tbuckley/cabot-search huggingface dataset:
The EGFR-targeting chimeric monoclonal IgG-1 antibody cetuximab (CTX) added either to gemcitabine (G) followed by docetaxel (D) or carboplatin/gemcitabine (CP/G) in chemonaive patients (pts) with advanced non-small cell lung cancer (NSCLC): Preliminary safety results of the ongoing GemTax IV trial.
Authors: C. Manegold, S. Cicenas, C. Eschbach, J. Kollmeier, C. Kortsik, G. Schmid-Bindert, C. Schumann, M. H. Serke, M. Steins, L. R. Pilz
Journal: Journal of Clinical Oncology (2010)

e18010 Background: CTX has been registered for head and neck and colorectal cancer. Our randomized phase II/III trial is to assess the efficacy and safety of CTX in combination with two different chemotherapy (CT) regimens. Methods: Chemonaive pts with histologically confirmed stage IIIB or IV NSCLC and PS 0–2 received CTX 400 mg/m2 (loading dose) and then 250 mg/m2 weekly either combined with G 1,000 mg/m2 days 1 + 8 for 2 cycles (3qw) followed by D 75 mg/m2 day 1 for 2 cycles (q3w) (arm A) or CP AUC5 day 1 and G 1,200 mg/m2 days 1 + 8 for 4 cycles (q3w) (arm B). If pts did not progress single agent CTX was continued (“maintenance”) until tumor progression or unacceptable toxicity. Results: 340 pts received 2,826 infusions of CTX combined with CT and 2,015 infusions without CT. Toxicities requiring clinical intervention are shown below (Table). 142 pts on single-agent CTX received up to 33 cycles without significant toxicity (arm A: 64 pts, range 1-33 cycles, median 3, mean 5.6, and 11 pts ≥10 cycles; arm B: 78 pts, range 1-23 cycles, median 4, mean 4.8 and 8 pts ≥10 cycles). CTX in combination with CT, grade 3 or 4 hematological toxicity was more common in pts receiving CP/G (anemia 4%, leukopenia 17%, neutropenia 26%, and thrombopenia 3%, arm A vs. anemia 10%, leukopenia 31%, neutropenia 39%, and thrombopenia 42%, arm B, respectively). Skin reactions were common and occurred in 83% (arm A) and 79% (arm B) of pts, respectively. Conclusions: CTX in combination with single agent G and D and with CP/G is well tolerated. In addition, pts on weekly single agent CTX received up to 33 cycles without significant toxicity. Arm A Arm B Maintenance Cycles Cetuximab/gemcitabine n = 167 (pts) Cetuximab/docetaxel n = 102 (pts) Cetuximab/carboplatin/gemcitabine n = 173 (pts) Single-agent cetuximab n = 142 (pts) Total number of cycles 300 181 542 734 Median number of cycles per patient 2 2 4 4 Anemia + ≥ 1 blood transfusion 2% 2% 4% - Thrombopenia + ≥ 1 platelet transfusion <1% - 6% - Febrile neutropenia + IV antibiotics 2% 3% 1% - Skin reaction (any/grade 3) 55%/6% 17%/4% 37%/5% 10%/1% Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Merck Serono, Roche AstraZeneca, GlaxoSmithKline, Lilly, Merck Serono, Roche, sanofi-aventis Lilly, Merck Serono Lilly
Abstract 423: Toxicity and efficacy probability intervals design for phase I dose-finding in oncology trials
Authors: Daniel H. Li, Jim Whitmore, Yuan Ji
Journal: Cancer Research (2016)

Abstract We propose a toxicity and efficacy probability interval (TEPI) design for dose-finding in phase I oncology studies. This approach incorporates efficacy outcomes to inform dosing decisions to optimize both efficacy and safety. Decision rules can be prespecified, allowing for transparency to clinicians and non-statisticians. The TEPI design is an extension over the modified toxicity probability interval (mTPI) design, which uses only dose-limiting toxicity (DLT) data for dose escalation. The TEPI method is motivated by recent promising data from cancer immunotherapies, for which response or a biomarker for response can be observed in the same interval as a DLT. The TEPI method is based on a two-way decision table constructed by combining the target probability intervals of DLT and efficacy. It uses a beta/binomial hierarchical model to compute the posterior probabilities of intervals for toxicity and efficacy. The dosing decision depends on the joint unit probability mass of toxicity and efficacy data, which follows the Bayes rule under independent beta prior distributions. TEPI can pre-calculate all dosing actions for any possible combination of toxicity and efficacy outcome at a certain time point during a trial. For example, dose escalation or de-escalation decisions at time of 6, 9, and 12 treated patients are provided in Table 1. In the current era of potent novel agents in oncology, phase I trials that simultaneously optimize antitumor activity and safety may accelerate development of these therapies. The proposed TEPI method recognize this needs, and is appealing to clinicians because all dose escalation or de-escalation can be prespecified. Simulation studies have been performed to evaluate the performance of TEPI, and compared to other designs. No. of RespondersNo. of Treated Patients at Current Dose LevelNo. of DLTs01-45-660-1EUES2-3SSS4-6DUDUDU01-67-990-2EUES3-4SSS5-9DUDUDU0-12-78-12120-3EUES4-6SSS7-12DUDUDU Table 1. The letters in cells are computed based on the decision rules under the TEPI method and represent different dose-finding actions. EU: Unacceptable efficacy; DU: Unacceptable safety. Target toxicity probability = 0.3 and target response rate probability = 0.5. Citation Format: Daniel H. Li, Jim Whitmore, Yuan Ji. Toxicity and efficacy probability intervals design for phase I dose-finding in oncology trials. [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 423.
Coronary-prone behavior and coronary heart disease: a critical review. The review panel on coronary-prone behavior and coronary heart disease.
Journal: Circulation (1981)

A panel of biomedical and behavioral scientists were charged with the task of critically evaluating all available research and theory linking behavior to coronary heart disease. The task was divided into five topic areas: (1) association of coronary-prone behavior and coronary heart disease; (2) assessment of the "type A" behavior pattern; (3) physiologic mechanisms linking behavior to coronary heart disease; (4) cultural and developmental factors; and (5) intervention strategies. The review panels developed summary statements which delineated the perceived strengths and short-comings of the theory and data for their respective sections and provided recommendations to the National Heart, Lung, and Blood Institute concerning future research.
Identification of additional therapeutic options for <i>de novo</i> acute myeloid leukemia (AML) patient enabled by next generation sequencing (NGS).
Authors: Jason G Harb, Amber N Essenmacher, Karen-Sue Carlson, Matthew W Anderson, Durga P. Dash
Journal: Journal of Clinical Oncology (2015)

e18027 Identification of Additional Therapeutic Options for de novo Acute Myeloid Leukemia (AML) Patient enabled by Next Generation Sequencing (NGS) Jason G. Harb1, Amber N Essenmacher2, Karen-Sue B. Carlson2, Matthew W. Anderson1, Dash DP1 1 BloodCenter of Wisconsin 2 Cancer Center - Froedtert Hospital & Medical College of Wisconsin Background: The prognosis for those diagnosed with AML remains poor; therefore, additional treatment strategies are needed. We present a case study which following mutation identification by NGS; an actively recruiting clinical trial was identified, thereby illustrating the potential of NGS to provide alternative treatment options for the patient. Methods: NGS of 148 exons, covering 30 genes of either prognostic value or actionable, was performed on an AML patient using Illumina’s TSCA Technology. The clinical utility of the mutation was determined through clinical trial, literature reviews performed by N of One and the BCW. Results: With NGS, a low frequency missense mutation (c.35G > C, p.G12A, published in Catalogue of Somatic Mutations in Cancer, COSM565) in the N-Ras gene was identified. N-Ras mutations, primarily at codons 12, 13, and 61, are reported in 10.2-13% of AML cases (Bowen et al., 2005; Bacher et al., 2006; Schlenk et al., 2008; Berman et al., 2011; Bachas et al., 2014). This mutation lies within the first
Age, race, and survival of men with de novo distant metastatic prostate cancer (M1PC).
Authors: Brandon David Bernard, Jennifer R. Rider, Christopher Sweeney, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2016)

5031 Background: Older age at diagnosis is associated with a higher frequency of de novo M1PC and worse cancer-specific survival (CSS). In the PSA era, outcomes with androgen deprivation therapy in clinical trials for M1PC are similar for whites (W) and blacks (B) however it is unknown if this is true at the population level; the relationship between age, race and CSS is also unknown. The aim of this study was to describe the frequency and rate of de novo M1PC and CSS for a contemporary cohort of men with de novoM1PC and assess for associations with age and race. Methods: The Surveillance, Epidemiology, and End Results (SEER) registry was used to identify W and B men diagnosed with de novoM1PC (pelvic node only disease excluded) from 2004-2012. Age groups were defined as ≤ 74 or ≥ 75 years. Frequency, rate and CSS were determined for W and B in the two age groups. Descriptive endpoints were used to define associations of age and race with frequency, rate and CSS. Frequencies, age-adjusted rates and survival were calculated using SEER*Stat. Chi-square tests were used to evaluate the associations between age group, race and frequency; a 2-sided p < 0.05 was considered statistically significant. Results: From 2004-2012, prostate cancer was diagnosed in 452,698 men. The table shows frequency (% M1PC of all PC within race/age group), rate per 100,000 and CSS of men with de novo M1PC (*p < 0.05 between and within age groups). Compared to men ≤ 74, there was a significantly higher frequency of de novoM1PC in men ≥ 75 regardless of race (p < 0.0001). CSS was also significantly worse in men ≥ 75 regardless of race. Within both age groups, the proportion of de novoM1PC was greater for B than for W (p < 0.0001). Conclusions: The rate of de novoM1PC is significantly higher and CSS significantly lower in men ≥ 75, irrespective of race. Given the poor CSS in men ≥ 75, due consideration for chemohormonal therapy in men fit for docetaxel should be undertaken despite older age. De novo M1PC ≤ 74 ≥ 75 W B W B Frequency (%)* 8,732 (2.9) 2,793 (4.6) 8,091 (9.9) 1,165 (12.6) Rate per 100,000* 3.1 8.3 58.4 108.9 CSS - - - - Median (months) 36 34 22 20 1 yr (95% CI) 82.2 (81.3-83.1) 80.1 (78.5-81.7) 66.8 (65.6-68.0) 64.4 (61.2-67.4) 5 yr (95% CI) 34.6 (33.2-36.0) 33.4 (30.9-35.9) 22.7 (21.3-24.2) 21.1 (17.7-24.8)
Abstract 893: Diffuse gastric adenocarcinoma often harbors <i>KMT2C</i> mutations resulting in malignant phenotypes and worse overall survival
Authors: Soo-Jeong Cho, Changhwan Yoon, Jun Ho Lee, Kevin K. Chang, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon
Journal: Cancer Research (2016)

Abstract Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA) is genomically stable compared to the intestinal type, but the primary driver mutations in DGA are still being defined. Lysine (K) -specific methyltransferase 2C (KMT2C), also known as mixed lineage leukemia 3 (MLL3), is a histone methyltransferase involved in transcriptional coactivation and can be mutated in gastric cancer. The purpose of this study was to determine the frequency of KMT2C mutation in DGA and to elucidate the role of KMT2C in DGA tumorigenesis and progression. Methods: Whole exome sequencing was performed on matched tumor samples of 27 patients with DGA who underwent potentially curative surgical resection. Immunohistochemistry (IHC) was performed for KMT2C protein expression on these same tumors and on an additional 289 tumors from a separate cohort of patients with DGA. KMT2C overexpression in DGA cell lines (MKN-45 and SNU-668) using lentiviral transduction and KMT2C shRNA knockdown in normal gastric epithelial cells were examined in several in vitro assays. Results: Thirty-eight percent of the 27 sequenced DGA specimens harbored somatic mutations in KMT2C. The next most frequent mutation, CDH1, which encodes E-cadherin, was found in 28% of specimens. Patients with KMT2C mutation tended to have worse overall survival (OS) compared to patients without the mutation (p = 0.194). Additional tumor tissue for IHC analysis was only available from 11 of 27 patients. Among this group, patients with tumors expressing KMT2C protein had better OS compared to patients whose tumors did not express KMT2C (p = 0.034). In an external validation set of 289 DGA samples, KMT2C expression again correlated with better OS (p = 0.009). In the DGA cell lines, KMT2C overexpression reduced proliferation by 32-39%, soft agar colony formation by 75-77%, spheroid cell formation by 77-78%, cell migration by 52-60%, and cell invasion by 50-74%. KMT2C overexpression also increased resistance to 5-FU and cisplatin chemotherapy. KMT2C shRNA knockdown in gastric epithelial cells increased proliferation, soft agar colony formation, migration, and invasion by 1.7- to 25-fold. Conclusions: KMT2C is frequently mutated in DGA, and loss of KMT2C protein expression correlates with worse OS. Restoration of KMT2C expression in DGA cell lines reduces cancer stem-like cell and malignant phenotypes. Thus, KMT2C may be a novel therapeutic target for patients with DGA. Citation Format: Soo-Jeong Cho, Changhwan Yoon, Jun Ho Lee, Kevin K. Chang, Bulent A. Aksoy, Do Joong Park, Sam S. Yoon. Diffuse gastric adenocarcinoma often harbors KMT2C mutations resulting in malignant phenotypes and worse overall survival. [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 893.
Myocardial Fibrosis Assessment by LGE Is a Powerful Predictor of Ventricular Tachyarrhythmias in Ischemic and Nonischemic LV Dysfunction
Authors: Marcello Disertori, Marta Rigoni, Nicola Pace, Giancarlo Casolo, Michela Masè, Lucio Gonzini, Donata Lucci, Giandomenico Nollo, Flavia Ravelli
Journal: JACC. Cardiovascular imaging (2016)
Abstract 3315: Breast cancer stem cell induction by COX-2 via EP4/PI3K-AKT/NOTCH-WNT axis: EP4 as therapeutic target
Authors: Mousumi Majumder, Xiping Xin, Ling Liu, Elena Tutunea-Fatan, Mauricio Rodriguez-Torres, Krista Vincent, Andrew Deweyert, Lynne-Marie Postovit, David Hess, Peeyush K. Lala
Journal: Cancer Research (2016)

Abstract Cancer stem-like cells (SLC) resist conventional therapies, necessitating searches for SLC-specific targets. We established that cyclo-oxygenase(COX)-2 expression promotes human breast cancer progression by activation of the prostaglandin(PG)E-2 receptor EP4. Present study revealed that COX-2 induces SLCs by EP4-mediated NOTCH and WNT up-regulation. EP4 antagonist (EP4A) treatment ablated SLCs both in vitro and in vivo. Ectopic COX-2 over-expression in MCF-7 and SKBR-3 human breast cancer cell lines (named MCF-7-COX-2 and SKBR-3-COX-2) resulted in aggressive phenotypes: increased migration/invasion/proliferation, EMT, elevated SLCs, evidenced by spheroid formation for successive generations, increased ALDH activity and co-expression of COX-2/SLC markers. These changes were reversed with COX-2 inhibitor or EP4A, indicating dependence on COX-2/EP4 activities. COX-2 overexpression or EP4 agonist treatment of COX-2 low cells caused up-regulation of NOTCH/WNT pathway genes, blocked with PI3K/AKT inhibitors. Supporting above findings, micro-array analysis showed up-regulation of numerous SLC-regulatory and EMT-associated genes in MCF-7-COX-2 cells. MCF-7-COX-2 cells showed increased orthotopic tumorigenicity and spontaneous multi-organ metastases in NOD/SCID/IL-2Rγ-deficient mice for successive generations with limiting cell inocula. Orthotopic tumors showed significant up-regulation of VEGF-A/C/D, Vimentin and phospho-AKT, down-regulation of E-Cadherin and enrichment of SLC marker positive and spheroid forming cells. MCF-7-COX-2 cells also showed increased lung colonization in NOD/SCID/GUSB-null mice, an effect reversed with EP4 knockdown or EP4A treatment. COX-2, EP4 and ALDH1A expression in situ in human breast cancer tissues were highly correlated with one other, more marked in progressive stage of disease. High COX-2/EP4 expression was linked with poor survival. Thus EP4 represents a novel SLC-ablative target in human breast cancer. (Supported by a grant of the OICR to PKL and a TBCRU fellowship to MM) Citation Format: Mousumi Majumder, Xiping Xin, Ling Liu, Elena Tutunea-Fatan, Mauricio Rodriguez-Torres, Krista Vincent, Andrew Deweyert, Lynne-Marie Postovit, David Hess, Peeyush K. Lala. Breast cancer stem cell induction by COX-2 via EP4/PI3K-AKT/NOTCH-WNT axis: EP4 as therapeutic target. [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 3315.
Abstract 4471: Overcoming the resistance to the anti CD20 treatments in chronic lymphocytic leukaemia
Authors: Annarita Scialdone, Jesper Kofoed Damm, Urban Gullberg, Kristina Drott
Journal: Cancer Research (2016)

Abstract Chronic lymphocytic leukaemia is the most common leukaemia in the Western countries. Treatment of CLL and other lymphomas is based on cytostatic drugs in combination with rituximab or other monoclonal antibodies targeting the B-cell surface marker CD20. Although the CD20-antibodies have revolutionized the therapeutic perspectives of indolent B-cell lymphomas, the treatment of CLL with CD20-antibodies is often inefficient, a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown previously that CD20 is epigenetically regulated in some lymphoma cell lines and that some histone deacetylase inhibitors (HDACi) can increase CD20 expression in B-cell lymphomas both in vitro and in vivo. Therefore, we utilized the HDACi valproate to upregulate CD20 both in CLL cell lines and in patients.Two CLL patients with del13q were treated with valproate at serum levels around 800 μM for three days in three 21-day cycles. CD20 expression was analyzed by Real time-PCR and flowcytometry on the B-CLL cells isolated from peripheral blood.In addition, the valproate-induced histone modifications and changes in repressor/activator complexes of the CD20 promoter were investigated in the CLL cell lines and in patients.In the patient 1, CD20 expression was increased 2 times after 2 weeks of treatment, suggesting long-term effects by valproate. Neither the mRNA stability nor the protein stability seems to be affected by Valproate, suggesting transcriptional effects. However, no effects were observed in the patient 2. In contrast to patient results, Valproate increases CD20 transcript and protein levels by 2,5 times in the CLL-cell line I83-E95 after 48 hours. Here, the activating histone mark, acetylated H3K9, is enriched on the CD20 promoter suggesting valproate-related effects on the epigenome. Our study will continue the characterization of valproate-related effects on the epigenetic signatures of the CD20 promoter in CLL cells in vitro and in vivo, dissecting the mechanisms underling low CD20 expression in CLL. Citation Format: Annarita Scialdone, Jesper Kofoed Damm, Urban Gullberg, Kristina Drott. Overcoming the resistance to the anti CD20 treatments in chronic lymphocytic leukaemia. [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 4471.
International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma
Authors: Shaji Kumar, Bruno Paiva, Kenneth C Anderson, Brian Durie, Ola Landgren, Philippe Moreau, Nikhil Munshi, Sagar Lonial, Joan Bladé, Maria-Victoria Mateos, Meletios Dimopoulos, Efstathios Kastritis, Mario Boccadoro, Robert Orlowski, Hartmut Goldschmidt, Andrew Spencer, Jian Hou, Wee Joo Chng, Saad Z Usmani, Elena Zamagni, Kazuyuki Shimizu, Sundar Jagannath, Hans E Johnsen, Evangelos Terpos, Anthony Reiman, Robert A Kyle, Pieter Sonneveld, Paul G Richardson, Philip McCarthy, Heinz Ludwig, Wenming Chen, Michele Cavo, Jean-Luc Harousseau, Suzanne Lentzsch, Jens Hillengass, Antonio Palumbo, Alberto Orfao, S Vincent Rajkumar, Jesus San Miguel, Herve Avet-Loiseau
Journal: The Lancet Oncology (2016)
Abstract 4413: Thrombospondin-1 is a master regulator of glioblastoma vascularization and infiltration
Authors: Thomas Daubon, Celine Leon, Kim Clarke, Mathilde Poulet, Hrvoje Miletic, Francesco Falciani, Rolf Bjerkvig, Andreas Bikfalvi
Journal: Cancer Research (2016)

Abstract Glioblastoma are heterogeneous tumours composed of different subpopulations of cells with different behavioral characteristics. Areas of highly angiogenic cells co-exist with populations of non-angiogenic but highly invasive and infiltrative cells. This heterogeneity is a key clinical challenge in glioma treatment. We used a large scale RNA sequencing approach to investigate the molecular components which differentiate infiltrative from angiogenic cells, in a Patient Derived Xenograft (PDX) mouse model. Our bioinformatic analysis revealed TGFβ1 to be a master regulator of tumor development, and Thrombospondin-1 (Tsp1) to be up regulated in infiltrative areas as compared to angiogenic area. Thrombospondins are known as anti-angiogenic factors, however the full roles of these multi domain proteins in tumor development remain to be elucidated. We found Tsp1 expression to be upregulated in grade IV-GBM and in silico in the GBM mesenchymal subclass. It is expressed not only in tumor cells, but also in tumor blood vessel endothelial cells (ECs). TGFβ1 transcriptionally regulated Tsp1 via Smad1 and Smad3. However, contrary to previous results, we found that Tsp1 was not involved in TGFβ1-activation in tumor cells. We showed that Tsp1 regulates cell migration and invasion both in vitro and in vivo. Inhibition of Tsp1 expression in vivo correlated with increased tumor vascularization in both the chick CAM assay and the PDX mouse model. Anti-angiogenic treatments in the PDX mouse model leads to increased tumor hypoxia and invasive tumor cell behavior, as described in our previous work. In this context, both TGFβ1 and Tsp1 were upregulated in tumor cells. Downregulation of tumor-derived Tsp1 by shRNA in the presence of anti-angiogenic therapy led to reduced tumor growth and invasion in vivo. Finally, peptide-mediated inhibition of Tsp1 activity demonstrated that Tsp1/CD47 interaction is involved in the invasive capacity of GBM cells. Taken together, our data suggest that Tsp1 inhibition may be a promising therapeutic approach to limit tumor infiltration induced by treatment with anti-angiogenic agents. Citation Format: Thomas Daubon, Celine Leon, Kim Clarke, Mathilde Poulet, Hrvoje Miletic, Francesco Falciani, Rolf Bjerkvig, Andreas Bikfalvi. Thrombospondin-1 is a master regulator of glioblastoma vascularization and infiltration. [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 4413.
PD-1 Axis Inhibitors in EGFR- and ALK-Driven Lung Cancer: Lost Cause?
Authors: Scott Gettinger, Katerina Politi
Journal: Clinical Cancer Research (2016)

Abstract Programmed death axis 1 (PD-1) inhibitors have ushered in a new error of cancer immunotherapeutics for advanced smoking-associated non–small cell lung cancer. Their role in treating EGFR-mutant and ALK-rearranged lung cancer has yet to be determined. Clin Cancer Res; 22(18); 4539–41. ©2016 AACR. See related article by Gainor et al., p. 4585