tbuckley/cabot-search huggingface dataset:
Survival outcomes in the PRIME study for patients (pts) with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC), by baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS).
Authors: Marc Peeters, Salvatore Siena, Josep Tabernero, Jean-Yves Douillard, Reija Koukakis, Jan-Henrik Terwey, Roger Sidhu
Journal: Journal of Clinical Oncology (2014)

3557^ Background: In PRIME, panitumumab (pmab) + FOLFOX4 improved overall survival (OS) for RAS WT mCRC pts vs FOLFOX4 alone (Douillard et al 2013). Prespecified subgroup analysis identified only ECOG PS ≥2 as a negative predictive factor for pmab efficacy; BRAF mutant (MT) status was a strong negative prognostic factor. Here, we further evaluate the benefit:risk profile of pmab in pts with ECOG PS 0/1 RAS/BRAFWT mCRC. Methods: PRIME was a randomized (1:1) phase 3 1st-line mCRC study comparing pmab 6.0 mg/kg Q2W + FOLFOX4 vs FOLFOX4. This exploratory analysis, conducted when ≥80% of pts had an OS event, included pts with RAS/BRAF WT (KRAS/NRAS exons 2-4 [incl. codon 59] and BRAF exon 15 assessed) mCRC. Median progression-free (PFS) and OS were estimated by baseline ECOG PS (stratification factor). Data were summarised descriptively and tested for significance using Cox’s proportional hazards models. Results: Of 439 pts with RAS/BRAF WT mCRC, 438 had baseline ECOG PS recorded. Pts were well balanced with respect to sex, age and metastatic sites. Median PFS and OS were longer in ECOG PS 0/1 RAS/BRAF WT mCRC pts receiving pmab + FOLFOX4 vs FOLFOX4 (Table). Corresponding values were numerically shorter in ECOG PS 2 pts receiving pmab. Among RAS WT/BRAFMT pts, 49 were ECOG 0/1 at baseline (pmab + FOLFOX4 vs FOLFOX4 median PFS 6.7 vs 5.4 months, p=NS and OS 11.1 vs 9.1 months; p=NS); only 4 pts were ECOG 2. Conclusions: This post hoc analysis suggests that the PFS and OS benefits observed in pts with RAS/BRAF WT mCRC receiving pmab + FOLFOX4 are confined to those with a baseline ECOG PS of 0/1. Clinical trial information: NCT00364013. RAS/BRAF WT (n=438) Pmab + FOLFOX4 (n=222) FOLFOX4 (n=216) ECOG 0/1 (n=411) Median PFS (95% CI), months 12.3 (10.0-14.5) 9.3 (7.7-10.6) HR (95% CI); p valuea 0.69 (0.56-0.86); <0.001 Median OS (95% CI), months 29.7 (25.2-32.7) 23.1 (19.1-26.0) HR (95% CI); p valuea 0.71 (0.57-0.88); 0.002 ECOG 2 (n=27) Median PFS, months 6.4 (2.7-14.6) 7.6 (3.7-11.1) HR (95% CI); p valuea 0.94 (0.38-2.31); 0.891 Median OS, months 7.6 (4.6-28.7) 8.9 (5.3-13.0) HR (95% CI); p valuea 0.95 (0.41-2.21); 0.904 Abbreviations: CI, confidence intervals; HR, hazard ratio. a Descriptive p value.
Dasatinib and navitoclax act synergistically to target NUP98-NSD1+/FLT3-ITD+ acute myeloid leukemia
Authors: Jarno L. Kivioja, Angeliki Thanasopoulou, Ashwini Kumar, Mika Kontro, Bhagwan Yadav, Muntasir M. Majumder, Komal K. Javarappa, Samuli Eldfors, Juerg Schwaller, Kimmo Porkka, Caroline A. Heckman
Journal: Leukemia (2018)
Chlorella-gold nanorods hydrogels generating photosynthesis-derived oxygen and mild heat for the treatment of hypoxic breast cancer
Authors: Changkyu Lee, Kyungseop Lim, Sung Soo Kim, Le Xuan Thien, Eun Seong Lee, Kyung Taek Oh, Han-Gon Choi, Yu Seok Youn
Journal: Journal of Controlled Release (2018)
Abstract 16581: Pre-existing Venous Intimal Hyperplasia Explains Post-operatory Neointima Growth but Fails to Predict Arteriovenous Fistula Failure: The Matched-pair Cohort Study
Authors: Luis A Escobar, Marwan Tabbara, Juan C Duque, Laisel Martinez, Wensong Wu, Yue Pan, Natasha Fernandez, Omaida Velazquez, Loay Salman, Roberto I Vazquez-Padron
Journal: Circulation (2015)

Introduction: Arteriovenous fistulae (AVF) failure is the most common complication in hemodialysis patients. It compromises dialysis treatment, worsens patients’ quality of life and increases the medical costs associated with the maintenance of vascular accesses. There is a belief that AVF failure is mainly due to occlusive neointimal hyperplasia. This study assesses for the first time the impact of pre-existing venous intimal hyperplasia on post surgical neointima development and AVF function (patency). Methods and Results: Fifty one patients undergoing two-stage brachiobasilic AVF creation at the University of Miami Hospital and Jackson Memorial Health System were enrolled. Matched pair tissue samples were taken from each patient. The proximal basilic vein was procured during vascular access creation while the second biopsy was obtained at the time of AVF transposition for its superficialization. Tissues were rapidly formalin-fixed and cross-sectioned for histomorphometric measurements of the neointima and media areas. Pre-existing intima hyperplasia was persistent among most basilic veins with neointima to media ratios (N/M) ranging between 0.075 and 0.709 (mean: 0.289). The neointimal lesion size experienced a 2.26 fold increased during fistula maturation (p&lt;0.0001, paired t-test). A general linear regression model controlled for multiple baseline covariates revealed the existing positive correlation between the venous intima hyperplasia and the later neointimal growth in the corresponding AVF (B=0.728, p=0.0311). Unexpectedly, the venous N/M ratio failed to predict primary AVF patency using a COX proportional hazard model that included 9 baseline-covariates (age, gender, time between surgeries, diabetes, previous AVF and catheter, statins, anti-platelet and anti-hypertensive drugs). Conclusions: While pre-existing intimal hyperplasia correlates with the size of the post-operatory neointima in the AVF as revealed in this matched-pair cohort study, it has no impact on the future AVF function and success.
Phase I Study of the Selinexor in Relapsed/Refractory Childhood Acute Leukemia
Authors: Andrew E. Place, Traci M. Blonquist, Elliot Stieglitz, Todd M Cooper, Lia Gore, Richard Aplenc, Mignon L. Loh, Melinda Pauly, Rachel E. Rau, Michael J. Burke, Julia Etchin, A. Thomas Look, Maria Luisa Sulis, Lewis B. Silverman
Journal: Blood (2018)
Abstract 16730: Hydrogel Mediated Delivery of siRNA-cocktail Leads to Improved Cardiac Function Post MI
Authors: Perwez alam, Arghya Paul, Rafeeq P Ahmed
Journal: Circulation (2017)

Background: Myocardial infarction (MI) results in cardiac scar formation, remodeling, reduced heart function, and culminating in cardiac failure. Adult mammalian cardiomyocytes (ACMs) lack the abil...
Abstract 12194: Finding Out a Useful Parameter of Sleep Disordered Breathing in Chronic Heart Failure Patients
Authors: Tadamitsu Nakashima, Tomoko Ohkusa, Tomoko Nao, Noriko Harada, Yasuaki Wada, Takeshi Ueyama, Shigeki Kobayashi, Yasuhiro Ikeda, Hiroyuki Sawatari, Akiko Chishaki, Shin-ichi Ando, Masafumi Yano
Journal: Circulation (2014)

Background and Purpose: Sleep disordered breathing (SDB) is highly prevalent in patients with chronic heart failure (CHF). Though severity of SDB has been commonly assessed by apnea hypopnea index (AHI) using standard polysomnography (PSG), this method necessitates especially dedicated facilities and trained personnel. Thus, we tried to determine a practical threshold for detecting moderate SDB by investigating all admitted CHF patients with the use of pulse-oximetry data. Methods: Consecutive stable CHF patients (N=136) were prospectively screened for the presence of SDB according to Japanese guideline for treatment of SDB. In patients who were suspected of having SDB from the data showing 3% oxygen desaturation index (ODI), standard PSG was performed. The relationship between parameters obtained by the PSG and pulse-oximetry were investigated. Results: Of the 136 patients (81 male), average NYHA class and left ventricular ejection fraction (LVEF) were 2.2±0.7 and 46.9±17.9%, respectively. In 123 patient...
Health-related quality of life, symptom burden, and comorbidity in long-term survivors of acute promyelocytic leukemia
Authors: Fabio Efficace, Massimo Breccia, Giuseppe Avvisati, Francesco Cottone, Tamara Intermesoli, Erika Borlenghi, Paola Carluccio, Francesco Rodeghiero, Francesco Fabbiano, Mario Luppi, Claudio Romani, Marco Sborgia, Stefano D’Ardia, Francesco Nobile, Nicola Cantore, Monica Crugnola, Gianpaolo Nadali, Marco Vignetti, Sergio Amadori, Francesco Lo Coco
Journal: Leukemia (2018)
Moving Beyond Limited and Extensive Staging of Small Cell Lung Cancer
Authors: Howard (Jack) West
Journal: JAMA Oncology (2018)

Ahmed Salem, FRCR; Hitesh Mistry, PhD; Matthew Hatton, FRCR; Imogen Locke, FRCR; Isabelle Monnet, MD; Fiona Blackhall, PhD; Corinne Faivre-Finn, PhD
Misclassification of Both Chronic Obstructive Pulmonary Disease and Heart Failure
Authors: Frans H. Rutten, Berna D. L. Broekhuizen
Journal: JAMA Network Open (2018)

Claire A. Lawson, PhD; Mamas A. Mamas, PhD; Peter W. Jones, PhD; Lucy Teece, MSc; Gerry McCann, MD; Kamlesh Khunti, PhD; Umesh T. Kadam, PhD
Venetoclax Enhances the Efficacy of Therapeutic Antibodies in B-Cell Malignancies
Authors: Fotini Vogiatzi, Julia Heymann, Thies Rösner, Lennart Lenk, Gunnar Cario, Martin Schrappe, Beat Bornhauser, Jean-Pierre Bourquin, Simon Bomken, Thomas Valerius, Matthias Peipp, Christian Kellner, Denis Martin Schewe
Journal: Blood (2018)
The efficacy and safety of rechallenge with an alternative immune checkpoint inhibitor in metastatic malignant melanoma
Authors: A.A. Suwaidan, S. Zhang, G. Faust
Journal: Annals of Oncology (2018)

Background: Immune checkpoint inhibitors (ICIs) have become standard of care in the management of advanced melanoma. While some evidence suggests that rechallenge in the setting of toxicity with prior ICIs is safe, there is rather limited evidence on the efficacy and safety of rechallenge with alternative ICI in the context of disease progression on initial ICI. Methods: We retrospectively analysed all patients with advanced melanoma who received ICIs between March 2016 and August 2017 at our centre. We used i) RECIST criteria to estimate objective overall response rate (ORR) & ii) Kaplan-Meier method to calculate the progression-free survival (PFS) and overall survival (OS). Results: Overall, 60 melanoma patients received ICIs, 31 patients discontinued initial ICI due to toxicity (N = 7) or disease progression (N = 24). 17 patients (54.8%) were rechallenged with an alternative ICI and three (17.6%) were rechallenged again with a third ICI. Of the 17 rechallenged patients, their initial treatment was discontinued due to either disease progression (14/17, 82%) or toxicity (3/17, 18%). The types of ICIs in rechallenged patients were as follows: first ICI; ipilimumab [anti-CTLA4] (9), combination ipilimumab and nivolumab [anti-PD-1] (1) and pembrolizumab [anti-PD-1] (7) and subsequent ICI; pembrolizumab (10), ipilimumab (6) and nivolumab (1). The three patients rechallenged for a second time all received nivolumab. The ORR in rechallenged patients was 23.5% vs 51.2% in the non-rechallanged patients. Rates of adverse events were not significantly different compared to first ICIs (Grade 3 irAE: 17.5% vs 23.5%). The median PFS and OS of rechallenged patients were 20 months [95% CI: 3.9-36.0] and 29.4 months [95% CI: 14.6-44.3] respectively, compared to 4 months [95% CI: 1.1-6.8] and 8.4 months [95% CI: 1.9-14.8] for patients who discontinued but not rechallenged. The authors note that comparing these groups should be interpreted with caution as they may constitute different patient cohorts. Conclusions: In the setting of disease progression or toxicity in the management of advanced melanoma with an initial ICI, rechallenge with alternative ICIs shows some ORR and reasonable PFS and OS. This strategy maybe a viable plan for selected patients. Legal entity responsible for the study: Guy Faust. Funding: Has not received any funding. Disclosure: G. Faust: Educational sponsorship to conferences, advisory board: MSD, BMS. All other authors have declared no conflicts of interest.
Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma
Authors: Massimiliano Cadamuro, Simone Brivio, Joachim Mertens, Marta Vismara, Anja Moncsek, Chiara Milani, Christian Fingas, Maria Cristina Malerba, Giorgia Nardo, Luigi Dall'Olmo, Eleonora Milani, Valeria Mariotti, Tommaso Stecca, Marco Massani, Carlo Spirli, Romina Fiorotto, Stefano Indraccolo, Mario Strazzabosco, Luca Fabris
Journal: Journal of Hepatology (2018)
Detection of pediatric bacterial meningitis pathogens from cerebrospinal fluid by next-generation sequencing technology
Authors: Ling-yun Guo, Yong-jun Li, Lin-lin Liu, Hong-long Wu, Jia-li Zhou, Ye Zhang, Wen-ya Feng, Liang Zhu, Bing Hu, Hui-li Hu, Tian-ming Chen, Xin Guo, He-ying Chen, Yong-hong Yang, Gang Liu
Journal: Journal of Infection (2018)
Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia
Authors: Duohui Jing, Yizhou Huang, Xiaoyun Liu, Keith C.S. Sia, Julia C. Zhang, Xiaolu Tai, Meng Wang, Cara E. Toscan, Hannah McCalmont, Kathryn Evans, Chelsea Mayoh, Rebecca C. Poulos, Miriam Span, Jianqing Mi, Chao Zhang, Jason W.H. Wong, Dominik Beck, John E. Pimanda, Richard B. Lock
Journal: Cancer Cell (2018)
Cancer mortality and predictions for 2018 in selected Australasian countries and Russia
Authors: G. Carioli, M. Malvezzi, P. Bertuccio, F. Levi, P. Boffetta, E. Negri, C. La Vecchia
Journal: Annals of Oncology (2018)

Predicted cancer mortality figures and rates are useful for public health planning.We retrieved cancer death certification data for 10 major cancer sites and total cancers from the World Health Organization (WHO) database and population data from WHO and United Nations Population Division databases. We obtained figures for Russia, Israel, Hong Kong, Japan, the Philippines, Korea, and Australia in 1970-2015. We predicted numbers of deaths by age group and age-standardized rates (world population) for 2018 by applying a linear regression to mortality data of each age group over the most recent trend segment identified by a joinpoint regression model.Russia had the highest predicted total cancer mortality rates, 158.5/100 000 men and 84.1/100 000 women. Men in the Philippines showed the lowest rates for 2018 (84.6/100 000) and Korean males the most favourable predicted fall (21% between 2012 and 2018). Women in Korea had the lowest total cancer predicted rate (52.5/100 000). Between 1993 and 2018, i.e. by applying the 1993 rates to populations in subsequent years, a substantial number of cancer deaths was avoided in Russia (1 000 000 deaths, 821 000 in men and 179 000 in women), Israel (40 000 deaths, 21 000 in men and 19 000 in women), Hong Kong (63 000 deaths, 40 000 in men and 23 000 in women), Japan (651 000 deaths, 473 000 in men and 178 000 in women), Korea (327 000 deaths, 250 000 in men and 77 000 in women), and Australia (181 000 deaths, 125 000 in men and 56 000 in women). No appreciable reduction in cancer deaths was found in the Philippines.Overall, we predicted falls in cancer mortality. However, these are less marked and later compared with the European Union and United States. Substantial numbers of deaths were avoided in all countries considered except the Philippines. Lung cancer mortality remains exceedingly high in Russian men, despite recent falls.
Anti-human CD117 CAR T-cells efficiently eliminate hematopoietic stem and CD117-positive AML cells
Authors: R. Myburgh, J. Kiefer, N. Russkamp, A. Simonis, S. Pfister, C. Magnani, M. Wilk, A. Müller, M. van den Broek, B. Becher, D. Neri, M.G. Manz
Journal: Annals of Oncology (2018)

Background: Acute Myeloid Leukemia (AML) is a clonal disease of the hematopoietic system. Disease relapses are common with current treatment approaches. As an alternative, immunological eradication of leukemic cells by adoptively transferred chimeric-antigen receptor T-cells (CAR T-cells) might be considerably more efficient. To date, however, the search for AML-specific surface antigens has remained largely elusive. To circumvent this problem, we propose to target the stem cell antigen c-Kit (CD117) that is expressed by physiological HSPC as wells as by leukemic blasts in > 90% of AML patients. Methods: A lentiviral vector was generated expressing a second generation CAR targeting human CD117 followed by a T2A sequence and RQR8 as selection marker and depletion gene (surface expression of CD34 and CD20 epitopes). Results: In vitro, CAR T-cells eliminated over 90% of CD117high leukemia cell lines within 24 hours. In long–term cytotoxicity assays (45d), only CD117low cells were able to escape CAR-mediated killing compared to CD117high and CD117intermediate cells which were not able to survive. Anti-CD117 CAR T-cells effectively depleted >90% of lin-CD117+CD34+CD38+ and >70% of lin-CD117+CD34+CD38- cells from healthy bone marrow in vitro. Similarly, >70% of patient derived leukemic blasts were eliminated by autologous anti-CD117 CAR T-cells within 48 hours. In vivo, immunodeficient mice were engrafted with umbilical cord blood derived CD34+ cells. A single injection of 2x106 anti-CD117 CAR T-cells resulted in > 90% depletion of CD117+ cells in the bone marrow within 6 days. Finally, humanized mice transplanted with bone marrow from AML patients were treated with autologous CAR T-cells. At 6 weeks after injection of CAR T-cells, >98% of hu-CD45 CD117+ cells were depleted in the bone marrow. Conclusions: We provide proof of concept for the generation of highly-potent CAR T-cells against CD117. Anti-CD117 CAR T-cells exhibit high cytotoxic activity against CD117+ cell lines as well as primary healthy HSPC and patient AML cells in vitro and in vivo in murine xenograft models. Strategies for the complete elimination of CAR T-cells (immunologic or small molecule based) are required before translation of this approach to the clinical setting. Legal entity responsible for the study: University Hospital Zurich. Funding: PROMEDICA stiftung, URPP University of Zuric, Krebsliga Schweiz. Disclosure: All authors have declared no conflicts of interest.
Pre-clinical evaluation of bifunctional SIRPα-antibody fusion proteins for the treatment of acute myeloid leukemia
Authors: L. Pascual Ponce, C. Heitmüller, J.-H. Kozik, M. Subklewe, N.C. Fenn, K.-P. Hopfner
Journal: Annals of Oncology (2018)

Background: CD47 is a ubiquitously expressed cell surface marker responsible of maintaining self-tolerance under physiological conditions. Upon binding to its receptor signal regulatory protein alpha (SIRPα) on myeloid cells, CD47 triggers a negative signal that ultimately inhibits phagocytosis. The upregulation of CD47 is an escape mechanism frequently used by tumor cells to gain immune resistance. Thus, the blockade of the CD47-SIRPα interaction by high affinity monoclonal antibodies (mAbs) is a promising strategy to restore phagocytosis and enhance tumor cell clearance. However, CD47 expressed on healthy cells may act as potential site of toxicity and antigen sink for high affinity CD47 mAbs. We developed bifunctional antibody derivatives, herein referred to as local inhibitory monoclonal antibodies (licMABs), to restrict the blockade of the CD47-SIRPα innate immune checkpoint to tumor cells and therefore reduce systemic toxicities. Methods: LicMABs are SIRPα-antibody fusion proteins that target a tumor antigen with high affinity and block the CD47-SIRPα interaction with the endogenous SIRPα domain, which has a physiologically low affinity to CD47. For proof or principal studies, we developed licMABs targeting CD33, a validated antigen for Acute Myeloid Leukemia (AML). The anti-tumor efficacy of SIRPα-αCD33 licMABs via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) mechanisms was evaluated in vitro. Furthermore, the potential toxicity of SIRPα-αCD33 licMABs on CD33-negative cells was addressed by preferential binding assays and ex vivo cytokine release studies in whole blood. Results: SIRPα-αCD33 licMABs mediated specific lysis of AML cell lines and primary, patient-derived AML cells by ADCC and induced a higher phagocytosis of AML cells than CD33 mAbs. Most importantly, SIRPα-αCD33 licMABs showed a potentially safe cytokine profile and preferentially bound to tumor cells co-expressing CD33 and CD47 even in an excess of healthy CD47-positive CD33-negative cells. Conclusions: Our results demonstrate the high efficacy and potentially low toxicity of SIRPα-αCD33 licMABs and qualify these molecules as a novel and promising immunotherapy for the treatment of AML. Legal entity responsible for the study: AG Hopfner, Gene Center, LMU. Funding: DFG CRC1243, m4-Award of the Bavarian Ministry of Economic Affairs and Graduate School of Quantitative Biosciences Munich. Disclosure: All authors have declared no conflicts of interest.
Clinical Characteristics and Outcomes of an Analysis of a Single Institution Experience of the 2017 World Health Organization (WHO) Classification of Post-Transplant Lymphoproliferative Disorders (PTLD)
Authors: Thomas M. Habermann, Angelo Fama, Kay M. Ristow, Matthew J. Maurer, William R. Macon, Stephen M. Ansell, Nabila Nora Bennani, Yogish C Kudva, Randall C. Walker, Kimberly D. Watt, Thomas R. Schwab, James R. Cerhan, Rebecca L King
Journal: Blood (2018)
Haemodynamic definitions and updated clinical classification of pulmonary hypertension
Authors: Gérald Simonneau, David Montani, David S. Celermajer, Christopher P. Denton, Michael A. Gatzoulis, Michael Krowka, Paul G. Williams, Rogerio Souza
Journal: European Respiratory Journal (2018)

Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management.Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup "pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers", due to the specific prognostic and management of these patients, and a subgroup "PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement", due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH.