bluuebunny/crossref_metadata_2025_split huggingface dataset:
HOUT-09. DEVELOPING OMMAYA CLINICS FOR LEPTOMENINGEAL CARCINOMATOSIS (LMC): STANDARDIZED TREATMENT, IMPACT ON SURVIVAL/NEUROLOGIC DISABILITY AND ROLE FOR ADVANCED PRACTITIONERS
Authors: Leese Erika , Manikowski Jesse , Mahadevan Anand , Conger Andrew , Mongelluzzo Gino , Tosha Gatson Na 
Published: November 2019

Abstract
Leptomeningeal carcinomatosis (LMC), first described in 1870, involves leptomeningeal and CSF invasion by neoplastic cells and portends poor survival. Among solid tumor LMC, breast cancer is the most common followed by lung and melanoma. With an estimated 100,000+ new cases yearly, the dual-edged sword of systemic treatment drives the increasing incidence as cancer patients live longer and on non-CNS penetrating therapies. Addition of immuno-oncotherapies has impacted LMC survival. At time of diagnosis, most patients have multiple neurologic disabilities. Multiple reports on the topic have not yielded consistent treatment standards to extend patient survival. Most agree that local CNS control coupled with systemic therapy offers the best survival. Still, there are few established Ommaya clinics (OC). Importantly, LMC is a common exclusionary criterion for clinical trials. A single institutional evaluation of 147 patients (2012–2019) with a diagnosis of LMC was completed. 69 of 147 were excluded, leaving 48 pre-OC and 30 OC patients. The mOS (weeks) of those treated with intrathecal chemotherapy (ITC) versus no ITC was compared between cohorts: pre-OC and OC (3.36, 15.29****). Average KPS at time of diagnosis in pre-OC and OC was 70–80 (ECOG 2–3). The mOS was compared between breast (5, 28*), lung (3, 3) and melanoma (5,10*) in the pre-OC and OC respectively. The treatment standardized for the OC includes whole-brain radiation, Ommaya reservoir placement, systemic treatment, treatment with ITC (2x weekly – q other month) and MR imaging every 3 months. Breast cancer patients fared the best followed by melanoma and lung patients in the OC. With use of advanced practitioners (APs), standardization of treatment and surveillance is achievable. Patients treated according to a standardized OC regimen experienced longer overall survival along with a 10% improvement in KPS after two months of treatment. Development of institutional OCs reduces treatment variability and increases clinical surveillance.
HOUT-10. TREATMENT OUTCOME IN ADOLESCENTS AND YOUNG ADULTS (AYAS) WITH GLIOBLASTOMA
Authors: An Josiah , Chennamadhavuni Adithya , Mott Sarah , Garje Rohan 
Published: November 2019

Abstract

BACKGROUND
Glioblastoma is one of the most aggressive and commonly encountered brain tumors. Standard of care includes surgical resection with adjuvant or concurrent chemoradiation which is predominantly based on adult clinical trials. Our study objective was to assess whether survival differed in AYA compared to older adults.

METHODS
The National Cancer Database was used to identify patients with at least surgically resected glioblastoma from 2004 to 2016. Cox regression models were utilized to estimate the effect of treatment on overall survival (OS) while accounting for immortal time bias (3-months) and clustering within facility.

RESULTS
Among 51,718 patients with glioblastoma identified, 2,930 patients were AYA. Multivariable analysis (MVA) shows OS was significantly higher in AYA, female, non-white, high income, unilateral cancer patients with private insurance receiving treatments in high volume facilities. OS among AYA patients was significantly lower in surgery + (radiation or chemotherapy: S+(RT or CT) group compared to surgery only (S) (HR=1.33, 95% CI 1.06–1.65), but no significant survival difference between surgery + chemoradiation (S+C+RT) groups and surgery only (HR=0.97, 95% CI 0.83–1.14). Median survival is ~28 months in AYA among S and S+C+RT groups whereas significantly lower survival (median OS ~18 months) is seen in S+RT or CT. Non-AYA patients were at 2 times increased risk of death compared to AYA patients who received the same type of treatment.

CONCLUSIONS
In conclusion, AYA population has more than twice the median OS in comparison to non-AYA patients. Worse overall survival was seen among S+RT or CT in comparison to S and S+RT+CT in AYA group. For patients needing either chemotherapy or radiation with surgery, possibly a trimodal approach might provide better survival advantage. Prospective studies are needed to further explore optimal treatment modalities in this unique population.
HOUT-11. EXTENSIVE BRAINSTEM INFILTRATION, NOT MASS EFFECT, IS A COMMON FEATURE OF END-STAGE CEREBRAL GLIOBLASTOMAS
Authors: Drumm Michael , Dixit Karan , Grimm Sean , Kumthekar Priya , Lukas Rimas , Raizer Jeffrey , Kam Kwok-Ling , McCord Matthew , Sachdev Sean , Kruser Timothy , Steffens Alicia , Javier Rodrigo , McCortney Kathleen , Horbinski Craig 
Published: November 2019

Abstract

BACKGROUND
Progress in extending the survival of glioblastoma (GBM) patients has been slow, suggesting that preclinical and clinical trial approaches may not fully take into account the nature of this cancer. A better understanding of why GBM patient survival remains poor is critical to developing new strategies. Postmortem studies on GBM can shed light on how GBM spreads and how GBM patients are dying.

METHODS
The brains of 25 GBM patients were autopsied and examined for gross and microscopic abnormalities. Clinical-pathologic correlations were accomplished through detailed chart reviews. Data were compared with older published autopsy GBM studies that predated the use of concurrent radiation and temozolomide (RT/TMZ).

RESULTS
In pre-RT/TMZ GBM autopsy series, mass effect was observed in 72% of brains, with herniation in 50% of cases. Extensive infiltration of tumor into the brainstem occurred in only 21% of those older cases. In the current series, only 7 of 25 (28%) GBMs showed mass effect (P=0.0004), and none (0%) showed herniation (P< 0.0001). However, extensive GBM infiltration through the cerebral peduncles, into the brainstem, was present in 17 cases (68%, P< 0.0001), with accompanying destruction of the brainstem and white matter tracts. There was a direct correlation between longer patient survival and the presence of brainstem infiltration (P=0.001).

CONCLUSIONS
With improving care, severe mass effect is less common in GBM patients today, whereas life-threatening brainstem invasion is now more frequent. This has major implications regarding preclinical GBM models, as well as the design of clinical trials aimed at further improving patient survival.
HOUT-12. RETURN TO WORK FOLLOWING AWAKE SURGERY FOR GLIOMAS IN SPEECH-ELOQUENT AREAS
Authors: Forster Marie-Therese , Lortz Irina , Seifert Volker , Senft Christian 
Published: November 2019

Abstract

OBJECTIVE
Pursuing a profession is an indispensable component of human happiness. The aim of this study was to analyze patients′ professional, socio-economic and psychological outcomes besides their neuro-oncological and functional evaluation after awake surgery for gliomas in eloquent areas.

METHODS
The neuro-oncological and functional outcomes of patients with gliomas other than glioblastoma undergoing awake surgery during a period of 5 years were prospectively assessed within our routine oncological follow-up. Repercussions of the disease on their professional status, socio-economic situation, and neurocognitive function were evaluated retrospectively with structured interviews.

RESULTS
We analyzed data of 37 patients with gliomas (3 WHO Grade I, 6 WHO grade II, 28 WHO grade III). Gross total and subtotal tumor resections were performed in 20 (54.1%) and 11 (29.7%) patients, respectively, whereas in 7 patients (16.2%) resection had to remain partial. Median follow up was 24.1 months (range: 5–61 months). 31 patients (83.8%) had stable disease, 2 (5.4%) patients suffered from tumor progression and 4 (10.8%) patients died. Prior to surgery, all but one patient were employed. At the time of analysis, 24 (72.7%) of 33 alive patients had resumed their profession. 5 patients (15.2%) were on incapacity pension, 2 patients were on sick leave, and 2 had retired. The median time until return to work following surgery was 5.9 ±4.6 months. Young age (< 40 years) was the only factor statistically significantly associated with the ability to return to work (p< 0.001).

CONCLUSION
Despite brain tumor surgery in eloquent regions, the majority of patients with WHO grade II or III gliomas are able to return to work. Employing awake techniques in order to preserve neurological function is of utmost relevance for individual patients′ quality of life and may also decrease the economic burden due to work loss frequently encountered in glioma patients.
HOUT-23. ADULT MEDULLOBLASTOMA TREATMENT IMPACT SINCE 2006: A CANADIAN UNIVERSITY CENTER EXPERIENCE
Authors: Camila Quinones Ninos Maria , Belanger Karl , Lemieux Blanchard Emilie , Lemieux Bernard , Bahary Jean-Paul , G Masucci Laura , Roberge David , Menard Cynthia , Lambert Carole , Moumdjian Robert , Berthelet France , Florescu Marie 
Published: November 2019

Abstract

INTRODUCTION
Medulloblastoma (MB) is an aggressive primary brain tumor rare in adults. Prospective studies in adults are limited by the small number of patients.

METHODS
We retrospectively reviewed all MB patients treated at the CHUM between 2006 and 2017 in our clinical database adult SARDO. We don’t have the children follow up. We divided our cohort in 2 groups, those diagnosed between 2006–2013 and those diagnosed between 2014–2017.

RESULTS
49 patients were treated, 23 (47%) were children referred for radiation only from a pediatric center and 26 (53%) were adults. Median follow up of adults was 26 months. At 5 years, the entire cohort OS was 58%, but specifically for adults, the 5yOS was 80%. First line therapy had a 5y PFS 77% for adults, negatively influenced by the absence of adjuvant radiotherapy (83% vs 0%; p < 0.001) and the absence of adjuvant chemotherapy (80% vs 39%; p < 0.008). 96% of adult patients received radiotherapy and 52% of them received concomitant radiosensitizing chemotherapy with no impact on survival. Complete surgical resection was performed on 88% of patients, but the extent of resection did not have an impact on survival and did not change with time. From 2006–2013, the most common chemotherapy treatment (80%) in adults was Vincristine, Cisplatin and Lomustine. From 2014–2017, the chemotherapy was replaced by Cisplatin, Etoposide and Cyclophosphamide in 82% with no impact on survival (specific mortality for this chemo 3yOS 100% for both, 3y PFS 100%). Non Cisplatin based chemotherapy regimens were associated with decrease in PFS (67% at 3y). 78% of the progressive patients received second line chemo.

CONCLUSION
In our adult MB population, the demographic and tumor factors did’nt have an impact on prognosis but adjuvant radiotherapy and chemotherapy had a favorable impact on survival especially with Cisplatin, Etoposide and Cyclophosphamide regimen.
HOUT-24. CHALLENGES AND SUCCESSES IN THE GLOBAL REIMBURSEMENT OF A BREAKTHROUGH MEDICAL TECHNOLOGY FOR TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Kelly Justin , Proescholdt Christina 
Published: November 2019

Abstract

OBJECTIVE
To highlight the challenges and differences regarding the reimbursement of breakthrough medical device technologies, by example of a novel cancer treatment using Tumor Treating Fields (TTFields).

BACKGROUND
TTFields is a breakthrough cancer treatment modality. The treatment is delivered through a medical device with the brand name Optune. Its efficacy was first established in glioblastoma multiforme. Reimbursement challenges for medical devices vary by. Common issues for novel device technologies like Optune however, are the difficulties to classify the treatment in the respective country’s health care system with the ability to develop a value-based reimbursement pathway.

MATERIALS/METHODS
We reviewed reimbursement decisions of payers for Optune from a total of 6 countries. We assessed their classification of the device, the flexibility of their health care framework and how Optune was implemented.

RESULTS
All 6 countries implemented Optune in their respective health care systems. 3 countries consider Optune to be an outpatient treatment delivered by durable medical equipment, one country classifies Optune as a hospital dispensed medical device, one country classifies Optune as an extended medical service and the last country as rehab services.The differential fitting of Optune in the respective country’s health care system allows each of the countries to take a positive, value-based reimbursement decision for this breakthrough technology. Generally, the speed of payer adoption for Optune varied based on the ability to assess the clinical data, rather than the more technical aspects of how the device is delivered to patients.

CONCLUSIONS
Classification of a breakthrough technology like Optune in the traditional framework of health care systems is challenging and handled differently by each country. Countries with a flexible approach regarding this novel oncological treatment modality however, were able to reach positive reimbursement decisions by classifying Optune in the category most suitable in the respective country’s health care system.
IMMU-14. ONCOLYTIC VIRUS EXPRESSING A POSITIVE IMMUNE CHECKPOINT MODULATOR AS A THERAPEUTIC APPROACH FOR DIPG
Authors: Laspidea Virginia , Puigdelloses Montse , Iñigo-Marco Ignacio , Garcia-Moure Marc , Ausejo Iker , Gallego Jaime , Fueyo Juan , Gomez-Manzano Candelaria , Alonso Marta M 
Published: November 2019

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor, being the leading cause of pediatric death caused by cancer. We previously showed that administration of the oncolytic virus Delta-24-RGD to DIPG murine models was safe and led to an increase in the median survival of these animals. However, not all the animals responded, underscoring the need to improve this therapy. In order to increase the antitumoral effect of the virus, we have engineered Delta-24-RGD with the costimulatory ligand 4-1BBL (Delta24-ACT). 4-1BB is a costimulatory receptor that promotes the survival and expansion of activated T cells, and the generation and maintenance of memory CD8+ T cells. In this project, we evaluated the oncolytic effect of Delta24-ACT and the antitumor immune response in DIPG murine models. In vitro, Delta24-ACT was able to infect and induce cell death in a dose-dependent manner in murine DIPG cell lines. In addition, Delta24-ACT was able to replicate in these tumor cells and to express viral proteins. Moreover, infected cells expressed 41BBL in their membranes. Delta24-ACT could induce immunogenic cell death due to an increased secretion of ATP and calreticulin translocation to the membrane of infected cells (in no-infected cells it located in the ER), DAMPs that can trigger the immune response activation. In vivo, Delta24-ACT demonstrated to be safe in all the tested doses and was able to induce a significant increase in the median survival of the treated animals. Moreover, long-term survivors display immunological memory. Delta24-ACT treatment led to antitumoral effect in DIPG murine cell lines in vitro. Of significance, we have demonstrated that in vivo administration of Delta24-ACT is safe and results in an enhanced antitumor effect. Future in vivo studies will explore the underlying immune mechanism of the virus.
IMMU-19. QUINOLINATE-INDUCED IMMUNE SUPPRESSION IN GLIOBLASTOMA
Authors: Kesarwani Pravin , Kant Shiva , Prabhu Antony , Chinnaiyan Prakash 
Published: November 2019

Abstract
Glioblastoma continues to be an invariably fatal malignancy with limited treatment options. We performed integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived tumors to provide insight into metabolic programs that may be driving the aggressive phenotype of this malignancy. A persistent theme that emerged was the interplay between metabolic remodeling and immune response. Most notable was a 64-fold accumulation of quinolinate, which represents a downstream intermediary of tryptophan metabolism, in glioblastoma, when compared to low-grade astrocytoma. We discovered a dynamic interaction between cells within the tumor microenvironment that contributes to the generation of quinolinate. Specifically, neither tumor cells nor immune cells demonstrated the capacity to completely metabolize tryptophan. Tumor cells were required to metabolize tryptophan to kynurenine, while only cells of monocyte lineage, including M1/M2 macrophages and microglial cells, demonstrated the capacity to generate quinolinate from tumor-generated kynurenine. We next sought to determine if the observed accumulation of quinolinate in glioblastoma had immune consequences. We discovered a novel role quinolinate plays in increasing (~50%) immunosuppressive M2 macrophage (CD45+CD11b+F4/80+ and CD206+) polarization and promoting a suppressive molecular phenotype (IL4Rα +). These findings were functionally recapitulated, with quinolinate-induced M2 macrophages demonstrating potent inhibition of CD8+T-cell proliferation. Intriguingly, quinolinate also skewed M1 polarization towards an “M2-like” phenotype both molecularly (CD45+CD11b+F4/80+CD206+) and functionally, by inhibiting CD8+T-cell proliferation and decreasing phagocytosis efficiency. Targeting quinolinate’s upstream enzyme kynurenine-3-monooxygenase (KMO) inhibited M2 polarization in vitro and deceased M2 macrophage levels in vivo by 60%. This was unique to KMO, as targeting tryptophan metabolism by inhibiting the more established, upstream target IDO1 did not influence M2 macrophage levels. As emerging studies suggest M2 macrophages play a central role in contributing towards the potent immunosuppressive microenvironment in glioblastoma, therapeutic strategies designed to target quinolinate metabolism may serve as a novel immuno-metabolic checkpoint with direct clinical implications in this malignancy.
IMMU-30. UTILIZING A NOVEL MASS CYTOMETRY-BASED IMMUNOMONITORING PLATFORM FOR THE CHARACTERIZATION OF VACCINE-REACTIVE, EPITOPE-SPECIFIC CD8+ T-CELLS IN HLA-A*0201+ PATIENTS WITH K27M+ DIFFUSE MIDLINE GLIOMAS
Authors: Taitt Jared , Watchmaker Payal , Nejo Takahide , Almeida Neil , Okada Kaori , Shahin Maryam , Gilbert Ryan , Mueller Sabine , Okada Hideho 
Published: November 2019

Abstract
Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal expansion of vaccine-reactive CD8+ T-cells was observed in all of patients (n = 4) who completed a minimum of 18 weeks on the study. These T-cells were subsequently stratified into discrete clusters on a tSNE plot using canonical CD8+ T-cell markers. Resultant clusters were further classified by their expression profiles, revealing distinct effector memory and exhausted subpopulations. Chronological monitoring of these groups indicates the time course-dependent development and persistence of vaccine-reactive exhausted and effector memory CD8+ T-cells in 75% of patients analyzed. Furthermore, a comparative analysis of myeloid subpopulations revealed an inverse correlation between the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) and length of enrollment in the trial. Future plans include the analysis of regulatory T-cells (Tregs) and MDSCs of all enrolled patients to solidify the relationship between the length of stay on the study and prevalence of immunosuppressive populations. This methodology offers insight into the progression of vaccine-induced patient immune responses and exhibits promise as a platform that may be extrapolated to other immunotherapies.
IMMU-36. THE ROLE OF PD-L1 IN GLIOBLASTOMA-DERIVED EXTRACELLULAR VESICLES IN THE INDUCTION OF IMMUNOSUPPRESSIVE MONOCYTES
Authors: Himes Benjamin , Peterson Timothy , Tyson Jasmine , Lee Helen , deMooij Tristan , Cumba-Garcia Luz , Jung Mi-Yeon , Gustafson Michael , Dietz Allan , Johnson Aaron , Dong Haidong , Maus Rachel , Svetomir Markovic , Lucien-Matteoni Fabrice , Yan David , Uhm Sarah , Abukhadra Mina , Parney Daniel , Parney Ian 
Published: November 2019

Abstract
Glioblastoma (GBM) is the most common and lethal primary brain tumor, and novel therapeutic strategies that make a substantial impact on outcomes are sorely needed. Immunotherapies have shown great promise in the treatment of a number of cancers in recent year, and a concerted effort is being made to apply these treatment paradigms to GBM. However, many GBM patients exhibit profound immunosuppression, likely limiting the efficacy of such approaches. The mechanisms of this immunosuppression are poorly understood, but tumor-derived extracellular vesicles (EVs), may play a role. We demonstrate that GBM-derived EVs induce the development of myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). We further demonstrate that these EV-induced monocytic cells are immunosuppressive, resulting in impaired T cell proliferation upon co-culture. We found that the immunosuppressive effects of tumor-derived EVs appear to be driven by the induction of these immunosuppressive monocytes, as EV treatment of T cells did not significantly impact T cell proliferation. Further, we sought to characterize the important of programmed death ligand 1 (PD-L1) in the induction of these immunosuppressive monocyte populations. We found PD-L1 to be expressed in the EVs from GBM cell lines, and that modulation in PD-L1 expression via either constitutive overexpression or shRNA-mediated knockdown resulted in concordant changes in expression in tumor-derived EVs. We demonstrate that PD-L1 is important for the induction of NCM but not for MDSCs. Taken together, these findings point to a significant role for tumor-derived EVs in the induction of immunosuppressive monocytes in GBM, and that these cells may be a driving force of systemic immunosuppression. PD-L1 is one factor expressed in EVs that has immunomodulatory properties, but additional EV cargo likely plays a major role in the induction of immunosuppressive cells.