tbuckley/cabot-search huggingface dataset:
TCT-638 Clinical Outcomes of Hemodialysis Patients With Coronary Artery Disease After Newer Generation Drug-Eluting Stent Implantation
Authors: Shota Okuno, Takayuki Ishihara, Mitsutoshi Asai, Osamu Iida, Masaharu Masuda, Shin Okamoto, Kiyonori Nanto, Takashi Kanda, Takuya Tsujimura, Yasuhiro Matsuda, Yosuke Hata, Hiroyuki Uematsu, Toshiaki Mano
Journal: Journal of the American College of Cardiology (2018)
Endogenous arginase 2 as a biomarker for PEGylated arginase 1 treatment in squamous cell lung carcinoma xenograft models.
Authors: James C. M. Ho, Shi Xu, Paul Ning-Man Cheng, Sze Kwan Lam
Journal: Journal of Clinical Oncology (2018)

e20538 Background: Arginine depletion induced by PEGylated arginase 1 (BCT-100, PEG-BCT-100 or rhArg1peg5000) has shown promising anticancer effects among arginine auxotrophic cancers that are deficient in argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). High endogenous arginase 2 (ARG2) was previously found in human lung cancers. Although high ARG2 does not induce immunosuppression nor affect disease progression, it may potentially affect the efficacy of BCT-100 treatment. ARG2 was highly expressed in H520 squamous cell lung carcinoma (lung SCC) xenograft while undetectable in SK-MES-1 and SW900 lung SCC xenografts. We postulated that high endogenous ARG2 expression might hamper anticancer effect of PEGylated arginase 1 in lung SCC. Methods: The in vivo effect of PEGylated arginase 1 was studied using 3 lung SCC xenograft models (SK-MES-1, SW900 and H520). Protein expression, arginine concentration and apoptosis were investigated by Western blot, ELISA and TUNEL assay respectively. ARG2 in H520 xenograft was knocked down using shRNA technique. Results: PEGylated arginase 1 (60 mg/kg) suppressed tumor growth in SK-MES-1 and SW900 but not in H520 xenograft. Serum arginine level was decreased significantly by BCT-100 in all xenografts. On the other hand, intratumoral arginine level was reduced by BCT-100 treatment in SK-MES-1 and SW900 xenografts. In H520 xenograft, intratumoral arginine level in control arm could not be further lowered in BCT-100 treatment arms. G1 arrest was indirectly evidenced by downregulation of cyclin A2, B1, D3, E1 and CDK4 with BCT-100 in SK-MES-1 xenograft only. Moreover, activation of apoptosis was induced by BCT-100 in SK-MES-1 and SW900 xenografts. Knockdown of ARG2 in H520 xenograft restored sensitivity to BCT-100 treatment partially induced by G1 arrest via arginine depletion. Conclusions: PEGylated arginase 1 treatment was effective in lung SCC xenograft with low endogenous ARG2 expression. High endogenous ARG2 level may explain resistance of BCT-100 treatment in lung SCC xenograft. ARG2 may serve as an additional predictive biomarker, other than ASS1 and OTC, in BCT-100 treatment in lung SCC.
The incidence and risks of adverse events in randomized controlled trials (RCTs) of cancer drugs downplaying the harms.
Authors: Bishal Gyawali, Kazunori Honda, Tomoya Shimokata, Yuichi Ando
Journal: Journal of Clinical Oncology (2017)

e14036 Background: Proper assessment of harms of cancer treatment is essential to make risk-benefit trade off decisions in oncology clinic. CONSORT guidelines require the authors of RCTs to provide exact data for adverse events (AEs) grade 3 or higher (severe AEs), serious AEs (SAEs) and fatal AEs (FAEs) and avoid using general terms (such as well-tolerated) that downplay the harms. We aimed to assess the incidence and risks of severe AEs, SAEs and FAEs in such RCTs of cancer drugs that downplayed the harms. Methods: We extracted all the phase 2 and 3 RCTs of cancer drugs from the five major journals (NEJM, Lancet, Lancet Oncology, JAMA, JCO) from 2016 January to 2016 December. The abstracts/full texts of the papers were studied to assess if the harms of the experimental arm were downplayed. Use of any of the following terms while describing toxicities or AEs or safety was assumed to downplay the harms: acceptable, feasible, tolerable (or well-tolerated) , favorable, safe, manageable. Data on severe AEs, SAEs and FAEs for both the experimental and control cohorts were extracted from these RCTs and pooled using random-effects model to determine the overall incidence and risk. Results: Of 122 phase 2/3 RCTs of cancer drugs identified, 53 (43.4%) reports used terms downplaying the toxicities of the experimental arm and were included in this analysis. The overall incidence of severe AEs, SAEs and FAEs with these cancer drugs were 50.6% (95% CI: 41.5%-59.7%), 21.9% (95% CI: 16.3%-28.7%) and 1.6% (95% CI: 1.2%-2.2%) respectively. Compared with control, the risk of severe AEs and SAEs were significantly increased with the use of these cancer drugs: severe AEs (RR 1.15, 95% CI: 1.04-1.27, p = 0.005) and SAEs ( RR 1.49, 95% CI: 1.26-1.77, p &lt; 0.001) . However, the risk of FAEs was similar across the experimental and control arms ( RR 0.89, 95% CI: 0.72-1.11, p = 0.306) Conclusions: Our analysis shows that considerable proportions of patients suffer severe AEs, SAEs and FAEs and significantly increased risk of severe AEs and SAEs in the trials that downplay the toxicities of cancer drugs. Terms that falsely downplay the toxicities of cancer drugs should be avoided in the reporting of RCTs to encourage accurate risk-benefit assessment.
Prognostic value of positron emission tomography and preoperative CA19-9 in patients treated on a prospective phase II trial of neoadjuvant therapy and surgery.
Authors: Chad Barnes, Mohammed Aldakkak, Kathleen K. Christians, Parag Tolat, Paul S. Ritch, Ben George, William Adrian Hall, Beth Erickson, Douglas B. Evans, Susan Tsai
Journal: Journal of Clinical Oncology (2017)

e15766 Background: The role of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of pancreatic cancer (PC) has not been well defined. We evaluated the prognostic value of FDG-PET imaging in patients with localized PC enrolled in a prospective trial of personalized molecular-directed neoadjuvant therapy. Methods: Pretreatment FDG-PET was classified as high or low based on a standardized uptake value (SUV) cutpoint of 7.2 (population median). Carbohydrate antigen 19-9 (CA19-9) was measured after the completion of neoadjuvant therapy (preoperative) and classified as normal (≤35 U/mL) or elevated. Results: Pretreatment FDG-PET imaging was performed on 100 consecutive patients; SUV was high in 50 and low in 50. Preoperative CA19-9 values were available in 99 of 100 patients; 54 (55%) were elevated and 45 (45%) were normal. Of the 100 patients, 81 completed neoadjuvant therapy and surgery, and 19 were not resected. Among the 81 resected patients, SUV was high in 37 (46%) and low in 44 (54%); preoperative CA19-9 was elevated in 40 (49%) and normal in 41 (51%). The median overall survival (OS) for all patients was 39 months; 45 months for who completed all intended neoadjuvant therapy and surgery and 9 months for patients who were not resected. The median OS for patients with normal CA19-9/low SUV, normal CA19-9/high SUV, elevated CA19-9/low SUV, and elevated CA19-9/high SUV were not reached, 35, 24, and 18 months, respectively (p = 0.0001). Conclusions: Pretreatment FDG-PET avidity and preoperative CA19-9 are important prognostic markers and may be used to estimate the anticipated benefit of surgery; information of immediate clinical significance for both treatment sequencing and the application of surgery to patients who are frequently of advanced age or high-risk.
Abstract 18269: Modified Management Strategies to Improve Survival Chances Following Pediatric Out of Hospital Cardiac Arrest
Authors: Paul E Pepe, Paul R Banerjee, Amninder Singh, Latha Ganti
Journal: Circulation (2017)

Introduction: In pediatric out-of-hospital cardiac arrest (POHCA) cases, EMS crews commonly limit on-scene care and try to provide treatment while transporting. Hypothesis: Prioritizing on-site car...
Mutations in RECQL are not associated with breast cancer risk in an Australian population
Authors: Na Li, Simone M. Rowley, David L. Goode, Kaushalya C. Amarasinghe, Simone McInerny, Lisa Devereux, Michelle W. Wong-Brown, Richard Lupat, Jue Er Amanda Lee, Siobhan Hughes, Ella R. Thompson, Magnus Zethoven, Jason Li, Alison H. Trainer, Kylie L. Gorringe, Rodney J. Scott, Paul A. James, Ian G. Campbell
Journal: Nature Genetics (2018)
Role of fibrinolysis and α<sub>2</sub>-macroglobulin in growth of primary adenocarcinoma and rectal polyps.
Authors: Evgeniy N. Kolesnikov, Elena Alekseevna Nikipelova, Elena Mikhaylovna Frantsiyants, Larisa Kozlova, Irina V. Kaplieva, Lidia K. Trepitaki, Lyudmila Dmitriyevna Tkalya, Alexander V. Snezhko, Michail Averkin, Mikhail Anatolievich Kozhushko, Sergey Vladimirovich Sanamyanc, Roman E. Myagkov, Leonid Kharin, Vladimir Trifanov, Oleg I. Kit
Journal: Journal of Clinical Oncology (2017)

e15093 Background: An important role in tumor angiogenesis induction is played by hydrolytic systems, in particular plasmin one which provides degradation of the extracellular matrix, activates growth factors and metalloproteinases. Our purpose was to analyze the tissue fibrinolytic system and α2-macroglobulin (α 2 M) in primary adenocarcinoma (PA) and polyps (P) of the rectum (R). Methods: Tissues of tumors (РА, G2, T 2-3 N 0 M 0, 42-73 years) and their perifocal zone (PZ) in R (n = 24) and Р (n = 27) were studied by ELISA; the result was calculated per 1 mg of tissue. Results: Resection line (RL) tissues contained levels of tРА antigen and its active form (tРА-Ag and tРА-act) 6.7 and 33.8 times higher than prourokinase and urokinase levels (uPA-Ag and uPA-act). RL tissues in P did not differ significantly from R tissues at PA resection. uPA-act in PA was higher than in RL by 3.2 times, uPA-Ag - 8 times higher, tРА-act - 2.3 times lower; tPA-Ag was similar to RL tissue values. Plasmin-α2-antiplasmin complex (PAP) in PA was 1.4 times higher than in RL. Plasminogen (PG) in PA was 1.5 times lower than in RL (p &lt; 0.01). Activity of α 2 M in PA and RL did not differ. PAP and α 2 М in PA PZ were similar to RL, and PG did not differ from PA. Other indices were between tumor and RL levels. P tissue did not show changes in uPA; tPA-act activity was 1.3 times lower than in RL, and tPA-Ag 1.3 times higher (p &lt; 0.01). PAP in tissues of 88.2% P was 1.5 times higher than in RL and 1.7 times lower than in PA. PG and α 2 М were similar in P and RL. PAP in PZ of P was 2.3 times higher than in RL and 1.5 times higher than in PA PZ. PG in P PZ was 1.4 times lower than in RL (p &lt; 0.01). α 2 М activity in P PZ was higher than in RL and P by 5.4 times on average. uPA in P PZ did not differ from RL; tРА-Ag and tРА-act were higher than in RL by 1.5 and 1.9 times and exceeded P by 2.1 and 1.5 times (p &lt; 0.01). Prevalence of uPA, activation of PG in PA and its PZ indicated degradation of the extracellular matrix compared with the corresponding P tissues. Conclusions: The role of R tumor PZ as a "metabolic" tumor field in neoplasm progression was confirmed. Activation of fibrinolysis in PA and its PZ with a deficiency of inhibitors stimulates the migration and proliferation of cells. Increasing tРА, РАР and α 2 М in PZ of polyps has a protective effect.
Mutation burden in conjunction with MAPK-pathway mutation status as a prognostic biomarker of overall melanoma survival.
Authors: John Cadley, Danny Simpson, Robert Ferguson, Adur Pandya, Taymor Hekal, Taj Richards, Kareem Ibrahim, Jeffrey S. Weber, Iman Osman, Tomas Kirchhoff
Journal: Journal of Clinical Oncology (2018)

9584 Background: The high tumor mutation burden (TMB) in melanoma triggers the increased presentation of neoantigens, which are required to elicit an immune response. As a result, TMB has been proposed as a potential biomarker of immunotherapy treatment (IT). It is highly plausible that immunogenicity is also likely to play a role in melanoma progression. Thus, we explored whether the TMB and neoantigen burden (NB) impact melanoma overall survival (OS), independent of IT treatment. Methods: Excluding all patients treated with IT, we used 356 metastatic melanomas from The Cancer Genome Atlas (TCGA), and designed discovery (N = 240 patients) and validation sets (N = 116 patients) by random sampling. For all samples, we calculated total TMB as the number of non-synonymous mutations detected in each sample. We have also calculated NB as a function of specific mutations and HLA-type. Using total TMB and NB separately, we assessed their impact on OS using Kaplan-Meier survival analysis. Finally, we repeated this analysis restricted to a subset of patients with MAPK-pathway mutations (N = 260). Results: We found that total TMB predicts better OS in both the discovery and validation sets (p = 2e-04, p = 5e-04, respectively). Patients with fewer than 125 mutations showed significantly worse survival, and this result was replicated by repeated sampling. Restricting the analysis to the patients with a mutation in the MAPK-pathway (BRAF or NRAS), using the same mutation cutoff, we demonstrated a significantly stronger association between total TMB and OS (p = 4e-07). As our final analysis, we determined that NB and total TMB are highly correlated (r2 = 0.977), and a NB of fewer than 50 neoantigens associated with worse OS (p = 9e-07). Conclusions: We have shown that lower total TMB and NB is strongly associated with worse OS in melanoma patients. When restricted to tumors containing MAPK-pathway mutations, we found even greater significance, demonstrating the interdependence of specific mutation status (BRAF- or NRAS-positive), total TMB, and OS. Importantly, this result indicates the potential utility of TMB as a biomarker of melanoma prognosis, outside of the context of IT.
Abstract 14749: Use of Rho-associated coiled-coil forming kinase (ROCK) Activity for Rejection Surveillance in Heart Transplant Recipients
Authors: David Y Zhang, Savitri E Fedson, Pat P Ongusaha, Gabriel T Sayer, Gene H Kim, Nir Uriel, Maura Knapp, James K Liao
Journal: Circulation (2014)

Background: Acute rejection and consequences remain a major factor limiting long-term survival despite continued advancement in the use of immunosuppression. Routine surveillance with invasive, expensive endomyocardial biopsy (EMB) remains the gold standard for the detection of acute rejection . Gene-expression profiling has good sensitivity for cellular rejection but has limitations. The ROCK activity is elevated during inflammatory conditions and in heart failure. We aimed to determine whether ROCK activity in peripheral leukocytes is increased in patients with acute rejection, prior to the onset of specific clinical findings. Methods: A prospective study was performed to determine the association between leukocyte ROCK activity and graft rejection. Subjects were enrolled immediately after cardiac transplantation. All subjects underwent standard of care scheduled surveillance right heart catheterization, endomyocardial biopsy, and a collection of peripheral blood for leukocytes. The ROCK activity in leu...
Prognostic neutrophil-to-lymphocyte ratio in head and neck cancer: A single center experience.
Authors: Pina Ziranu, Elena Massa, Marco Puzzoni, Laura Demurtas, Clelia Madeddu, Grazia Pusole, Alessio Cubeddu, Giorgio Astara, Roberta Mascia, Valeria Pusceddu, Andrea Pretta, Mariele Dessi, Francesco Atzori, Eleonora Lai, Simona Tolu, Nicole Liscia, Anna Grazia Pireddu, Valentino Impera, Roberto Puxeddu, Mario Scartozzi
Journal: Journal of Clinical Oncology (2017)

e17540 Background: The Neutrophil-to-Lymphocytes ratio (NLR) represents a potential prognostic and predictive marker in a different tumor types. The purpose of our study was to investigate the prognostic value of the pretreatment inflammatory marker NLR in patients with head and neck squamous cell carcinoma (HNSCC). Methods: Pretreatment NLR were retrospectively investigated for correlation with overall survival (OS). Kaplan-Meier statistic and long rang test were used. Univariate analysis for categorical and descriptive variables were performed. Results: Thirty-nine patients, from local to advanced stage disease, were included in our analysis. At a median follow up of 9.44 months (2.04 – 30.3), of the total patients 30.7% died and 41.9% had progression of disease. The median PFS was 4.6 months (2.9 – 27.2) and the median OS (mOS) was 18.9 months. Following ROC curve analysis the optimum cut-off value of NLR was 3.93 (p = 0.017). Patient with NLR &gt; 3.92 had a mOS of 11.9 months, whereas the mOS for NLR ≤ 3.92 was 30.3 months (Log-rank p = 0.189). The 1 year Kaplan-Meier estimates of OS for NLR ≤ 3.92 vs. &gt;3.92 was 72% vs. 45% respectively (Log-rank p = 0.243). According to COX univariate analysis, the risk of death increases of 7.7% each unitary rise of NLR mean value (p = 0.3407). Conclusions: In our limited case series NLR was not significantly associated with clinical outcome. Therefore, multicenter studied are needed to determine an optimal NLR cutoff value. [Table: see text]
Prognostic significance of tumor-associated macrophages in pancreatic neuroendocrine tumors.
Authors: Alejandro Cruz, Nahiro Uraoka, Edwin Roger Parra Cuentas, Luisa Maren Solis, A. Dasari, Michael J. Overman, Jonathan M. Loree, James C. Yao, Ignacio Ivan Wistuba, Daniel M. Halperin, Jeannelyn Estrella
Journal: Journal of Clinical Oncology (2018)

e16178 Background: Neuroendocrine tumors (NETs) are a highly heterogeneous group of malignancies with variable clinical course. Checkpoint inhibitors have shown modest antitumor activity, but rational immunotherapy strategies have been hampered by a lack of understanding of the NET immune milieu. Methods: Resection specimens from 55 patients with metastatic pancreatic NETs were evaluated. Characterization of the tumor microenvironment (i.e. tumor-associated lymphocytes and macrophages) was performed using immunohistochemistry for CD4, CD8, FoxP3, and CD68. Areas of highest density were quantitated using computer-assisted image analysis with Aperio© ImageScope Version 12.3.3.7031. Time-to-event analyses were performed with the Kaplan-Meier method. Cox regression was used to evaluate the relationship between each cell type and survival, both from initial diagnosis and from date of establishment of metastatic disease. Results: Whereas T cell infiltrates did not correlate with survival, tumor-associated macrophages (TAMs), identified by CD68 staining, strongly correlated with overall survival. Comparing the median overall survival between patients with the lowest quartile and highest quartile of TAMs, the hazard ratio for survival was 0.157 (95% CI 0.043-0.574, p = 0.0051). Median overall survival from diagnosis in patients with the highest quartile of TAMs was 78 months (95%CI 72.56-83.44), while it was not reached in patients with the lowest quartile of TAMs, despite median follow-up of 132 months. Conclusions: TAMs were significantly correlated with inferior survival in pancreatic NETs. TAM depletion may therefore present an appealing and rational target for immunotherapeutic approaches in NETs.
The limitations of cross-sectional data: perinatal risk factors for asthma
Authors: Cristina Ardura-Garcia, Eva S.L. Pedersen, Myrofora Goutaki
Journal: European Respiratory Journal (2018)

The relationship between perinatal factors and lung function or development of asthma has been studied for decades and we have increasing evidence for the importance of early life factors for respiratory health in adulthood [1]. Pregnancies in adolescent and older women have implications for maternal and child health. The topic is relevant at present, as first-birth rates for women aged >35 years have increased exponentially [2]. A number of studies showed an association between maternal age and respiratory symptoms and asthma in childhood, suggesting that lung development might differ between children born to very young or very old mothers [3]. However, the evidence for longer lasting effects is scarce. Adjusting for residual confounding when studying perinatal factors and offspring health can be difficult but it is very important for designing future studies <http://ow.ly/H78y30kPxMZ>
TCT-16 Incidence, Outcomes, and Microbiologic Profile of Prosthetic Valve Endocarditis after TAVR and SAVR: Insights from PARTNER
Authors: Matthew Summers, Martin Leon, Craig Smith, Susheel Kodali, Vinod Thourani, Howard Herrmann, Raj Makkar, Philippe Pibarot, John Webb, Jonathon Leipsic, Maria Alu, Aaron Crowley, Samir Kapadia, E. Murat Tuzcu, Lars Svensson, Wael Jaber
Journal: Journal of the American College of Cardiology (2018)
TCT-191 Impact of post-procedural minimal stent area by IVUS on 2-year outcome after PCI in the SYNTAX II trial.
Authors: Yuki Katagiri, Giovanni Luigi De Maria, Norihiro Kogame, Javier Escaned, Carlos Collet, Nicola Ryan, Simon Walsh, Manel Sabate, Justin Davies, Maciej Lesiak, Raul Moreno, Ignacio Cruz-Gonzalez, Stephan Hoole, Nick West, Jan Piek, Azfar Zaman, Rod Stables, Clare Appleby, Nicolas Van Mieghem, Neal Uren, Javier Zueco, Pawel Buszman, David Hildick-Smith, Andrzej Ochala, Dariusz Dudek, Colm Hanratty, Rafael Cavalcante, David Taggart, Gerrit-Anne Van Es, Marie-Angele Morel, Yoshinobu Onuma, Vasim Farooq, Patrick Serruys, Adrian Banning
Journal: Journal of the American College of Cardiology (2018)
The effectiveness, safety and economic rationality of the neoadjuvant chemotherapy with biosimilar of Trastuzumab in HER2+ breast cancer in Russian clinical practice.
Authors: Irina Vladimirovna Kolyadina, I. Ganshina, Lyudmila Zhukova, Olga Gordeeva, Vahan Yurikovich Bokhian, Dmitrii Komov, Olga Pavlikova, Yana V Vishnevskaya, Irina Poddubnaya
Journal: Journal of Clinical Oncology (2018)

e12656 Background: The biosimilar of trastuzumab (Herticad ®) used in Russian clinical practice since March 2016, but the effectiveness, safety and economic rationality of biosimilar of trastuzumab (BT) in the neoadjuvant chemotherapy in HER2+ breast cancer (BC) have not been previously reported. Methods: In our study included 55 women with HER2+ BC stage II-III treated in National Research Cancer Center since March 2016 to December 2017 (median age- 52; range - 28-80 years). Neoadjuvant chemotherapy was used in all women (sequential combination of anthracyclines and taxanes, AC→T - 59,3%, taxanes plus carboplatin, DC -37%, taxanes only -3,7%) with BT at a standard dose 6 mg/kg (loading first dose 8 mg/kg), every 3 weeks. Primary-operable stages were in 45,5%, locally advance stages - in 54,4%. Grade of tumors was G2 in 83%, G3- in 17%; luminal HER2+ BC was seen in 45,5%, non-luminal HER2+ BC - in 54,5%. After neoadjuvant chemotherapy with BT all women had radical surgery with an assessment of the pathological response. We analyzed the rate of complete pathological response (pCR), the safety and economic rationality of neoadjuvant chemotherapy with BT, statistical analysis was made by SPSS 20,0. Results: The rate of pCR was 55,6% (breast) and 45,8% (breast and lymph nodes). The rate of pCR was the same in women with primary-operable and locally-advance stages (58,6 vs 52%, p = 0,625), as well as in luminal and non-luminal BC (54,2 vs 56,7%, p = 0,854). But the rate of pCR was significantly depend from grade of tumors (G2- 49%, G3- 86%, p = 0,01), regime of chemotherapy (AC→T – 45,2%, DC -70%, р = 0,033) and number of neoadjuvant cycles of BT (4 cycles- 48,5%, 6 cycles- 65%, 8 cycles- 100%, p = 0,01). Toxicity corresponded well with the chemotherapy-regimen chosen. No treatment-associated cardiac dysfunction occurred in any of the patients enrolled in the study. No infusion-related reactions were registered. The cost of neoadjuvant therapy with BT decreased to 75% from March 2016 to December 2017. Conclusions: Neoadjuvant chemotherapy with BT was effective, safe and economically reasonable in Russian women with breast cancer stage II-III.