bluuebunny/crossref_metadata_2025_split huggingface dataset:
RARE-37. TREATMENT OF H3K27M MUTANT GLIOMAS WITH PANOBINOSTAT
Authors: Balakrishnan Samantha , Carabenciov Ivan , Ruff Michael , Uhm Joon , Kizilbash Sani 
Published: November 2019

Abstract

Panobinostat (PBST) is a histone deacetylase inhibitor with biologic rationale in the treatment of gliomas harboring H3 K27M mutation.

METHODS
We performed a retrospective medical record review of adult patients with H3 K27M mutant diffuse midline glioma treated with PBST at Mayo Clinic (Rochester, MN).

RESULTS
Four patients were identified with a mean age 40 years (range 22–62 years). Tumor location was: spinal cord (thoracic n=1, cervical n=1), brainstem (n=1), and thalamus (n=1).Two patients underwent biopsy alone while two underwent a partial resection. Three patients were treated with radiation (36–54 Gy) immediately prior to PBST monotherapy, and one patient was treated with PBST monotherapy without preceding radiation. All patients were otherwise chemotherapy naïve and did not receive any concurrent chemotherapy with PBST. PBST was dosed at either 10 mg (n=1) or 20mg (n=3) administered on days 1, 3, 5, 8, 10 and 12 of 21 day cycles. The mean duration of PBST therapy was 5 months (range 2–11 months). PBST was well tolerated overall. One patient experienced an objective response per RANO criteria. Two patients continue on therapy (5 cycles, 12 cycles) with stable disease. One patient rapidly progressed after 2 cycles of PBST therapy. In contrast with the patients who derived benefit from PBST, this patient was younger (22) and had multifocal disease with leptomeningeal involvement at treatment onset. The average progression free survival post PBST initiation was 8 months.

CONCLUSION
This single institution case series shows promise that PBST may have therapeutic benefit in adult patients with H3 K27M mutant diffuse midline glioma.
RARE-39. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) WITH LOMUSTINE (CCNU) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS - A BI-CENTRIC ANALYSIS
Authors: Lazaridis Lazaros , Schäfer Niklas , Schmidt Teresa , Weller Johannes , Tzaridis Theophilos-Dimitrios , Scheffler Björn , Pierscianek Daniela , Kleinschnitz Christoph , Stuschke Martin , Sure Ulrich , Herrlinger Ulrich , Kebir Sied , Glas Martin 
Published: November 2019

Abstract

BACKGROUND
TTFields combined with TMZ chemotherapy demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial; independent of MGMT-promoter methylation-status, age, grade of resection, and performance status. Recently, improved efficacy of lomustine/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial. As TTFields demonstrated a favorable safety profile as well as a high potential for being combined with other modalities and the encouraging results for methylated MGMT-promoter GBM patients in the CeTeG trial, there is a strong rationale for combining these treatment regimens. Here, we present a case series of patients receiving a combination of TTFields and lomustine/TMZ.

METHODS
Patients with ndGBM and MGMT-promoter methylation underwent combined therapy of TTFields plus lomustine/TMZ after surgery and radiochemotherapy. MGMT-promoter status was measured by pyrosequencing. Safety, feasibility, and first efficacy results are reported at data cut-off (April 26, 2019).

RESULTS
Sixteen patients with MGMT-promoter methylated ndGBM (median, range: age 50, 27–70; KPS 90, 60–100) have been treated with a combination of TTFields plus lomustine/TMZ. The analysis included patients with complete resection (n=7), partial resection (n=8), as well as biopsy (n=1). CTCAE grade 3 hematotoxicity was observed in seven patients (44%) but was unlikely related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in six patients (38%). At data cut-off, the analyzed patient population demonstrated a median PFS of 20 months; the median OS was not yet reached.

CONCLUSION
The results of this analysis indicate that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and increased sample size are required and planned for further safety and efficacy assessment of this treatment regimen.
RARE-44. CLINICAL, PATHOLOGICAL AND IMMUNE MICROENVIRONMENT EVALUATION FOR TUMOR IMMUNITY IN GERMINOMA PATIENTS
Authors: Nishimoto Masaaki , Ohara Kentaro , Kamamoto Dai , Tamura Ryota , Miwa Tomoru , Yoshida Kazunari , Sasaki Hikaru 
Published: November 2019

Abstract
Pure germinomas are pathologically composed by large polygonal undifferentiated cells, accompanied by infiltrating small lymphocytes. Tumor immunity in intracranial germinomas have not been studied well and their role remains unclear. This study aimed to evaluate the clinical value of tumor immunity in intracranial germinomas. We investigated the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and tumor-infiltrating lymphocytes (TILs) in 8 patients of intracranial germinomas by immunohistochemistry to analyze the association with their clinical courses and radiological features. We divided the patients into group with more than one year from onset to diagnosis as long-term onset group (LTOs), and the group with less than one year as short-term onset group (STOs). Three patients are in LTOs and five patients are in STOs. Median duration from onset to diagnosis in LTOs is 35 months (29–47), while median duration in STOs is 5.1 months (0.5–10). Mortality and recurrence were not observed in all patients. Radiological analysis showed that tumor locations in LTOs are relatively atypical and tumor size in LTOs is smaller than in STOs. TILs in LTOs are having higher expression than STOs. PD-L1 expression was observed in all 8 tumors. CD3, CD8 and PD-1 expressions were observed in all TILs. The ratio of PD-L1 positive-tumor cells was lower in LTOs than in STOs (p=0.012). CD8+ TIL density is higher in LTOs (p=0.003), whereas PD-1/CD8 ratio is lower in LTOs (p=0.047). Our data suggest that PD-1/PD-L1 pathway is associated with pathogenesis and tumor growth of germinomas, therefore immune checkpoint molecule inhibitors against PD-1/PD-L1 may be effective for refractory germinomas.
RARE-54. MEK INHIBITION FOR AGGRESSIVE GLIOMAS IN ADULTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Romo Carlos , Slobogean Bronwyn , Blair Lindsay , Blakeley Jaishri O 
Published: November 2019

Abstract

BACKGROUND
Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. Central nervous system malignancies have an overall standardized incidence ratio of 37.5 in population studies, with higher rates of aggressive gliomas in adults with NF1. Further, the response to standard glioma therapies in this population is mixed in published series. MEK1/2 inhibitors have shown activity in both NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about their optimal dose or sequencing relative to standard glioma therapies for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and newly diagnosed aggressive gliomas.

METHODS
A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program from 2016 to 2018.

RESULTS
Four patients met selection criteria. Median age at diagnosis was 37 years [25–43]. Histologic diagnoses were: pilocytic astrocytoma (1), diffuse astrocytomas (2), and anaplastic astrocytoma (1). All tumors were IDH1 wild-type. Three received trametinib as frontline therapy (2 mg daily), one as second line treatment. All achieved a partial radiographic response within 2 months from the start of trametinib. Median overall survival was 15 months [4–19]; three patients are alive at publication, with a median of 12 months from diagnosis. Median progression-free survival was 2.5 months [1–11].

CONCLUSIONS
Astrocytomas in adults with NF1, including histologically low-grade tumors, often have a more aggressive course than suggested by histology. These cases demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in people with NF1, however, prospective investigation is needed.
STEM-02. GLIOBLASTOMA CANCER STEM CELLS UTILIZE ASYMMETRIC CELL DIVISION TO PROMOTE THERAPEUTIC RESISTANCE
Authors: Hitomi Masahiro , P Chumakova Anastasia , Silver Daniel , Knudsen Arnon , Kristensen Bjarne , Lathia Justin 
Published: November 2019

Abstract
Asymmetric cell division (ACD) enables the maintenance of a stem cell population while simultaneously generating differentiated progeny. Cancer stem cells (CSCs) undergo multiple modes of cell division during tumor expansion and in response to therapy, yet the functional consequences of these division modes has yet to be determined. Using a fluorescence-based system that reports the mitotic distribution of lipid rafts enriched in cell surface receptors, we found that ACD in glioblastoma CSCs generated a daughter cell with enhanced resistance to radiation and temozolomide. Single-cell analyses using our reporter system revealed that ACD also increased the co-inheritance of epidermal growth factor receptor (EGFR) and neurotrophin receptor (p75NTR), which was validated across four additional glioblastoma CSC models. Stimulation of both receptors maintained self-renewal under differentiation conditions, and stimulation with p75NTR ligands rescued the reduction in STAT3, AKT, and ERK induced by erlotinib-mediated EGFR inhibition. Finally, knockdown of p75NTR enhanced the therapeutic efficacy of EGFR inhibition in vivo. Taken together, our data indicate that co-inheritance of p75NTR and EGFR promotes resistance to EGFR inhibition through a redundant mechanism. Overall, these findings demonstrate that ACD produces progeny with enhanced growth factor receptors, which contributes to the generation of a more therapeutically resistant CSC population, and suggest that ACD needs to be considered in the development of next-generation targeting strategies.
STEM-10. BIDIRECTIONAL INTERACTION BETWEEN TUMOR-ASSOCIATED PLATELETS AND GLIOMA STEM CELLS IN GLIOBLASTOMA MULTIFORME
Authors: Raghavan Alankrita , Lee-Poturalski Christine , Willis John , Kerstetter-Fogle Amber , Harris Peggy , Rich Jeremy , Vogelbaum Michael , Jankowsky Eckhard , Sloan Andrew 
Published: November 2019

Abstract
Glioblastoma Multiforme (GBM) is the most common and lethal malignant primary adult brain tumor. Therapy resistance and tumor recurrence in GBM have been attributed to glioma stem cells (GSCs), which are found in hypoxic but perivascular niches. We hypothesized that the clinically documented and prognostically relevant increase in platelets in GBM promotes formation of functional hypoxic but perivascular niches that support GSCs due to formation of intravascular thromboses, a hallmark of GBM. Our preliminary in silico analysis from TCGA GBM samples indicates significant correlation of platelet and stemness signature expression (P < 0.001). High expression of platelet gene signatures also inversely correlates with overall survival in GBM patients (P < 0.02). Furthermore, we found significant co-localization of known platelet and stemness markers in primary GBM specimens, supporting our hypothesis and motivating further interrogation of GSC-platelet crosstalk. Our preliminary data suggest that GSCs exposed to either tumor or healthy platelets demonstrate increased self-renewal and stemness, as determined by a significant increase in OCT4, NANOG, and OLIG2 expression compared to unexposed GSCs. This increase in stemness and self-renewal markers was not seen in platelet-exposed differentiated glioma cell (DGC) counterparts. Conversely, platelets are stimulated by GSCs and GSC-conditioned media while DGCs elicit no stimulatory effects as measured by ATP release and aggregation assays. Our results implicate a functional role for platelet-GSC interactions in the maintenance of tumor cellular hierarchy that ultimately contributes to poor clinical outcomes in GBM. RNA-Seq of platelet-privileged GSCs is currently underway to elucidate the mechanism by which platelets impact GSC self-renewal. Successful characterization of potential crosstalk between platelets and GSCs may offer new clinical perspectives into GBM and inform development of a novel treatment paradigm to target these specific cell-to-cell interactions.
STEM-12. INCREASING INDUCED NEURAL STEM CELL PERSISTENCE IN THE TUMOR RESECTION CAVITY
Authors: Bomba Hunter , Sheets Kevin , Carey-Ewend Abigail , Goetz Morgan , Bago Juli , Khagi Simon , Hingtgen Shawn 
Published: November 2019

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Afflicted patients have a median survival rate of only 15 months, and patient survival statistics have remained stagnant for over three decades. Current standard of care includes maximal safe tumor resection, chemotherapy, and radiation. Nevertheless, GBM is aggressive, making recurrence and deeper tumor infiltration inevitable. Neural stem cells transdifferentiated from a skin biopsy, i.e. induced neural stem cells (iNSCs), have the innate ability to home to tumors, and, when engineered with cytotoxic proteins, can actively kill cancer cells. However, direct injection of these cells into the hostile immune environment of the tumor resection cavity results in an accelerated clearance rate and therefore a shortened therapeutic window. To combat this clearance issue, we investigated the FDA-approved hemostatic matrix, Floseal, as a cell delivery platform to increase iNSC persistence. In vitro, SEM imaging showed homogeneous iNSC distribution throughout Floseal. Using our surgical resection model of GBM in mice, we delivered iNSCs into the post-surgical cavity in Floseal and by direct injection to model current clinical delivery strategies. Serial kinetic imaging showed that human iNSC persistence delivered into the cavity in Floseal persisted over 90 days, while cells directly injected into the brain parenchyma persist less than 20 days. When we investigated the impact on tumor kill, we found the increase in persistence increased survival of GBM-bearing mice more than 30 days compared to control cells. Light-sheet microscopy showed wild-type neural stem cells migrate into invasive GBM-8 tumors in the contralateral hemisphere, and we are now using this approach to validate the homing of iNSCs delivered via Floseal. Administration of iNSCs encapsulated in the biocompatible Floseal matrix offers a promising, clinically-translatable therapeutic strategy for GBM.
STEM-13. CANCER STEM CELL CYTOTOXICITY ASSAY-GUIDED TREATMENT IN RECURRENT GLIOBLASTOMA AND PROGRESSIVE ANAPLASTIC GLIOMA
Authors: Ranjan Tulika , Howard Candace , Yu Alexander , Xu Linda , Aziz Khaled , Jho David , Leonardo Jodi , Hameed Muhammad , Karlovits Stephen , Wegner Rodney , Fuhrer Russell , Lirette Seth , Denning Krista , Valluri Jagan , Paolo Claudio Pier 
Published: November 2019

Abstract

BACKGROUND
The presence of chemotherapy-resistant cancer stem cells (CSC) leading to tumor recurrence is postulated to be one of the major factors in the poor response to the current standard of care treatments in progressive high-grade gliomas. Unfortunately, in spite of several new drug discoveries for other tumor types, not many advances have been reported for this disease and therefore recurrent and progressive high-grade glioma survival remains dismal.

METHODS
We have used a CLIA and CAP accredited Cancer Stem Cell Cytotoxicity Assay(ChemoID) to guide most effective chemotherapy treatments from a panel of FDA approved drugs or their combinations for 12 recurrent glioblastoma (GBM) patients and 2 progressive anaplastic gliomas, all eligible to receive a stereotactic biopsy. Patients were evaluated by MRI scans and response was assessed according to RANO criteria.

RESULTS
The median age of our patient cohort was 49 years (21–63), with 11 males (79%) and 3 females (21%). We observed 6 complete responses (CR) 43%, 6 partial responses (PR) 43%, and 2 progressive diseases (PD) 14%. Of note, the two PD were observed in patients that could not be treated with assay recommended therapy due to their health status. Patients treated with ChemoID assay-directed therapy had a longer median overall survival (OS) of 13.3 months (5.4-NA) compared to the historical median OS of 9.0 months (8.0–10.8 months) previously reported (1). Notably, our recurrent and progressive high-grade glioma patient cohort treated with assay-guided therapy had a 57% probability to survive at 12 months, compared to the 27% historical probability of survival at 12 months observed in previous studies (1).

CONCLUSIONS
The data suggests that the ChemoID Cancer Stem Cell Cytotoxicity Assay has the potential to help guide individualized chemotherapy choices to improve recurrent and progressive high-grade glioma patient outcome. 1) Friedman, H.S. et. al. JCO2009 27:28, 4733–4740.
STEM-26. ALTERED LIPID METABOLISM MARKS GLIOBLASTOMA STEM AND NON-STEM CELLS IN SEPARATE TUMOR NICHES
Authors: Wallace Lisa , Gromovsky Anthony , Hale James , Knudsen Arnon , Prager Briana , Silver Daniel , Sloan Andrew , Kristensen Bjarne , Lathia Justin , Mark Brown J , Rich Jeremy , Hubert Christopher 
Published: November 2019

Abstract
Clinical glioblastoma is marked by a strikingly heterogeneous mix of cell types, cellular metabolisms, and cellular microenvironments spread in different spatial locations throughout a tumor. We have created 3-dimensional organoid models that partially mimic the transition zone between nutrient-rich cellular tumor regions and nutrient-poor psuedopallisading and perinecrotic tumor zones. We found a dramatic disparity in lipid droplet presence between these regions with high lipid accumulation in the hypoxic organoid cores of a wide spectrum of patient derived specimens. This is accompanied by regionally restricted upregulation of HILPDA gene expression in the cores of our models, in clinical GBM specimens but not lower grade brain tumors, and localized specifically to pseudopallisading regions of patient tumors. We further show that lipid droplet accumulation overall marks perinecrotic and pseudopallisading regions in clinical GBM, indicating broadly altered lipid metabolism between these distinct cell populations. High lipid droplet accumulation is largely restricted to the non-stem cell populations of GBM organoids and sorted xenograft tumors whereas the stem cells are lipid-poor, suggesting lipid levels may not be simply a product of the microenvironment but also may be a reflection of cell state. We performed global lipidomic analysis on prospectively sorted stem and non-stem cells of multiple patient-derived models and found that GBM stem cells have comparatively decreased levels of neutral lipids, indicating a significant metabolic shift compared to non-stem cells from the same patient. Conversely, GBM stem cells have significantly increased levels of rare specific lipid species, and also display altered phospholipid synthesis and species specific alterations in phospholipid classes. Our findings suggest avenues for therapy by targeting the altered lipid metabolic pathways of these disparate tumor cell populations.
Chlamydia trachomatis infection of the neovagina in transgender women
Authors: Radix Asa E , Harris Alexander B , Belkind Uri , Ting Jess , Goldstein Zil G 
Published: November 2019

Abstract
We report two cases of neovaginal Chlamydia trachomatis infection in transgender women who underwent penile-inversion vaginoplasty procedures with integrated peritoneum and urethral grafts. These tissue types may have facilitated C. trachomatis infection. Medical providers should implement neovaginal screening for bacterial STIs in transgender patients at risk for infection.
A Biopsychosocial Model of Chronic Pain for Older Adults
Authors: Miaskowski Christine , Blyth Fiona , Nicosia Francesca , Haan Mary , Keefe Frances , Smith Alexander , Ritchie Christine 
Published: November 2019

AbstractPopulationComprehensive evaluation of chronic pain in older adults is multifaceted.Objective and MethodsResearch on chronic pain in older adults needs to be guided by sound conceptual models. The purpose of this paper is to describe an adaptation of the Biopsychosocial Model (BPS) of Chronic Pain for older adults. The extant literature was reviewed, and selected research findings that provide the empiric foundation for this adaptation of the BPS model of chronic pain are summarized. The paper concludes with a discussion of specific recommendations for how this adapted model can be used to guide future research.ConclusionsThis adaptation of the BPS model of chronic pain for older adults provides a comprehensive framework to guide future research in this vulnerable population.
Managing Colonial Diets: Wartime Nutritional Science on the Korean Population, 1937–1945
Authors: Ko Sunho 
Published: November 2019

Summary
This article examines nutrition studies on Korean diets between 1937 and 1945 as a case study on the liaison between nutritional science and total war regimes in the twentieth century. Building on critical scholarship on nutritional science, this article argues that nutritional science—as a scientific governmental technology and racial discourse—served the wartime colonial regime in the Japanese empire aimed at managing the Korean population in the most scientific manner. As a governmental technology, nutritional science produced scientific frameworks and data that shaped state food policies for the efficient mobilisation of Korean diet and labor for war. As a racial discourse, nutritional science construed Korean diets as a scientifically defined nutrition problem. By construing the nutrition problem as an expression of colonial backwardness in need of governmental intervention, nutritional science justified wartime state policies like the school lunch programme as welfare measures to improve the colonial diet and body.
Searches for cosmic magnetic monopoles: past, present and future
Authors: Patrizii Laura , Sahnoun Zouleikha , Togo Vincent 
Published: November 2019

A paper titled ‘Quantised singularities in the electromagnetic field’ by P.A.M. Dirac appeared in 1931 in the
Proceedings of the Royal Society A
. The paper concerned ‘[ ·
s
] the reason for the existence of a smallest electric charge.’ Dirac showed that the quantization of the electric charge follows from the existence of at least one free magnetic charge, finding ‘a connection between the smallest electric charge and the smallest magnetic pole’, a connection called since then the ‘Dirac relation’. That seminal paper marked the opening of a new research field that has grown considerably since then. The search for magnetic monopoles in cosmic radiation encompasses many fields, from particle physics to astrophysics, from the extremely small to cosmology.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.