tbuckley/cabot-search huggingface dataset:
Abstract 117: Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas
Authors: Nathalie Johnson, Sarit Assouline, Miguel Alcaide, Arezoo Mohajeri, Celia Greenwood, Yasser Riazalhosseini, Koren Mann, Ryan Morin
Journal: Cancer Research (2016)

Abstract Purpose: Relapsed or refractory diffuse large B cell lymphoma (rrDLBCL) is fatal in 90% of patients and yet little is known about its biology. Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions. Results: Based on the a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3, CCND3, NFKBIZ and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes. Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Citation Format: Nathalie Johnson, Sarit Assouline, Miguel Alcaide, Arezoo Mohajeri, Celia Greenwood, Yasser Riazalhosseini, Koren Mann, Ryan Morin. Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 117.
A new method to analyze adverse events longitudinally in oncology clinical trials.
Authors: Gita Thanarajasingam, Paul J. Novotny, Charles L. Loprinzi, Axel Grothey, Pamela J. Atherton, Jeff A. Sloan
Journal: Journal of Clinical Oncology (2014)

3622 Background: There are significant limitations to the current method for displaying treatment-related adverse events (AE) in clinical trials. Tables displaying grade 3 and 4 AEs do not capture toxicity profiles that evolve over time and do not provide clinically relevant information on when a given AE could arise, its probable duration and its severity at a given point in therapy. We developed a novel method of analysis to better capture and represent longitudinal AE data. Methods: Graphical and analytical routines were developed to analyze adverse events longitudinally. Mean symptom and toxicity values are plotted over time on a single axis for direct comparison. Butterfly plots compare adverse events by treatment arms longitudinally. Multiple longitudinal techniques (repeated measures modeling, profile analysis, area under the curve analysis, change from baseline, and time to event) are included. Heat maps, event charts and stream plots are produced for individual patient results over time. Results: The methodology was validated in two completed clinical trials in colorectal cancer treatment (N9741) and cancer control (979254). In N9741, a higher incidence and severity of diarrhea, nausea and vomiting in patients on IROX (irinotecan/oxaliplatin) versus FOLFOX (fluorouracil/oxaliplatin) was most pronounced in the first treatment cycle and declined sharply by cycle 2. An increased incidence of alopecia in this cohort was also most apparent upfront, from the first to the second cycle, as compared to a lower overall incidence of alopecia with a gradual rise from cycles 1 through 5 in patients on FOLFOX. In study 979254, a higher incidence of dry mouth in patients using venlafaxine 150 mg/d as compared with placebo was most prominent only later in therapy, at weeks 4 and 5 (incidence of 22% for placebo and 13% for venlafaxine 150 mg/d at week 1, p=0.25, versus, 2.2% and 49%, respectively, at week 5, p=0.0001). Conclusions: A new method of analyzing AEs in clinical trials that incorporates the dimension of time offers a more complete depiction of chemotherapy toxicity than current methods. Longitudinal analyses of toxicity over time can provide enhanced patient education and guide clinical management on a given chemotherapy strategy.
Abstract 809: Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung cancer
Authors: Liren Zhang, Yuanquing Ye, Huakang Tu, Michelle A.t. Hildebrandt, John V. Heymach, Jack A. Roth, Jian Gu, Xifeng Wu
Journal: Cancer Research (2016)

Abstract As an essential nutrient that facilitates DNA synthesis, cell proliferation and metabolism, iron is involved in carcinogenesis. While epidemiological studies suggest a J-shaped model for the relationship of serum iron level and cancer risk with both too low and too high levels associated with increased cancer risks, the effect of genetic variants related to intracellular iron regulatory pathway and dietary iron intake on non-small cell lung cancer (NSCLC) risk is little known. In this study, we evaluated a panel of miRNA related genetic variants in iron regulatory pathway genes on the risk of NSCLC. In discovery phrase, 157 miRNA related single nucleotide polymorphisms (SNPs) from 81 genes of iron regulatory pathway were genotyped in 1656 NSCLC cases and 1486 healthy controls. Eight SNPs in 6 genes were significantly associated with risk of NSCLC. A SNP in 3’ UTR of Iron-Responsive Element Binding Protein 2 (IREB2) gene at 15q25 region was subsequently replicated in dbGaP lung cancer GWAS dataset. Combining all subjects (7,352 cases, 7,296 controls), the overall P-value was 4.9 × 10−9 (Odds ratio (OR) = 0.86). eQTL analysis showed that the SNP on IREB2 alters IREB2 gene expression (P = 3.0 × 10−11). The SNP is predicted to alter a miR-29 binding site on IREB2 gene and indeed the expression of miR-29 is inversely correlated with IREB2 expression in tumor tissues. We then determined the expression of serum miR-29a in 150 early-stage NSCLC patients and 172 healthy controls and found that miR-29a was significantly associated with higher risk of cancer (OR = 1.78, P = 0.03). By analyzing dietary intake information of the discovery population, iron intake was significantly associated with risk of NSCLC in logistic regression analysis and there was also evidence of a synergistic interaction with between the SNP and iron intake in modulating NSCLC risk (P for interaction = 0.01). Taken together, SNPs at miRNA binding sites of iron regulatory pathway genes and dietary iron intake may modify risk of NSCLC individually and jointly. Citation Format: Liren Zhang, Yuanquing Ye, Huakang Tu, Michelle A.t. Hildebrandt, John V. Heymach, Jack A. Roth, Jian Gu, Xifeng Wu. Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 809.
Abstract 2965: <i>In vitro</i> and <i>in vivo</i> activity of a site-specific SeriMab antibody-drug conjugate (ADC) using an indolino-benzodiazepine DNA-alkylating agent
Authors: Dilrukshi Vitharana, Alan Wilhelm, Luke Harris, Katie Archer, Manami Shizuka, Erin Maloney, Olga Ab, Rassol Laleau, Xiuxia Sun, Jan Pinkas, Michael Miller, Ravi Chari, Thomas Keating, Nathan Fishkin
Journal: Cancer Research (2016)

Abstract Previously we have described the characterization of a proprietary class of indolino-benzodiazepine dimers, IGNs, with high potency against many cancer lines. Antibody-drug conjugates (ADCs) made with mono-imine containing IGNs were designed to only alkylate DNA and not cause DNA crosslinking. ADCs with the IGN linked via lysine residues of the antibody were shown to be highly potent and antigen specific. Here we apply our SeriMab site-specific technology platform, which employs N-terminal conjugatable aldehydes derived from oxidation of a serine residue, to link an IGN molecule to the antibody using a peptide linker. This ADC (SeriMab-IGN-P1) has exactly 2 IGN molecules per antibody conjugated to the N-termini of the heavy chains, as determined by MS analysis. Serimab-IGN-P1 was found to maintain binding to the target antigen with comparable affinity to the unconjugated antibody by FACS analysis (Kd = 300 pM). The conjugate was highly potent (IC50 = 4 pM) against a cancer cell line with high target expression (3 × 106 antibodies bound per cell) as well as a cell line with much lower target expression (2 × 104 antibodies bound per cell, IC50 = 22 pM). SeriMab-IGN-P1 also demonstrated strong bystander killing activity against proximal target-negative cancer cells, likely due to a cell permeable metabolite identified in cells expressing the target antigen. The unique oxime linkage in SeriMab-IGN-P1 was found to be stable in circulation in mice for 3 days, as determined by affinity capture LC-MS; the conjugate species with 2 IGNs per antibody remained predominant over this period with an estimated t1/2 of &amp;gt;10 days for payload release. In vivo, SeriMab-IGN-P1 was found to be effective against human lung cancer xenografts (NCI-H2110), with anti-tumor activity observed at single doses as low as 2 μg/kg (payload dose), and complete responses observed at 5 μg/kg. This conjugate was also well tolerated in CD-1 mice at doses significantly higher than the minimum effective dose that produced tumor regression. These data are highly encouraging for new ADC therapies using the SeriMab site-specific conjugation platform with potent DNA-acting payloads. Citation Format: Dilrukshi Vitharana, Alan Wilhelm, Luke Harris, Katie Archer, Manami Shizuka, Erin Maloney, Olga Ab, Rassol Laleau, Xiuxia Sun, Jan Pinkas, Michael Miller, Ravi Chari, Thomas Keating, Nathan Fishkin. In vitro and in vivo activity of a site-specific SeriMab antibody-drug conjugate (ADC) using an indolino-benzodiazepine DNA-alkylating agent. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2965.
Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control
Authors: Damien C. Croteau-Chonka, Weiliang Qiu, Fernando D. Martinez, Robert C. Strunk, Robert F. Lemanske, Andrew H. Liu, Frank D. Gilliland, Joshua Millstein, W. James Gauderman, Carole Ober, Jerry A. Krishnan, Steven R. White, Edward T. Naureckas, Dan L. Nicolae, Kathleen C. Barnes, Stephanie J. London, Albino Barraza-Villarreal, Vincent J. Carey, Scott T. Weiss, Benjamin A. Raby
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches.Objectives: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control.Methods: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4+ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute).Measurements and Main Results: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide.Conclusions: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1).
Innate Immunity in Asthma
Authors: Talal A Chatila
Journal: New England Journal of Medicine (2016)

It is appreciated that the marked increase in the prevalence of asthma over the past few decades reflects changes in environmental exposures and living conditions associated with modern lifestyles.1 Of particular interest is the documentation of a protective effect of exposures associated with traditional farming, the influence of which has waned with increased urbanization and the advent of mechanized agriculture.2 On small family-based farms where children are reared in close proximity to farm animals and their sheds, increased exposure to the microbial products found in these environments, including lipopolysaccharides, has been associated with protection against asthma.3,4 It remains unclear . . .
Alternative Donor Hematopoietic Transplantation For Patients Older Than 50 Years With AML In First Complete Remission: Unrelated Donor and Umbilical Cord Blood Transplantation Outcomes
Authors: Daniel J. Weisdorf, Mary Eapen, Annalisa Ruggeri, Mei-Jie Zhang, Xiaobo Zhong, Claudio Brunstein, Celalettin Ustun, Vanderson Rocha, Eliane Gluckman
Journal: Blood (2013)
Patient-reported outcomes from a phase III multicenter, randomized, double-blind, placebo-controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemotherapy: Cancer Oesophagus Gefitinib (COG).
Authors: Susan J. Dutton, Jane M. Blazeby, Russell D. Petty, Wasat Mansoor, Joyce Thompson, Mark Harrison, Haider Abbas, Asa Dahle-Smith, Anirban Chatterjee, Stephen Falk, Angel Garcia-Alonso, David Walter Fyfe, Richard Hubner, Tina Gamble, Lynnda Peachey, Christine Harvey, Patrick Julier, Janusz Jankowski, Rachel Midgley, David R. Ferry
Journal: Journal of Clinical Oncology (2013)

6 Background: There are no randomised trials of 2 nd line chemotherapy for esophageal cancer. The phase III COG trial of gefitinib versus placebo in patients with esophageal cancer progressing after chemotherapy did not show significant overall survival (OS) benefit, however the trial incorporated patient reported outcomes (PRO) using validated tools. The PRO data are therefore critical to inform practice and the initial results are presented here. Methods: Adults with measurable/evaluable metastatic esophageal or types I/II junctional adeno or squamous cell carcinoma progressing after prior chemotherapy, with performance status 0-2 were randomised 1:1 to 500mg gefitinib (G) or placebo (P), treated until progression. Primary outcome: OS. Secondary outcomes include safety, PFS, PRO (assessed by EORTC QLQ-C30 and EORTC QLQ-OG25 at baseline 4, 8 and 12 weeks until progression) and predictive biomarkers. Pre-specified PRO domains were global quality of life, dysphagia, eating and odynophagia. Analysis by ANCOVA of change in PRO at 4 weeks adjusted for baseline. Results: 450 patients were recruited from 51 UK centres and no difference in OS was detected. There was evidence that PFS was better in the intervention arm (P 35 days, G 49 days; HR=0.795, 95%CI 0.66, 0.96, p=0.017). Questionnaire compliance rates were excellent at baseline (94%) and at 4 weeks (77%). Patients in the gefitinib arm reported significantly better social function (9.26; 95%CI 1.94 to 16.58; p=0.013) and significantly fewer problems with odynophagia (-8.61; 95%CI -14.49 to -2.73; p=0.004), constipation (-15.24; 95%CI -22.83 to -7.65; p=0.0001) and speech (-10.40; 95%CI -16.13 to -4.67; p=0.0004) than patients receiving placebo but more problems with diarrhoea (19.23; 95%CI 11.79 to 26.27; p&lt;0.0001). All other PRO domains were similar between the two groups. Conclusions: Gefitinib did not improve overall survival in esophageal cancer patients after chemotherapy however there was significant PFS improvement and improvement in quality of life and palliation of symptoms albeit with an excess of diarrhoea. Clinical trial information: 29580179.
Endoscopic ultrasound-guided pancreaticogastrostomy using a lumen-apposing metal stent plus a double-pigtail plastic stent
Authors: Joan Gornals, Claudia Consiglieri, Francesc Vida, Carme Loras
Journal: Endoscopy (2016)

Endoscopic ultrasound (EUS)-guided pancreatic duct drainage remains one of the most technically challenging endosonography interventions. There is a lack of specific devices for the technique, and the question of which kind of stent should be used remains controversial: plastic (straight, single or double pigtail) or self-expanding metal [1] [2] [3] [4].
Abstract 2247: A multicenter clinical trial of lung cancer circulating tumor cell assay with the largest sample size (1210 cases) in China
Authors: Jiatao Lou, Caicun Zhou, Jing Wu, Lihua Qiao, Xiaohui Liang, Xiaoqian Wang, Xiaoxia Chen, Xuefei Li, Chao Zhao
Journal: Cancer Research (2016)

Abstract Background: As a novel biomarker of primary tumors, circulating tumor cells (CTCs) are well known to play an important role in cancer diagnosis, recurrence and metastasis, and disease monitoring. This study investigated the application of CTCs in lung cancer therapy by quantitative determination of folate receptor-positive CTCs. Methods: This study enrolled 1210 subjects (including 560 lung cancer patients, 350 patients with benign lung diseases, 150 healthy subjects and 150 non-lung cancer malignant tumor patients) and quantified the tiny amounts of CTCs in peripheral blood by negative enrichment using immunomagnetic beads in combination with folate receptor-directed polymerase chain reaction (PCR). Results: Following ROC curve analyses of CTC levels in the patients with benign lung diseases or benign lung diseases and the healthy subjects, the cut-off of CTCs was 8.70 CTC Units/3mL with a specificity of 88.2% (441/500) and a sensitivity of 79.6% (446/560) as determined by the method mentioned above. The ROC area under curve of more than 0.8 (AUC = 0.8797, P&amp;lt;0.0001) suggested the excellence of ligand-directed PCR to diagnose lung cancer. For stage II-IV lung cancer patients, the sensitivities were 70.8%(34/48), 79.6% (125/157), and 90.2% (185/205) respectively, and the sensitivity in stage I patients can reach up to 68.0% (102/150) as well. CTC levels appeared to have greater accuracy to diagnose lung cancer (AUC: 0.8833, P&amp;lt;0.0001) than the combination of the other four lung cancer-specific serum tumor markers (CEA, NSE, CYFRA21-1 and SCC)(AUC: 0.8557, P&amp;lt;0.0001). CTCs were related to tumor stage and tumor size other than pathological type. By quantitative determination of folate receptor-positive cells in 150 different types of cancers, the CTC level in lung cancer was found to be higher than those in gastric, breast, colorectal, liver, and esophageal cancers. Conclusions: LT-PCR achieves quantitative determination of folate receptor-positive CTCs to diagnose lung cancer with high sensitivity and specificity, and significantly greater diagnosis accuracy than the model of combined lung cancer-specific serum tumor markers. Citation Format: Jiatao Lou, Caicun Zhou, Jing Wu, Lihua Qiao, Xiaohui Liang, Xiaoqian Wang, Xiaoxia Chen, Xuefei Li, Chao Zhao. A multicenter clinical trial of lung cancer circulating tumor cell assay with the largest sample size (1210 cases) in China. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2247.
Prognostic Impact Of Serum Heavy/Light Chain Pairs In Patients With MGUS and Smoldering Myeloma: Long-Term Results From a Single Institution
Authors: Carlos Fernández de Larrea, Laura Magnano, Montserrat Elena, María Teresa Cibeira, Natalia Tovar, Juan I. Aróstegui, Fabiola Pedrosa, Laura Rosiñol, Xavier Filella, Jordi Yagüe, Joan Bladé
Journal: Blood (2013)
Clinical outcome of first-line melanoma patients who continue tremelimumab in spite of early disease progression.
Authors: D. I. Healey, P. S. Carlson, B. Huang, M. A. Marshall
Journal: Journal of Clinical Oncology (2010)

2574 Background: Tremelimumab (CP-675,206) is an immune activating agent that stimulates the immune system rather than having a direct effect on tumors. Due to the potential for a delayed tumor effect, treatment guidelines in tremelimumab protocols allow patients to continue dosing in spite of progressive disease (PD) at the first assessment as long as the patient is not deteriorating clinically. The clinical outcome of melanoma patients (pts) who continued tremelimumab after early progression in the phase III study (A3671009) is described. Methods: Pts with unresectable stage IIIc-IV melanoma without brain metastasis, LDH below 2x ULN, and no prior systemic treatment for advanced melanoma were randomized 1:1 to either tremelimumab 15 mg/kg IV q90d, or physician's choice of TMZ 200 mg/m2 p.o. d1-5 q28d or DTIC 1,000 mg/m2 IV q21d (chemotherapy arm). Results: 328 pts were randomized to the tremelimumab arm, with 324 treated. 225 pts had PD at the first assessment (≤ 100 days) according to the investigator. Of these, 52 continued dosing with tremelimumab. Five of these pts achieved an objective response (OR) compared to baseline and 3 additional pts achieved an OR relative to their status at the first assessment. The median OS was 21.0 months for pts who continued treatment after early PD and was 12.6 for all pts randomized to the tremelimumab arm. Of 327 pts randomized to the chemotherapy arm, no subsequent ORs were reported for the 16 patients who received at least one more dose of chemotherapy after PD at the first assessment (≤ 65 days). Conclusions: The fact that some pts who had initial PD but continued dosing subsequently experienced tumor responses to tremelimumab indicates that early progression on tremelimumab is not always a sign of treatment failure. The long survival that was seen in pts who had PD at the 3-month disease assessment but continued dosing with tremelimumab was likely affected by the fact that these pts were selected for lack of clinical deterioration at the 3-month visit. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer