tbuckley/cabot-search huggingface dataset:
Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition
Authors: Xian Chen, Kwang-Huei Low, Angela Alexander, Yufeng Jiang, Cansu Karakas, Kenneth R. Hess, Jason P.W. Carey, Tuyen N. Bui, Smruthi Vijayaraghavan, Kurt W. Evans, Min Yi, D. Christian Ellis, Kwok-Leung Cheung, Ian O. Ellis, Siqing Fu, Funda Meric-Bernstam, Kelly K. Hunt, Khandan Keyomarsi
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. Experimental Design: Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E–mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines. Results: Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E–low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy. Conclusions:Cyclin E is a potential biomarker of response (i) for AZD1775 as monotherapy in cyclin E–high TNBC tumors and (ii) for sequential combination therapy with CDK2 inhibitor or carboplatin followed by AZD1775 in cyclin E–low TNBC tumors.
Abstract 12161: Toll-like Receptor 9 Plays a Pivotal Role in Angiotensin II-induced Atherosclerosis
Authors: Sachiko Nishimoto, Daiju Fukuda, Yasutomi Higashikuni, Kimie Tanaka, Yoichiro Hirata, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Michio Shimabukuro, Masataka Sata
Journal: Circulation (2015)

Background: Chronic vascular inflammation causes atherosclerosis. Toll-like receptor (TLR) 9 recognizes bacterial unmethylated DNA and plays a role in innate defense, whereas it can also provoke inflammation in response to fragmented DNA released from damaged mammalian cells. However, the role of TLR9 in the development of atherosclerosis remains unknown. Here, we investigated whether genetic deletion of TLR9 attenuates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. Methods and Results: We generated TLR9/ApoE double knockout (dKO) mice by crossing ApoE KO mice and TLR9 KO mice, and infused angiotensin II (Ang II) (1000 ng/kg/min) subcutaneously for 28 days using osmotic pump. There were no differences in blood pressure and plasma lipid levels between ApoE KO mice and TLR9/ApoE dKO mice. Ang II infusion significantly increased plasma levels of single-stranded DNA and double-stranded DNA, endogenous ligands of TLR9, in both strains of mice (P&lt;0.001, respectively). TLR9/ApoE dKO mice showed less atherosclerotic lesion progression in the aortic arch and less lipid accumulation in atherosclerotic plaques in the aortic root compared with ApoE KO mice (P&lt;0.05, respectively). TLR9/ApoE dKO mice also showed less gene expression of inflammatory molecules (e.g., ICAM-1, MCP-1) in the abdominal aorta. The result of cell sorting experiment using atherosclerotic aorta obtained from Ang II-infused ApoE KO mice demonstrated that macrophage population mainly expressed TLR9 in this tissue. We, therefore, performed in vitro experiments using thioglycolate-stimulated peritoneal macrophages. CpG ODN, agonistic oligonucleotide for TLR9, markedly promoted the expression of inflammatory molecules (e.g., ICAM-1 and MCP-1) in wild-type macrophages but not in TLR9 KO macrophages. Furthermore, conditioned medium (CM) of human umbilical vein endothelial cells (HUVECs) treated with Ang II promoted gene expression of ICAM-1 and TNF-α in THP-1 macrophages compared with CM of non-treated HUVECs. Conclusion: Our results suggested that Ang II infusion activates the TLR9 signaling in macrophages, leading to the promotion of vascular inflammation and atherosclerosis. TLR9 may serve as a potential therapeutic target for atherosclerotic diseases.
Phase II trial of irinotecan/temozolomide/dinutuximab/granulocyte macrophage colony stimulating factor (I/T/DIN/GMCSF) in children with relapsed/refractory neuroblastoma (NBL): A report from the Children's Oncology Group (COG).
Authors: Rajen Mody, Arlene Naranjo, Alice L. Yu, Emily Hibbitts, Wendy B. London, Barry L. Shulkin, Marguerite T Parisi, Sabah-E-Noor Servaes, Mitchell B Dicciani, Paul M. Sondel, Julia Glade-Bender, Howard Katzenstein, John Maris, Julie R. Park, Rochelle Bagatell
Journal: Journal of Clinical Oncology (2018)

10508 Background: COG ANBL1221 was a randomized Phase II selection design trial for patients (pts) with relapsed/refractory NBL. Randomization was stopped early when I/T/DIN/GMCSF was shown be the optimal combination for further study. In the small cohort assigned to I/T/DIN/GMCSF, the objective response rate was 53%. An expanded cohort was evaluated to more accurately assess response rate and better define the toxicity profile of this combination. Methods: Pts were eligible at first relapse/progression or first designation of refractory disease. Cycles were administered every 21 days. Objective responses were confirmed centrally. Toxicities were graded according to CTCAE v4.0. Results: 53 eligible pts were assigned to I/T/DIN/GMCSF; 17 during the randomized portion, 36 during study expansion. Median age was 5.1 years (range 1.3-15.9), 39 pts (74%) had measurable disease. Fourteen (26%) had MYCN amplified tumors, 20 (38%) had previously undergone high-dose chemotherapy with stem cell rescue, and 14 (26%) had received prior anti-GD2 antibody. 22 (42%) had relapsed disease and 31 (58%) had refractory/progressive disease (PD). Subjects received 378 total cycles (median 6). Of 53 pts assigned to I/T/DIN/GMCSF, 21 experienced objective responses [40%; 95% CI (26, 53)]; 10 PR, 11 CR. Seven had PD, 23 had stable disease. Two did not receive protocol therapy and did not undergo disease evaluations, but were included in the intention-to-treat analysis. Among responders, 4 (19%) had MYCN amplified tumors and 9 (43%) had previously received an anti-GD2 antibody. Of the 51 evaluable for toxicity, 13 (25%) had Grade 3 pain, 8 (16%) had Grade 3 diarrhea, and 4 (8%) had Grade 3 vomiting. Neutropenia (³Grade 3) was observed in 14 (27%), Grade 3 thrombocytopenia in 5 (10%), and Grade 3 fever/infection in 11 (22%). Conclusions: I/T/DIN/GM-CSF showed significant anti-tumor activity in pts with relapsed/refractory NBL. This combination was well-tolerated in a cohort of > 50 pts. Studies of biomarkers that may identify pts most likely to respond to this chemo-immunotherapeutic regimen are in progress. Clinical trial information: NCT01767194.
Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT).
Authors: Dalvinder Mandair, George Demetriou, Leonidas-Nikolaos Diamantopoulos, Haran Devakumar, Rickin Popat, Faidon Laskaratos, Martyn E. Caplin, Christos Toumpanakis
Journal: Journal of Clinical Oncology (2017)

4090 Background: The efficacy of peptide-radiolabelled receptor targeted therapy (PRRT) in patients with well differentiated neuroendocrine tumours has been demonstrated in Phase II and Phase III studies. The recently completed phase IV NETTER-01 demonstrated disease stabilisation or partial response in approximately 80% of patients. However, more studies are needed to identify predictors of PRRT response. We sought to investigate the clinic-pathological characteristics in patients that had radiological progression or death within 12 months of completion of treatment with PRRT. Methods: We performed a retrospective analysis of all patients who had PRRT from 2011-2016. Patient with at least one year of follow-up data from the last treatment dose were included. Patients with evidence of radiological progression within one year of finishing treatment (Group 1) were compared to a similar group with disease stabilisation/response (Group 2)that were matched for age, grade, primary and distribution of metastases. The indication for PRRT was defined as either small volume progression ( &lt; 20%) or progression by RECIST. Results: 307 patients underwent PRRT with Lu-177 or Y-90 DOTATATE during this period. 66 patients in Group 1 were compared to 64 patients in Group 2. There was a significant difference in median overall survival, Group 1 = 21 months compared to Group 2 = 35 months, (p &lt; 0.002). A significantly higher proportion of patients in group 1 had more than 50% liver volume (p &lt; 0.0001). Mean CgA was significantly higher in Group 1, 1250 pg/ml vs 608 pg/ml in Group 2 ( p &lt; 0.03). 18 patients in Group 2 had small volume progression prior to treatment commencement compared to 6 in Group 1 (p &lt; 0.003). Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be conisdered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.
Plasminogen activators and PAI-1 in esophageal cancer tissues.
Authors: Evgeniy N. Kolesnikov, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Larisa Kozlova, Yulia A. Pogorelova, Natalia D. Cheryarina, Natalya Chugunova, Mikhail Anatolievich Kozhushko, Tanzila Beksultanovna Kazieva, Adlan Lechaevich Bazaev
Journal: Journal of Clinical Oncology (2016)

e15508 Background: The most important mechanism of cancer progression is the destruction of surrounding basement membrane and extracellular matrix by tumor-associated enzymes. The purpose of the study was to determine prourokinase, urokinase (uPA-Ag, uPA-act), prothromboplastin, thromboplastin (tPA-Ag, tPA-act), PAI-1 ingibitor (PAI-1-Ag, PAI-1-act) in tissues of adenocarcinoma (A, n = 9) and squamous cell carcinoma (SCC, n = 27) of the esophagus. Methods: Resected A (G2, рTNM) and SCC (G2, рTNM) tissues were studied by ELISA. All components were determined in 10% homogenates prepared using standard physiological saline. Results: Tissues of tumor (T) and perifocal zone (PZ) of A and SCC showed significant increasein uPA-Ag, uPA-act, PAI-1-Ag and PAI-1-act (p < 0.01) compared to resection line (RL). tPA level in PZ of SCC was significantly higher than in RL and T (p < 0.01), while in A it was decreased in T and PZ compared to RL (p < 0.01). PAI-1-act/uPA-act balance decreased from RL to T in SCC and was sharply escalated in A T compared to RL and PZ (p < 0.01). PAI-1-act/tPA-act balance was significantly increased in SCC T compared to RL and PZ and increased from RL to T in A. PAI-1-Ag/PAI-1-act balance increased from RL to T in SCC and was sharply increased in SCC PZ compared to RL and T (p < 0.01). uPA plays the main role in progression of both SCC and A. tPA role requires to be clarified but probably it has defensive function in SCC PZ and in A it is inhibited by tumor toxins. It was implied by 1.4 times decrease in uPA-Ag/uPA-act in T and PZ of SCC and 2.1-2.9 times decrease in PZ and T of A. tPA-Ag/tPA-act balance was increased by 2.7 times in SCC T only, while in other samples it was decreased (p < 0.01) or tended to decrease. Conclusions: uPA and PAI-1 concentration in T was significantly higher than in RL in SCC and A. tPA content was higher in A RL than in its T and PZ, but in SCC PZ it was higher than in other tissue samples. uPA can be a target for SCC and A therapy.
Pattern of bone metastasis of primary-known cancers spreading through vertebral venous plexus.
Authors: Ming-Yu Zhu, Xin Liu, Yuan Qu, Silong Hu, Yingjian Zhang, Wentao Li, Xiaoyan Zhou, Huijuan Yang, Liangping Zhou, Qifeng WANG, Yifeng Hou, Yong Chen, Yan-Li Wang, Yaohui Wang, Zhong-Wu Lu, Zhi-Guo Luo, Xi-Chun Hu
Journal: Journal of Clinical Oncology (2018)

e24020 Background: Bone metastasis of cancer can be a result from systemic blood spreading or vertebral venous plexus spreading. Systemic blood pathway induced bone metastasis can happen in any bone in the body since the spreading is considered to be random. However, it remains unknown whether there is any pattern of vertebral venous plexus related bone metastasis. This study was undertaken to explore bone metastasis pattern in patients with known primaries. Methods: Of 2559 consecutive cancer patients with bone metastases diagnosed by PET/CT scan between Jan 2015 and Oct 2017 in Fudan University Shanghai Cancer Center, 298 patients with no visceral metastases were enrolled. The distribution and pattern of skeletal metastases were analyzed. Results: Of 298 cancer patients, there were 29 patients with head and neck tumors,183 thoracic tumors, 49 abdominal tumors and 37 pelvic tumors.110 (37%) patients had bone metastasis of solitary region and 118 (63%) had multiple regions. Overall, the thoracic skeleton was more frequently metastasized in patients with thoracic tumors than the other patients (79% vs 65%, p = 0.01). Cervical spine or thoracic bones was more frequently metastasized in patients with primary tumors above the diaphragm than those below the diaphragm (80% vs 64%, p= 0.004). Among 110 patients with bone metastasis of solitary region, patients with head and neck tumors had a higher incidence of cervical spine metastasis than other patients (22% vs 2%, p = 0.033), patients with thoracic tumors had a higher incidence of thoracic bone metastasis than other patients (52% vs 33%, p = 0.048), patients with pelvic tumors had a higher incidence of pelvis bone metastasis than other patients (70% vs 26%, p = 0.0001). Conclusions: In relatively early stage patients with bone metastases but no visceral diseases, we observed the characteristics of bone metastatic distribution that neighboring bones to the primary were more likely to be first metastasized, probably providing valuable clues to search for primary in patients with cancer of unknown primary.
P04.54 High Dose Progesterone Induces Growth Inhibition in Human U87 and A172 Glioblastoma Cell With Concomitant Changes in Mitochondrial and Cytoskeleton Proteins
Authors: M A Altinoz, M Yilmaz, Y Ucal, A Ozpinar, O Baskan, I Elmaci
Journal: Neuro-Oncology (2018)

BackgroundWe have previously shown that medroxyprogesterone acetate (MPA) induces growth inhibition and procarbazine sensitization in C6 rat glioblastoma cells. In this study, we aimed to determine the effects of high dose progesterone (HDP, 300 microM) on monolayer growth and proteomic changes in human U87 and A172 glioblastoma cells.
Can a cancer antigen (CA)15-3 directed monitoring strategy be resource sparing in metastatic breast cancer (MBC)?
Authors: Santam Chakraborty, Chandran Nallathambi, Subhosmito Chakraborty, Ishita Ghatak, Sandip Ganguly, Joydeep Ghosh, Rosina Ahmed, Sanjit Agrawal, Sanjoy Chatterjee
Journal: Journal of Clinical Oncology (2018)

e13104 Background: Serial monitoring of CA 15-3 levels can be used as a marker of disease activity in MBC. But the utility over and above image based monitoring remains controversial. We analyzed if such marker based monitoring would reduce imaging requirements and consequently lower direct costs in tertiary care practice. Methods: We retrospectively divided patients with MBC (between 2011-2016) into two groups- regular testers (TG) (≥ four serial CA 15-3 tests) and the rest as irregular/non-testers (NTG). CT and Bone Scans were performed to stage patients as per symptomatic requirement, clinicians judgement or if CA 15-3 level was rising. PETCT was reserved for select clinical dilemmas. Average imaging episodes and cost per year were calculated, and differences between groups tested for significance (t-test). A nearest neighbor propensity score matching method was used to match the baseline characteristics between groups and the analysis repeated. Results: Of 207 MBC, 117 were in TG and 90 NTG group with more ER-positive (87% v 78%) and less visceral metastases (31% vs 49%) ) in TG . The average number of CA 15-3 tests in TG was 7.56 (NTG: 0.82, p < 0.01). Patients in TG had a longer FU of 29.2 months (NTG 17.43, p < 0.01). TG patients needed fewer imaging tests annually (3.4 vs 5.0, p < 0.01) with reduced annual direct costs ($ 607.5 versus NTG : $ 872.2, p < 0.01) (Table 1). This difference persisted after propensity score-based matching (imaging TG vs NTG : 3.6 vs 5.0, p < 0.01) and annual costs (TG vs NTG: $ 645.3 vs $ 872.2, p < 0.01). Conclusions: Use of a serial CA 15-3 testing in MBC resulted in a clinically meaningful and statistically significant reduction in imaging requirement with direct cost savings of up to 30%. Also, indirect travel cost, pressure on hospital services and stress of extra imaging studies may be avoided using CA15-3 monitoring. Table 1:. Average annual number (standard deviation) of images and costs in two groups Modality TG (N = 117) NTG (N = 90) P value CT 2.1 (1.6) 3.3 (2.0) < 0.01 Bone Scan 1.2 (0.8) 1.7 (1.7) 0.01 PET CT 0.1 (0.4) 0.1 (0.2) 0.19 Total Cost (USD) 607.5 ( 403.3) 872.2 (540.4) < 0.01
Association of high baseline ferritin with tocilizumab administration for CRS in relapsed/refractory multiple myeloma patients treated with bb2121 anti-BCMA CAR T cells.
Authors: Jesus G. Berdeja, Yi Lin, James Kochenderfer, Noopur S. Raje, Nikhil C. Munshi, David Samuel DiCapua Siegel, Michaela Liedtke, Deepu Madduri, Jacalyn Rosenblatt, Marcela Valderrama Maus, Ashley Turka, Lyh Ping Lam, Kristen Hege, Timothy Brandon Campbell, Monica Massaro, Fabio Petrocca, Sundar Jagannath
Journal: Journal of Clinical Oncology (2018)

e15062 Background: Cytokine release syndrome (CRS) is the most common risk associated with chimeric antigen receptor (CAR) T cell therapies. Identification of predictors of severe CRS may enable earlier, more aggressive treatment of patients (pts) at high risk. We report key parameters associated with grade 2 CRS requiring tocilizumab or grade 3 CRS (tCRS) in an ongoing phase I trial of anti-BCMA CAR T cell therapy bb2121 in relapsed/refractory multiple myeloma [CRB-401, NCT02658929]. Methods: Pts who received active doses in Part A (150 [6], 450 [9], or 800 [3] × 106 CAR T cells) were included. Standard criteria for grading CAR T-associated CRS were used (Lee 2015). Results: Four of 18 (22%) pts developed tCRS, all within 30 days of bb2121 infusion. Pretreatment serum ferritin > 1500 µg/L was seen in 5 pts (min, max: 1516, 4653 µg/L); 4 developed tCRS. None of 13 pts with ferritin ≤ 1500 (min, max: 17, 381 µg/L) experienced tCRS. Serial ferritin levels were measured in 11 evaluable pts; ferritin further increased 1-2 days prior to tCRS in 3 of 3 evaluable tCRS pts, but not in 7 of 8 (87.5%) evaluable pts with CRS not requiring tocilizumab (non-tCRS; median peak, 9902 vs 324 mg/L). Baseline C-reactive protein and IL-6 levels were not associated with tCRS; both increased 1-2 days prior to tCRS and non-tCRS (median peak CRP, 163 vs 68 mg/L; median peak IL-6, 413 vs 17 pg/mL). Extensive bone marrow (BM) involvement ( > 50% plasma cells) was seen in 3 of 4 tCRS pts. All 4 tCRS pts had CAR T cell expansion after infusion (peak vector copies min, max: 361,474, 959,041 copies/µg gDNA), but comparable expansion was observed in 8 of 12 evaluable non-tCRS pts. All 4 tCRS pts received ≥ 450 × 106 CAR T cells. The fifth patient with baseline ferritin > 1500 µg/L had extramedullary disease with no BM involvement and received 800 × 106 CAR T cells, but only developed grade 1 CRS. We found no association between tCRS and age, gender, number of prior lines of therapy, bridging therapy, immunoglobulin subtype, or high-risk cytogenetics. Conclusions: The overall frequency of tCRS in this study was relatively low and associated with high baseline ferritin. High BM involvement and CAR T cell dose may contribute to risk. Clinical trial information: NCT02658929.
Alcohol consumption adjusted by aldehyde dehydrogenase 2 genotype: A potential risk factor for gastric cancer?
Authors: Botian Ye, Haojie Li, Xuefei Wang, Hongyong He, Heng Zhang, Lingqiang Min, Yihong Sun, Fenglin Liu
Journal: Journal of Clinical Oncology (2017)

e15541 Background: The role of aldehyde dehydrogenase 2 (ALDH 2) in alcohol metabolism has been ascertained, yet the association between ALDH2 genotype and the carcinogenesis of gastric cancer remains controversy. Methods: We retrospectively collected data of 292 subjects hospitalized in Zhongshan Hospital in Shanghai during March 2016 to September 2016. All subjects were divided into case group (identified with gastric cancer by postoperative pathology) and control group. Distribution of aldehyde dehydrogenase 2 genotype, drinking status along with other clinical variables were compared. Logistic regression model included age, gender, smoking and drinking status, family history and ALDH2 genotype. Adjusted odds ratios (ORs) were calculated. Results: There was a significant elevation of alchohol consumption in case group (P = 0.033). Subjects with ALDH2 *1/*2 and *2/*2 genotype showed less inclination for drinking than ALDH2 *1/*1 (P &lt; 0.001). The risk for gastric cancer showed no differences among subjects with ALDH2 genotype adjusted drinking status [OR 1.121, 95% confidence interval (CI) 0.555-2.263 in Never/rare drinkers; OR 3.380, 95% CI 0.232-49.240 in Light drinkers and OR 2.416, 95% CI 0.326-14.151). Further analysis indicated that high body weight index (BMI) and heavy smoking were individual risk factors for gastric cancer among Light/heavy dringkers with ALDH2 *1/*2 or *2/*2 genotype (OR 84.736, P = 0.021 for BMI and OR 3.904, P = 0.037 for smoking). Conclusions: A dose-response relationship between alchohol consumption and risk for gastric cancer was observed in primary analysis. However ALDH2 genotype failed to modify the alchohol consumption. Our findings suggested that there might be other pathways to further explain the mechanisim of the role of alchohol consumption in carcinogenisis of gastric cancer.