tbuckley/cabot-search huggingface dataset:
Abstract 18726: Single Cell Expression Profiling Reveals Up-Regulation of Radiation Sensitive Genes After Cardiac Computed Tomographic Angiography
Authors: Patricia Nguyen, Won Hee Lee, Shijun Hu, Veronica Sanchez-Freire, Patricia De Almeida, Kazim Narsinh, Andrew Lee, Dominik Fleischmann, Joseph Wu
Journal: Circulation (2012)

Introduction: High dose radiation activates radiation sensitive genes involved in the DNA damage response pathway, which is responsible for tumor suppression. Whether low dose radiation from medical imaging tests, such as cardiac computed tomographic angiography (CTA), changes the expression of these genes is unknown. Hypothesis: We hypothesize that low dose radiation alters the gene expression of 3 genes involved in tumor suppression: 1) MDM2 (a negative regulator of p53-induced cell cycle arrest and apoptosis), 2) BAX (a mediator of p53-induced apoptosis), and 3) DDB2 (a mediator of DNA repair). Methods: To determine the optimal time point for collection of blood in vivo, we performed an in vitro study. Blood from healthy volunteers (n=4) received either irradiation with a single dose of 25 mGy or 5,000 mGy, or received sham-irradiation. Whole blood was maintained at 37° for 6, 12, 24, and 38 hours following irradiation. Blood was collected from adult patients immediately before and 24 hours after CTA (n=10) or echocardiography (n=5). After separation of lymphocytes, gene expression was analyzed by single cell polymerase chain reaction. Results: The in vitro study showed significant up-regulation of MDM2, BAX, and DDB2 after low and high dose irradiation compared with sham-irradiated controls (Figure 1A, B, C). Similarly, up-regulation of these genes was noted in patients undergoing CTA (3-15 mSv) for various indications but not in patients undergoing echocardiography (Figure 1D). Of note, only 50% of patients had changes in gene expression. Conclusions: Low dose radiation from CTA alters the expression of genes involved in regulating tumor suppression. These findings, however, are seen in only 50% of patients. Further investigation is needed to determine how to identify these “radiosensitive” patients.
Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade
Authors: Alexandra Eichten, Jia Su, Alexander P. Adler, Li Zhang, Ella Ioffe, Asma A. Parveen, George D. Yancopoulos, John Rudge, Israel Lowy, Hsin Chieh Lin, Douglas MacDonald, Christopher Daly, Xunbao Duan, Gavin Thurston
Journal: Cancer Research (2016)

Anti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF-resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept. Compared with the parental tumors, A431-V tumors secreted greater amounts of IL6 and exhibited higher levels of phospho-STAT3. Notably, combined blockade of IL6 receptor (IL6R) and VEGF resulted in enhanced activity against A431-V tumors. Similarly, inhibition of IL6R enhanced the antitumor effects of aflibercept in DU145 prostate tumor cells that displays high endogenous IL6R activity. In addition, post hoc stratification of data obtained from a clinical trial investigating aflibercept efficacy in ovarian cancer showed poorer survival in patients with high levels of circulating IL6. These results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results. Cancer Res; 76(8); 2327-39. ©2016 AACR.
Novel phase I design for oncology research
Authors: L. Lupinacci, K. Anderson, L. Sun, Y. Tymofyeyev
Journal: Journal of Clinical Oncology (2009)

2517 Background: Phase I studies in oncology patients seek to identify a dose of a new investigational agent that is tolerable and has the potential to be effective. Toxicity data are the key to defining dose levels of the new agent that are acceptable for further study. Several Phase I designs are available to researchers. Some are practical and easy to implement. Others are complex but yield better information on the toxicity of studied doses. We sought a Phase I design that had a high probability of selecting a dose with acceptable toxicity, allowed adaptation based on observed dose-limiting toxicity (DLT) data and did not create considerable enrollment delays. Methods: We compared the 3+3 design, an algorithmically-determined adaptive method proposed by Ji, et al. (2007), and variations on Ji's design including a 2-stage design combining a 3+3 with a modified Ji design. We simulated Phase I trials with 6 dose levels and 12 dose response relationships and studied the properties of the designs including how often the dose with the target toxicity level was selected, the expected percentage of patients with a DLT and the expected sample size. We also implemented operational conventions on top of the preferred design to enhance the practicality and clinical usefulness of the design. Results: In general, the adaptive, Ji-based designs outperformed the 3+3, selecting the target dose up to 18% more often. The 2- stage and other Ji-based designs were comparable in most scenarios and performed the best when the target dose was among the middle doses in the dose range tested. When the target dose was the highest dose or higher than all of the doses tested, the 3+3 and 2-stage designs outperformed some of the other Ji-based designs. Conclusions: For single agent studies, we prefer a 2-stage design in which a 3+3 is implemented until a preliminary maximum tolerated dose (MTD) is identified. Then, a modified Ji design (target toxicity rate = 20%) is used to confirm the MTD and allow further dose refinement. While this design may underperform slightly compared with the complex continuous reassessment methods, this design is easier to implement and more intuitive to investigators and ethical and regulatory review boards. In addition, it maximizes enrollment continuity while ensuring appropriate patient safety. [Table: see text]
Chemo-radiotherapy versus radiotherapy alone for nasopharyngeal carcinoma: A meta-analysis of 78 randomized controlled trials (RCTs) from English and non-English databases
Authors: K. Thephamongkhol, J. Zhou, G. Browman, R. K. W. Wong, J. C. K. Chan, Y. Zeng, L. Thabane, I. Hodson, T. Oliver
Journal: Journal of Clinical Oncology (2004)

5522 Background: To obtain the best estimate for survival benefits of chemo-radiotherapy (CT + RT) compared with radiotherapy alone (RT) in nasopharyngeal cancer (NPC) and to evaluate the optimal timing of CT Methods: Datasources: 10 English language databases, 6 Chinese, including hand searching 26 Chinese Oncology Journals, 3 Korean, 2 Japanese, 1 African and 1 South East Asian databases. The Cochrane search strategy was used. Study Selection: Published reports or abstracts of RCTs comparing CT + RT versus RT for newly diagnosed NPC. Data Extraction: 2 reviewers independently extracted data and scored for trial quality.Where available, authors were contacted for actual number of events. Quality Scores: 2 points for randomization, 1 for completeness of follow up and 1 for intention-to-treat analysis (score range 0–4) Results: Data Synthesis: 101 RCTs were identified, 88 from Chinese and 13 from English language. 78 RCTs (9279 pts) reported 2 year or longer survival with characteristics as follows: median quality score 2, median sample size 89, number of RCTs : neoadjuvant (N) only 28, concurrent (C) only 19, adjuvant (A) only 8, C+A 3, N+C 5, N+A 14, N+C+A 6 ( > 2 arms in 3 RCTs). CT was cisplatin in 68, non-cisplatin in 10. Pooled Analysis: [table] Across all trials, CT + RT improve overall survival (OS) and disease free survival (DFS). Concurrent CT with or without adjuvant CT and neoadjuvant CT alone all improve OS and DFS. Sensitivity analysis of 3 year OS was done by excluding poor quality studies. The results were unchanged; however the effect of all trials and of neoadjuvant CT are borderline when all Chinese trials were excluded. Conclusions: CT administered concurrently with or without adjuvant therapy + RT improves OS and DFS in NPC. The role of CT as neoadjuvant remains controversial when Chinese trials are excluded from the analysis. No significant financial relationships to disclose.
Bidirectional induction of the cognate receptor-ligand α4/VCAM-1 pair defines a novel mechanism of tumor intravasation
Authors: Laura Bogetto, Elena Gabriele, Roberta Cariati, Riccardo Dolcetti, Paola Spessotto, Claudio Doglioni, Mauro Boiocchi, Roberto Perris, Alfonso Colombatti
Journal: Blood (2000)
Inhibition of Transplanted Rat Tumors by Immunization With Identical Tumor Cells Infected With Friend Virus
Authors: Hiroshi Kobayashi, Fujiro Sendo, Hiroshi Kaji, Toshikazu Shirai, Hiroshi Saito, Noritoshi Takeichi, Masuo Hosokawa, Takao Kodama
Journal: JNCI Journal of the National Cancer Institute (1970)

We previously reported that rat tumor cells infected with Friend virus were not transplantable as continuously growing neoplasms in otherwise susceptible strains of rats because they possessed Friend virus-related antigens. In the present investigation rat tumor cell lines WST-5, DLT, and KMT-68 did not grow in otherwise susceptible rats if they had received injections of the Friend virus-infected cells of these same lines before challenge. The immunizing effect of the virus-infected cells on the transplanted noninfected tumor cells was notably greater than the effect of other immunizing procedures we had tested. Even when the same immunizing methods were used, the immunogenicity of tumor cells infected with Friend virus on the transplanted noninfected tumor cells was definitely stronger than that of noninfected tumor cells. The possibility of immunologic treatment of tumors with virus-infected tumor cells is discussed.
Multibiomarker analysis homing in on EGFR-TKIs therapy in non-small cell lung cancer.
Authors: H. Bai, T. An, M. Zhuo, J. Zhao, M. Wu, J. Duan, L. Yang, Z. Wang, J. Wang
Journal: Journal of Clinical Oncology (2010)

e18025 Background: EGFR mutation has been identified to be a strong predictive biomarker to EGFR-TKIs in non-small cell lung cancer (NSCLC), but it isn't exclusive molecular mechanism to TKI therapy. So developing platforms of serial of biomarkers detection is important for personalized TKI therapy. This study investigated the relationships between genetic factors and clinical outcome in Chinese NSCLC patients treated by gefitinib. Methods: A total of 156 NSCLC were enrolled for genetic screening and 101 of which were treated by gefitinib. EGFR AKRAS mutation (mEGFR, mKRAS) were identified by denaturing high performance liquid chromatography (DHPLC) and EGFR copy number AEML4-ALK rearrangement were detected using fluorescent in situ hybridization (FISH). A polymorphic dinucleotide repeat (CA simple sequence repeat1 [CA-SSR1]) was determined by DNA sequencing. Results: mEGFR, mKRAS, EGFR FISH positive and EML4-ALK rearrangement were detected in 62 (39.7%),13 (8.3%), 49 (20.2%), 6 (3.8%) pts, respectively. Pts with shorter (CA)n repeat genotype (< 18) account for 45.5%. The mKRAS was found to be significantly higher in the shorter (CA)n than in the longer group (≥ 18) (p = 0.018), but EGFR FISH positive was higher in longer (CA)n group (p = 0.004) and the associations between (CA)n length and EGFR mutations and EML4-ALK rearrangement were observed. Among 102 pts with gefitinib therapy, EGFR mutant had significantly higher ORR than wild-type group (28/47, 60% versus 9/54, 17% p = 0.000). Further analyzing 54 patients with EGFR wild-type, 32 was in longer (CA)n and 22 in shorter (CA)n. Of 9 pts carrying wild-type EGFR who had response to gefitinib, 8 showed longer (CA)n polymorphism, and only 1 was in shorter (CA)n (p = 0.048). All of 6 mKRAS pts were present in the 22 shorter (CA)n group. The survival analysis showed the pts with mEGFR (9.4months ver 6.8months, p = 0.055), KRAS wild-type (8.4 months ver 3.1months, p = 0.019) and longer (CA)n (9.4months ver 6.2months, p = 0.073) had longer PFS. Conclusions: Multibiomarkers analysis may be more accurate for predicting response to TKI than single biomarker. The valid combination of molecular testing should be validated by large- samples study. No significant financial relationships to disclose.
Epirubicine-vinorelbine (EV) intravenous combination followed by oral vinorelbine (VNR) as first-line treatment in advanced breast cancer (ABC) patients: A POLONORD Group study
Authors: L. Frontini, A. Ardizzoia, M. Giordano, D. Fagnani, A. Scanni, L. Isa, G. Scognamiglio, T. Pressiani, I. Colombo, A. Bertolini
Journal: Journal of Clinical Oncology (2005)

770 Background: Epirubicin and Vinorelbine alone or in combination are considered active in ABC.The optimal duration of a chemotherapic treatment in ABC patients is not know. Otherwise Epirubicin has a limiting-dose due to its own toxicity. Methods: In this multicenter phase II study we analyzed the feasibility and the efficacy of 6 cycles of i.v. EV, followed, in responder-patients, by oral VNR alone. Our preliminary results are referred to 26 patients with advanced or recurrence breast cancer (21 ER +) treated with a first-line combination of Epirubicin 75 mg/m2 die 1 and Vinorelbine 25 mg/m2 die 1–8, every 21 days, for a maximum of 6 cycles. At the end of these 6 cycles, in case of a non-progression disease, an oral VNR treatment was considered (Vinorelbine 60 mg/m2 die 1–8 every 21 days for 3 cycles). Toxicity and response were analyzed according to WHO scales. Results: Median age of these patients was 63 years (range 42–78); predominant sites of metastasis were: 65% bone, 50% liver, 31% lung. Stages of disease at the first diagnosis were: 15% stage I, 31% IIa, 11% IIb, 6% IIIa, 4% IIIb, 31% IV. Of these 26 patients, 18 were recurrent breast cancer (with a median DFS of 75,5 months), the others were metastatic at the diagnosis. At the moment, 20 pts ended the i.v. EV treatment. 1 had a CR, 11 a PR (OR 60%), 2 a SD and 6 a PD. Main toxicities were: neutropenia (G1–2 in 50%, G3–4 in 50%), anemia (G1–2 in 58%) and alopecia (G1–2 in 33%). 12 pts started the treatment with oral VNR. Only 7 pts ended this treatment. 1 had a SD, 6 had a PD. Main toxicities of oral VNR were: neutropenia (G1–2 in 28%, G3–4 in 28%) and stipsi (G1–2 in 28%). Conclusions: EV confirmed to be active and well tolerated in ABC. The following therapy with oral VNR seems to be safe but only partially active; further data will be reported. No significant financial relationships to disclose.
Final results of NKTR-102, a topoisomerase I inhibitor-polymer conjugate, in patients (Pts) with pretreated metastatic breast cancer (MBC) demonstrating significant antitumor activity.
Authors: A. Garcia, A. Awada, S. Chan, G. H. M. Jerusalem, R. E. Coleman, M. T. Huizing, A. Mehdi, S. M. O'Reilly, J. T. Hamm, P. J. Barrett-Lee, V. Cocquyt, K. Sideras, D. E. Young, M. Brown, C. Zhao, A. L. Hannah, A. C. F. Leung, L. K. Masuoka, E. A. Perez
Journal: Journal of Clinical Oncology (2011)

269 Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate with reduced peak concentration and a continuous concentration profile. Methods: This was an open-label phase II study in MBC pts following PD on a taxane (T). Pts were randomized to NKTR-102 given IV at 145 mg/m 2 over 90-min every 14 or 21 days. Efficacy endpoints included ORR by RECIST v1.0; PFS and OS. Results: 70 pts (35 per schedule) randomized from Feb 2009 to May 2010 (median follow-up: 10 mo). Median age: 55 (range 33–83). ECOG PS 0/1: 40%/60%. Neoadjuvant and/or adjuvant: 74%. Median number of prior cytotoxic regimens for metastatic disease: 2. All pts had received prior T: 7% (adjuvant); 93% (metastatic). 89% had received prior anthracyclines (A): 63% (adjuvant); 26% (metastatic). 63% had received prior AT only (23% in MBC); an additional 26% had received prior AT/capecitabine (ATC). 61% were ER/PR+; 30% had TNBC; 86% had visceral metastases. Median PFS for q14d, q21d and overall were 3.5 mo, 5.3 mo and 4.6 mo. Median OS for q14d, q21d and overall were 8.8 mo, 13.1 mo and 10.3 mo. Toxicity was manageable, with diarrhea as the most common grade 3+ toxicity, with median time to onset ∼3 mo. Discontinuation from study drug due to AEs: 20%/14% for q14d/q21d. Neuropathy was absent; alopecia was minimal (20%/11% grade 1–2 for q14d/q21d). Conclusions: NKTR-102 demonstrates significant anti-tumor activity in pts with advanced MBC, including poor prognosis pts with TNBC and having received prior ATC. A phase III study is being planned in patients with MBC previously treated with taxanes. [Table: see text]
Bispecific T-Cell Engagers (BiTEs) as Treatment of B-Cell Lymphoma
Authors: Nicole C. Smits, Charles L. Sentman
Journal: Journal of Clinical Oncology (2016)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study. February 16, 2016 ARTICLE CITATION DOI: 10.1200/JCO.2015.64.9970 Journal of Clinical Oncology - published online before print February 16, 2016 PMID: 26884583 Bispecific T-Cell Engagers (BiTEs) as Treatment of B-Cell Lymphoma Nicole C. SmitsxNicole C. SmitsSearch for articles by this author , Charles L. SentmanxCharles L. SentmanSearch for articles by this author Show More Geisel School of Medicine at Dartmouth, Lebanon, NH https://doi.org/10.1200/JCO.2015.64.9970 First Page Full Text PDF Figures and Tables © 2016 by American Society of Clinical Oncology Companion Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study
Abstract 9035: Epigenetic Modifications are Associated with Ascending Thoracic Aneurysm Formation in Patients with Bicuspid Aortic Valve
Authors: Asad A Shah, Sheng Feng, Deidre Krupp, Carol Haynes, Elizabeth Grass, Shu S Lin, Elizabeth R Hauser, William E Kraus, Simon G Gregory, Svati H Shah, G. Chad Hughes
Journal: Circulation (2012)

Objective: Bicuspid aortic valve (BAV) disease predisposes to early and more frequent ascending thoracic aortic aneurysm formation, but the mechanisms underlying this aortopathy remain incompletely characterized. The objective of this study was to identify genes predisposing to ascending aneurysm formation in patients with BAV aortopathy using a multipronged molecular approach. Methods: Ascending aortic aneurysm tissue samples were collected at the time of ascending aortic replacement in subjects with bicuspid (N=16) and trileaflet (N=16) aortic valves. All patients in the trileaflet valve group had degenerative aneurysms and those with connective tissue disorders were excluded. Using the aortic tissue samples, genome-wide DNA methylation status was determined using Illumina 450K methylation chips. Gene expression was determined using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet groups using Wilcoxon Rank Sum tests. Results: Twenty-six genes were differentially methylated between the bicuspid and trileaflet groups, and six of these genes also had significantly different gene expression between groups. Protein tyrosine phosphatase, non-receptor type 22 ( PTPN22 ) was strongly hypermethylated (beta: bicuspid 0.68 vs. trileaflet 0.55, P=4x10 -5 ) and had a resultant highly significant decrease in gene expression (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10 -5 ). Conclusions: In patients with ascending thoracic aortic aneurysms, there exist differential DNA methylation and gene expression signatures between those with BAV aortopathy versus acquired degenerative aneurysms and trileaflet aortic valves. The strongest finding was for PTPN22 , a gene involved in T-cell receptor signaling and associated with various autoimmune disorders. These differences may highlight novel mechanisms of aneurysm development in the BAV population, potentially serving as biomarkers and/or pharmacologic targets.
Abstract 15892: Symptom Diary Use Improves Outcomes for Heart Failure Patients
Authors: Linda G Park, Kathleen Dracup, Mary A Whooley, Michele M Pelter, Debra K Moser, Martha Biddle, Robyn A Clark, Jill Howie-Esquivel
Journal: Circulation (2015)

Introduction: Attention to symptoms of weight gain and dyspnea are central tenets in heart failure (HF) patient education. Daily diary use can be one method for HF patients to acknowledge and attend to their symptoms. However, it is not known whether diary use improves patient outcomes. We aimed to compare mortality among rural HF patients who did versus did not complete a daily diary of weight and symptom self-assessment. Methods: This study was a secondary analysis of a 3-arm randomized controlled trial with two intervention groups (Fluid Watchers LITE and PLUS) and usual care. The two intervention groups were given daily diaries for 2 years to track daily weight, HF symptoms, and response to symptom changes. Intervention group patients received self-care education and a script to call their health care provider, but the 2 groups varied on the number of follow-up phone calls received. Patient groups were categorized by duration of adherence to diary use: None, Low (1-3 months), Medium (4-12 months), and High (13-24 months). Cox regression analysis assessed survival from cardiac and non-cardiac death for 2 years while controlling for age and depression. Results: The mean age was 66 ± 13, 58% (n=227) were male, and 67% (264/393) completed diaries with no difference in diary use between the 2 intervention groups. As compared with the 129 patients with no diary use, the 117 patients with High diary use had fewer non-cardiac (p=0.001) and cardiac (p=0.01) deaths; the 89 patients with Medium diary use had fewer non-cardiac deaths (p=0.007) but similar cardiac deaths (p=0.79). Conclusions: This is the largest trial to examine daily diary use in HF patients over 2 years. Improved non-cardiac survival was associated with at least 4 months of diary use, while cardiac survival was associated with at least 12 months of diary use. It is unclear why non-cardiac survival improved, but it is speculated that attention to cardiac symptoms may have increased attention to non-cardiac symptoms.
Beta-2-microglobulin (B2M) expression in the urinary sediment correlates with clinical markers of kidney disease in patients with type 1 diabetes
Authors: Maria Beatriz Monteiro, Karina Thieme, Daniele Pereira Santos-Bezerra, Márcia Silva Queiroz, Viktoria Woronik, Marisa Passarelli, Ubiratan Fabres Machado, Daniel Giannella-Neto, Maria Oliveira-Souza, Maria Lúcia Corrêa-Giannella
Journal: Metabolism (2016)