tbuckley/cabot-search huggingface dataset:
Geographical isolation and uptake of adjuvant chemotherapy for stage III colon cancer: Results from the New Zealand PIPER Cohort study.
Authors: Melissa J. Murray, Christopher G. C. A. Jackson, Katrina J. Sharples, Mark Jeffery, Ross A. Lawrenson, Victoria A. Hinder, Michael P. N. Findlay
Journal: Journal of Clinical Oncology (2015)

e17504 Background: Geographical isolation is cited as a reason for inequitable outcome in colorectal cancer, with patients in more rural locations at risk of lower delivery of potentially curative treatment than those in urban areas. This may be due to prescriber behaviour, patient access to services or patients declining therapy. New Zealand (NZ) is a country of 4.5million people with the majority of Medical Oncology care led from 6 government-funded Cancer Centres, servicing urban and rural populations with medical staff on a center-satellite model. We explored whether rurality or geographical distance to treatment center resulted in variation in the uptake of adjuvant chemotherapy. Methods: We undertook a retrospective national cohort study of all patients diagnosed with colorectal cancer in NZ (n = 5667) between 1 Jan 2007 and 31 Dec 2008, with manual review of all case records (the PIPER Project). Oxaliplatin was funded for use in stage III colon cancer on 1 Dec 2007. We analysed receipt of any adjuvant therapy and uptake patterns of oxaliplatin based on urban/rural classification of residential area and geographical distance to treatment centre. Results: 915 patients with stage III colon cancer were identified. 535 (58%) received adjuvant chemotherapy over the 2 year period. Amongst these, the use of oxaliplatin increased from 15% in the year before funding to 58% in the first 6 months after funding (p < 0.0005) and remained at 51% during the following 6 months. There was no evidence of variation in oxaliplatin use by rurality (p = 0.4). Use did differ by distance from treating center (p = 0.04), however only for those living more than 50km from the treating center, where usage was higher (50% vs. under 40%). Conclusions: In a center-satellite model of care, we found no negative impact of rurality or geographical distance to treatment center on utilisation of chemotherapy or rate of uptake of adjuvant oxaliplatin when introduced.
Development of a new switchable CAR system.
Authors: CÃ©cile BAUCHE
Journal: Journal of Clinical Oncology (2015)

e14024 Background: Chimeric antigen receptors-modified T cells have shown very promising clinical results in hematological malignancies. CAR are usually composed of a scFv antigen binding domain linked to a spacer and intracellular signaling domains. CAR introduction into T cells leads to cells with optimal effector functions and with a new antigen binding ability. This strategy is well suited to skirt immune escape mechanisms. Despite their efficacy, CAR-T cells still show toxicity due to a cytokine storm. Improving the safety while maintaining or even improving the anti-tumor efficacy of CAR-T cells is therefore a crucial therapeutic challenge. Methods: We are developing a CAR-T cell platform aiming at producing innovative switchable CAR-T cells based on a RUSH (Retention Using Selective Hook) system. This system is based on the streptavidin anchored to the membrane of the endoplasmic reticulum (ER) through a hook, and on the SBP (streptavidin binding protein) introduced into the CAR structure. The interaction between the streptavidin-hook and the SBP-CAR allows the CAR retention inside the ER. The addition of biotin displaces the equilibrium of binding of streptavidin towards biotin instead of SBP, thus leading to the release of the CAR from the ER and its expression to the cytoplasmic membrane. The release of the CAR will stop with drug exhaustion (or antagonist) and remaining cells can be easily reactivated through reintroduction of biotin. This system will increase safety of CAR-T cells. A CD19-CAR RUSH will be used as a proof-of-concept of the RUSH system. Most of the scFv used to date are of murine origin. Neutralizing antibodies against these murine scFv can limit the efficacy of CAR. As an alternative, we will develop camelid nanobodies to be used as binding domains since they are highly homologous to the human VH domain of antibodies and they display high antigen binding capacities. The proof-of-concept will be made with a second generation CAR containing a nanobody directed against Her2 as a binding domain. Results: In vitro and in vivo results are expected on Q2 2015. Conclusions: Theravectys’ technological platforms allows flexibility and reactivity in the CAR design, production and evaluation, thus leading to the generation of optimal CAR-T cells.
Abstract P187: The Associations of White Coat and Masked Hypertension With Cardiovascular Disease and Mortality in the Jackson Heart Study
Authors: Rikki M Tanner, John Booth, Yuichiro Yano, Olugbenga Ogedegbe, Laura P Cohen, Swati Sakhuja, Bharat Poudel, Donald Clark, Emily O’Brien, Eyal Shahar, Mario Sims, Adolfo Correa, Joseph Schwartz, Daichi Shimbo, Paul Muntner
Journal: Circulation (2019)

Introduction: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline uses lower clinic and out-of-clinic BP thresholds to define hypertension compared to previous US guidelines. Using these thresholds, we determined the associations between white coat hypertension (WCH) and masked hypertension with cardiovascular disease (CVD) events and mortality. Methods: We included 993 African Americans participating in the Jackson Heart Study who had clinic BP measured during their baseline study visit between 2000 and 2004 and underwent ambulatory blood pressure monitoring (ABPM). We defined normotension, WCH/white coat effect (WCE), masked/masked uncontrolled hypertension, and sustained hypertension using clinic BP and mean awake BP on ABPM (Table). CVD events (i.e., coronary heart disease and stroke; n=107), and all-cause mortality (n=185) were adjudicated from baseline through December 2014 and December 2016, respectively. Results: The mean age of participants was 59 years and 68% were female. Among those not taking antihypertensive medication, 38% had normotension, 27% had WCH, 33% had masked hypertension, and 31% had sustained hypertension. WCH, masked hypertension, and sustained hypertension were each associated with an increased risk for CVD and mortality compared to normotension (Table). Among those taking antihypertensive medication, 26% had controlled normotension, 25% had a WCE, 45% had masked uncontrolled hypertension, and 39% had treated sustained hypertension. Masked uncontrolled hypertension was associated with a higher risk for CVD and a lower risk for mortality compared to controlled normotension. WCE was not associated with CVD events or all-cause mortality. Conclusions: According to the ACC/AHA BP guideline, WCH and masked hypertension are common among African American adults. ABPM could have an important role in guiding antihypertensive medication initiation and intensification to reduce CVD and mortality risk among African Americans.
Long-Term Exposure to Wind Turbine Noise and Risk for Myocardial Infarction and Stroke: A Nationwide Cohort Study
Authors: Aslak Harbo Poulsen, Ole Raaschou-Nielsen, Alfredo Peña, Andrea N. Hahmann, Rikke Baastrup Nordsborg, Matthias Ketzel, Jørgen Brandt, Mette Sørensen
Journal: Environmental Health Perspectives (2019)

Background: Noise from wind turbines (WTs) is reported as more annoying than traffic noise at similar levels, raising concerns as to whether WT noise (WTN) increases risk for cardiovascular disease, as observed for traffic noise. Objectives: We aimed to investigate whether long-term exposure to WTN increases risk of myocardial infarction (MI) and stroke. Methods: We identified all Danish dwellings within a radius 20 times the height of the closest WT and 25% of the dwellings within 20–40 times the height of the closest WT. Using data on WT type and simulated hourly wind at each WT, we estimated hourly outdoor and low frequency (LF) indoor WTN for each dwelling and derived 1-y and 5-y running nighttime averages. We used hospital and mortality registries to identify all incident cases of MI (n=19,145) and stroke (n=18,064) among all adults age 25–85 y (n=717,453), who lived in one of these dwellings for ≥one year over the period 1982–2013. We used Poisson regression to estimate incidence rate ratios (IRRs) adjusted for individual- and area-level covariates. Results: IRRs for MI in association with 5-y nighttime outdoor WTN >42 (vs. <24) dB(A) and indoor LF WTN >15 (vs. <5) dB(A) were 1.21 [95% confidence interval (CI): 0.91, 1.62; 47 exposed cases] and 1.29 (95% CI: 0.73, 2.28; 12 exposed cases), respectively. IRRs for intermediate categories of outdoor WTN [24–30, 30–36, and 36–42 dB(A) vs. <24 dB(A)] were slightly above the null and of similar size: 1.08 (95% CI: 1.04, 1.12), 1.07 (95% CI: 1.00, 1.12), and 1.06 (95% CI: 0.93, 1.22), respectively. For stroke, IRRs for the second and third outdoor exposure groups were similar to those for MI, but near or below the null for higher exposures. Conclusions: We did not find convincing evidence of associations between WTN and MI or stroke. https://doi.org/10.1289/EHP3340
Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure
Authors: Gianluigi Savarese, Ola Vedin, Domenico D'Amario, Alicia Uijl, Ulf Dahlström, Giuseppe Rosano, Carolyn S.P. Lam, Lars H. Lund
Journal: JACC Heart Failure (2019)
Ten-Year Clinical Outcomes From a Trial of Three Limus-Eluting Stents With Different Polymer Coatings in Patients With Coronary Artery Disease
Authors: Sebastian Kufner, Michael Joner, Anna Thannheimer, Petra Hoppmann, Tareq Ibrahim, Katharina Mayer, Salvatore Cassese, Karl-Ludwig Laugwitz, Heribert Schunkert, Adnan Kastrati, Robert A. Byrne
Journal: Circulation (2019)

New-generation drug-eluting stents offer the potential for enhanced late outcomes in comparison with early generation drug-eluting stents. However, assessment of extended long-term outcomes for these devices is lacking, especially regarding the comparison between new-generation drug-eluting stents with biodegradable or permanent polymers. The aim of this study is to compare the efficacy and safety of biodegradable polymer-based sirolimus-eluting stents (BP-SES; Yukon Choice PC) versus permanent polymer-based everolimus-eluting stents (PP-EES; Xience) versus early generation permanent polymer-based sirolimus-eluting stents (PP-SES; Cypher) at 10-year follow-up.Overall, 2603 patients were randomized to treatment with BP-SES (n=1299), PP-EES (n=652), or PP-SES (n=652). The primary end point of this analysis was major adverse cardiac event, the composite of death, myocardial infarction, or target lesion revascularization. The main secondary end point of interest was definite/probable stent thrombosis. Follow-up at 10 years was available in 83% of the study patients.The 10-year incidence of major adverse cardiac event (BP-SES 47.7% versus PP-EES 46.0% versus PP-SES 54.9%, P=0.003) and mortality (BP-SES 31.8% versus PP-EES 30.3% versus PP-SES 37.2%, P=0.02) was different among the groups. Definite/probable stent thrombosis was not significantly different among the groups (BP-SES 1.8% versus PP-EES 2.5% versus PP-SES 3.7%, P=0.09). Definite stent thrombosis was significantly different among the groups (BP-SES 1.1% versus PP-EES 0.8% versus PP-SES 2.4%, P=0.03). There were no significant differences between BP-SES and PP-EES.In this unique long-term outcome analysis, BP-SES and PP-EES showed comparable clinical outcomes out to 10 years. PP-SES had higher rates of major adverse cardiac events and definite stent thrombosis.URL: https://www.clinicaltrials.gov . Unique identifier: NCT00598676.
Results of observational study to determine K-ras mutation rates in 2458 patients with metastatic colorectal cancer in Turkey (TURKRAS Study).
Authors: Mahmut Gumus, Faysal Dane, Bulent Karabulut, Kazim Uygun, Kubra Aydin, Bulent Orhan, Berna Oksuzoglu, Oktay Tarhan, Suleyman Buyukberber, Kerem Okutur, Idris Yucel, Nurullah Zengin, Abdurrahman Isikdogan, Tugba Unek, Sinan Yavuz, Hakan Harputluoglu, Ridvan Seckin Ozen
Journal: Journal of Clinical Oncology (2015)

e14516 Background: Primarily we aimed to investigate the frequency of K-ras mutation in colorectal cancer patients in Turkey, and secondly to determine the frequency of sub-types of the K-ras mutation and the relationship between demographic characteristics. Methods: Prospective, single-arm, multi-center, non-comparative, case-based, epidemiologic observational study of two years duration. All samples for K-ras examination were evaluated by an accredited, independent central laboratory in Turkey. The laboratory procedures to be performed for pathologic specimens obtained from the patients are sample preparation, DNA isolation, amplification by polymerase chain reaction method and identification of the mutations in codons 12 and 13 of the K-ras gene using minisequencing method. Results: We have planned to enroll 2500 metastatic colorectal cancer patients to the study from 52 centers in Turkey. This is the final analysis with the data obtained from 2458 mCRC patients. 38.8% of patients were female. Majority of the patients (42.5%) were from Marmara region. Patients from other regions were distributed as the Middle Anatolia, Aegean, Mediterranean and Southeastern Anatolia, Black Sea regions; and the percentage of patients included from these regions were 21.6%, 13.2%, 11.9%, and 10.9% respectively. The frequency of K-ras mutations in all patients were 45%. There is significantly high K-ras mutation frequency in female patients. Mutation frequency in female was 48.8% (p = 0.002). G12D and G12V mutations are the common mutations with the mutation rates of 28% and 25.9% respectively. G12V mutation is significantly more frequent in female when compared with male patients (14.8% vs 11.1%, p = 0.007). There is no significant difference between the frequency of G12 and G13 mutations when compared according to regional distribution. (p > 0.05). Conclusions: In our study, the detection rate of KRAS mutation is higher in female mCRC patients than the males. In Turkish population, G12V mutation is significantly more frequent in female patients when compared with male patients. Further prospectively generated detailed investigations are necessary to confirm and define these data.
Systemic endocrine disorders in patients with head and neck cancer.
Authors: Margarita Kozlova, Elena Mikhaylovna Frantsiyants, Ludmila Rozenko, Marina Engibaryan, Irina Viktorovna Pustovaya, Viktoriya L. Volkova, Ayna Mayerbekovna Salatova
Journal: Journal of Clinical Oncology (2015)

e17023 Background: Head and neck tumors are characterized by a variety of biological properties and behavior, as well as by heterogeneity of the disease course which can be caused by different effects on the regulatory systems of the body. As to the processes in this localization, the problem is poorly studied. Taking into account the leading multifunctional regulatory role of the neuroendocrine system, the purpose of this study was the comparative assessment of some characteristics of thyroid and glucocorticoid homeostasis in patients with oral mucosa cancer (OMC) and nasopharyngeal cancer (NPC). Methods: Levels of total and free T3 and T4, thyroid-stimulating hormone (TSH) and cortisol were determined by radioimmunoassay in blood of male patients with NPC (n = 14) and OMC (n = 32), N3T0M0 st. mainly. Results: In all NPC patients content of total T4 was 1.4-2.6 times higher than the norm, while TSH secretion was decreased by 1.7 times, and total T3 was equal to the control. Detection of biologically active forms of hormones showed deficiency of free T4 and increased by 1.8 times free Т3 level. Levels of total Т4 and TSH in 21 OMC patients did not differ from the norm but were changed in the other 11 cases, while the level of total T3 in all patients was reduced by 1.4-1.7 times. OMC did not show abnormalities in the content of free Т4 (in all patients) and Т3 (in 20/32 patients; the level was decreased by 1.4 times in 12 cases). Circulating cortisol levels in all NPC patients and in 50% of OMC patients was increased by 1.9 and 1.7 times, respectively. Conclusions: NPC and OMC changed the structure of thyroid homeostasis in different ways, but affected cortisol status similarly. Revealed differences in character and/or degree of hormonal disruptions showed the role of individual characteristics of an organism in its interaction with tumor which can be a significant factor in characteristics of the disease course.
The effect of androgen receptor splice variant 7 on the growth of castration-resistant prostate cancer and the efficacy of taxane chemotherapy.
Authors: Yasuomi Shimizu, Minoru Kato, Yuji Takeyama, Kosuke Hamada, Taro Iguchi, Satoshi Tamada, Tatsuya Nakatani
Journal: Journal of Clinical Oncology (2019)

302 Background: Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as a mechanism associated with the development of castration-resistant prostate cancer (CRPC), but a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. We clarify the relationship between AR-V7 expression and resistance to taxanes. Furthermore, we assess the inhibitory effect of EPI-002, an antagonist of AR amino-terminal domain (NTD), to an AR-V7 driven CRPC cell line with acquired resistance to docetaxel. Methods: LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel, was developed. WST-1 assay or BrdU ELISA assay was performed to evaluate the inhibitory effect of drugs. We examined alterations of AR and AR-V7 signaling using Western blot analyses, real-time RT-qPCR and reporter gene assay. Results: LNCaP95-DR cells showed cross-resistance to cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002 had an inhibitory effect on the proliferation of LNCaP95-DR cells that was similar to that achieved with the parental LNCaP95 cells, whereas enzalutamide had no effect on the proliferation of either cell line. Conclusions: Our results suggest that EPI-002 may be an option for the treatment of AR-V7-driven CRPC that is resistant to taxanes.
Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis
Authors: Tatiana Lobry, Roy Miller, Nathalie Nevo, Celine J. Rocca, Jinzhong Zhang, Sergio D. Catz, Fiona Moore, Lucie Thomas, Daniel Pouly, Anne Bailleux, Ida Chiara Guerrera, Marie-Claire Gubler, Wai W. Cheung, Robert H. Mak, Tristan Montier, Corinne Antignac, Stephanie Cherqui
Journal: Kidney International (2019)
The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival in recurrent ovarian cancer patients: An individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) of 1,213 patients.
Authors: Hannah Woopen, Rolf Richter, Radoslav Chekerov, Timo Siepmann, Jalid Sehouli
Journal: Journal of Clinical Oncology (2015)

5533 Background: In ovarian cancer patients prevalence of comorbidity and quantities of prescribed comedications increase with age. We aimed to evaluate the influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival. Methods: Synthesized raw data of three phase II/III studies (“Tower”, “Topotecan phase III” and “Hector”) of the North-Eastern German Society of Gynecological Oncology (NOGGO) including 1213 patients were analyzed using logistic regression and cox regression analyses. Results: In our analysis 349 patients (28.8%) were older than 65 years at initial diagnosis. Most patients were in an advanced stage at the time of diagnosis (1047 patients FIGO III/IV, 86.3%). Hematological grade III/IV toxicity was documented in 715 cases (58.9%), non-hematological grade III/IV toxicity occurred in 531 cases (43.8%). While 110 patients (9.1%) were naive to comedication, 530 patients (43.7%) were prescribed less than five co-drugs, 683 patients (56.3%) were treated with five or more co-drugs, and 267 (22.0%) were treated with ten or more co-drugs. Most frequent comedications were beta-blockers (211 cases, 17.4%), diuretics (163 patients, 13.4%) and ACE-inhibitors (133 patients, 11.0%). In the multiple regression models, an increasing amount of comedications was associated with overall (p < 0.001; OR 1.120), hematological (p < 0.001; OR 1.056) and non-hematological (p < 0.001; OR 1.134) toxicity. Prior discontinuation of therapy was not associated with the amount of comedications (p = 0.196). Increasing number of comedication was not associated with overall survival (p = 0.068). Conclusions: Our synthesized data analysis suggests that polypharmacy in ovarian cancer recurrence may be a clinically useful predictor of increased risk of grade III/IV toxicity during chemotherapy. Patients with increasing amount of comedication had no disadvantage regarding survival. Hence, polypharmacy should not be a criterion for exclusion of clinical studies in ovarian cancer.
Circulating cell-free methylated DNA (cfmeDNA) to predict postoperative recurrence in patients with muscle-invasive bladder cancer (MIBC).
Authors: Pier Vitale Nuzzo, Sandor Spisak, Norbert Solymosi, Ankur Chakravarthy, Shu Yi Shen, Mark Pomerantz, Francesco Boccardo, Amin Nassar, Gwo-Shu Mary Lee, Guru Sonpavde, Toni K. Choueiri, Daniel De Carvalho, Matthew L Freedman
Journal: Journal of Clinical Oncology (2019)

454 Background: CfmeDNA is a promising non-invasive biomarker to assess solid tumor burden: i) CpG island methylation changes in cfDNA are stable ii) methylation is tissue- and tumor- specific iii) methylation target size is larger and more sensitively detected than genomic alterations. CfmeDNA Immunoprecipitation and high throughput sequencing (cfMeDIP-seq) is an innovative assay for genome-wide bisulfite-free plasma DNA methylation profiling, that permits CpG enrichment. We tested the feasibility of cfmeDNA to predict recurrence of MIBC post- radical cystectomy (RC). Methods: We selected 12 pts who underwent RC for MIBC: 6 pts who had recurrent disease within 2-3yrs after RC (A) and 6 pts who did not (B). 119 healthy pts without BC were controls. cfDNA isolated from 1ml of plasma samples collected after RC and before recurrence (A) or during follow-up in those who did not recur (B) was analyzed by the cfMeDIP-seq using 10ng cfDNA. The data were analyzed using the MEDIPS program and differentially methylated regions (DMR) between the cohorts were studied. ENCODE ChIP-seq analytical pipeline was used for fastq file processing and peak calling. Results: The average cfDNA isolated from 1ml of plasma was 13.1 ng (6.4-19.7) in A and 17.1 ng (13.6-21.2) in B. The median time from RC to plasma collection were respectively 9.3 mos (3.4-91.3) vs 12.3 mos (2.9-150). Median time from plasma collection to recurrence was 21.9 mos (0.25-141.3). We identified ~137,000 peaks in ≥1 sample. The supervised classification identified 61 DMR (FDR&lt;0.050), predominantly located in intergenic region, which distinguished A from B. Randomized sample tests proved the discriminatory power of the identified set. Supervised analysis comparing the status of the identified DMRs relative to healthy controls showed 28 regions were differentially methylated (logFC &gt; +/- 1, FDR &lt; 0.05). The study is limited by retrospective design and sample size. Conclusions: This is the first study to demonstrate that cfmeDNA can be readily harvested from MIBC pts to detect cancer-specific methylation patterns and predict recurrence post-RC. Prospective validation will enable the selection of suitable pts for adjuvant therapy.