC control with extended survival after standardization of Ommaya clinic IT treatment regimens, although with increased incidence of DNL.

METHODS
We retrospectively analyzed patients with LMC treated with IT chemotherapy after WBRT between 2017 – 2020. We reviewed sequential brain imaging over the treatment course to determine if there were predictive CSF markers associated with the development of DNL.

RESULTS
Of the 41 patients evaluated, 24% (n=10) developed DNL at a median 24-weeks after start of IT chemotherapy and WBRT. Of the patients with radiographically assessed DNL, 80% (n=8) experienced elevated CSF protein and 40% (n=4) had elevated white blood cells within 8-weeks prior to radiographic determination of DNL. Cytology remained benign and glucose was not significantly changed prior to DNL development.

CONCLUSION
Given the poor outcome of LMC, there is a need for treatment standardization and better understanding of treatment-associated radiographic changes. Evaluation of CSF markers to predict impending development of DNL in this treatment population might limit radiographic misdiagnoses and patient clinical decline as well as offer a potential window of opportunity for treatment de-escalation.
NCMP-06. METASTATIC CENTRAL NERVOUS SYSTEM DISEASE SECONDARY TO BURKITT LYMPHOMA IN A PATIENT WITH PRIOR HISTORY OF MELANOMA
Authors: Momah Uju , Brewer Jennifer , Tran Anthony , Shapiro David 
Published: December 2020

Abstract
Sporadic Burkitt’s Lymphoma accounts for only 1–2% of Non Hodgkin’s Lymphoma, and metastasizes to the central nervous system (CNS) is uncommon, occurring in about 13–17% of adult patients. 1 Melanoma is far more likely to metastasize to the CNS, occurring in about 37% of adult patients.2 Here we present the case of a 69 year old Gambian female with a prior medical history of plantar melanoma. She initially presented to her primary care provider with back pain and adenopathy, and was referred to surgical consultation for diagnosis and concern for recurrent melanoma. Her workup revealed metastatic Burkitt’s Lymphoma with disease in the abdomen, lungs and likely CNS involvement. This report chronicles her disease course and approach to management.
NCMP-12. RAPIDLY PROGRESSIVE NEUROPATHIES AS THE SOLE PRESENTATION OF NEUROLYMPHOMATOSIS
Authors: Guillermo Prieto Eibl Pilar , Rayi Appaji , Alnahhas Iyad , Giglio Pierre , Epperla Narendranath 
Published: December 2020

Abstract
Neurolymphomatosis (NL) is a rare and challenging entity characterized by hematological neoplastic infiltration of the peripheral nervous system. Only 40% of the cases have malignant cells on CSF sampling. We present a 52-year-old Caucasian male with primary refractory diffuse large B-cell lymphoma (DLBCL) who relapsed within 3 months of achieving complete remission to R-CHOP. First, he experienced right tongue numbness and lumbar pain. Initial MRI of the face, brain and entire spine, and CSF analysis were unremarkable. Three weeks later, he noticed left facial numbness, dysphonia, and left leg weakness. Neuraxis MRI revealed enhancement of left CN V3 and several cervical, thoracic, and lumbar nerve roots. PET/CT showed increased uptake at L4 nerve root. EMG/NGS showed left L5 denervation. After one week, he further developed new right CN VI palsy, left-sided ptosis, anisocoria, and right arm weakness. Repeat MRI showed worsening enhancement and thickening of multiple cranial nerves, cervical and lumbosacral plexus. Extensive testing for infectious, inflammatory, and paraneoplastic processes was negative. Patient underwent plasmapheresis with no response. Biopsy of nerve root was deferred due to potential permanent deficits that would impair his quality of life. Repeat CSF testing was negative for malignancy and PET/CT showed SUV of 23.8 at L4-5 with multiple new hypermetabolic foci in muscle and ribs. He received R-HD-methotrexate with clinical and radiographic (PET/CT) improvement following 2 cycles. He completed 4 cycles of R-HD methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation. Most of his symptoms resolved and he remained stable for about a year when PET/CT showed disease progression. He subsequently received CAR-T cell therapy with adequate tolerance and remains clinically stable. Even with negative initial imaging and CSF studies, a careful exam and attention to uncommon presentations along with serial advanced imaging (MRI, PET/CT) surveillance are key to early detection and timely treatment.
NCMP-22. SECOND MALIGNANCIES FOLLOWING TREATMENT FOR PRIMARY CENTRAL NERVOUS SYSTEM TUMORS IN PEDIATRIC PATIENTS: A SINGLE-INSTITUTIONAL RETROSPECTIVE REVIEW
Authors: Pytel Nicholas , Dedekam Erik , Salamat Shahriar M , Puccetti Diane 
Published: December 2020

Abstract
Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.