tbuckley/cabot-search huggingface dataset:
A chemical genetics approach to identify therapeutic vulnerabilities in Gefitinib resistant, EGFR T790M
Authors: J. Low, J.L.Y. Koh, H.S. Leong, D.P. Lau, X. Zhang, X.L. Kwang, J.V. Chan, S. Rikka, D S W Tan, G. Periyasamy, N.G. Iyer, R. Dasgupta
Journal: Annals of Oncology (2017)
Significance of MSH2 promoter methylation in endometrial cancer with MSH2 deficiency
Authors: J. Haraga, T. Nagasaka, K. Nakamura, T. Haruma, T. Nishida, A. Nyuya, K. Yasui, T. Fujiwara, A. Goel, H. Masuyama
Journal: Annals of Oncology (2017)

Background: Inactivation of MSH2 was frequently observed in endometrial cancer (EC) with microsatellite instability (MSI) or mismatch repair complex deficiency (dMMR). With respect to MSH2 deficiency (dMSH2), most of dMSH2 were caused by germline mutations in the MSH2 gene or EpCAM deletions. Meanwhile, heritable germline epimutations in MSH2 reported in a few Lynch syndrome families that lacked germline mutations in the MSH2 gene. We previously provided evidence for frequent MSH2 hypermethylation in Lynch syndrome colorectal tumors with dMSH2 and MSH2 methylation may serve as the "second hit" at the wild-type allele. Herein, we examined precise epigenetic alteration in MSH2 promoter and tried to reveal associations to family history of Lynch syndrome related tumors. Methods: We analyzed MSH2 promoter methylation status, as well as MLH1 methylation status, and expression status of the mismatch repair proteins (MLH1, MSH2, PMS2, and MSH6) by immunohistochemistry in 326 EC patients. DNA was extracted from formalin-fixed, paraffin-embedded tissue, and analyzed MSI status by four mononucleotide markers and both MLH1 and MSH2 promoter methylation status by a fluorescent quantitative bisulfite PCR assay. Results: MSI or dMMR was observed in 82 (25.2%) or 89 ECs (27.3%), respectively. ECs with dMSH2 were observed in 18 (5.5%) of 326 ECs (20.2% of dMMR). MSH2 promoter methylation was detected in 8 tumors (2.5% in 319 tumors excluding not available 7 ECs), and significantly correlated with dMSH2 (P = 0.0072, Fisher's exact probability test). Then, we also examined the family history of first-degree relatives. In this cohort, although patients with dMMR were significantly associated with family history of Lynch syndrome related tumor (P = 0.0312), patients with this family history are more frequently observed in patients with dMSH2 (P = 0.0052). Interestingly, patients with MSH2 promoter methylation were strongly associated with the family history of Lynch syndrome related tumor (P = 0.0053), though patients with MLH1 methylation were not (P = 0.8345). Conclusions: MSH2 methylation significantly correlated with ECs with dMSH2 and may have strong relation with family history of Lynch syndrome related tumor, suggesting it takes a role as "second hit" to the MSH2 gene. Legal entity responsible for the study: Takeshi Nagasaka Funding: None Disclosure: All authors have declared no conflicts of interest.
IDO-1 and PD-L1 predict response to immunotherapy in advanced non small cell lung cancer: An NGS and multiplex IHC analysis
Authors: L. Leroy, J. Massé, J. Adam, V. Brouste, N. Signolle, I. Soubeyran, V. Velasco, E. Khalifa, B. Lortal, A. Italiano, B. Besse, S. Le Moulec
Journal: Annals of Oncology (2017)
Early palliative care for improving quality of life and survival time in adults with advanced cancer: Meta-analytical findings from a Cochrane Review.
Authors: Markus W. Haun, Stephanie Estel, Gerta Ruecker, Hans-Christoph Friederich, Michael Thomas, Matthias Villalobos, Mechthild Hartmann
Journal: Journal of Clinical Oncology (2016)

10132 Background: Incurable cancer often constitutes an enormous challenge to patients, affecting their physical and psychosocial well-being profoundly. Targeted types of treatment (early palliative care) have been developed in recent years to support people in this stage. This review summarises what is currently known about the effects of these treatments regarding improving health-related quality of life, depression, symptom intensity and survival in adults diagnosed with advanced cancer compared with treatment as usual/standard cancer care. Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE , EMBASE , CINAHL, PsycINFO and Opengrey together with three clinical trial registers and reference lists of articles. Additionally, we contacted authors of completed and on-going studies. All randomised and cluster-randomised controlled trials (RCTs) on professional palliative care services that provided palliative specialist or co-ordinated comprehensive care for patients in early advanced stages of cancer were included. The review was conducted within the Cochrane Palliative and Supportive Care Group. Results: We could include six randomised and cluster-randomised controlled trials involving 1407 participants. Three trials evaluated interventions delivered by specialized palliative care teams and the others evaluated models of coordinated care. Compared with usual cancer care alone, early palliative care significantly increased health-related quality of life with small effect size (SMD 0.17, 95% confidence interval, CI 0.02 to 0.32, participants = 1176, odds ratio = 1.36, 95% CI 1.04 to 1.79). For survival, levels of depresson and symptom intensity quality of evidence was not yet sufficient. Conclusions: Early palliative care interventions are effective for increasing quality of life in advanced cancer patients. Although we found only small effect sizes, we consider this as clinically relevant in an advanced disease stage with limited prognosis. Upcoming results from several on-going trials will improve decisions on further outcomes.
Validating Utility of Dual Antiplatelet Therapy Score in a Large Pooled Cohort From 3 Japanese Percutaneous Coronary Intervention Studies
Authors: Yusuke Yoshikawa, Hiroki Shiomi, Hirotoshi Watanabe, Masahiro Natsuaki, Hirokazu Kondo, Toshihiro Tamura, Yoshihisa Nakagawa, Takeshi Morimoto, Takeshi Kimura
Journal: Circulation (2017)

The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the utility of the DAPT score in the Japanese population.In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto [Coronary Revascularization Demonstrating Outcome Study in Kyoto] Registry Cohort-2, RESET [Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial], and NEXT [NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial]), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score <2 (low DS).Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%, P=0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%, P=0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%, P=0.03; 1.5% versus 0.8%, P=0.002; 0.7% versus 0.3%, P<0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%, P<0.001; 1.0% versus 1.6%, P=0.03, respectively).In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.
Development of a fully human t-cell engaging bispecific antibody for the treatment of multiple myeloma.
Authors: Ben Buelow, Priya Choudhry, Starlynn Clarke, Kevin Dang, Laura Davison, Shelley Force Aldred, Katherine Harris, Duy Pham, Payal Pratap, Udaya Rangaswamy, Ute Schellenberger, Nina Shah, Nathan Trinklein, Harshad Ugamraj, Arun Wiita, Wim Van Schooten
Journal: Journal of Clinical Oncology (2018)

60 Background: T-cell engaging bispecific antibody (T-BsAb) therapies are highly efficacious and well suited for targets with low expression on tumor cells. Recently, T-BsAbs with high activation of CD3 have been shown to overstimulate T cells, leading to toxicity and decreased efficacy. Teneobio has developed a fully human BCMA-specific T-BsAb using a low-activating αCD3 that is highly effective in vitro and in vivo against MM but stimulates minimal cytokine release. Methods: UniRats were immunized with either CD3 or BCMA antigens and antigen-specific UniAbs were identified by Ab repertoire sequencing and high-throughput gene assembly, expression, and screening. Antigen-specific VH sequences with the desired target affinity were selected using recombinant proteins and cells. In vitro efficacy studies included T-cell activation by cytokine- and tumor cell kill by calcein-release assays. In vivo efficacy of the molecules was evaluated in NSG mice harboring myeloma cells and human PBMCs. Results: BCMA-specific UniAbs bound plasma cells with sub-nM affinity. Strong and weak T cell agonists were identified that bound human T cells with high and low affinities respectively. T-BsAbs with a strong and a weak αCD3 demonstrated T-cell activation and tumor-cell cytotoxicity in vitro; T-BsAbs with a weak αCD3 showed markedly reduced cytokine production even at doses that showed maximum tumor cell lysis. In vivo, BCMAxCD3 T-BsAbs reduced tumor load and increased survival when co-administered with human PBMCs as compared to controls. Conclusions: Our results suggest that T-BsAbs with low-activating αCD3 arms may have a favorable toxicity profile while maintaining efficacy in the treatment of MM.
EPHA2 receptor is involved in in vivo acquired resistance to anti-Epidermal Growth Factor Receptor (EGFR) treatment in metastatic colorectal cancer (mCRC)
Authors: G. Martini, V. Belli, P.P. Vitiello, T. Troiani, C. Cardone, S. Napolitano, N. Matrone, V. Sforza, R. Franco, F. Morgillo, D. Ciardiello, E. Giunta, V. De Falco, N. Zanaletti, P. Vitale, E. Martinelli, F. Ciardiello
Journal: Annals of Oncology (2017)
Une épidémie d'hépatite A persistante en Italie dans les Pouilles, 1996 : suivi épidémiologique
Authors: P L Lopalco, P Malfait, S Salmaso, C A Germinario, M Quarto, S Barbuti, R Cipriani, A Mundo, G Pesole
Journal: Eurosurveillance (1997)

Une augmentation du nombre de declarations d'hepatite A a ete observee dans la region des Pouilles, au sud-est de l'Italie, au debut de l'annee 1996. Une investigation epidemiologique realisee en mai 1996 montrait une forte association entre la maladie et la consommation de fruits de mer crus (odds ratio (OR) = 31,8 [12,1-118]) ; le stockage des fruits de mer dans de l'eau de mer sur le lieu de vente etait egalement associe a une augmentation du risque d'infection (1). Malgre les recommandations qui avaient ete faites sur la manipulation et la consommation des fruits de mer, le nombre de nouveaux cas augmenta les mois suivants dans toute la region des Pouilles, avec un pic en aout 1996 dans la province de Bari. Une nouvelle investigation fut entreprise pour identifier d'autres facteurs de risque pouvant etre responsables de la persistance de cette epidemie.
Chemosensitivity and stratification by a five monoclonal antibody IHC test in the NSABP B20 trial
Authors: D. T. Ross, C. Kim, G. Tang, O. M. Mejia, R. A. Beck, B. Z. Ring, R. S. Seitz, S. Paik, J. P. Constantino, N. Wolmark
Journal: Journal of Clinical Oncology (2007)

529 Background: We previously reported the association between a five monoclonal antibody test staining p53, NDRG1, SLC7A5, CEACAM5 and HTF9C and recurrence-free interval (RFI) in 711 ER+ N- breast cancer patients from Tamoxifen (Tam) arm of the NSABP trials B14 and B20 (SABCS 2006). In this study, we examined interaction between the test and chemotherapy in the B20 trial. Subjects and Methods: Tissue array sections from B20 paraffin blocks were stained using standard IHC protocols (N=457). Pre-defined scoring rules and cut- points were applied. RFI was defined as time from entry to any local, regional or distant recurrence. Log-rank test was applied to assess the effect of chemotherapy for each risk stratum pre-defined by this IHC test. Interaction between risk strata and treatment was assessed by the likelihood ratio test in a Cox model with age and clinical tumor size adjusted. Results: The IHC test identified high and low risk groups that both showed significant improvement upon treatment with cytotoxic chemotherapy. The moderate risk group was poorly populated and showed no significant difference between chemo-treated and Tam-only patients. Conclusion: It appears that five monoclonal antibodies may be able to identify groups of ER+, node negative patients who have greater absolute benefit from adjuvant Chemo compared to un-stratified patient populations. However, the formal test for interaction between Chemo and the risk group was not significant (p- value=0.127). This may be due to small sample size and a lack of statistical power. The results suggest that this test deserves further evaluation as a method for identifying subsets of patients who may receive more benefit from Chemo. [Table: see text] No significant financial relationships to disclose.
Bevacizumab eligibility in patients with metastatic cervical cancer: A retrospective review.
Authors: William Paul Skelton, Merry Jennifer Markham
Journal: Journal of Clinical Oncology (2017)

e17021 Background: Bevacizumab (BEV) is approved for use in combination with chemotherapy for metastatic/recurrent cervical cancer (CC) based on the GOG 240 trial, which showed increased survival and response rates (RR). However, because of its contraindications, use of BEV is not always feasible or safe. The purpose of this study was to identify the percentage of metastatic/recurrent CC patients at our institution who would have been eligible to receive BEV according to eligibility criteria from GOG 240. Methods: A retrospective study was conducted to identify metastatic CC patients treated at UFHealth between 2006-2016. Chart review was performed to determine their kidney, liver, and bone marrow function, ECOG performance status (PS), presence of an active bleeding condition or nonhealing wound, or inadequately treated venous thromboembolism. Data analysis was performed to determine if the patient would have been eligible to receive BEV based on eligibility criteria from GOG 240. Results: We identified 62 patients with metastatic CC treated at UFHealth between 2006-2016: 1 patient was excluded due to insufficient data. 55 patients (90.2%) would have been ineligible to receive BEV based on the GOG 240 exclusion criteria, and 6 patients (9.8%) would have been eligible. The most common reason for exclusion from BEV use was active bleeding (45 of 61 pts: 73.8%); 42 of the 45 with bleeding (93.3%) had vaginal bleeding. 18 of 61 (29.5%) would be excluded due to poor PS, 17 of 61 (27.9%) due to poor renal function, and 13 of 61 (21.3%) due to an inadequately anticoagulated thromboembolism. Conclusions: Despite the improved survival and higher RR associated with BEV use in combination with chemotherapy, only 9.8% of metastatic CC patients treated at UFHealth over a ten year period would have been eligible to receive BEV. Most patients would have been excluded due to active bleeding, most commonly vaginal bleeding. Though clinical trial data supports the use of BEV with chemo, many patients are simply not eligible due to complications from their disease. Identifying novel therapies for metastatic/recurrent CC patients with improved safety profiles that would allow for their use in this challenging population is critical.
BRCA1 large gene rearrangements (LGRs) in Russian breast cancer patients: the development of the droplet digital PCR assay for LGR detection and the identification of recurrent exon 8 deletions
Authors: E. Imyanitov, E. Preobrazhenskaya, I. Bizin, E. Kuligina, E. Anisimova, S. Laptiyev, E. Suspitsin, S. Aleksakhina, A. Togo, A. Sokolenko
Journal: Annals of Oncology (2017)
A phase Ib study of NUC1031 and carboplatin for patients with recurrent ovarian cancer.
Authors: Sarah Patricia Blagden, Ajithkumar Sukumaran, Chathunissa Gnanaranjan, Mark R. Middleton, Hani Gabra, Christopher McGuigan, Essam Ahmed Ghazaly
Journal: Journal of Clinical Oncology (2016)

5565 Background: Acelarin is a first-in-class nucleotide analogue utilising phosphoramidate chemistry to overcome the key gemcitabine resistance mechanisms and generate high intracellular levels of the active cytotoxic dFdCTP. In a Phase I, single agent, dose escalation study, Acelarin was well tolerated with impressive clinical activity. In a subset of 13 patients (pts) with ovarian cancer, Acelarin achieved a durable disease control rate, DCR intention-to-treat (ITT) 69%; on-treatment analyses (OTA) 90% and median PFS 8.3 months in evaluable pts. Therefore, we undertook a Phase Ib dose escalation study combining Acelarin with carboplatin in women with advanced ovarian cancer. Methods: Acelarin was administered as an injection on days 1 & 8 with carboplatin at AUC 4 or 5 on day 1, every 3 weeks for ≤ 6 cycles. Primary endpoint was RP2D; secondary endpoints included safety, ORR, PFS and PK/PD. Results: To date, 15 pts (mean age 65 yrs) with metastatic ovarian cancer, a median platinum free interval of 4 months and an average of 2.9 prior lines of chemotherapy, have been enrolled. Four dose cohorts of Acelarin (500; 625 and 750 mg/m2) with carboplatin (AUC4 or 5) have been studied. Nine pts completed 6 cycles of treatment and 3 pts remain on study. Strong early efficacy signals were achieved: 1 RECIST Complete Response (7%); 2 Partial Responses (13%) and 11 Stable Diseases (73%) resulting in a DCR ITT 93%; OTA 100%. Median PFS was 6.0 months (range 1.2 - 11.5) and 7 pts have ongoing disease control. PK showed that Acelarin was stable in the plasma (t1/2 = 3.8 hrs). The combination regimen rapidly generated very high intracellular dFdCTP levels (Cmax = 12.1 µM/mgTP/500mg/m2 and Tmax = 30 min) and significant levels were maintained for 24 hrs. The combination regimen was well tolerated. SAEs were reported in 4 pts: febrile neutropaenia (2); thrombocytopaenia (2); dyspnoea (1) and dizziness (1). Two DLTs were observed: grade 4 thrombocytopaenia at Acelarin 625mg/m2 and 750mg/m2 plus carboplatin AUC4. Conclusions: The combination of Acelarin with carboplatin was well tolerated and demonstrated remarkable clinical activity with durable disease control rate (ITT 93%; OTA 100%). Phase II studies in ovarian cancer are being planned. Clinical trial information: NCT02303912.
GW28-e0579 Different Effect of Fenofibrateon LDL-C: Subgroup Analysis of Statin-Fenofibrate Combination Therapy Trial
Authors: Shuiping Zhao, Fang Wang, Yangyang Dai, Ling Lin, Qiguang Tong, Yuhua Liao, Yugang Dong
Journal: Journal of the American College of Cardiology (2017)
Pembrolizumab plus chemoradiation (CRT) for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC): Phase 3 KEYNOTE-412 trial
Authors: J-P. Machiels, L. Licitra, D. Rischin, J. Waldron, B. Burtness, V. Grégoire, T. Shekar, H.M. Brown, J. Cheng, L.L. Siu
Journal: Annals of Oncology (2017)
Associations of ambient coarse particulate matter, nitrogen dioxide, and carbon monoxide with the risk of kidney disease: a cohort study
Authors: Benjamin Bowe, Yan Xie, Tingting Li, Yan Yan, Hong Xian, Ziyad Al-Aly
Journal: The Lancet Planetary Health (2017)

Experimental evidence and preliminary clinical evidence suggest that environmental air pollution adversely effects kidney health. Previous work has examined the association between fine particulate matter and risk of kidney disease; however, the association between ambient coarse particulate matter (PM10; ≤10 μm in aerodynamic diameter), nitrogen dioxide (NO2), and carbon monoxide (CO) and risk of incident chronic kidney disease, chronic kidney disease progression, and end-stage renal disease is not clear.We merged multiple large databases, including those of the Environmental Protection Agency and the Department of Veterans Affairs, to build a cohort of US veterans, and used survival models to evaluate the association between PM10, NO2, and CO concentrations and risk of incident estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1·73 m2, incident chronic kidney disease, eGFR decline of 30% or more, and end-stage renal disease. We treated exposure as time-varying when it was updated annually and as cohort participants moved.Between Oct 1, 2003, and Sept 30, 2012, 2 010 398 cohort participants were followed up over a median of 8·52 years (IQR 8·05-8·80). An increased risk of eGFR of less than 60 mL/min per 1·73 m2 was associated with an IQR increase in concentrations of PM10 (hazard ratio 1·07, 95% CI 1·06-1·08), NO2 (1·09, 1·08-1·10), and CO (1·09, 1·08-1·10). An increased risk of incident chronic kidney disease was associated with an IQR increase in concentrations of PM10 (1·07, 1·05-1·08), NO2 (1·09, 1·08-1·11), and CO (1·10, 1·08-1·11). An increased risk of an eGFR decline of 30% or more was associated with an IQR increase in concentrations of PM10 (1·08, 1·07-1·09), NO2 (1·12, 1·10-1·13), and CO (1·09, 1·08-1·10). An increased risk of end-stage renal disease was associated with an IQR increase in concentrations of PM10 (1·09, 1·06-1·12), NO2 (1·09, 1·06-1·12), and CO (1·05, 1·02-1·08). Spline analyses suggested a monotonic increasing association between PM10, NO2, and CO concentrations and risk of kidney outcomes.Environmental exposure to higher concentrations of PM10, NO2, and CO is associated with increased risk of incident chronic kidney disease, eGFR decline, and end-stage renal disease.US Department of Veterans Affairs.