tbuckley/cabot-search huggingface dataset:
Long-term results of endoscopic treatment vs. esophagectomy with lymphadenectomy in patients with high-risk early esophageal cancer including detailed analysis of lymph node micrometastases
Authors: M. Kollar, J. Krajciova, L. Prefertusova, E. Sticova, J. Maluskova, A. Pazdro, T. Haruštiak, J. Spicak, Z. Vackova, J. Martinek
Journal: Annals of Oncology (2019)
Appendicular skeleton MRI in multiple myeloma: Utility and clinical implications.
Authors: Navid Faraji, Daniel Arnold Smith, Kai Laukamp, Keval Parikh, Christos Kosmas, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2019)

e19527 Background: Skeletal MRI plays an integral role in diagnosing Multiple Myeloma and, in many cases, dictates need for treatment. While axial skeleton MRI is performed with established clinical utility, appendicular MRI is performed sparingly with utility not fully ascertained. We aim to assess the utility of appendicular MRI while establishing clinical factors which may predict outcomes. Methods: 107 appendicular skeleton MRIs were included for retrospective analysis over 15 years. No statistically significant age or gender related variability was noted. Variables including patient age, diagnosis, disease stage/activity, indication, transplant status, MRI result, treatment course, and survival were analyzed via Likelihood Ratio Chi-Square test or logistic regression. Results: Patient age, disease stage, presence of active marrow disease, history of relapse, and presence of axial or appendicular osseous disease were found to have a statistically significant correlation with MRI result. Disease stage and presence of active hematologic disease correlated with post MRI management alterations. Additionally, presence of active hematologic disease at time of MRI demonstrated a correlation with post MRI management strategy. Furthermore, MRI result was a predictor of downstream development of additional skeletal lesions. Interestingly, MRI result was not a predictor of survival. Conclusions: Several parameters may be used to determine a clinical pre-test probability of appendicular disease at the time of MRI. In addition, these clinical parameters and MRI results correlate with trends in subsequent patient treatment strategies. [Table: see text]
Abstract 4194: Rare cancer’s ‘valley of death’: Critical gaps in data, research, and funding
Authors: Robert L. Treuting, Sean Murphy, Niall Murphy, Bovey Rao, Anekha Goyal, Nico Tuccillo, Ryan Ki-Hoon Kim, Dylan Parker, Katherine Arline
Journal: Cancer Research (2019)

Abstract Over 370 forms of rare cancer compose at least 29.7% of all U.S. cancer diagnoses, or over 500,000 Americans per year. And yet, available data, research, and public funding related to these indications is insufficient in comparison with the 20 forms of non-rare cancers. Rare cancer is defined by the American Cancer Society as a cancer having an incidence of &amp;lt;6 per 100,000 per year. A review of the AACR Annual Proceedings 2018 showed that at least 150 rare cancers were not the focus of any abstract. Non-rare forms of breast cancer, expected to represent 11.9% of new cancer cases in 2018, had almost the same coverage (1081 abstracts, 25.6%) as all rare cancers combined (1155 abstracts, 27.3%). Rare cancers which were included in AACR 2018 were the focus of an average of 5 abstracts each, while the 20 non-rare cancers were the focus of an average of 154 each. That gap in basic science is also visible in broader data sources. A computational review of the 10,000 most recent cancer-related publications in PubMed showed that over 100 rare cancers had no publications, while that was true of only 1 non-rare cancer. Included rare cancers had an average of 3.2 mentions in PubMed abstracts, while non-rare cancers had an average of 115. Adequate patient-derived tumor gene expression data is critical for targeted drug development. Analysis of the Gene Expression Omnibus (GEO) repository demonstrated that, while all 20 non-rare cancers had DataSets, over 100 rare cancers had none. On average, each rare cancer included in GEO had 1.04 DataSets, while each non-rare cancer had 22.8. Government grants to companies are an important tool for bridging the drug development “valley of death” between basic science and the clinic. Between 2013 and 2017, 781 SBIRs and STTRs related to cancer research, development, or treatment were identified. 489 of them related to a specific cancer or cancers. Of those grants, 41.5% were related to breast, lung, or prostate cancers. 22.3% were related to rare cancers. Among rare cancers, glioblastoma was the specific focus of the most grants (18). 356 forms of rare cancer were not the specific focus of any grant. Pediatric cancers, which are all rare, were the focus of 8 grants (1%). These data highlight a significant gap in rare cancer-focused data, research, and public funding which contributes to lower availability of clinical trials and therapeutics for over half a million U.S. patients per year. Citation Format: Robert L. Treuting, Sean Murphy, Niall Murphy, Bovey Rao, Anekha Goyal, Nico Tuccillo, Ryan Ki-Hoon Kim, Dylan Parker, Katherine Arline. Rare cancer’s ‘valley of death’: Critical gaps in data, research, and funding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4194.
Abstract 2056: Combined FLT3 and Pim kinase inhibitor treatment downregulates c-Myc early in apoptosis induction in acute myeloid leukemia with FLT3-ITD
Authors: Jonelle K. Lee, Mario Scarpa, Shivani Kapoor, Maria R. Baer
Journal: Cancer Research (2019)

Abstract Background: fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in acute myeloid leukemia (AML) in 30 % of patients, with poor treatment outcomes due to rapid relapse. FLT3 inhibitors have limited activity and rapid onset of resistance. The oncogenic serine/threonine kinase proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is upregulated downstream of FLT3-ITD and phosphorylates and stabilizes FLT3 in a positive feedback loop in cells with FLT3-ITD. Dual inhibition of FLT3 and Pim kinases is therefore a promising treatment strategy for AML with FLT3-ITD. The proto-oncogene c-Myc, upregulated in many cancer types, drives proliferation and causes resistance to apoptosis. We previously showed that concurrent FLT3 and Pim inhibition in cells with FLT3-ITD increases apoptosis through downregulation of the anti-apoptotic protein Mcl-1. Here we demonstrate downregulation of c-Myc upstream of Mcl-1. Methods: Ba/F3-ITD and MV4-11 cells, with FLT3-ITD, were cultured with the FLT3 inhibitors gilteritinib (15 nM) or quizartinib (1 nM) and the pan-Pim inhibitor AZD1208 (1 μM) alone and in combination, and with DMSO control. c-Myc and Mcl-1 protein expression was measured by immunoblotting and c-Myc mRNA by qPCR using SybrGreen. Cells were cultured with cycloheximide (100 μg/mL) with and without the proteasome inhibitor MG-132 (20 μM). Ba/F3-ITD cells were stably transfected with a lentiviral c-Myc plasmid or a retroviral Mcl-1 plasmid and corresponding empty vectors. Apoptosis was detected by Annexin V and propidium iodine staining, measured by flow cytometry. Results: Combined FLT3 and Pim inhibitor treatment decreased c-Myc protein expression in Ba/F3-ITD and MV4-11 cells within 30 minutes, preceding Mcl-1 downregulation. c-Myc mRNA levels did not change, but c-Myc protein half-life decreased with combination treatment, and this decrease was abrogated by proteasome inhibitionMcl-1 overexpression did not abrogate c-Myc downregulation by combination treatment, and c-Myc overexpression decreased apoptosis induction by combination treatment from 65% to 45%. Conclusion: Combined FLT3 and Pim kinase inhibitor treatment enhances apoptosis in FLT3-ITD cells through c-Myc downregulation, which precedes Mcl-1 downregulation. c-Myc downregulation is post-translational, via increased proteasomal degradation. Citation Format: Jonelle K. Lee, Mario Scarpa, Shivani Kapoor, Maria R. Baer. Combined FLT3 and Pim kinase inhibitor treatment downregulates c-Myc early in apoptosis induction in acute myeloid leukemia with FLT3-ITD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2056.
Neutrophil extracellular traps drive inflammatory pathogenesis in malaria
Authors: Sebastian Lorenz Knackstedt, Athina Georgiadou, Falko Apel, Ulrike Abu-Abed, Christopher A. Moxon, Aubrey J. Cunnington, Bärbel Raupach, Deirdre Cunningham, Jean Langhorne, Renate Krüger, Valentina Barrera, Simon P. Harding, Aase Berg, Sam Patel, Kari Otterdal, Benjamin Mordmüller, Evelin Schwarzer, Volker Brinkmann, Arturo Zychlinsky, Borko Amulic
Journal: Science Immunology (2019)

Neutrophils are essential innate immune cells that extrude chromatin in the form of neutrophil extracellular traps (NETs) when they die. This form of cell death has potent immunostimulatory activity. We show that heme-induced NETs are essential for malaria pathogenesis. Using patient samples and a mouse model, we define two mechanisms of NET-mediated inflammation of the vasculature: activation of emergency granulopoiesis via granulocyte colony-stimulating factor production and induction of the endothelial cytoadhesion receptor intercellular adhesion molecule-1. Soluble NET components facilitate parasite sequestration and mediate tissue destruction. We demonstrate that neutrophils have a key role in malaria immunopathology and propose inhibition of NETs as a treatment strategy in vascular infections.
A phase I trial of ruxolitinib, lenalidomide, and methylprednisolone for patients with relapsed/refractory multiple myeloma (MM).
Authors: James R. Berenson, Jennifer To, Tanya M. Spektor, Daisy Martinez, Armando Jose Sanchez, Matthew Ghermezi, Carley Turner, Regina A. Swift, Benjamin M Eades, Gary Schwartz, Shahrooz Eshaghian, Laura Stampleman, Robert A. Moss, Youram Nassir, Ravindranath Patel, Alberto Bessudo, Stephen Lim, Robert A. Vescio
Journal: Journal of Clinical Oncology (2019)

8048 Background: Preclinical studies from our laboratory have demonstrated that ruxolitinib (RUX) in combination with lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in MM cells. Thus, RUX may restore sensitivity to LEN. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and methylprednisolone (MP) for relapsed/refractory (RR) MM patients (pts) who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods: A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 pts. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, pts received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results: As of September 1, 2018, 36 pts were enrolled, and 32 were evaluable for efficacy. The median age was 66 years (range, 46-81), and 21 (58%) were male. Pts received a median of 6 prior treatments including LEN and steroids to which they were all refractory and a proteasome inhibitor. No DLTs occurred, and DL+3 was expanded. Among evaluable pts, the CBR and ORR were 47% and 41%, respectively (1 CR, 2 VGPR, 10 PR and 2 MR), and 14 and 3 pts showed SD and PD. All 15 responding pts were refractory to LEN. G3 AEs included anemia (17%), neutropenia (14%), sepsis (14%), lymphocytopenia (11%), thrombocytopenia (11%), and pneumonia (11%). Most common SAEs included sepsis (14%) and pneumonia (11%). Conclusions: This Ph 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RR MM pts. These promising results are leading to expansion of the current clinical trial to 78 pts, and represents a novel therapeutic approach for treating MM. Clinical trial information: NCT03110822.
Abstract 2215: SLFN11 and EZH2 protein expression and localization in circulating tumor cells to predict response or resistance to DNA damaging therapies in small cell lung cancer
Authors: Lauren Averett Byers, Allison Stewart, Carl Gay, John Heymach, Luisa Fernandez, David Lu, Robin Rich, Lincy Chu, Yipeng Wang, Ryan Dittamore
Journal: Cancer Research (2019)

Abstract Background: A recent phase II trial in recurrent small cell lung cancer (SCLC) demonstrated that patients with high SLFN11 expression in tissue biopsies had improved survival when treated with PARP inhibition (PARPi). EZH2 is also highly expressed in SCLC tissue and is associated with chemo-resistance through epigenetic silencing of SLFN11. Here we developed a liquid biopsy test to explore the clinical feasibility of utilizing SLFN11 and EZH2 expression on circulating tumor cells (CTCs) to aid in the prediction of drug response/resistance of DNA damaging chemotherapy or PARPi in SCLC. Material and methods: 26 blood samples (19 baseline and 7 on-therapy) from SCLC patients treated at MDACC were sent to Epic Sciences for CTC enumeration (intact DAPI, CK+, cancer cell morphology) and characterization with SLFN11 and EZH2 immunoassays. Nuclear localization and expression of SLFN11 and EZH2 were quantified. Results: 17/19 (89%) of baseline and 5/7 (71%) post-therapy samples had detectable CTCs. 19/26 (73%) samples had SLFN11+ CTCs and 8/26 (31%) samples had nuclear localized SLFN11. For samples with SLFN11+ CTCs detected, the percentage of SLFN11+ cells ranged from 2.4 to 100%. 10/26 (38%) samples had EZH2+ CTCs and 9/26 (35%) samples had nuclear localized EZH2. For samples with EZH2+ CTCs, the percentage of EZH2+ cells ranged from 19 to 83%. 6 samples had both nuclear localized SLFN11 and EZH2 CTCs detected. Conclusions: Inter- and intra-sample heterogenous SLFN11 and EZH2 protein expression was observed in SCLC patients. Use of these assays is underway in SCLC patient samples to assess correlation with PARPi and platinum agent response. Citation Format: Lauren Averett Byers, Allison Stewart, Carl Gay, John Heymach, Luisa Fernandez, David Lu, Robin Rich, Lincy Chu, Yipeng Wang, Ryan Dittamore. SLFN11 and EZH2 protein expression and localization in circulating tumor cells to predict response or resistance to DNA damaging therapies in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2215.
Abstract 369: Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy
Authors: Frank T. Zenke, Astrid Zimmermann, Heike Dahmen, Brian Elenbaas, John Pollard, Philip Reaper, S Bagrodia, M E. Spilker, C Amendt, Andree Blaukat
Journal: Cancer Research (2019)

Abstract The protein kinase ataxia telangiectasia mutated and Rad3-related ATR is one of the key mediators of the DNA damage response. ATR is recruited to regions of single-stranded DNA, which most commonly arise during replication stress (RS). RS occurs during S-phase when the cell’s DNA replication machinery encounters problems such as unresolved DNA lesions. In addition, treatment of cells with DNA-damaging agents can lead to RS as cells progress to S-phase without resolving damage incurred by such agents. Elevated levels of RS are evident in some cancer cells, even in the absence of a DNA-damaging agent resulting from expression of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways. RS in cancer cells can drive reliance on ATR for survival and, accordingly, ATR inhibitors may have benefit as monotherapy. M4344 was determined to be an adenosine triphosphate (ATP)-competitive, highly potent, and tight-binding inhibitor of ATR with a Ki of &amp;lt; 150 pM. Minimal inhibitory activity was observed against a large panel of unrelated protein kinases, with 308 of 312 kinases tested having a measured Ki corresponding to more than 100-fold selectivity. M4344 potently inhibits ATR-driven phosphorylated checkpoint kinase-1 (P-Chk1) phosphorylation with an IC50 of 8 nM. Profiling on a selected set of cancer cell lines showed synergy with several types of DNA damaging chemotherapeutics as well as PARP1/2 and CHK1 inhibitors. In monotherapy efficacy studies M4344 showed tumor stasis to regression in tumor models with alternative lengthening of telomeres (ALT). In combination with PARP inhibitors, tumor regression could be observed in triple-negative breast cancer xenograft models. A dose-escalation phase 1 study in patients with advanced solid tumors is currently ongoing. Citation Format: Frank T. Zenke, Astrid Zimmermann, Heike Dahmen, Brian Elenbaas, John Pollard, Philip Reaper, S Bagrodia, M E. Spilker, C Amendt, Andree Blaukat. Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 369.
Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study
Authors: Anne Quinquenel, Luc-Matthieu Fornecker, Rémi Letestu, Loïc Ysebaert, Carole Fleury, Grégory Lazarian, Marie-Sarah Dilhuydy, Delphine Nollet, Romain Guieze, Pierre Feugier, Damien Roos-Weil, Lise Willems, Anne-Sophie Michallet, Alain Delmer, Katia Hormigos, Vincent Levy, Florence Cymbalista, Fanny Baran-Marszak
Journal: Blood (2019)
Breast-conserving surgery after neoadjuvant chemotherapy for stage III breast cancer patients.
Authors: Hee-Chul Shin, Wonshik Han, Hyeong-Gon Moon, Woo Kyung Moon, Seock-Ah Im, Tae-You Kim, In-Ae Park, Dong-Young Noh
Journal: Journal of Clinical Oncology (2012)

e11532 Background: Neoadjuvant chemotherapy (NCT) is a reasonable option for operable breast cancer in terms of downsizing large tumor and increasing the rate of breast-conserving surgery (BCS). However, BCS in patients with large breast tumors down-staged by NCT remains still controversial because of the possibility of residual tumor and resistance to NCT. Aims of this study were to evaluate the long-term survival results of patients who received NCT and BCS compared to patients who received BCS first and to compare recurrence and survival rates between patients who received preplanned BCS and those who received down-staged BCS among patients who underwent NCT. Methods: Between 2000 and 2007, 70 patients with clinical stage III breast cancer who received BCS after NCT (NCT group) and 72 patients with clinical stage III breast cancer who underwent BCS first (Surgery group) were retrospectively reviewed. Among 70 patients received NCT, 45 patients (64.3%) received preplanned BCS (preplanned BCS group) and 25 patients (35.7%) received down-staged BCS (down-staged BCS group). The long-term results including ipsilateral breast tumor recurrence (IBTR), locoregional recurrence (LRR), disease recurrence and survival rates were compared with groups. Results: There was no significant difference in IBTR-free survival, LRR-free survival rates, disease-free survival and overall survival rates between the NCT and the Surgery group (p=0.971, p=0.294, p=0.863 and p=0.933, respectively). Among patients who received NCT, IBTR-free survival, LRR-free survival, disease-free survival and overall survival rates was not also different between the preplanned BCS group and the down-staged BCS group (p=0.278, p=0.501, p=0.776 and p=0.412, respectively). Conclusions: Our study demonstrated that patients who received BCS after NCT showed similar long-term resutls compared to patients who received BCS first in clinical stage III breast cancer patients. Also, down-staged BCS shows is oncologically as safe as preplanned BCS in clinical stage III breast cancer patients in terms of recurrence and survival.
Abstract 12641: Improvements in Mitral Regurgitation are Associated with Reductions in Mechanical Dyssynchrony in Patients Supported by a Continuous Flow Left Ventricular Assist Device
Authors: Akiko Mano, Toshinari Onishi, Stephanie C Haberman, Tetsuari Onishi, Mohamed Ahmed, Jeffrey J Teuteberg, Robert L Kormos, John Gorcsan
Journal: Circulation (2012)

Background: The reduction of mechanical dyssynchrony is a major contributing factor to improvement of mitral regurgitation (MR) after cardiac resynchronization therapy. However, the impact of mecha...
Abstract 1400: C1GALT1 regulates malignant phenotypes of cholangiocarcinoma cells
Authors: Po-Da Chen, Ai-An Chang, Min-Chuan Huang, Yao-Ming Wu
Journal: Cancer Research (2019)

Abstract Identifying molecular targets for cholangiocarcinoma is an urgent need to overcome the treatment failure and death from cancer cell invasion and metastasis. Core 1 β1,3-galactosyltransferase (C1GALT1) has been documented as the key enzyme in morphogenesis and cellular adhesion, for it adds galactose to form Gal-GalNAc-Ser/Thr structure (T antigen); whereas abnormal C1GALT1 expression and aberrant O-glycans are commonly associated with tumor progression. However, functional roles of C1GALT1 in cholangiocarcinoma remains unclear. With clinical correlation, the immunohistochemistry confirmed that higher expression of C1GALT1 in cancer tissue is associated with larger tumor size, advanced cell grade and overall staging. Consistently, stable knockdown of C1GALT1 regarding cholangiocarcinoma cell lines inhibits cell viability, migration, and invasion; whereas the overexpressed C1GALT1 promotes cell viability, migration, and invasion of cholangiocarcinoma cell lines. Additionally, control of C1GALT1 regulates the colony formation, as well as sphere formation of cholangiocarcinoma cells. Moreover, our data suggest that down-regulated C1GALT1 modifies AAL, VVA, PNA, LEL, and MALII lectin, in correlation with the cell malignant behaviors. Given that, C1GALT1 is sufficient to regulate malignant behaviors of cholangiocarcinoma cells with a significant correlation between gene expression and clinical prognosis, implying that C1GALT1 plays a crucial role in cancer progress of cholangiocarcinoma. Citation Format: Po-Da Chen, Ai-An Chang, Min-Chuan Huang, Yao-Ming Wu. C1GALT1 regulates malignant phenotypes of cholangiocarcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1400.