tbuckley/cabot-search huggingface dataset:
IMiDs enhance tumor cell apoptosis in tumor/PBMC co-cultures
Authors: Yuedi Wang, Dan Zhu, Laura Corral, Wendy Hong, Bernd Stein
Journal: Cancer Research (2005)

809  Immunomodulatory drugs (IMiDs) are thalidomide analogues that have been developed for improved anti-cancer and anti-inflammatory properties and decreased side effects. IMiDs have shown activities in hematologic cancers and solid malignancies, as well as having profound effects on the bone arrow microenvironment. IMiDs exert functions mainly by altering the production of cytokines and growth factors that in turn enhance immune responses against tumor cells. IMiDs also reduce production of VEGF and bFGF by both tumor cells and bone marrow stromal cells, thus inhibiting tumor angiogenesis. Importantly IMiDs are far more potent co-stimulators for T-cell activation than thalidomide, including increasing production of T cell cytokines and activation of CD8 and NK cells, therefore promoting a much stronger anti-tumor response. Because of those indirect effects of IMiDs on tumor cells there are only special cases where IMiDs have demonstrated antiproliferative activity in simple tumor cell proliferation assays. Therefore, there is the need for an in vitro assay system capable of revealing the anti-tumor activity of IMiDs in both hematological and solid tumor cell lines in a more physiologically relevant manner. We have developed a co-culture assay of PBMC and tumor cells as an in vitro model of tumor-host immune system interaction, to further explore the anti-tumor potential of IMiDs. This assay is non-radioactive and flow cytometry based. In this co-culture system, both Actimid and Revlimid strongly increased K562 tumor cells apoptosis while there was no effect of the drugs on K562 cells alone. Results from NK cell depletion and isolation experiments indicated that NK cells are essential in inducing K562 apoptosis by PBMC. Our data also indicated that NK activation by IMiDs was dependent on other cell types within the PBMC population. Moreover, it was shown that IMiDs enhanced CD56 expression and downregulated CD161 in NK and NKT cells. In further studies of this model, it was shown that the induction of apoptosis required cell-cell contact between the target cell K562 and the effector cell in the PBMC population. We have extended this study to other hematological cancers as well as solid tumors and have observed significant apoptosis-enhancing activities of IMiDs. In summary our data suggest that this co-culture system mimics at least partially the physiological environment of a tumor and allowed us to discover IMiD effects not seen with simple tumor cell proliferation models.
NIMG-56. PREDICTIVE MARKERS FOR MGMT PROMOTER METHYLATION IN GLIOBLASTOMAS
Authors: Tokunori Kanazawa, Hirokazu Fujiwara, Masahiro Jinzaki, Masahiro Toda, Kazunari Yoshida, Hikaru Sasaki
Journal: Neuro-Oncology (2018)

BACKGROUND AND PURPOSE: The Promoter methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene has been described as one of the most important predictors for chemotherapeutic response and patients survival in glioblastomas (GBs). Therefore, prediction of the MGMT promoter methylation status by imaging would help to preoperatively decide the overall treatment strategy as well as surgical strategy including placement of BCNU wafers. This study aimed to detect imaging parameters to predict MGMT promoter methylation in GBs using a commercially available software. MATERIALS AND We investigated 3 imaging features (ring enhancement, location and laterality) and apparent diffusion coefficient (ADC) parameters in 48 newly diagnosed glioblastomas treated at Keio University Hospital in 2006 or later. For ADC, texture analyses were performed. Regions of interest (ROIs) were drawn manually with reference to the relatively higher signal on contrast-enhanced T1-weighted images excluding necrotic and cystic regions. Mean ADC value and ADC histogram parameters including kurtosis, skewness and entropy were compared with MGMT promoter methylation. Each parameter was evaluated if any correlation with MGMT promoter methylation, and the parameters with significant association with the methylation status were correlated with MGMT positive cell ratio in immunohistochemistry. ADC entropy and mean ADC value were significantly associated with MGMT promoter methylation. The combination of ADC entropy and mean ADC value predicted MGMT promoter methylation with PPV of 81.2%, specificity of 88.9%. ADC entropy and mean ADC value were negatively correlated with MGMT positive cell ratio in immunohistochemistry. CONCLUSIONS: This study demonstrated that texture analyses of apparent diffusion coefficient histograms in GBs using a commercially available software were useful for predicting MGMT promoter methylation.
Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer
Authors: Yoshikazu Johmura, Ichiro Maeda, Narumi Suzuki, Wenwen Wu, Atsushi Goda, Mariko Morita, Kiyoshi Yamaguchi, Mizuki Yamamoto, Satoi Nagasawa, Yasuyuki Kojima, Koichiro Tsugawa, Natsuko Inoue, Yasuo Miyoshi, Tomo Osako, Futoshi Akiyama, Reo Maruyama, Jun-ichiro Inoue, Yoichi Furukawa, Tomohiko Ohta, Makoto Nakanishi
Journal: Journal of Clinical Investigation (2018)

The agonistic/antagonistic biocharacter of selective estrogen receptor modulators (SERMs) can have therapeutic advantages, particularly in the case of premenopausal breast cancers. Although the contradictory effects of these modulators have been studied in terms of crosstalk between the estrogen receptor α (ER) and coactivator dynamics and growth factor signaling, the molecular basis of these mechanisms is still obscure. We identify a series of regulatory mechanisms controlling cofactor dynamics on ER and SERM function, whose activities require F-box protein 22 (Fbxo22). Skp1, Cullin1, F-box-containing complex (SCFFbxo22) ubiquitylated lysine demethylase 4B (KDM4B) complexed with tamoxifen-bound (TAM-bound) ER, whose degradation released steroid receptor coactivator (SRC) from ER. Depletion of Fbxo22 resulted in ER-dependent transcriptional activation via transactivation function 1 (AF1) function, even in the presence of SERMs. In living cells, TAM released SRC and KDM4B from ER in a Fbxo22-dependent manner. SRC release by TAM required Fbxo22 on almost all ER-SRC-bound enhancers and promoters. TAM failed to prevent the growth of Fbxo22-depleted, ER-positive breast cancers both in vitro and in vivo. Clinically, a low level of Fbxo22 in tumor tissues predicted a poorer outcome in ER-positive/human epidermal growth factor receptor type 2-negative (HER2-negative) breast cancers with high hazard ratios, independently of other markers such as Ki-67 and node status. We propose that the level of Fbxo22 in tumor tissues defines a new subclass of ER-positive breast cancers for which SCFFbxo22-mediated KDM4B degradation in patients can be a therapeutic target for the next generation of SERMs.
EPID-16. CONSIDERATIONS FOR A SURGICAL RCT IN LOW-GRADE GLIOMAS: A SURVEY
Authors: Alireza Mansouri, Michael Cusimano
Journal: Neuro-Oncology (2018)

The management of diffuse low grade gliomas (LGGs) has seen a paradigmatic shift favoring maximal safe surgical resection (MSR). While this approach is not based on randomized-controlled trials (RCTs), the extent of evidence from observational data has prompted arguments against equipoise in LGG management, thus suggesting an RCT comparing MSR with other surgical options unethical. To explore opinions within the SNO neuro-oncology community regarding feasibility, ethics, and endpoints for a putative RCT comparing MSR with other management options. A survey of 19 questions was developed on the Qualtrics® platform and distributed to the SNO members on a one-time basis. Among 128 participants, 111 (87%) were consultants. The majority were neuro-oncologists (70, 55%), followed by neurosurgeons (41, 32%), and radiation oncologists (7, 6%). Thirty-five of 111 (32%) thought there was equipoise in LGG management. An RCT was thought to be ethical in 56/116 (48%) and potentially feasible in 66/108 (61%). Potential willingness to participate in an RCT was expressed by 73/108 (68%). There were no correlation between sub-specialty and any of the responses. The ideal patient for randomization was thought to be age < 40 years with minimal neurological symptoms presenting with a small (0-3cm) non-enhancing lesion in an eloquent/deep location. The ideal endpoint selected by most 39/97, 40% was the combination of overall survival and quality of life. The majority of respondents ruled out equipoise. However, LGGs are heterogeneous and an RCT may be needed to define the ideal management approach in a specific subset of this population. Quality of life and other patient-centered parameters must be incorporated as primary endpoints, alongside survival. Due to anticipated challenges such as a small sample size, heterogeneous management approaches, and a protracted clinical course, careful consideration of feasibility and a large-scale, multi-center approach would be necessary.
Abstract 14849: Gender Differences in Impact of CYP2C19 Polymorphism and Low Grade Inflammation on Coronary Spasm in Patients with Vasospastic Angina (VSA)
Authors: Tomonori Akasaka, Seiji Hokimoto, Noriaki Tabata, Kenji Sakamoto, Kenichi Tsujita, Sunao Kojima, Koichi Kaikita, Hisao Ogawa
Journal: Circulation (2014)

Background: Several cytochrome P450 (CYP) enzyme families have been identified in extra hepatic tissues such as heart, vasculature, kidney, and lung. CYP2C19 localized in vascular smooth muscle and endothelium contributes to the regulation of vascular tone and homeostasis. However, it is unknown whether CYP2C19 genotype is associated with the vascular tonus in patients with VSA. The aim of this study was to examine the impact of CYP2C19 genotype on coronary artery spasm in patients with VSA. Methods: We examined the distribution of CYP2C19 genotype in patients with VSA (n=129) who were diagnosed by intra-coronary acetylcholine infusion test and healthy subjects (n=455) as control group. CYP2C19 genotypes were divided into 3 groups; (1) CYP2C19*1/*1: EM, (2) one loss-of-function allele (*1/*2, *1/*3: IM), and (3) two loss-of-function alleles (*2/*2, *2/*3, *3/*3: PM). Moreover, we measured the level of high-sensitive CRP (hs-CRP) as a degree of low glade inflammation in each group. Results: The ratios of CYP2C19 genotype (EM, IM, and PM) were 30, 42, and 28% in VSA group, and 32, 49, and 19% in control group. In short, PM frequency was significantly higher in VSA than in control (28% vs 19%, P=0.026). In VSA group, the ratios of CYP2C19 genotype were 36, 44, and 20% in male, and 20, 39, and 41% in female, respectively. Briefly, the PM frequency was significantly higher in female than in male (41% vs 20%, P&lt;0.001). Moreover, the level of hs-CRP was significantly higher in VSA group than in control group (0.17±0.367 vs 0.10.±0.240, P=0.02). When patients were stratified by gender, the level of hs-CRP was significantly higher in VSA group in female (0.11±0.198 vs 0.06±0.105, P=0.031) and male (0.20±0.438 vs 0.12±0.277, P=0.044). Multivariate analysis for coronary spasm indicated high age, hypertension, and high level of hs-CRP as predictive factors among all subjects. PM is a predictive factor for coronary spasm in female group only (OR3.1, 95%RI 1.525-6.317, P=0.002), but not in male (OR0.829, 95%RI 0.453-1.518, P=0.543). Conclusion: The CYP2C19 two loss-of-function alleles (PM) and low grade inflammation may be associated with pathophysiology of coronary artery spasm and the regulation of coronary tonus, especially in female.
ACTR-22. A PHASE I STUDY OF CYTOSINE DEAMINASE-EXPRESSING NEURAL STEM CELLS (CD-NSCs) ADMINISTERED INTRACRANIALLY AND IN COMBINATION WITH ORAL 5-FLUOROCYTOSINE (5-FC) AND LEUCOVORIN IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA
Authors: Jana Portnow, Timothy Synold, Behnam Badie, Suzette Blanchard, Julie Kilpatrick, Revathiswari Tirughana, Marianne Metz, Vivi Tran, Karen Aboody
Journal: Neuro-Oncology (2018)

Human NSCs are tumor tropic, making them attractive vehicles for delivery of therapeutics. An immortalized, clonal NSC line was retrovirally transduced to express CD, which converts 5-FC to 5-fluorouracil (5-FU). The primary objectives of this study were to assess the feasibility of serially administering CD-NSCs intracranially via a Rickham catheter and determine the recommended doses for phase II testing (RP2D). Adult patients with recurrent high grade gliomas underwent tumor resection or biopsy and placement of a Rickham. CD-NSCs were injected during surgery and thereafter infused through the Rickham every 2 weeks. Three days after each dose of CD-NSCs, patients took 5-FC (and leucovorin—dose level 3 patients only) orally every 6 hours for 7 days. The dose of CD-NSCs was escalated from 50 x 106 to 150 x 106 using a standard 3 + 3 design. 5-FC and leucovorin doses were 37.5 mg/kg and 25 mg, respectively. A treatment cycle was 28 days, with CD-NSCs administered on days 1 and 15, followed by 5-FC (and leucovorin) on days 4–10 and 18–24. Blood samples were drawn to assess for possible anti-NSC antibody and T cell responses. Fifteen evaluable patients received a median of 2 (range 1–5) cycles of study treatment. One dose-limiting toxicity occurred: grade 3 wound infection. Three patients developed anti-NSC antibodies after receiving 3 doses of NSCs. There was no correlation between these results and use of dexamethasone or number of cycles. Analyses of PK and possible anti-NSC T cell responses are ongoing. Three patients had stable disease for 5 months. Use of a Rickham to serially administer CD-NSCs intracranially is safe and feasible. Study treatment was well tolerated. There were no clinical signs of immunogenicity to these allogeneic CD-NSCs. The RP2D is 150 million CD-NSCs, 37.5 mg/kg of 5-FC, and 25 mg of leucovorin per dose.
Oncology in Transition
Authors: Deborah Schrag, Ethan Basch
Journal: JAMA (2018)

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DDIS-15. A NOVEL DOPAMINE RECEPTOR 3 ANTAGONIST INHIBITS THE GROWTH OF PRIMARY AND TEMOZOLOMIDE RESISTANT GLIOBLASTOMA CELLS
Authors: Sarah Scott, Catherine Libby, Anita Hjelmeland
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common, lethal primary adult brain tumor with patient survival of only 14 months. The location and invasion of GBM leads to rapid recurrence after therapy. The standard of care chemotherapy is DNA damaging agent temozolomide (TMZ), to which resistance is common and is due, partly, to expression of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase(MGMT), regulated by promoter methylation. To improve treatment of GBMs, including those resistant to TMZ, we explored targeting dopamine receptor signaling. Prior reports indicated roles for dopamine receptor 2 and 4 in GBM, with these inhibitors being effective in combination with EGFR inhibitors or temozolomide, respectively. We demonstrate that dopamine receptor 3 (DRD3) is an alternative target for therapy, with an expected low risk of severe side effects due to restricted expression in non-tumor brain. Six novel antagonists of DRD3 decreased the growth of GBM xenograft-derived neurosphere cultures, with minimal toxicity against human astrocytes and neurons. For those compounds, with a potential therapeutic window, two (SRI-21979 and SRI-30052) readily crossed the BBB and yielded no signs of liver or kidney dysfunction. In orthotopic models, 10 mg/kg of SRI-21979 per day for ten days, alone or combined with TMZ, trends toward increased survival. In striking contrast, we observed no benefit for haloperidol treatment in combination with TMZ beyond that for TMZ alone. Further analysis of TCGA data demonstrated that, unlike DRD2 and DRD4, DRD3 levels were not reduced in MGMT unmethylated GBMs and higher levels of DRD3 were associated with worse prognosis, suggesting that DRD3 antagonists may remain efficacious in TMZ resistant GBMs. SRI-21979, but not haloperidol or TMZ, significantly reduced the growth of TMZ resistant U251 cells and neurospheres derived from a TMZ-resistant xenograft. Our data demonstrate that DRD3 antagonist based combinatorial therapies may provide a potential, novel therapeutic treatment for GBM.
CMET-29. PRE-OPERATIVE DURAL CONTACT IS ASSOCIATED WITH SURGICAL CAVITY RECURRENCE AFTER POST-OPERATIVE STEREOTACTIC RADIOSURGERY
Authors: Matthew Susko, Yao Yu, Lijun Ma, Philip Theodosopoulos, Michael McDermott, Penny Sneed, Steve Braunstein
Journal: Neuro-Oncology (2018)

Brain metastases can be expected in 20–40% of patients diagnosed with cancer. Resection of a solitary or symptomatic brain metastasis provides immediate decompression and has been shown to improve overall survival, generally with some form of adjuvant postoperative radiation to reduce risk of recurrence. We sought to evaluate risk factors for local recurrence after postoperative single-fraction stereotactic radiosurgery (SRS). Patients who underwent surgical resection of a brain metastasis between 2006 and 2016 were retrospectively reviewed. Characteristics of the pre-surgical tumor, surgical resection, and post-surgical treatment were collected. Patients who received single fraction post-operative stereotactic radiosurgery (SRS) to the resection cavity were included for analysis. Surgical cavity recurrences were evaluated based on the location of their centroid within the dose distribution and categorized as infield, marginal, and out-of-field. A total of 58 patients with 60 resection cavities receiving post-operative SRS met the criteria for inclusion in study. During a median follow up of 20 months, 12 patients were noted to have surgical cavity recurrences with actuarial 1 and 2-year local failure rates of 15% and 18% respectively. Of the recurrences. 5 were infield, 5 were marginal, and 4 were out of field. Evaluation of the pre-operative tumor characteristics revealed that tumors with dural/meningeal contact had a significantly higher risk of local failure using Fishers exact test (p=0.025). Quadratic-mean-diameter, target volume, dose, and conformity index were not significantly associated with local recurrence. 1-year actuarial rate of adverse radiation effect (ARE) was 8% in this cohort. Dural/meningeal contact was associated with an increased risk of surgical cavity failure in patients undergoing post-operative SRS. In light of these results, and the recent consensus guidelines regarding contouring of post-operative surgical cavity for SRS, further consideration should be the addition of a dural margin in post-operative surgical cavity target delineation.
Upregulation of proline oxidase transcriptional activity by peroxisome proliferator-activated receptor-gamma (PPAR-γ)
Authors: Jui Pandhare, Sandra K. Cooper, Yongmin Liu, Steven P. Donald, James M. Phang
Journal: Cancer Research (2004)

4350   Proline oxidase (POX), also known as proline dehydrogenase, is a mitochondrial membrane-bound enzyme catalyzing the conversion of proline to pyrroline-5-carboxylate coupled to the transfer of electrons to cytochrome  c . We and others have shown that  POX  is a p53-induced gene and hyperexpression of  POX  in colon cancer cells is sufficient for initiating the apoptotic cascade. Despite the demonstrated role of POX in p53-mediated growth inhibition and apoptosis, the molecular mechanisms regulating its expression are not defined. To gain an understanding of these mechanisms, we cloned the human  POX  promoter region and produced a  POX  promoter/luciferase reporter construct. By transient transfection studies using expression constructs of several transcription factors in human colon cancer (LoVo) cells and human embryonic kidney (HEK293) cells, we character-ized mechanisms involved in POX expression. Analysis of the promoter nucleotide sequence revealed a number of putative transcription factor-binding sites including C/EBP, AP-1, Sp1, RAR, PPAR, RXR and others which became the basis for our initial studies. In LoVo cells, several transcription factors (PEA3, p300, c-Jun, c-Fos, Fra 1, Jun-D) were modestly active in  POX  expression, but the most active was PPAR-γ. We found a similar response in HEK 293 cells in which expression of PPAR-γ resulted in a seven- to ten-fold activation of the  POX  promoter. This effect of PPAR-γ was further enhanced by PPAR-γ ligands, troglitazone and ciglitizone, in a concentration-dependent manner. Peroxisome proliferator-activated receptors (PPARs) have received recent attention because these nuclear hormone receptors, which function as ligand-activated transcription factors regulating lipid metabolism and homeostasis, are involved in genetic control of many cellular processes. Recent reports by others suggest that PPAR-γ ligands induce apoptotic cell death in colon cancer cells and suppress colon carcinogenesis in mice. Our current results establish a significant role for PPAR-γ in regulation of  POX  expression and suggest that  POX  is a target gene of PPAR-γ mediating the apoptotic process.
SURG-18. COMPARISON OF SURVIVAL OUTCOMES BETWEEN PARTIAL RESECTION AND BIOPSY FOR PRIMARY GLIOBLASTOMA: A PROPENSITY SCORE-MATCHED STUDY
Authors: Jeong Hoon Kim, Joonho Byun, Sae Min Kwon
Journal: Neuro-Oncology (2018)

OBJECTIVES: Gross total resection (GTR) for glioblastoma (GBM) is associated with a better prognosis. However, GTR is not always feasible and the threshold of the extent of resection for better prognosis is controversial. Therefore, we compared the survival and clinical outcomes of GBM between partial resection (PR) and biopsy. Methods Thirty-two and 78 patients who underwent PR and biopsy, respectively, were enrolled this study to identify differences in clinical outcomes. There were no differences in patient demographics between the PR and biopsy groups except for tumor location and mean tumor volume (p=0.02 and <0.01, respectively). Propensity score matching (PSM) between the PR and biopsy groups was performed, in which 20 patients each were matched in the PR and biopsy groups. Results The overall survival (OS) and progression-free survival (PFS) did not differ significantly between the PR and biopsy groups (p=0.84 and 0.48, respectively). After PSM, the difference in OS and PFS difference between the groups was not statistically significant (p=0.51 and 0.75, respectively). The hazard ratios for OS and PFS of PR to biopsy were 0.98 and 0.73, respectively; however, the difference was not statistically significant (p=0.96 and 0.39, respectively). The surgical complication rate was higher in the PR group (14 of 32, 43.7%) than that in the biopsy group (9 of 78, 11.5%) (p<0.01). Conclusion PR failed to improve survival compared to biopsy in patients with GBM. Moreover, the surgical complication rate in the PR group was higher than that in the biopsy group.