tbuckley/cabot-search huggingface dataset:
RARE-10. INITIAL EXPERIENCE IN EPENDYMOMA WITH INVESTIGATIONAL CANCER-TARGETING BXQ-350 SapC-DOPS NANOVESICLES: A RARE TUMOR CASE STUDY
Authors: Vinay Puduvalli, John Villano, Trisha Wise-Draper, John Morris, Angela Johnson, Karen SantaCruz, Audra Kerwin, Karen Cline-Parhamovich, Edouard Dupis, Marc Mabray, Olivier Rixe
Journal: Neuro-Oncology (2018)

Ependymomas are rare primary nervous system tumors accounting for about 3% of adult brain tumors in the United States. The current standard of care includes surgical resection and radiation therapy, with more than half experiencing relapse and poor outcomes. Saposin C and dioleylphosphatidylserine (SapC-DOPS) nanovesicles are a novel investigational treatment agent that can cross the blood-brain barrier and selectively target externalized phosphatidylserine that is expressed on tumor cell surfaces. We examined a rare complex ependymoma case enrolled in the ongoing Phase 1b study of SapC-DOPS cancer-targeting agent BXQ-350 (NCT02859857). The patient received cycle 1 (BXQ-350 2.4 mg/kg IV infusion at Day 1–5, 8, 10, 12, 15, 22) and 3 additional cycles (1x28 days), and was followed until death for safety, response, RANO, and ECOG. A 67-year old white male with recurrent Grade III anaplastic ependymoma diagnosed 3 years before enrollment and with a history of surgical intervention exhibited measurable extra-axial (6.4x3.2 cm) and inferolateral intracranial components on MRI, accompanied by palpable skull mass. At baseline, the lesion was 6.4 x 3.2 cm with stable disease per RANO and ECOG of 1. After 2 cycles, minor decrease in size of intracranial enhancing components was reported (overall stable disease per RANO). The patient received 4 total cycles of BQX-350 without related adverse events or toxicities, and cycle 5 was withheld due to volume progression on MRI. He died 6 months post-enrollment. Post-mortem histology and gross anatomy showed extensive tumor necrosis with chondroid differentiation and gross signs of metastatic disease in the lungs, thoracic, and lumbar spine on microscopy. CONCLUSIONS: While further study of cancer-targeting SapC-DOPS nanovesicle efficacy in adult patients with ependymoma is needed, good tolerability in rare aggressive tumors was observed. The role of extensive necrosis and possibly treatment-related intracranial mass reduction supports additional investigations in this indication.
TMOD-24. PATIENT-DERIVED BRAIN TUMOUR IPSCS: MODELS FOR INVESTIGATING GLIOMA STEMNESS AND DRUG DISCOVERY
Authors: Ryan Mathew, Barbara da Silva, Euan Polson, Jennifer Williams, Daniel Tams, Orla O’Shea, Claire Taylor, Gary Shaw, Stephane Ballereau, Susan Short, Christian Smith, James Rutka, Paul Chumas, Florian Markowetz, Heiko Wurdak
Journal: Neuro-Oncology (2018)

Dysregulated, stem cell-like self-renewal has been implicated in glioma treatment resistance and tumour recurrence. Drugs that eliminate tumour cells possessing this malignant characteristic are urgently needed. It remains, however, an experimental challenge to link heterogeneous glioma genotypes to drug response at scale. To this end, we successfully derived patient-specific induced pluripotent stem cell (iPSC) models from both low- (LGG) and high-grade gliomas (HGG) and developed an initial drug discovery application. Brain tumour tissue, acquired at surgery, was reprogrammed. Derived iPSC models were characterised using pluripotency markers, tri-germinal layer differentiation, gene expression, karyology and deep whole genome sequencing (WGS, iPSC versus parental tumour). Glioma iPSC differentiation in 2-dimensional (adherent, optically clear 96-well imaging plates) and 3-dimensional (organoid) culture was carried out. Gene expression of neural induction and neuronal differentiation was analysed using mRNA-seq. Neural cancer stem cells from each glioma iPSC line were orthotopically implanted in vivo. Reprogrammed cells were confirmed as fully-reprogramed/stable iPSCs, with mutational variants (SNPs, CNVs) preserved as compared to the parental tumours. Glioma iPSC maturation and quantification of TUJ-1 expression indicated a ‘differentiation block’ in the HGG iPSC models. This phenotype was concordant in HGG iPSC-derived tumour organoids which displayed SOX2/MKI67-positive neural rosettes. Consistently, mice developed xenograft tumours with GBM histopathological characteristics. Expression profiling during neuronal differentiation (from iPSC to neural stem cells to neurons) has revealed candidate genes that may be responsible for the phenotypic differences between HGG and control/LGG iPSC models. Our adherent, organoid and in vivo iPSC models may uncover genetic mutations and regulatory networks underlying glioma stem cell self-renewal capability, and provide a basis for industrial-scale drug discovery. Here we have successfully implemented the first stages towards this development (in a 96-well assay format). Ultimately, our patient-derived iPSC-based approach may enable personalised precision medicine strategies against glioma.
NCMP-18. PLATELET COUNT IS ASSOCIATED WITH OUTCOME IN CANCER PATIENTS STROKE
Authors: Bernardo Cacho-Diaz, Hector Spinola-Maroño, Laura G Mendoza-Olivas, Myrna Candelaria
Journal: Neuro-Oncology (2018)

Cerebrovascular disease (CVD) and cancer are among the most common causes of mortality worldwide, preceded only by ischemic heart disease (IHD). Thrombocytopenia was shown to be associated with poor outcomes in IHD and CVD in the general population. This study aimed to assess the relationship of thrombocytopenia with poor outcomes in cancer patients with CVD. MATERIALS AND Data on patients with concomitant CVD and cancer who were initially treated at a cancer referral center between January 2010 and December 2017 were included. Thrombocytopenia was defined as a platelet count <150,000/mm3 during the first 24 h of CVD symptom onset. The review of clinical records was approved by the IRB. Among 268 cancer patients with CVD included in the study, 210 met the inclusion criteria. Median overall survival of the entire cohort was 7.2 months, which was significantly shorter in males (p 0.029) and patients with hematologic tumors (p = 0.009), hemorrhagic CVD (p < 0.001), altered mental status (p < 0.001), and thrombocytopenia (p < 0.001). Multiple regression logistic analysis revealed that thrombocytopenia (risk ratio [RR] 1.6, 95% confidence interval [CI] 1.12.4) and altered mental status (RR 2.7, 95%CI 1.94.0) remained statistically significant risk factors for mortality. In cancer patients with CVD, thrombocytopenia at the time of CVD diagnosis and altered mental status during initial clinical evaluation were associated with higher mortality, which should be confirmed in future studies.
EXTH-15. TARGETING ANDROGEN SIGNALING IN GLIOBLASTOMA (GBM) USING SEVITERONEL (SEVI), A CYP17 LYASE AND ANDROGEN RECEPTOR (AR) INHIBITOR, ALONE AND IN COMBINATION WITH RADIATION (RT)
Authors: Hanshi Sun, Christian Werner, Joseph Dresser, Kari Wilder-Romans, Edwina Baskin-Bey, Joel Eisner, Theodore Lawrence, Daniel Spratt, Corey Speers, Daniel Wahl
Journal: Neuro-Oncology (2018)

The AR is a therapeutic target and a driver of growth and treatment resistance in prostate and breast cancer. Male sex is associated with increased GBM incidence and worsened prognosis but whether the AR is expressed or represents a therapeutic target in GBM is unknown. Using RNAseq and immunoblot, we found that GBM tumors, patient-derived xenografts and immortalized cell lines were frequently (i.e., >50%) AR (+) with expression levels that overlapped with prostate cancer. AR expression was 2-fold higher in GBM samples than normal brain tissue and was highest in the classical molecular subtype. Exogenous testosterone promoted the engraftment and growth of AR (+) T98G GBM xenografts in immunocompromised mice. SEVI, a blood-brain barrier permeable inhibitor of CYP17 lyase and the AR with clinical activity in prostate and breast cancer, inhibited the growth of AR (+) (T98G, LN18) but not AR(-) (8MGBA, AM38) GBM cell lines at achievable in vivo concentrations (GI50 = 3–4.0 uM) as measured by colony formation. Enzalutamide, an antiandrogen used clinically in prostate cancer but not GBM, also selectively inhibited colony formation in AR (+) GBM models, albeit at concentrations 3-6-fold higher than SEVI. SEVI selectively potentiated the action of RT in AR (+) GBM with enhancement ratios of 1.3–1.5 in clonogenic survival assays. Daily SEVI or RT slowed the growth of established androgen-driven T98G xenografts, which were further diminished by the combination of SEVI and RT. These results suggest that AR is frequently expressed in GBM and that androgen signaling promotes GBM growth in preclinical models. Inhibition of AR signaling alone or in combination with radiotherapy using clinical grade blood-brain barrier permeable antiandrogens may be a promising new treatment strategy for GBM.
CMET-42. BONE METASTASIS PREDICTS POOR PROGNOSIS OF PATIENTS WITH BRAIN METASTASES FROM COLORECTAL CARCINOMA POST AGGRESSIVE TREATMENT
Authors: Hao Duan, Xiaobing Jiang, Zhenqiang He, Juehui Li, Yonggao Mou
Journal: Neuro-Oncology (2018)

The presence of brain metastasis (BM) in patients with colorectal cancer (CRC) is usually associated with terminal stage illness; however, a subgroup of patients receiving aggressive treatment can have a satisfactory prognosis. This study was designed to investigate the profile of prognostic factors in CRC patients with BM treated aggressively. CRC patients with BM were retrospectively reviewed. Survival analysis was performed to identify potential prognostic factors in the entire cohort of patients and a subgroup of patients treated aggressively. Aggressive treatments included surgical resection, radiotherapy, and/or chemotherapy. Overall survival (OS) was defined as the time between the diagnosis of BM and death or until the date of the last follow-up visit. A total of 78 CRC patients were confirmed as having BM. Sixty-eight of them had extracranial metastases at the time of their BM diagnosis. The most common sites of extracranial metastases were lung (n=51, 65.4%), followed by liver (n=25, 32.1%), and bone (n=12, 15.4%). Fifty-one patients who were treated aggressively had significantly longer OS than those who accepted palliative care (14.1 months vs. 2.0 months, p<0.0001). Multivariate analysis was applied and results showed that aggressive treatment (n=51), recursive partitioning analysis (RPA) class I/II (HR=0.27, 95% CI: 0.12–0.6, p=0.001), and fewer BM (HR=0.4, 95% CI: 0.21–0.78, p=0.07) predicted longer survival. In contrast, the presence of bone metastasis, rather than lung or liver metastasis, at the time of diagnosis of BM (HR=2.38, 95% CI: 1.08–5.28, p=0.032) predicted a poor prognosis. Although the prognosis of CRC patients that have BM is frequently very poor, those with good performance status and few brain lesions responded to aggressive treatment, while those with bone metastasis at the time of diagnosis of BM had relatively dismal survival rates, even when treated aggressively.
IMMU-28. HIGH-DIMENSIONAL SINGLE CELL CHARACTERIZATION OF THE SYSTEMIC INFLUENCE OF NEOADJUVANT PD-1 BLOCKADE IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Aaron Mochizuki, Joey Orpilla, Alexander Lee, Alejandro Garcia, Linda Liau, Timothy Cloughesy, Robert Prins
Journal: Neuro-Oncology (2018)

PD-1 blockade has demonstrated efficacy in numerous cancer types; however, responses vary widely. Consequently, numerous studies have sought to identify reliable biomarkers that predict response to PD-1 inhibition. Documented responses to PD-1 blockade in GBM are limited to patients with hypermutated phenotypes, which are rare in this disease. We opened a multi-institutional pilot study of pembrolizumab in patients with recurrent, surgically resectable GBM, randomizing patients 1:1 to receive neoadjuvant plus adjuvant pembrolizumab or adjuvant-only therapy. We hypothesized that neoadjuvant PD-1 blockade would lead to statistically significant differences in peripheral immune cell populations, using time-of-flight mass cytometry (CyTOF) to achieve our aims. Patients who received neoadjuvant pembrolizumab demonstrated decreases in a CD33+CD11b+CD11c+CD14+CD16+ intermediate monocyte population between baseline and after surgery (adjusted P value = 0.027), whereas no changes were seen in the adjuvant-only group. When evaluating the median expression of markers of antigen experience and activation on various cell populations, we noted increases in CD127 and CTLA4 (P = 0.016 and 0.006, respectively) as well as decreases in PD-1 and CD25 (P = 0.016 and 0.027, respectively) expression on CD4+ T-cells in the neoadjuvant group before and after the first dose of pembrolizumab, but not the adjuvant-only cohort. On CD8+ T-cells, there was a significant decrease in PD-1 expression in the neoadjuvant group only (P = 0.004). Furthermore, in penalized regression survival analyses, a CD4+ T-cell population has emerged as a potential predictor of clinical response. Leveraging time-of-flight mass cytometry, we have demonstrated that neoadjuvant PD-1 blockade elicits distinct changes in myeloid and lymphoid cell populations in patients with recurrent, surgically resectable glioblastoma. We hypothesize that this is reflective of tumor-specific T-cell activation in the presence of tumor antigens; these T-cells are subsequently expanded and activated in a tumor- and interferon-γ-driven process following surgical resection.
Abstract 14719: Patients With Dofetilide-associated Torsades De Pointes Have at Least One Modifiable Risk Factor
Authors: Niyada Naksuk, Alan Sugrue, Deepak Padmahavan, Krishna Kancharlar, Christopher McLeod, Michael J Ackerman, Peter Noseworthy
Journal: Circulation (2017)

Introduction: Dofetilide is an effective medication for rhythm control in patients with symptomatic atrial fibrillation (AF). Its major adverse risk is torsades de pointes (TdP) which is reported a...
ACTR-01. SAFETY ANALYSES OF TUMOR TREATING FIELDS IN COMBINATION WITH LOMUSTINE IN THE EF14 PHASE 3 CLINICAL STUDY
Authors: Adrian Kinzel, Gitit Lavy-Shahaf, Eilon Kirson
Journal: Neuro-Oncology (2018)

INTRODUCTION: Tumor Treating Fields (TTFields) are low intensity (1-3V/cm), intermediate frequency (100–300 KHz) alternating electrical fields approved for glioblastoma (GBM). In the EF-14 phase 3 study, TTFields showed a significant overall and progression-free survival benefit for patients with newly diagnosed GBM in combination with Temozolomide (TMZ). TTFields were not associated with systemic toxicity. At recurrence, patients continued TTFields with second line therapies. We analyzed the safety and feasibility of TTFields + lomustine (CCNU) combination. Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed in both groups after tumor progression. We compared patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the two groups. Baseline characteristics were well balanced; there were less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29–83) versus 50.0 years (19–71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in rates of systemic adverse events compared to lomustine therapy alone (number of patients with ≥ 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups. CONCLUSION: The combination of TTFields and lomustine is safe and feasible. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other therapy modalities. This data is especially important in light of the recently presented promising data from a small randomized trial that tested the combination of lomustine plus TMZ in newly diagnosed (MGMT promotor-methylated only) GBM patients.
TMOD-26. CYTOMEGALOVIRUS PROMOTES GLIOBLASTOMA GROWTH VIA PDGF-D DRIVEN PERICYTE RECRUITMENT AND ANGIOGENESIS
Authors: Harald Krenzlin, Prajna Behera, Carmela Passaro, Mykola Zdioruk, Korneel Grauwet, C David James, Hirotaka Ito, Charles Cobbs, Charles Cook, E Antonio Chiocca, Sean Lawler
Journal: Neuro-Oncology (2018)

Human cytomegalovirus (HCMV) is highly prevalent, and like other herpes viruses, can persist for life in its host in a latent state. However, HCMV can be severely pathogenic in immunocompromised individuals. Interestingly, HCMV proteins and nucleic acids have been identified in up to 90% of patients with the incurable brain tumor glioblastoma (GBM) as well as some other cancers. Accumulating data supports the clinical relevance of HCMV in GBM, with some encouraging responses reported with HCMV-targeted immunotherapies. Although various HCMV proteins increase cell proliferation and invasion, a mechanistic link between HCMV and cancer in vivo has not been established, and the role of HCMV in GBM remains a subject of debate. In the current report we show that perinatal murine CMV (MCMV) infection induces a pro-angiogenic secretome, increasing tumor growth, pericyte accumulation, angiogenesis and tumor blood flow in a murine GBM model. Specifically, we identify platelet-derived growth factor-d (PDGF-D) as a CMV-induced factor essential for tumor growth. In our model, MCMV can be seen in tumor cells and vascular pericytes, a finding that we confirm in human GBM specimens. The anti-viral drug cidofovir improves survival in MCMV-infected mice, inhibiting MCMV activation, PDGF-D expression, pericyte recruitment and tumor angiogenesis. Together these data provide the first mechanistic explanation of how CMV potentiates GBM growth in vivo, identify PDGF-D as a potential therapeutic target, and support the application of anti-viral approaches for GBM therapy.
Foetal hypoxia impacts methylome and transcriptome in developmental programming of heart disease
Authors: Lei Huang, Xin Chen, Chiranjib Dasgupta, Wanqiu Chen, Rui Song, Charles Wang, Lubo Zhang
Journal: Cardiovascular Research (2018)

Antenatal hypoxia negatively impacts foetal heart development, and increases the risk of heart disease later in life. The molecular mechanisms remain largely elusive. Here, we conducted a genome-wide analysis to study the impact of antenatal hypoxia on DNA methylome and transcriptome profiling in foetal and adult offspring hearts.
Mlh1 as a tumor suppressor of skin
Authors: Mari Kuraguchi, Qingcong Lin, Nana Ohene-Baah, Joshua Gillum, Tao Yuan, Roderick Bronson, Raju Kucherlapati
Journal: Cancer Research (2007)

5712  DNA mismatch repair (MMR) is critical for maintaining both mitotic and meiotic genomic integrity. Hereditary defects in MMR are directly involved in the etiology of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) in humans, an autosomal dominant disorder that confers predisposition to colonic and other tumors. Germline mutations in hMLH1 are one of the most prominent of these and account for approximately 30% of the HNPCC kindreds. Somatic mutations in MMR genes also underlie some sporadic cancers. A series of mouse lines, each carrying inactivating germline mutation in a different MMR gene, have been developed to date. Mice that are deficient in Mlh1 are infertile and are predisposed to developing a spectrum of cancers, including tumors of the gastrointestinal tract. However, majority of the mice develop lymphoma and die of them, hindering the analysis of its role in other tissues. To create a model system to study the effects of Mlh1 deficiency in skin and to circumvent unnecessary tumorigenesis, we used the Cre-loxP technology to direct conditional inactivation of Mlh1 specifically in mouse epidermis. A mouse strain carrying conditional inactivating mutation of Mlh1 (Mlh1CKO), in which exon 2 of Mlh1 is flanked by loxP sites, was generated. Mice homozygous for Mlh1 conditional alleles developed normally and were fertile. This strain was crossed with K14-Cre transgenic mice that express Cre under the control of the human K14 gene promoter, a common epidermal promoter which is active in dividing cells of several stratified epithelia. K14-Cre; Mlh1CKO/CKO mice had decreased survival (13.5±1.5 months) and tumor susceptibility phenotype in both sexes. Skin malignancies, either basal cell or basosquamous carcinoma of skin, were most commonly seen with almost 100% incidence in male and 70% in female. Approximately half of the female mice also developed aggressive mammary adenocarcinoma with lung metastasis. We therefore show clearly that Mlh1 is an important tumor suppressor gene in skin tumorigenesis.
Abstract 12850: Complex Lesion Characteristics Would be the Potential Risk Factors for Ventricular Fibrillation With Acute Coronary Syndrome
Authors: Youichirou Sugizaki, Makoto Takemoto, Hiromi Toki, Yu Taniguchi, Nobuaki Igarashi, Takeomi Murata, Tomohumi Doi
Journal: Circulation (2015)

Background: In the setting of acute coronary syndrome (ACS), ventricular fibrillation (VF) was serious and fatal complication. However, even though ischemia was well known as the risk for occurrence of VF, what influential factors of ACS patients related to VF were still unclear. We performed extracorporeal cardiopulmonary resuscitation for VF with ACS patients taken to our institute and performed coronary angiography to make definite diagnosis. Accordingly, We sought to the risk factors for VF with ACS. Methods: Consecutive 246 ACS patients hospitalized and underwent emergent coronary revascularization from September 2010 to September 2014 were enrolled. In these, patients with VF were categorized into VF group, and patients without VF were into non-VF group. We reviewed patients’ characteristics, including medications, past histories and laboratory findings, and CAG findings (lesion characteristics with ACC/AHA classification, number of disease vessels, existence of chronic total occlusion (CTO) and left-main coronary artery (LMCA) lesion) retrospectively. Results: Fifty-seven patients developed ACS with VF (VF group), and 189 patients were without VF (non-VF group). Comparing between the groups, the morbidity of previous angina pectoris or coronary artery bypass grafting were significantly higher in VF groups (32.1%-16.0%, p=0.01, 14.3%-1.1%, p&lt;0.001, respectively). The prevalence of Complex lesion characteristics, such as multi vessel disease, CTO and LMCA lesion, was also higher in VF group (71.9%-42.8%, 43.9%-13.9%, 15.8%-6.3%, all p &lt; 0.025, retrospectively). Moreover, multiple logistic regression analysis revealed multi vessel disease and existence of CTO lesion were independent factors for VF. Conclusion: VF group had more complex characteristics of coronary artery disease. Complex lesion characteristics, such as multi vessel disease, CTO and LMCA lesion, would be potential risk factors of VF with ACS patients.