tbuckley/cabot-search huggingface dataset:
Use of Computerized Clinical Decision Support Systems to Prevent Venous Thromboembolism in Surgical Patients
Authors: Zachary M. Borab, Michael A. Lanni, Michael G. Tecce, Christopher J. Pannucci, John P. Fischer
Journal: JAMA Surgery (2017)

Health care professionals do not adequately stratify risk or provide prophylaxis for venous thromboembolism (VTE) among surgical patients. Computerized clinical decision support systems (CCDSSs) have been implemented to assist clinicians and improve prophylaxis for VTE.To evaluate the effect of implementing CCDSSs on the ordering of VTE prophylaxis and the rates of VTE.PubMed, MEDLINE via OVID, EMBASE via OVID, Scopus, Cochrane CENTRAL Register of Controlled Trials, and clinicaltrials.gov were searched in June 2016 for articles published in English from October 15, 1991, to February 16, 2016. A manual search of references from relevant articles was also performed.Clinical trials and observational studies among surgical patients comparing CCDSSs with VTE risk stratification and assistance in ordering prophylaxis vs routine care without decision support were included. Of the 188 articles screened, 11 (5.9%) were eligible for meta-analysis.Meta-analysis of Observational Studies in Epidemiology guidelines were followed. Two reviewers extracted data and assessed quality independently.Rates of prophylaxis for VTE and VTE events. Random- and fixed-effects models were used to summarize odds ratios and risk ratios.Eleven articles (9 prospective cohort trials and 2 retrospective cohort trials) comprising 156 366 individuals (104 241 in the intervention group and 52 125 in the control group) were included. The use of CCDSSs was associated with a significant increase in the rate of appropriate ordering of prophylaxis for VTE (odds ratio, 2.35; 95% CI, 1.78-3.10; P < .001) and a significant decrease in the risk of VTE events (risk ratio, 0.78; 95% CI, 0.72-0.85; P < .001).Use of CCDSSs increases the proportion of surgical patients who were prescribed adequate prophylaxis for VTE and correlates with a reduction in VTE events.
Evaluation of the prognostic value of p85 protein expression in HER2-positive and HER2-negative patients with advanced breast cancer treated with trastuzumab.
Authors: Kitty Pavlakis, Anna Koumarianou, Mattheos Bobos, Anna Batistatou, Vassiliki Kotoula, Anastasia G Eleftheraki, Anastasios Stofas, Eleni Timotheadou, George E. Pentheroudakis, Amanda Psyrri, Angelos Koutras, Dimitrios G. Pectasides, Pavlos Papakostas, Evangelia Razis, Konstantine T. Kalogeras, George Fountzilas, Christos Christodoulou
Journal: Journal of Clinical Oncology (2014)

e11577 Background: p85 is an enzyme that belongs to the class 1A phosphatidylinositol 3-kinases (PI3Ks). Taking under consideration the activation of p85 by HER2, as well as the role of p85 in the regulation of the PTEN/PI3K/Akt pathway, we sought to investigate the possible relation of the immunohistochemical expression of the p85 protein to the expression of the PTEN and phosphorylated Akt proteins, as well as to PIK3CA mutations in a cohort of metastatic breast cancer patients. The relation of p85 to parameters, such as time to progression and survival was also assessed. Methods: The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients treated with trastuzumab-based regimens in the metastatic setting. All samples were evaluated by immunohistochemistry for p85, ER, PgR, HER2, Ki67, PTEN and pAkt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization. PIK3CA mutational status was also evaluated. Results: Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients treated with trastuzumab (50.7 months) compared to HER2-negative patients (36.6 months), but this difference has not reached significance (p=0.068). In total 62% of patients were found positive for p85. p85 was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was associated with poor survival in HER2-positive patients only. Conclusions: In HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.
Delineation of MGMT promoter hypermethylation as a predictive biomarker for the A071102 clinical trial of veliparib combined with temozolomide (TMZ) using patient-derived xenograft (PDX) GBM models.
Authors: Jann Nagina Sarkaria, Shiv Gupta, Sani Haider Kizilbash, Brett Carlson, Ann Mladek, Katrina Bakken, Mark A Schroeder, Paul A. Decker, Erik P. Sulman, Jeanette Eckel-Passow, Gaspar Kitange, Robert B. Jenkins
Journal: Journal of Clinical Oncology (2015)

2052 Background: Poly-ADP-ribose polymerase inhibitors have potent sensitizing effects in pre-clinical models. This study was focused on identifying potential biomarkers of response to TMZ combined with veliparib in GBM. Methods: The efficacy of 3 cycles of TMZ alone or combined with veliparib (dosed days 1-5 every 28 days) was evaluated in 27 PDX models grown as orthotopic xenografts, with 8-10 mice randomized to each treatment group. Results: The combination of veliparib and TMZ was associated with significant survival prolongation (p < 0.05 by log-rank) in 8 of 20 MGMT methylated PDXs lines (range: 20 to 150 d increase vs. TMZ alone), as compared to 1 of 7 MGMT unmethylated lines (GBM6: 7 d increase). Comparing the survival ratios (median survival with treatment vs. placebo) across all lines, veliparib/TMZ was associated with a greater efficacy in MGMT methylated lines, as compared to TMZ alone, with an average survival ratio of 4.0 ± 2.0 and 3.0 ± 1.1, p = 0.0002 respectively, as compared to 2.4 ± 1.7 and 2.4 ± 1.5, p = 0.41 in unmethylated tumors. For the 8 responsive methylated lines, treatment with veliparib/TMZ resulted in an average median survival of 188 days (d) as compared to 121 d with TMZ alone. Exogenously expressed MGMT in GBM12 (MGMT methylated; 75 d prolongation in survival with veliparib/TMZ) resulted in a complete loss of TMZ efficacy with or without veliparib (36 d vs. 34 d, p = 0.87). Similar association between MGMT expression and lack of efficacy was observed in GBM28 sublines with an intact vs. homozygous deleted MGMT locus. In comparing in vivo DNA damage signaling, co-treatment with veliparib/TMZ, relative to TMZ alone, resulted in greater phosphorylation of Kap1 (S824), Chk1 (S345), Chk2 (T68), and H2AX (S139) only in MGMT methylated (GBM12, 39) lines. Conclusions: While veliparib combined with TMZ conferred profound sensitizing effect in MGMT hypermethylated tumors, the combination was ineffective in unmethylated tumors. Based on these data, MGMT methylation is a predictive biomarker and entry criteria for the randomized Phase II/III A071102 clinical trial testing this combination in newly diagnosed GBM.
Assessment of age as its own risk factor in AML.
Authors: Thomas Buchner, Wolfgang E. Berdel, Claudia Haferlach, Susanne Schnittger, Matthias Stelljes, Gerda Silling, Peter Staib, Andreas Grueneisen, Albrecht Reichle, Leopold Balleisen, Hartmut Eimermacher, Aristoteles Giagounidis, Herbert Rasche, Eva Lengfelder, Utz Krug, Maria Cristina Sauerland, Achim Heinecke, Bernhard J. Wormann, Wolfgang Hiddemann
Journal: Journal of Clinical Oncology (2012)

6610 Background: Patients’ age is an important issue in treatment decisions for AML, while its role in this disease remains poorly explained. Methods: In the AMLCG 1999 trial 1223 patients (pts) were 16-59y and 1470 pts were 60-85y of age. Their treatment was randomized between TAD-HAM vs HAM-HAM induction (TAD, standard dose thioguanine, cytarabine, daunorubicin 60mg/m² x 3; HAM, high-dose cytarabine 3g/m² x 6, mitoxantrone 10mg/m² x 3), TAD consolidation and monthly maintenance vs autologous SCT, any chemotherapy + vs - G-CSF priming. All randomization was done upfront. Pts of &lt;60y received routine double induction and full dose HAM while pts of 60+y preferentially received only one course induction and HAM at 1g instead of 3g cytarabine /m² x 6. Results: With little differences according randomizations, pts &lt;60y and 60+y achieved a complete remission rate (CR) of 70.2% and 53.5% (p&lt;.001), overall survival (OS) at 5y of 41.3% and 12.9% (p&lt;.001) and a relapse rate (RR) of 49.0 and 72.0% (p&lt;.001). We also focussed on pts around 60y of age and compared the 172 pts of 57-59y with the 261 pts of 60-62y excluding pts undergoing allogeneic stem cell transplantation. According to their similar age the two groups showed similar baseline characteristics. In contrast and due to the cut-off point for age adaption at 60y they differed considerably in treatment. Expressed by the cumulative dosage of cytarabine, the difference between the two groups was by factor 2.9. This difference, however, did not translate into a different outcome being 62% vs 60% CR, 28% vs 21% 5y OS (p=0.25), and 73% vs 73% RR at 5y. A multivariable analysis in all pts between 16 and 85y of age identified cytogenetik/ molecular risk and age as a continuous variable, to be risk factors predicting CR, OS, as well as RR. In pts of 16-60y those below and above the median age of 47y differed in their CR rate by 75% vs 66% (p&lt;.001), their OS by 49% vs 35% (p&lt;.001) and in their RR by 45% vs 53% (p=.007). In pts of 60-85y those below and above the median age of 67y differed in their CR rate by 57% vs 51% (p=.023), and their OS by 16% vs 11% (p&lt;.001), while their RR was similarly 71%. Conclusions: The outcome in pts with AML is substantially determined by patients’ age as its own risk factor, and not by treatment intensity.
Identification of a gene expression profile associated with progression-free survival (PFS) in relapsed or metastatic (RM) head and neck squamous cell cancer (HNSCC) patients (pts) treated with first-line cetuximab and platinum therapy.
Authors: Paolo Bossi, Loris De Cecco, Federica Perrone, Barbara Cortelazzi, Maria Cossu Rocca, Siano Marco, Andrea Sponghini, Cristiana Bergamini, Laura D. Locati, Aurora Mirabile, Roberta Granata, Carlo Resteghini, Silvana Pilotti, Silvana Canevari, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2013)

6027 Background: First-line chemotherapy with platinum and cetuximab is usually offered to RM-HNSCC pts. In the Extreme trial a median PFS time of 5.6 months was reported. However, a small fraction of pts achieves a prolonged PFS (&gt; than 12 months). Until now, no recognized predictive biological factor has been identified. Methods: A group of 14 pts treated with a first-line platinum and cetuximab with a PFS exceeding 12 months (long PFS) and a group of 26 pts with a PFS less than 5.6 months (short PFS) were selected. Tumor specimens of the recurrence (25 cases) or, if not available, of the primary tumor were collected. In order to identify molecular profiles deregulated between the 2 groups, a gene expression microarray analysis was performed using the Whole-Genome DASL assay and HumanHT-12_v4 BeadArray chips (lllumina). Results: The 2 groups were well balanced in regard to recognized prognostic factors (performance status, weight loss, prior radiotherapy, tumor grade, site of primary tumor, residual disease at primary tumor site). Mean PFS was 21 months in long (range 13-36) and 4 months in short PFS group (range 1-5). By class comparison analysis between the 2 groups, the expression pattern of 136 genes was found differentially expressed (FDR&lt;0.05). In long PFS group, EGFR and genes associated to EGFR pathway including CDCP1 and EPGN were up regulated, as well as its ligand (EREG). Several members of the Kallikrein serine proteases gene family are present among the most upregulated genes in long PFS group, suggesting the involvement of extracellular-matrix remodelling. In addition to cellular morphology, pathways analysis showed an enriched modulation of genes belonging to cell-to-cell signalling, DNA replication/DNA repair and lipid metabolism. Conclusions: Our analysis suggests that a specific molecular signature may be associated with long and short PFS after platinum/cetuximab first line chemotherapy in RM-HNSCC pts. To our knowledge, it is the first study attempting to generate hypotheses in this field and further validation is required.
Effect of coronary heart disease (CHD) risk factors and medications on invasive breast cancer risk in the Raloxifene Use for The Heart (RUTH) trial
Authors: J. Mershon, M. Geiger, E. Barrett-Connor, P. Collins, M. Kornitzer, S. Dowsett, S. Zheng, J. Song, N. Wenger
Journal: Journal of Clinical Oncology (2007)

1530 Background: RUTH enrolled 10,101 postmenopausal women at increased risk for major coronary events. Women were not enrolled based on their risk for breast cancer. The incidence of invasive breast cancer in the placebo group was low for this older population of women (mean age 67.5 years). The aim of this analysis was to determine whether CHD risk factors and selected cardiac medications were protective against invasive breast cancer in this population at increased risk for coronary events. Methods: Covariates assessed were baseline factors that are known CHD risk factors and selected medications ( Table ). Univariate analyses were performed for all covariates using placebo data. Results: The effect of baseline CHD risk factors and selected cardiac medications on the incidence of invasive breast cancer in women receiving placebo in RUTH (N=5057) Conclusions: In these postmenopausal women at increased risk for major coronary events, baseline CHD risk factors and selected cardiac medications assessed individually did not protect against invasive breast cancer. The low incidence of invasive breast cancer in the RUTH population does not appear to be due to the presence of CHD risk factors or use of cardiac medications. [Table: see text] [Table: see text]
Clinical outcome of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first line chemotherapy in metastatic pancreatic cancer.
Authors: Kazuo Watanabe, Yusuke Hashimoto, Kumiko Umemoto, Hideaki Takahashi, Mitsuhito Sasaki, Hiroshi Imaoka, Izumi Ohno, Shuichi Mitsunaga, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2017)

438 Background: FOLFIRINOX and Gemcitabine plus nab-paclitaxel (GN) have been established as first line chemotherapy in metastatic pancreatic cancer (mPC). But few data support preferable first line choice of these two regimens in “real-world” clinical setting. Methods: We retrospectively enrolled 135 chemotherapy-naive mPC patients treated with modified FOLFIRINOX (mFFX) or GN at National Cancer Center Hospital East between December 2013 and September 2015. mFFX is a modified regimen of reduced dose of irinotecan 150mg/m2 and eliminated bolus 5-FU from original FFX. GN consists of gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day1,8,15 every 4 weeks. We compared characteristics, efficacy and adverse events between mFFX and GN. Results: Seventy patients were treated with mFFX and 65 patients with GN as first line therapy. Demographic and baseline characteristics (mFFX/GN) were similar as follows: ECOG performance status (0-1): 100% / 99%, Gender (male): 66% / 69%, liver metastasis: 56%/49%, peritoneal metastasis: 34% / 31%, prior biliary drainage: 21%/17%, median observation period: 330 / 265 days, respectively. The population of elderly patients ( &gt; 75y) was smaller in mFFX than GN (4.3% vs. 12%, p = 0.05). Objective response rate (27% vs. 39%, p = 0.02) and disease control rate (79% vs. 92%, p = 0.02) were significantly lower in mFFX than in GN. Median OS was 11.5 months (95% CI: 9.7-16.8) in mFFX and 14.0 months (95% CI: 12.2 - not reached) in GN. Median PFS was 5.7 months (95% CI: 3.4-7.1) in mFFX and 6.5 months (95% CI: 6.1-7.9) in GN. One-year survival rate was significantly higher in GN than in mFFX (44% vs. 67%, p = 0.0006). Incidences of grade 3 or 4 neutropenia (47% vs. 45%), diarrhea (1.4% vs. 2.0%), and peripheral neuropathy (4.2% vs. 4.6%) were similar in each group. On the other hand, incidences of febrile neutropenia (8.5% vs. 2.0%, p = 0.06) and G-CSF use rate (21% vs. 0%, p &lt; 0.0001), anorexia (13% vs. 3%, p = 0.03) were significantly higher in mFFX than those of GN. Conclusions: Patients treated with GN showed more favorable efficacy and survival. Incidences of most adverse events did not differ between mFFX and GN,whereas febrile neutropenia occurred more frequently in mFFX.
Onartuzumab plus bevacizumab versus placebo plus bevacizumab in recurrent glioblastoma (GBM): HGF and MGMT biomarker data.
Authors: Timothy Francis Cloughesy, Gaetano Finocchiaro, Cristobal Belda, Lawrence Recht, Alba Ariela Brandes, Estela Pineda, Tom Mikkelsen, Olivier L. Chinot, Carmen Balana, David R. Macdonald, Manfred Westphal, Kirsten Hopkins, Michael Weller, Bo Liu, Jean-Marie Bruey, Wendy Verret
Journal: Journal of Clinical Oncology (2015)

2015 Background: The phase II GO27819 study assessed the monovalent MET inhibitor, onartuzumab, plus the anti-VEGF antibody, bevacizumab (O+B) versus placebo plus bevacizumab (P+B) in recurrent GBM. Exploratory univariate biomarker analyses correlated efficacy with levels of the MET ligand HGF and MGMT methylation. Methods: GBM patients (pts) at first recurrence after chemoradiation were randomized 1:1 to receive O (15 mg/kg, q3w) + B (15 mg/kg, q3w) or P+B until progression. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), safety; exploratory endpoint: biomarker analysis. Baseline tumor HGF levels were quantitatively assessed by cobas PCR; MGMT methylation was assessed by Quantitative Methylation Specific PCR. Results: In the ITT group (64 O+B, 65 P+B) no difference in PFS, OS or ORR was seen between the arms. A total of 119 pts (58 O+B, 61 P+B) had HGF-PCR results and 110 (56 O+B, 54 P+B) had MGMT data. Assessing the P+B arm only showed that GBM pts may have a worse prognosis if they have high expression of HGF-PCR (PFS HR 1.67; OS HR 1.65) or unmethylated MGMT (PFS HR 3.19; OS HR 3.39). In pts with HGF-PCR expression in the upper 25%, longer PFS (HR 0.37, 95% CI 0.16–0.86; p = 0.0201) and OS (HR 0.29, 95% CI 0.08–1.06; p = 0.0458) were seen with O+B (n = 14) v P+B (n = 16). These pts also had higher ORR with O+B (35.7% v 0%, p = 0.014). Shorter PFS (HR 1.39, 95% CI 0.87–2.20; p = 0.1589) and OS (HR 1.86, 95% CI 1.03–3.36; p = 0.0381) were seen with O+B (n = 44) v P+B (n = 45) in the lower 75% HGF-PCR group. Of the pts analyzed for MGMT methylation, 57.3% had unmethylated MGMT. These pts had higher ORR (15.6% v 8%) and extended PFS (HR 0.46, 95% CI 0.25–0.84; p = 0.0108) and OS (HR 0.53, 95% CI 0.26–1.10; p = 0.0836) with O+B v P+B. Pts with methylated MGMT had shorter PFS (HR 1.52, 95% CI 0.75–3.08; p = 0.2440) and OS (HR 3.18, 95% CI 1.19–9.51; p = 0.0150) with O+B v P+B. Conclusions: While the GO27819 ITT results showed no efficacy benefit for O+B, these exploratory data suggest that high HGF levels and unmethylated MGMT are prognostic in GBM and may be predictive of response to onartuzumab. Further research on onartuzumab in these subgroups may be warranted. NCT01632228. Clinical trial information: NCT01632228.
Health-related quality of life (HRQoL) in the KEYNOTE-045 study of pembrolizumab versus investigator-choice chemotherapy for previously treated advanced urothelial cancer.
Authors: David J. Vaughn, Joaquim Bellmunt, Ronald De Wit, Yves Fradet, Jae-Lyun Lee, Lawrence Fong, Nicholas J. Vogelzang, Miguel Angel Climent, Daniel Peter Petrylak, Toni K. Choueiri, Andrea Necchi, Winald R. Gerritsen, Howard Gurney, David I. Quinn, Stephane Culine, Cora N. Sternberg, Yabing Mai, Haojie Li, Rodolfo F. Perini, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2017)

282 Background: In KEYNOTE-045 (NCT02256436) (N = 542), pembro 200 mg Q3W significantly improved OS over investigator’s choice of paclitaxel, docetaxel, or vinflunine as second-line therapy for advanced UC following platinum-based chemo (HR 0.73; P = 0.0022). Fewer treatment-related AEs were reported with pembro. We present results of the prespecified HRQoL analysis of KEYNOTE-045. Methods: The EORTC QLQ-C30 HRQoL instrument was administered electronically at cycles 1–4, then every 2 cycles for up to 1 y and 30 d after discontinuation. The key HRQoL end points were 1) change from baseline to wk 15 and 2) time to deterioration (TTD) (defined as ≥ 10-point decrease from baseline) in the QLQ-C30 global health status/QoL score. HRQoL was assessed in patients (pts) who received ≥ 1 dose of assigned study treatment and completed ≥ 1 HRQoL instrument (N = 520). Score change from baseline was compared using a constrained longitudinal data analysis model. TTD was compared using a stratified log-rank test and Cox proportional hazards model. Results: Baseline global health status/QoL scores were similar between arms. HRQoL compliance at wk 15 was 88% for both arms. From baseline to wk 15, scores were stable for pembro (n = 266) (least squares [LS] mean +0.75 [95% CI –2.34 to +3.83]) but worsened for chemo (n = 254) (LS mean –8.30 [95% CI –11.76 to –4.83]); the difference in LS means between arms was 9.05 (95% CI 4.61-13.48; nominal 2-sided P &lt; 0.001). At wk 15, pts without PD had improved scores with pembro but worsened scores with chemo (LS mean +5.97 vs –4.31), while pts with PD had less worsening with pembro (LS mean –3.54 vs –13.95). TTD was prolonged with pembro (HR 0.70; 95% CI 0.55-0.90; nominal 1-sided P = 0.002; median 3.5 mo vs 2.2 mo). Rates of improvement (defined as ≥ 10-point increase from baseline) at wk 15 were 31.2% with pembro and 22.0% with chemo; rates of deterioration were 28.9% and 40.6%, respectively. Conclusions: Pembro was associated with substantially better HRQoL for a longer duration than investigator-choice chemo in pts with previously treated advanced UC. Along with superior OS, these data support pembro as a new standard-of-care in this population. Clinical trial information: NCT02256436.