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Spigel, David R., Thomas J. Ervin, Rodryg A. Ramlau, Davey B. Daniel, Jerome H. Goldschmidt, George R. Blumenschein, Maciej J. Krzakowski, et al. "Randomized Phase II Trial of Onartuzumab in Combination With Erlotinib in Patients With Advanced Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 31, no. 32 (November 10, 2013): 4105–14. http://dx.doi.org/10.1200/jco.2012.47.4189.
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Purpose Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) –targeted drugs in patients with non–small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. Patients and Methods Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. Results There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. Conclusion Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.
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Taminiau, Yvette, Stefan Heusinkveld, Claudia Visser, and Marlies Verschoor. "Strategisch HR-beleid van Big 4-accountantsorganisaties." Maandblad Voor Accountancy en Bedrijfseconomie 92, no. 3/4 (April 12, 2018): 111–24. http://dx.doi.org/10.5117/mab.92.23742.
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In dit exploratief onderzoek wordt geanalyseerd op welke wijze Big 4-accountantsorganisaties met hun HR-beleid strategisch reageren op de nieuwe wet- en regelgeving. Het onderzoek is gebaseerd op 24 diepte-interviews (merendeel met partners en HR-managers) binnen accountancy, consultancy en tax advisory. Uit ons onderzoek blijkt dat de gewijzigde wetgeving belangrijke implicaties heeft voor het HR-beleid op zowel korte als lange termijn. Tegelijkertijd laat het onderzoek zien dat de Big 4-accountantsorganisaties met dit HR-beleid een meer bureaucratische managementbenadering bevorderen in plaats van een benadering gebaseerd op professionaliteit. Deze meer bureaucratische benadering maakt het mogelijk om met hedendaagse institutionele druk om te gaan, maar zij creëert ook beperkingen voor het management van professionele organisaties.
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Haluska, F. G., A. Y. Bedikian, A. C. Pavlick, M. Millward, M. Gore, H. Pehamberger, U. Trefzer, and A. Eggermont. "Oblimersen in combination with dacarbazine prolongs prognostic factor-adjusted overall survival." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 18006. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.18006.
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18006 Backgound: In a stratified randomized study comparing dacarbazine (DTIC) and oblimersen (Obl) with DTIC alone in metastatic melanoma, overall survival (OS) was increased in the Obl+DTIC group (P = .077). We report results from a multivariate analysis, including prognostic factors. Methods: The study enrolled 771 patients; 2.2% data were missing. Stratification factors included elevated LDH (>1.1 ULN), performance status (PS) >0, and metastatic site (MET): MET A = liver, MET B = other visceral, MET C = skin, subcutaneous, or lymph nodes only. Each stratification factor was evaluated using monovariate analysis for treatment interaction. Cox model included treatment, any identified factor, gender, or interaction term for OS and progression-free survival (PFS), and a logistic regression for response rate (RR). Results: The stratification factor with the greatest impact on survival was elevated LDH (HR 2.212, P < .0001), followed by PS > 0 (HR 1.497, P < .0001), MET A (HR 1.456, P < .0001), and MET C (HR 0.670, P < .0004). Interaction significance between treatment and LDH, PS, MET A, and MET C were 0.023, NS (0.279), NS (0.419), and NS (0.329), respectively. MET B was used as the reference category for MET A and MET C. Conclusion: As expected, all stratification factors were prognostic, with LDH being the most important factor (HR 2.2). The addition of Obl to DTIC treatment improved outcomes for all efficacy end points. A statistical interaction between Obl treatment and LDH was found for survival. Multivariate analysis was significant in all efficacy end points. Patients with abnormal baseline LDH, already understood to have a poor prognosis, were unlikely to benefit from this therapy and should not be included in future trials of combination oblimersen treatments. [Table: see text] No significant financial relationships to disclose.
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Dahlrot, Rikke Hedegaard, Stine Asferg Petterson, Simon Kjaer Hermansen, Bjarne Winther Kristensen, and Steinbjorn Hansen. "C-met, a new prognostic biomarker in glioblastoma multiforme." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2088. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2088.
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2088 Background: C-met is a tyrosine kinase receptor involved in growth, invasiveness and malignant progression in glioblastoma multiforme (GBM). Activation of the C-met pathway increases resistance towards DNA damage in glioma cell lines and it has been shown that an orally administrated C-met kinase inhibitor inhibits intracranial glioma growth in immunodeficient mice, suggesting that C-met is a potential target in glioma treatment. The purpose of the present study was to investigate the prognostic value of C-met in GBMs and subsequently correlate the prognostic value to known clinical variables, identified in a population-based cohort. Methods: Tissue samples from 186 GBM patients were analyzed using immunohistochemical staining and advanced quantitative image analysis. This provided continuous measurements based on staining intensity. Results: Median intensity was 70.8 (range 15.5-200.1). When divided at the median C-met was not prognostic. Further exploration showed that dichotomizing at an intensity of 75 (60% vs. 40%), high levels of C-met were associated with poor survival. However; C-met is a time-dependent factor and no prognostic effect was observed within the first 8.5 months after diagnosis (HR 0.97, 95% CI 0.62-1.51, p = 0.892). After 8.5 months, patients with high levels of C-met had a significantly poorer survival as compared to patients with low levels (HR 2.06, 95% CI 1.33-3.18, p = 0.001). This was significant in multivariate analysis adjusted for clinical variables; C-met (HR 1.89, 95% CI 1.22-2.93, p = 0.004), age (HR 1.02, 95% CI 1.00-1.03, p = 0.037), performance status (HR1.55, 95% CI 1.38-1.74, p = 0.004), and tumor crossing midline (HR 1.72, 955 CI 0.75-3.92, p = 0.201). Interestingly; C-met was only prognostic in patients who received post-surgical treatment, whereas no effect was observed in the 31 patients who underwent surgery only (HR 0.54, 95% CI 0.26-1.15, p = 0.113). Conclusions: Using advanced quantitative image analysis, we found that C-met was an independent prognostic factor of poor survival in GBMs. The effect did not appear within the first 8.5 months after the diagnosis and it was only seen in patients who received post-surgical treatment.
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Pietrasz, Daniel, Shufang Wang-Renault, Laetitia Dahan, Julien Taieb, Karine Le Malicot, Yves Rinaldi, Solene Doat, et al. "Methylated circulating tumor DNA (Met-DNA) as an independent prognostic factor in metastatic pancreatic adenocarcinoma (mPAC) patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 4136. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4136.
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4136 Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p < 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p < 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 > 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.
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Bendell, Johanna C., Howard S. Hochster, Lowell L. Hart, Irfan Firdaus, Joseph Ronald Mace, Joshua Jemison McFarlane, Mark Kozloff, et al. "A randomized, double-blind, phase II study of first-line FOLFOX plus bevacizumab with onartuzumab versus placebo in patients with metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 663. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.663.
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663 Background: In mCRC, MET overexpression has been associated with poor prognosis and resistance to anti-VEGF therapy. We initiated a phase II study to evaluate the combination of onartuzumab (O), a ligand-blocking monoclonal antibody directed against the MET receptor, plus bevacizumab and FOLFOX, in first-line mCRC (GO27827; NCT01418222). Methods: This double-blind, randomized, multicenter phase II study randomized patients 1:1 to receive O (10 mg/kg iv) or placebo (P), plus mFOLFOX6 and bevacizumab (5 mg/kg iv). Stratification was by prior adjuvant therapy. All treatments were given on day 1–3 of a 2-week cycle. Oxaliplatin was given for up to 8–12 cycles; all other agents were continued until progression, unacceptable toxicity or death. Primary endpoint was progression-free survival (PFS) in ITT and MET+ subgroup by immunohistochemistry (IHC). MET status was determined by central laboratory IHC evaluation, with scores of 2+ or 3+ considered MET+. Results: From September 2011 to November 2012, 194 patients were enrolled. A recommendation was made to stop O after an interim efficacy and safety analysis in September 2013, due to lack of efficacy. The final analysis (cut-off Feb 2014) found that O did not improve PFS vs. P in the ITT (HR 0.75 [0.52–1.08]; p=0.12) or MET IHC+ populations (n=79; HR 1.03 [0.56–1.89]; p=0.93), although improvement was noted in the MET IHC− population (n=108; HR 0.60 [0.37–0.97]; p=0.03). Neither overall survival (OS) nor response rate (RR) was improved with O vs. P in any of the groups (OS HR 0.96 [0.61–1.50], p=0.85 for ITT; OS HR 1.24 [0.63–2.43], p=0.54 for MET IHC+; OS HR 0.83 [0.44–1.56], p=0.56 for MET IHC−; RR 57.3% vs. 57.7% for ITT, 43.2% vs. 57.1% for MET IHC+, 66.1% vs. 60.8% for MET IHC−). More edema (65.7% vs. 12.9%) and venous thromboembolic events (30.3% vs. 16.1%) were seen with O vs. P, respectively. Grade ≥3 events were similar (86.9% vs. 84.9%) and events leading to discontinuation were increased (48.5% vs. 37.6%) with O vs. P. Conclusions: Adding onartuzumab to FOLFOX/bevacizumab did not prolong PFS in first-line unselected or MET IHC+ mCRC. A trend towards PFS benefit was seen in those with MET IHC− mCRC, contrary to prior reports in other tumor types. Clinical trial information: NCT01418222.
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LEE, MIYOUNG, WEIMO ZHU, BRAD HEDRICK, and BO FERNHALL. "Estimating MET Values Using the Ratio of HR for Persons with Paraplegia." Medicine & Science in Sports & Exercise 42, no. 5 (May 2010): 985–90. http://dx.doi.org/10.1249/mss.0b013e3181c0652b.
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Keizman, Daniel, Maya Ish-Shalom, Avivit Peer, Maya Gottfried, Hans J. Hammers, Mario A. Eisenberger, Victoria J. Sinibaldi, et al. "Metformin use and outcome of sunitinib treatment in diabetic patients with metastatic renal cell carcinoma." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 440. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.440.
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440 Background: Sunitinib (Su) is a standard treatment (tx) for metastatic renal cell carcinoma (mRCC). Pre-clinical and clinical studies in several cancer types suggest that the antidiabetic agent metformin (Met) has antitumor activity. Met may negatively regulate mTOR activity. Its effect on the outcome of targeted therapies in mRCC is poorly defined. We analyzed the effect of Met use on the outcome sunitinib tx in diabetic patients (pts) with mRCC. Methods: We performed a retrospective study of an unselected cohort of diabetic pts with mRCC, who were treated with Su in 7 centers across 2 countries. Pts were divided into 2 groups: (1) Met users and (2) Met naive. The effect of Met use on response rate (RR), progression free survival (PFS) and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from Cox model. Furthermore, univariate and multivariate analyses of association between clinicopathologic factors and Met use, and outcome were performed using the entire pt cohort. Results: Between 2004-2014, 108 diabetic pts with mRCC were treated with sunitinib. There were 52 Met users (group 1) and 56 nonusers (group 2). The groups were balanced regarding the following clinicopathologic factors: age, gender, HENG risk, past nephrectomy, mRCC histology, ≥2 metastatic sites, lung/liver/bone metastasis, prior targeted tx, smoking status, use of angiotensin system inhibitors (ASIs), pre-tx neutrophil to lymphocyte ratio (NLR) >3, Su-induced hypertension (HTN), and Su dose reduction/tx interruption. Clinical benefit (partial response + stable disease) in group 1 vs. group 2 was 96% vs. 84%, while 4% vs. 16% had disease progression within the first 3 months of tx (p=0.054). Median PFS was 15 vs. 11.5 months (p=0.1). Median OS was 32 vs. 21 months (p=0.001). In multivariate analyses of the entire pt cohort (n=108), factors associated with PFS were active smoking (HR=2.7, p<0.0001) and pre-tx NLR >3 (HR 1.8, p=0.012). Factors associated with OS were Met use (HR 0.2, p<0.0001), HENG risk (HR 3.3, p=0.008), active smoking (HR=2.9, p<0.0001), liver metastases (HR 1.8, p=0.004), and pre-tx NLR >3 (HR 3.3, p<0.0001). Conclusions: Met use may improve the OS of diabetic pts with mRCC that are treated with Su.
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Teufel, Michael, Karl Köchert, Gerold Meinhardt, and Jordi Bruix. "Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4078. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4078.
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4078 Background: REG is a multikinase inhibitor which improved overall survival (OS; HR 0.63, 95% CI 0.50, 0.79; P<0.0001) and time to progression (TTP; HR 0.44, 95% CI 0.36, 0.55; P<0.0001) compared with placebo in patients with HCC who progressed during prior sorafenib treatment in the RESORCE trial. This exploratory analysis evaluated the impact of baseline AFP and c-Met on REG treatment benefit (OS and TTP) in the RESORCE trial. Methods: Circulating AFP and c-Met protein (shed ectodomain) levels were quantified by a Luminex assay (Myriad RBM) in plasma samples collected at baseline from patients enrolled in the RESORCE trial. Valid biomarker data were available from 497 (AFP) and 499 (c-Met) out of 573 patients. Patients were subgrouped according to the median protein concentration (high vs low), and the treatment effect HR and its 95% CI were evaluated using a Cox proportional hazards model. The predictive effect was modeledas a protein–treatment interaction effect and subjected to Akaike information criterion (AIC)-based selection to assess its association with OS and TTP. Results: Baseline characteristics of patients were balanced across protein subgroups. While increased levels of both AFP (HR 1.09, 95% CI 1.07, 1.12; P<0.001) and c-Met (HR 1.32, CI 95% 1.06, 1.63; P=0.011) were associated with a worse prognosis for OS, increased AFP levels were also associated with poor prognosis for TTP (HR 1.05, 95% CI 1.03, 1.07; P<0.001). REG treatment benefit for both OS and TTP was independent of AFP and c-Met protein expression (Table). The protein–treatment interaction effect was not statistically significant. Conclusions: The treatment benefit of REG in patients with HCC was independent of AFP and c-MET protein expression at baseline. So far, no single protein has been associated with REG clinical benefit. Clinical trial information: NCT01774344. [Table: see text]
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Adeel, Muhammad, Chien-Hung Lai, Chun-Wei Wu, Jiunn-Horng Kang, Jian-Chiun Liou, Hung-Chou Chen, Bor-Shing Lin, Meng-Jyun Hong, Chun-Ta Feng, and Chih-Wei Peng. "Modeling of Metabolic Equivalents (METs) during Moderate Resistance Training Exercises." Applied Sciences 11, no. 18 (September 21, 2021): 8773. http://dx.doi.org/10.3390/app11188773.
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Energy expenditure through metabolic equivalent (MET) prediction during resistance exercises in humans can be modeled by using cardiorespiratory parameters. In this study, we aimed to predict MET during six moderate-intensity resistance training sessions consisting of three different exercises. Eleven participants were recruited into two groups; an untrained (n = 5; with no resistance training experience) and a trained group (n = 6; with 2 months resistance training experience). Each participant completed six training sessions separated with a rest interval of 1–2 days. While wearing a mask for indirect calorimetric measurements using Cortex Metalyzer 3B, each participant performed training sessions consisting of three types of dumbbell exercises: shoulder press, deadlift, and squat. The metabolic equivalents (METs), respiratory exchange ratio (RER), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), blood lactate (BL), and Borg rate of perceived exertion (RPE) were measured. The MET was predicted using generalized estimating equations (GEE) for repeated measure data collected during exercise and rest periods. It was observed that during exercise period, RER, HR, SBP, and BL for the training group (QIC = 187, 95% CI = −0.012~0.915, p = 0.000*~0.033*) while RER, HR, SBP, DBP, and RPE (QIC = 48, 95% CI = −0.024~0.422, p = 0.000*~0.002*) during resting period for untrained group significantly predicted MET for moderate-intensity interval resistance training. It is concluded that the cardiorespiratory variables are significantly related to MET. During exercise, RER and HR significantly predicted MET for both groups along with additional parameters of SBP and BL for the training group. While during the resting period, RER, HR, SBP, DBP, and RPE related significantly for untrained and BL for training group respectively.
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Kim, Won Jun, Jung Hyun Noh, Kyungdo Han, and Cheol-Young Park. "The Association Between Second-Line Oral Antihyperglycemic Medication on Types of Dementia in Type 2 Diabetes: A Nationwide Real-World Longitudinal Study." Journal of Alzheimer's Disease 81, no. 3 (June 1, 2021): 1263–72. http://dx.doi.org/10.3233/jad-201535.
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Background: There are few reports that evaluated the association between various types of dementia and dual oral therapy with antihyperglycemic medication. Objective: The goal of this study was to investigate the association between treatment of dual antihyperglycemic medication and dementia subclass in type 2 diabetes mellitus using the Korean National Health Insurance System. Methods: This study included 701,193 individuals with diabetes prescribed dual oral therapy between 2009 and 2012 from the Korean National Health Insurance Service Database, which were tracked until 2017. All-cause, Alzheimer’s (AD) and vascular dementia (VaD) were investigated by dual oral therapy. Adjustments were made for age, sex, income, diabetes duration, hypertension, dyslipidemia, smoking, drinking, exercise, body mass index, glucose level, and estimated glomerular filtration rate. Results: Dual therapy with metformin (Met) + dipeptidyl peptidase-4 inhibitor (DPP-4i), Met + thiazolidinedione (TZD), and sulfonylurea (SU) + thiazolidinediones (TZD) were significantly associated with all-cause dementia (HR = 0.904, 0.804, and 0.962, respectively) and VaD (HR = 0.865, 0.725, and 0.911, respectively), compared with Met + SU. Met + DPP-4i and Met + TZD were associated with significantly lower risk of AD (HR = 0.922 and 0.812), compared with Met + SU. Dual therapy with TZD was associated with a significantly lower risk of all-cause dementia, AD, and VaD than nonusers of TZD (HR = 0.918, 0.925 and 0.859, respectively). Conclusion: Adding TZD or DPP-4i instead of SU as second-line anti-diabetic treatment may be considered for delaying or preventing dementia. Also, TZD users relative to TZD non-users on dual oral therapy were significantly associated with lower risk of various types of dementia.
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Sunakawa, Yu, Takeru Wakatsuki, Wu Zhang, Dongyun Yang, Mizutomo Azuma, Yan Ning, Sebastian Stintzing, et al. "Use of genetic variants in c-MET to predict clinical outcome in localized gastric cancer (GC) patients (pts) treated with surgery." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 50. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.50.
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50 Background: Dysregulation of the c-MET signaling pathway occurs in a wide range of human cancers including GC. Such derangements result from various molecular mechanisms, including mutations, amplification and overexpression of c-MET. Overexpression and amplification of c-MET have been correlated with poor clinical outcomes in pts with GC. However, the association between c-MET polymorphisms and prognosis in GC is not well defined. We examined the prognostic impact of c-MET polymorphisms on clinical outcomes in pts with localized GC treated with surgery. Methods: One-hundred and sixty-one Japanese pts were included, with localized GC (stage Ib-IV) treated with surgery alone (n=58), or surgery plus adjuvant therapy (n=103) between 2002 and 2010. Median follow up was 4 years. Genomic DNA was extracted from the pts’ blood or tissue. Six functionally significant c-MET SNPs (rs1621, rs40239, rs41736, rs41739, rs184953, rs10234854) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with disease free survival (DFS) and overall survival (OS) by uni- and multivariate analyses, adjusting for age, sex, stage and type of adjuvant therapy. Results: The MET rs40239 variant was associated with favorable clinical outcomes. Univariate analysis showed pts with any G (AG/GG) allele had significantly longer DFS and OS compared to those with the AA genotype (HR: 0.43; 95% CI: 0.25-0.74; P=0.001, HR: 0.47; 95% CI: 0.27-0.81; P=0.006, log-rank test, respectively); this remained significant upon multivariate analysis (HR: 0.48; 95% CI: 0.27-0.83; P=0.009, HR: 0.50; 95% CI: 0.28-0.88; P=0.017, respectively). In the subgroup analysis by gender, men, but not women, with the AG/GG genotypes maintained a DFS and OS benefit. Conclusions: Our results show for the first time that the c-MET polymorphism, rs40239, may serve as a prognostic marker in pts with localized GC treated with surgery. There also appears to be a gender-related difference in the impact on clinical outcome by genetic variants of c-MET. Prospective validation of this study is warranted.
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Shea, Chun, Abdul Rouf Khawaja, Khalid Sofi, and Ghulam Nabi. "Association of metabolic equivalent of task (MET) score in length of stay in hospital following radical cystectomy with urinary diversion: a multi-institutional study." International Urology and Nephrology 53, no. 7 (March 6, 2021): 1305–10. http://dx.doi.org/10.1007/s11255-021-02813-x.
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Abstract Purpose The Metabolic equivalent of task (MET) score is used in patients’ preoperative functional capacity assessment. It is commonly thought that patients with a higher MET score will have better postoperative outcomes than patients with a lower MET score. However, such a link remains the subject of debate and is yet unvalidated in major urological surgery. This study aimed to explore the association of patients’ MET score with their postoperative outcomes following radical cystectomy. Methods We used records-linkage methodology with unique identifiers (Community Health Index/hospital number) and electronic databases to assess postoperative outcomes of patients who had underwent radical cystectomies between 2015 and 2020. The outcome measure was patients’ length of hospital stay. This was compared with multiple basic characteristics such as age, sex, MET score and comorbid conditions. A MET score of less than four (< 4) is taken as the threshold for a poor functional capacity. We conducted unadjusted and adjusted Cox regression analyses for time to discharge against MET score. Results A total of 126 patients were included in the analysis. Mean age on date of operation was 66.2 (SD 12.2) years and 49 (38.9%) were female. A lower MET score was associated with a statistically significant lower time-dependent risk of hospital discharge (i.e. longer hospital stay) when adjusted for covariates (HR 0.224; 95% CI 0.077–0.652; p = 0.006). Older age (adjusted HR 0.531; 95% CI 0.332–0.848; p = 0.008) and postoperative complications (adjusted HR 0.503; 95% CI 0.323–0.848; p = 0.002) were also found to be associated with longer hospital stay. Other comorbid conditions, BMI, disease staging and 30-day all-cause mortality were statistically insignificant. Conclusion A lower MET score in this cohort of patients was associated with a longer hospital stay length following radical cystectomy with urinary diversion.
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Jarrard, David Frazier, Yu-Hui Chen, Glenn Liu, Michael Anthony Carducci, Mario A. Eisenberger, Yu-Ning Wong, Noah M. Hahn, et al. "Impact of metformin on prostate cancer (PC) outcomes in the E3805 CHAARTED trial." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 181. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.181.
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181 Background: To evaluate whether metformin (Met) a widely-used, nontoxic oral antidiabetic drug with putative anticancer properties leads to improvements in prostate cancer (PC) outcomes in the CHAARTED trial. Methods: In the CHAARTED database where metformin use at baseline was recorded prospectively, we identified patients with metastatic PC who underwent either ADT alone or ADT and docetaxel (D) chemotherapy. Cox proportional hazards models were used to determine the effect of Metformin on outcomes. Results: A total of 788 patients (median age, 63 y) had complete data after randomization. Comparison of ADT+D+Met (n = 39) to ADT+D (n = 357) and ADT+Met (n = 29) to ADT alone (n = 363) revealed similar clinicopathologic characteristics. Cause of death was PC in 13(81%) of ADT+D+Met, 72(85%) ADT+D, 9(82%) ADT+Met and 105(84%) ADT alone groups. See table for PC outcomes and overall survival by metformin use. Cox regression analysis for overall survival stratified by stratification factors at randomization demonstrates Met use was associated with a trend for worse overall survival (HR 1.47 95%CI: [0.95,2.26], p = 0.08) with adjustment for treatment arm and prior local therapy. In contrast, ADT+D use (HR 0.62; 95%CI: [0.47,0.81]) and prior local therapy with surgery or radiation (HR 0.56; 95% CI: [0.38, 0.82]) were associated with improved survival. Conclusions: In this study, baseline metformin did not improve PC outcomes. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]
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Rimassa, Lorenza, Giovanni Abbadessa, Nicola Personeni, Camillo Porta, Ivan Borbath, Bruno Daniele, Jean-Luc Van Laethem, et al. "Tumor and plasma biomarker analysis from the randomized controlled phase II trial (RCT) of tivantinib in second-line hepatocellular carcinoma (HCC)." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 197. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.197.
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197 Background: Tivantinib, an oral MET inhibitor, showed activity in patients (pts) MET-High at immunohistochemistry (IHC) in randomized, placebo controlled studies in HCC, NSCLC, CRC, and prostate cancer. ARQ 197-215 was a RCT of tivantinib in second-line HCC. The study randomized 107 pts 2:1 to tivantinib capsules or placebo, reached the primary endpoint of time to progression in the intent-to-treat population and the pre-specified secondary efficacy endpoints, including OS, in MET-High pts. Tumor MET was also found to be a strong independent prognostic factor. This analysis aims to study prognostic and predictive value of tumor and circulating biomarkers. Methods: Circulating MET, HGF, and AFP were centrally analyzed by ELISA and median values were used as cut-offs to determine High or Low status except for AFP, where the 75th percentile was also used. Tumor MET was centrally analyzed and considered High if staining was >2+ in >50% of cells at IHC. Results: Circulating MET was prognostic (N=102; OS: 4.6 vs 8.9 months in High vs Low, HR=0.61, p=0.023) and trended towards predicting tivantinib’s activity. MET was also a pharmacodynamic marker: pts on tivantinib with a MET reduction over time survived longer; MET was reduced in pts stable on tivantinib but not on placebo. Circulating HGF was prognostic (N=102; OS: 5.0 vs 9.0 months in High vs Low, HR=0.6, p=0.02) and changes over time correlated with outcome. AFP by the 75th percentile was prognostic (N=104; OS: 3.0 vs 7.9 months in High vs Low, HR=0.36, p<0.0001). Median IHC score (H-Score) was 175 for tumor MET-High, 40 for MET-Low pts (N=77). MET was highly expressed in 40% of biopsies taken before and in 82% of biopsies taken after sorafenib. A significant interaction between tivantinib and tumor MET in terms of OS was observed (p=0.039). No biomarker except for tumor MET was predictive of response to tivantinib. Conclusions: A clear prognostic value was found for circulating MET, HGF, and AFP by the 75th percentile. Tumor MET was highly prognostic and predictive. IHC results on over 900 tumor samples analyzed in the ongoing METIV-HCC phase 3 study will also be presented. Clinical trial information: NCT00988741.
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Keune, Maarten, Wike Been, and Frank Tros. "Ongelijkheid: Ontwikkelingen op de arbeidsmarkt en in de arbeidsverhoudingen." Tijdschrift voor HRM 23, no. 4 (December 1, 2020): 46–63. http://dx.doi.org/10.5117/thrm2020.4.keun.
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De arbeidsmarkt en de arbeidsverhoudingen in Nederland zijn in de afgelopen jaren sterk veranderd. Dit artikel gaat met name in op groeiende diversiteit, fragmentatie en ongelijkheid op de arbeidsmarkt en toenemende druk op de representativiteit en legitimiteit van met name vakbonden, maar ook van werkgeversorganisaties. De auteurs betogen dat deze trends niet los van elkaar staan, met name waar het gaat om de verschuivende machtsbalans in de richting van de werkgevers, blijvende loonmatiging en verdere flexibilisering van de arbeidsmarkt. De polderinstituties zijn in een impasse beland, de onderlinge relaties tussen werkgevers en vakbonden worden op sectoraal en nationaal niveau conflictiever en de sociale partners blijken steeds minder in staat om consensus te bereiken op de sociaaleconomische kernthema's van vandaag de dag. De relatie tussen deze bevindingen en de wereld van HRM is tweeledig. Enerzijds zal (de discussie over) het toekomstige HR-beleid sterk beïnvloed worden door de genoemde structurele veranderingen op de arbeidsmarkt en in de arbeidsverhoudingen. Anderzijds zijn deze veranderingen het resultaat van genomen keuzes in HR-strategieën en de HR-praktijken binnen de organisaties.
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Ando, Ryota, Masahiko Fujino, Ayami Kominami-Kiriyama, Ai Ito, Tomomi Koide, and Masafumi Ito. "Mesenchymal–epithelial transition gene amplification and protein overexpression in stage IV pulmonary adenocarcinoma." Japanese Journal of Clinical Oncology 49, no. 8 (April 26, 2019): 755–61. http://dx.doi.org/10.1093/jjco/hyz060.
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Abstract Background In non-small cell lung cancer (NSCLC), MET gene copy number gain, including gene amplification and chromosome 7 polysomy, is reportedly associated with patient prognosis. Although relationship between MET copy number gain and poor prognosis has been suggested in surgically resected non-small cell lung cancer, the clinical significance of MET copy number gain and protein overexpression in patients with advanced unresectable tumor is unclear. Methods We assessed MET copy number gain and protein expression using fluorescence in situ hybridization and immunohistochemistry in 88 patients with clinical stage IV pulmonary adenocarcinoma receiving chemotherapy, immunotherapy or palliative care. Results We found MET amplification, polysomy 7 and high MET protein expression in 10.2, 18.2 and 62.5% of 88 cases, respectively. Gene amplification and high protein expression were not significantly associated. A univariate analysis showed that MET amplification-positive patients had increased overall survival (HR 0.335, 95% CI: 0.119–0.945; P = 0.0388). Although it was not statistically significant in the multivariate analysis of the whole cohort, with the removal of patients who did not receive any treatment other than palliative care, MET amplification independently improved the overall survival (HR 0.178, 95% CI: 0.041–0.770; P = 0.0209). Chromosome 7 polysomy and high MET protein expression did not affect the overall survival. Conclusions Although MET amplification-positive tumor is considered aggressive, our results suggest that it has a more favorable prognosis than amplification-negative cases in stage IV pulmonary adenocarcinoma with medical treatment.
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Heil, Daniel Paul. "Characterizing Steady-State Cardiovascular and Metabolic Responses of Recreational Climbers During Motorized Treadmill Climbing." International Journal of Physical Education, Fitness and Sports 8, no. 1 (March 28, 2019): 58–71. http://dx.doi.org/10.26524/ijpefs1918.
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Given that the popularity of indoor climbing exceeds that of outdoor climbing, health professionals need a better understanding of how these indoor climbing activities can be used to prescribe exercise. The primary goal of this study was to characterize both cardiovascular and metabolic responses of motorized treadmill climbing with respect to thresholds for heart rate as a percent of maximum (%HR) and metabolic equivalents (METs). Additionally, this study used these data to generate MET and energy expenditure (EE) prediction equations for prescription purposes. Methods: Twenty non-competitive recreational climbers (16 men; 4 women) were recruited to climb six combinations of “slow” and “fast” climbing speed (4.6-9.1 m/min) across three treadmill grades: vertical (90°), overhang or negative incline (85-80°), positive incline (95-100°). A portable metabolic system was worn by climbers during testing to measure HR and oxygen uptake (VO2), the latter of which was converted to EE and METs using standard formulae. Mean HR% and MET values were compared to intensity thresholds (65%, or 3 and 6 METs) using one-sample t-tests, while standard multiple regression techniques were used to predict EE and METs from a pool of variables (climbing treadmill speed and grade, body mass, gender. Results: HR% (70.0-85.4%) was >65% at all test conditions (P<0.01) and mean MET values exceeded the 3-MET threshold and was ?6-MET threshold at all conditions (6.0-8.5 METs; P<0.01). Multiple prediction equations for both EE (R2=0.81; SEE=±0.83 kcals/min; P<0.001) and METs (R2=0.73; SEE=±0.6 METs; P<0.001) included speed, grade, and gender. Conclusions: The vigorous metabolic intensity for motorized treadmill climbing (?6 METs) in this study was clearly sufficient to promote positive health and metabolic fitness in healthy adults. In addition, health professionals can use the EE and MET prediction equations to prescribe specific motorized treadmill climbing intensities to clients, as well as generate climbing-specific testing protocols.
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Rias, Yohanes Andy, Maria Dyah Kurniasari, Victoria Traynor, Shu Fen Niu, Bayu Satria Wiratama, Ching Wen Chang, and Hsiu Ting Tsai. "Synergistic Effect of Low Neutrophil–Lymphocyte Ratio With Physical Activity on Quality of Life in Type 2 Diabetes Mellitus: A Community-Based Study." Biological Research For Nursing 22, no. 3 (May 11, 2020): 378–87. http://dx.doi.org/10.1177/1099800420924126.
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Background: Physical inactivity and Type 2 diabetes mellitus (T2DM)–associated inflammatory biomarkers are correlated with poor quality of life (QoL). However, no study has investigated the synergistic effect of physical activity (PA) and lower neutrophil–lymphocyte ratio (NLR) on QoL. Objective: We examined the independent and synergistic effects of PA and inflammatory biomarkers on three domains of QoL in T2DM. Methods: This cross-sectional study included 294 patients with T2DM from community clinics in Indonesia. The 36-item Short Form Survey and a questionnaire about PA engagement were used to measure QoL and metabolic equivalent of task (MET)-hr/week, respectively. Inflammatory biomarkers were measured in fasting blood. Adjusted coefficients β and 95% confidence interval (CI) were estimated using multiple linear regression. The synergistic effect was analyzed using additive interaction for linear regression. Results: Patients with PA ≥ 7.5 MET-hr/week exhibited significantly higher total QoL (β = 8.41, 95% CI = [6.04, 10.78]) and physical component score (PCS; β = 13.90, 95% CI = [10.52, 17.29]) than those with PA < 7.5 MET-hr/week. Patients with NLR < 1.940 had significantly higher total QoL (β = 4.76, 95% CI = [3.41, 6.11]), mental component score (MCS; β = 2.62, 95% CI = [0.75, 4.49]), and PCS (β = 6.89, 95% CI = [4.97, 8.82]) than patients with NLR ≥ 1.940. PA ≥ 7.5 MET-hr/week and NLR < 1.940 exhibited a synergistic effect on total QoL, MCS, and PCS. Conclusions: High PA level and low NLR had a positive synergistic effect on QoL among patients with T2DM.
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BOM, NVMO-commissie. "Alpelisib bij lokaal gevorderd of gemetastaseerd HR-positief, HER2-negatief mammacarcinoom met een PIK3CA-mutatie." Medische Oncologie 23, no. 8 (October 2020): 35–38. http://dx.doi.org/10.24078/onco.2020.10.125924.
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Elliott, Adrian D., Dominik Linz, Ricardo Mishima, Kadhim Kadhim, Celine Gallagher, Melissa E. Middeldorp, Christian V. Verdicchio, et al. "Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort." European Heart Journal 41, no. 15 (January 17, 2020): 1479–86. http://dx.doi.org/10.1093/eurheartj/ehz897.
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Abstract Aims Physical activity reduces cardiovascular disease burden and mortality, although its relationship with cardiac arrhythmias is less certain. The aim of this study was to assess the association between self-reported physical activity and atrial fibrillation (AF), ventricular arrhythmias and bradyarrhythmias, across the UK Biobank cohort. Methods and results We included 402 406 individuals (52.5% female), aged 40–69 years, with over 2.8 million person-years of follow-up who underwent self-reported physical activity assessment computed in metabolic equivalent-minutes per week (MET-min/wk) at baseline, detailed physical assessment and medical history evaluation. Arrhythmia episodes were diagnosed through hospital admissions and death reports. Incident AF risk was lower amongst physically active participants, with a more pronounced reduction amongst female participants [hazard ratio (HR) for 1500 vs. 0 MET-min/wk: 0.85, 95% confidence interval (CI) 0.74–0.98] than males (HR for 1500 vs. 0 MET-min/wk: 0.90, 95% CI 0.82–1.0). Similarly, we observed a significantly lower risk of ventricular arrhythmias amongst physically active participants (HR for 1500 MET-min/wk 0.78, 95% CI 0.64–0.96) that remained relatively stable over a broad range of physical activity levels between 0 and 2500 MET-min/wk. A lower AF risk amongst female participants who engaged in moderate levels of vigorous physical activity was observed (up to 2500 MET-min/wk). Vigorous physical activity was also associated with reduced ventricular arrhythmia risk. Total or vigorous physical activity was not associated with bradyarrhythmias. Conclusion The risk of AF and ventricular arrhythmias is lower amongst physically active individuals. These findings provide observational support that physical activity is associated with reduced risk of atrial and ventricular arrhythmias.
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Matos, Ignacio, Carolina Ortiz, Elena Elez, Guillem Argiles, Julieta Grasselli, Teresa Macarulla, Jaume Capdevila, et al. "Prognostic impact of primary tumor site location in metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 578. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.578.
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578 Background: CRC site is associated with differences in key molecular features that may impact survival in the metastatic (met) setting. We assessed the magnitude of outcome differences in a non-clinical trial scenario and explored how rectum cancer (RC) compares with right- and left-sided (RS and LS) colon tumors. Methods: Retrospective analysis of clinicopathological and molecular data from all mCRC patients (pts) treated at VHIO from January 2010 to June 2015. Targeted mutation (mut) profiling of driver oncogenes was performed by mass spectrometry (MassARRAY, Sequenom) or with next generation sequencing (Amplicon MiSeq, Illumina). Survival after relapse (SAR) was defined as time from diagnosis of met disease to death. Tumor site was categorized as RS (cecum, ascending, hepatic flexure, and transverse), LS (splenic flexure, descending, and sigmoid) or RC. We performed Cox proportional hazards models and adjusted for covariates including number and location of met sites, surgical resection of met lesions, and KRAS, BRAF and PIK3CA mut. Results: From 686 pts analyzed, primary site was RS/LS/RC in 29.4%/43.4%/27.2%, respectively. Pts with LS tumors were less likely to have ≥ 2 met sites (32%/20%/29%; p = 0.01). Lung metastases were more common in RC pts (20%/15%/36%; p < 0.001), peritoneal metastasis in pts with RS tumors (28%/14%/5%, p < 0.001). Surgical resection of any met disease was performed less frequently in pts with RS tumors (28%/46%/41%; p < 0.001). KRAS mut (59%/45%/44%), BRAF V600E mut (9%/5%/3%) and PIK3CAmut (25%/14%/11%) were more prevalent in RS tumors. In the overall population with survival data (n = 606, 424 events), SAR was significantly lower in pts with RS tumors (31/46/46 months; RS vs. LS HR = 1.54 [1.2-2.0], p < 0.001; rectum vs. left HR = 1.0 [0.7-1.3], p = 0.83). For comparison, worse SAR was also seen in the subset of pts (n = 337; 276 events) not eligible for surgical resection of met disease (26/31/35 months; right vs. left HR = 1.60 [1.2-2.2], p = 0.004; rectum vs. left HR = 0.9 [0.6-1.2], p = 0.42). Conclusions: The worse SAR of pts diagnosed with right-sided CRC tumors cannot be explained only by their distinctive met pattern or mutation profile of common oncogenes. Left-sided and rectum tumors have similar outcomes.
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Rimassa, Lorenza, Eric Assenat, Markus Peck-Radosavljevic, Vittorina Zagonel, Marc Pracht, Elena Rota Caremoli, Philippe Mathurin, et al. "Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4000. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4000.
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4000 Background: Tivantinib (T), a selective, oral MET inhibitor, improved overall survival (OS) and progression-free survival (PFS) versus placebo (P) in a phase II study in MET-High HCC pts. Methods: This randomized, placebo-controlled phase III trial (NCT01755767) enrolled pts with: advanced HCC; Child Pugh A; ECOG PS ≤1; adequate bone marrow, liver, kidney functions; no liver transplant; radiographic disease progression (PD) after or intolerance to sorafenib; tumor MET-High (MET ≥2+ in ≥50% of tumor cells) by centralized immunohistochemistry. Pts were randomly assigned 2:1 to oral T or P, stratified by vascular invasion (VI), extrahepatic spread (ES), AFP ( < / > 200ng/mL), treated until PD or unacceptable toxicity. Response (RECIST 1.1) was evaluated by CT / MRI every 8 weeks. Primary endpoint of OS and secondary endpoints including PFS and safety were assessed in the intent-to-treat (ITT) population. Results: From Dec 2012 to Dec 2015, 1209 pts were consented in Australia, the Americas, Europe, New Zealand: 589 MET-High, 43 initially randomized at the dose of 240mg BID, then reduced due to high neutropenia rate, 340 randomized at 120mg BID: 226 to T, 114 to P (ITT population). Characteristics of pts were balanced between arms: 306 (90%) male; median age: 67; PS 0: 207 (61%); VI: 117 (34%); ES: 197 (58%); AFP ≤200: 195 (57%); radiographic PD on sorafenib: 275 (81%). Median OS (95% CI) was 8.4 months (m) (6.8-10.0) in T, 9.1 m (7.3-10.4) in P, HR = 0.97 (0.75-1.25), P = 0.81. Median PFS (95% CI) was 2.1 m (1.9-3.0) in T, 2.0 m (1.9-3.6) in P, HR = 0.96 (0.75-1.22), P = 0.72. No OS difference was seen in pts with VI (HR 1.19, 0.79-1.79), ES (HR 1.09, 0.78-1.52), AFP > 200ng/mL (HR 1.00, 0.71-1.41). Grade (G) > 3 AEs were 55.6% in T, 55.3% in P. In T, most common G > 3 AEs were ascites (7.1%), general deterioration (5.8%), anemia (4.9%); most common serious AE was general deterioration (4.9%). Deaths within 30 days of last dose were 22.1% on T vs 15.8% on P (most common causes: general deterioration 3.5%, hepatic failure 2.6%). Conclusion: Tivantinib at the 120mg BID dose did not improve OS or PFS over placebo in patients with advanced MET-High HCC who failed previous treatment with sorafenib. Clinical trial information: NCT01755767.
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Bagchi, Aditi, Zachary Madaj, Kelly B. Engel, Ping Guan, Daniel C. Rohrer, Dana R. Valley, Emily Wolfrum, et al. "Impact of Preanalytical Factors on the Measurement of Tumor Tissue Biomarkers Using Immunohistochemistry." Journal of Histochemistry & Cytochemistry 69, no. 5 (March 1, 2021): 297–320. http://dx.doi.org/10.1369/0022155421995600.
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Analysis of formalin-fixed paraffin-embedded (FFPE) tissue by immunohistochemistry (IHC) is commonplace in clinical and research laboratories. However, reports suggest that IHC results can be compromised by biospecimen preanalytical factors. The National Cancer Institute’s Biospecimen Preanalytical Variables Program conducted a systematic study to examine the potential effects of delay to fixation (DTF) and time in fixative (TIF) on IHC using 24 cancer biomarkers. Differences in IHC staining, relative to controls with a DTF of 1 hr, were observed in FFPE kidney tumor specimens after a DTF of ≥2 hr. Reductions in H-score and/or staining intensity were observed for c-MET, p53, PAX2, PAX8, pAKT, and survivin, whereas increases were observed for RCC1, EGFR, and CD10. Prolonged TIF of 72 hr resulted in significantly reduced H-scores of CD44 and c-Met in kidney tumor specimens, compared with controls with 12-hr TIF. An elevated probability of altered staining intensity due to DTF was observed for nine antigens, whereas for prolonged TIF an elevated probability was observed for one antigen. Results reported here and elsewhere across tumor types and antigens support limiting DTF to ≤1 hr when possible and fixing tissues in formalin for 12–24 hr to avoid confounding effects of these preanalytical factors on IHC.
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Oliner, Kelly S., Rui Tang, Abraham Anderson, Yun Lan, Timothy Iveson, Ross C. Donehower, Yizhou Jiang, Sarita Dubey, and Elwyn Loh. "Evaluation of MET pathway biomarkers in a phase II study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or esophagogastric junction (EGJ) cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4005. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4005.
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4005 Background: R is an investigational, fully human, monoclonal antibody to HGF/SF, the ligand of the MET receptor. A double-blind, P-controlled, phase 2 study randomized 121 G/EGJ cancer pts 1:1:1 to 15 mg/kg R + ECX (Arm A, n = 40), 7.5 mg/kg R + ECX (Arm B, n = 42), or P + ECX (Arm C, n = 39). OS and PFS improved with the addition of R to ECX (Iveson et al, European Multidisciplinary Cancer Congress 2011; abstr 6.504). High tumor MET levels have been associated with poor prognosis in G cancer (Nakajima et al, Cancer 1999;85:1894-1902). We explored MET pathway biomarkers to identify pts who may benefit from R. Methods: MET protein levels and gene copy numbers were measured in archival tumor samples by immunohistochemistry (IHC) and fluorescence in situ hybridization, respectively. High and low MET subgroups were defined by several predefined strategies. Total HGF and soluble MET (sMET) protein in plasma were measured by ELISA and MSD assays, respectively. Treatment and biomarker effects on OS and PFS were analyzed by Cox proportional hazard models and Kaplan-Meier estimates. Results: Tumor samples were evaluable for MET protein from 62 pts in Arms A + B and 28 pts in Arm C. Pts with METHigh tumors (> 50% tumor cells positive) in Arms A + B had improved median OS than those in Arm C (11.1 mo [80% CI: 9.2-13.3] vs 5.7 mo [80% CI: 4.5-10.4]; HR = 0.29, 95% CI: 0.11-0.76, p = 0.012). Conversely, pts with METLow tumors (≤ 50% positive) in Arms A + B had a trend toward unfavorable OS compared with those in Arm C (HR = 1.84, 95% CI: 0.78-4.34). In the chemotherapy only arm (Arm C), pts with METHigh tumors had poorer OS (HR = 3.22, 95% CI: 1.08-9.63) than pts with METLow tumors. Similar trends were seen with PFS. Predefined dichotomization schemes for tumor MET gene copy number and baseline plasma levels of total HGF or sMET did not correlate with OS or PFS. Conclusions: High MET expression by IHC may predict clinical benefit to R + ECX in G/EGJ cancer pts. High MET expression may also be associated with poor prognosis for ECX-treated pts. Further investigation is needed to confirm these findings.
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Peters, Katherine B., Stevie Threatt, Patrick Healy, James Emmett Herndon, Eric S. Lipp, Sujata Panta, Dina Randazzo, Gordana Vlahovic, Henry S. Friedman, and Annick Desjardins. "Reductions in exercise behavior and tumor progression in newly diagnosed glioblastoma (GBM) patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e21636-e21636. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e21636.
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e21636 Background: At diagnosis, GBM patients face the immediate challenge of significant morbidity and mortality. In this population, we have shown that better exercise behavior is an independent prognostic factor for improved survival. The association between tumor progression and exercise behavior in newly diagnosed GBM patients was explored within a clinical study investigating the use of bevacizumab (BV) with concurrent chemoradiation, followed by BV and temozolomide with the continuation of BV following progression. Methods: In this prospective single-center study, exercise behavior was evaluated using the Modified Godin Leisure Questionnaire at time of study enrollment (before chemoradiation), after chemoradiation, and then every 6 mos until study discontinuation or subject demise. Physical activity was defined as MET-hr/wk with higher number equaling a better exercise behavior. Results: 68 newly diagnosed GBM patients were initially included with a mean age of 55.4 yrs (sd = 10.7 yrs). KPS range was 70-100 with the following being 70 (n = 4), 80 (n = 28), 90 (n = 34), and 100 (n = 2). Subjects who continued study participation 6 mos after the completion of chemoradiation were divided into two groups: subjects with (n = 13) and without (n = 34) tumor progression 6 mos after chemoradiation completion. Subjects that experience tumor progression < 6 mos after chemoradiation had a lower exercise behavior at baseline in comparison to their counterparts that did not experience progression < 6 mos after chemoradiation (mean = 12.8 MET-hr/wk (sd = 22.2) vs. mean = 22.4 MET-hr/wk (sd = 28.9). Moreover, this exercise behavior decreased in subjects that had tumor progression to mean = 6.6 MET-hr/wk (sd = 7.6) and remained relatively stable in subjects that did not progress with mean = 23.9 MET-hr/wk (sd = 44.9). Conclusions: Our observations of exercise behavior over time suggest that poorer baseline exercise behavior is associated with a disease progression within 6 mos of chemoradiation completion in newly diagnosed GBM patients. Moreover, this exercise behavior continues to decline after progression. Based on these observations, a greater understanding of the role of physical functioning is merited in GBM patients. Clinical trial information: NCT01740258.
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Jones, Eric J., Phil A. Bishop, James M. Green, and Mark T. Richardson. "Effects of Metered Versus Bolus Water Consumption on Urine Production and Rehydration." International Journal of Sport Nutrition and Exercise Metabolism 20, no. 2 (April 2010): 139–44. http://dx.doi.org/10.1123/ijsnem.20.2.139.
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This study compared the effects of a rapid bolus and a slower metered water-consumption rate on urine production and postexercise rehydration. Participants (n = 8) dehydrated by 2% body weight through moderate exercise in an environmentally controlled chamber (35 °C, 55% relative humidity). Breakfast and lunch were standardized for all participants during each 8-hr data-collection period. Rehydration was performed using a volume of water equal to that lost during exercise either as bolus consumption (100% of volume consumed in 1hr; BOL) or metered consumption (12.5% of volume every 30 min for 4 hr; MET). Urine volume was used to assess hydration efficiency (water retained vs. water lost) and net fluid balance at 8 hr. Mean urine outputs were 420 ml (MET) and 700 ml (BOL). A paired-samples t test showed that hydration efficiency was greater for MET (75%) than for BOL (55%; p = .018). These data suggest that metered administration was more effective in maintaining fluid balance. These findings suggest that rehydration rate is a factor in fluid-balance response. For situations in which available fluid volume is restricted, greater hydration efficiency is highly desirable.
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Shoji, Hirokazu, Yasuhide Yamada, Hirokazu Taniguchi, Natsuko Okita, Atsuo Takashima, Yoshitaka Honma, Satoru Iwasa, Ken Kato, Tetsuya Hamaguchi, and Yasuhiro Shimada. "Association between c-Met expression and tumor recurrence in colorectal cancer patients after liver resection." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3559. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3559.
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3559 Background: c-Met is a receptor for hepatocyte growth factor that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the correlation between c-Met protein expression in the primary lesion and relapse-free survival (RFS) in patients who had undergone curative hepatectomy for colorectal metastases. Methods: Between January 2004 and December 2009, formalin-fixed paraffin-embedded sections of surgical specimens from 108 CRC patients who had undergone hepatectomy were obtained at a single center. We performed immunohistochemical staining to detect c-Met expression. c-Met expression levels were scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. We defined scores 0 and 1 as c-Met-low, and scores 2 and 3 as c-Met-high. The Kaplan-Meier method and Cox proportional hazards model were used to investigate relationships between c-Met expression, patient characteristics, and RFS. Results: We identified 65 males and 43 females with a median age of 62 years. A total of 53% of patients underwent simultaneous resection of primary and metastatic liver lesions, and the others underwent metachronous resection. High levels of c-Met expression (c-Met-high) in the primary tumor were observed in 52% of patients. There were no differences in terms of size or number of metastatic liver lesions between the c-Met-low patients and the c-Met-high patients. RFS was significantly shorter in the c-Met-high patients (9.7 months) than that in the c-Met-low patients (21.1 months) in primary tumors (p=0.013). Multivariate analyses demonstrated that c-Met-high (hazards ratio [HR], 1.73; 95% confidence interval [95% CI], 1.08-2.79 for c-Met-high vs. c-Met-low) and hepatic resection for synchronous disease (HR, 2.17; 95% CI, 1.36-3.46 for synchronous vs. metachronous resection) were associated with worse RFS. Conclusions: High levels of c-Met expression in the primary tumor were associated with shorter RFS after hepatic metastasectomy.
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Evans, B. A., K. C. Song, S. C. Strom, R. Zarnegar, R. Bahnson, M. H. Bisceglia, G. K. Michalopoulos, and M. J. Becich. "Optimizing immunohistochemical staining for the HGF receptor c-MET in formalin-fixed paraffin-embedded archival human tissue." Proceedings, annual meeting, Electron Microscopy Society of America 52 (1994): 230–31. http://dx.doi.org/10.1017/s0424820100168888.
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Frozen tissue immunohistochemistry is a useful technique employed in diagnostic and research investigations and is often used despite a loss of morphological detail. Formalin fixation yields much better tissue preservation, but may mask the antigen sites. We have optimized a technique that allows us to study the distribution of the HGF receptor, c-MET, in formalin fixed, paraffin embedded tissue using commercially available polyclonal antisera in which we unmasked antigens sites with protease digestion. The technique we use is detailed below.Sections are incubated in the following:1)4 μm paraffin sections are deparaffinized and hydrated2)0.03% protease (Type XXIV: Sigma) for 2 min at RT3)0.5% H2O2 in methanol for 30 min at RT4)Protein Blocking Agent (Lipshaw/Immunon) for 1 hr at RT5)1° antibody ( Santa Cruz Biotech, Santa Cruz, CA) for 2 hr at RTa.)c-MET (c-12) rabbit polyclonal IgG, 1:200 dilution in PBSb.)h-MET (c-28) rabbit polyclonal IgG, 1:100 dilution in PBSc.)m-MET (c-21) rabbit polyclonal IgG, 1:100 dilution in PBS
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Scagliotti, Giorgio V., Denis Moro-Sibilot, Jens Kollmeier, Adolfo G. Favaretto, Eun Kyung Cho, Heidrun Grosch, Martin Kimmich, et al. "A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9019. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9019.
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9019 Background: MET expression is a mechanism of resistance to EGFR inhibition in EGFRmt NSCLC and correlated with poor prognosis. Emi (LY2875358) is a humanized IgG4 monoclonal bivalent MET antibody that blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared the clinical activity of Emi + E versus single agent E in 1st line EGFRmt metastatic NSCLC. Methods: Stage IV, EGFRmt NSCLC pts with disease control following an 8-week lead-in E (150 mg PO QD) treatment were randomized 1:1 to receive Emi (750 mg IV Q2W) + E or E alone. Pts were stratified by ECOG PS, ethnicity, MET expression status, and response at the end of the lead-in. The primary endpoint was PFS from randomization. Additional endpoints included safety, OS, PK, and exploratory analysis of MET-expressing populations. Results: Out of181 pts enrolled, 141 pts were randomized (Emi+E: 71; E: 70). In the ITT population, median PFS for EMI+E was 9.3 months (m) compared with 9.5 m for E (HR = 0.89: 90% CI 0.64-1.23; p = 0.534). Exploratory analysis of MET-high expressing pts (MET 3+ expression in ≥90% of tumor cells; n = 24 pts) showed a 15.3 m improvement in PFS (EMI+E: 20.7 m; E: 5.4 m [HR: 0.39; 90% CI: 0.17-0.91]). No difference in PFS was observed in the complementary population (HR: 1.1 [90% CI: 0.7-1.7]). Similar frequencies of related AEs were reported for both treatment arms. Drug-related TEAEs that were more frequent ( > 10%) for Emi+E were peripheral edema and fatigue (all grade 1 or 2). Emi serum concentrations were consistent with previously obtained PK results, and no apparent exposure-response was observed. Median OS in the ITT population was not achieved (NA) for either arm. In MET-high expressing pts, median OS was 20.6 m for E (90% CI: 8.87, NA) whereas it was not achieved for Emi+E (90% CI: NA, NA). Conclusions: No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E. Clinical trial information: NCT01897480.
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Hosseini, Ziagul, Linda Koopmans, and Sarike Verbiest. "De impact van flexibele arbeids-contracten op de vitaliteit en productiviteit van de flexwerkers." Tijdschrift voor HRM 23, no. 1 (March 1, 2020): 1–26. http://dx.doi.org/10.5117/thrm2020.1.hoss.
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Het aantal werknemers met een flexibel contract neemt toe. De vraag die dit artikel behandelt is hoe verschillende typen flexibele contracten en baanonzekerheid verband houden met vitaliteit en productiviteit in vergelijking met een vast contract. De uitkomsten van deze studie laten zien dat werknemers met een tijdelijk contract zonder uitzicht op vast en uitzendkrachten lager scoren op vitaliteit dan vaste werknemers, vanwege hun hogere baanonzekerheid. Werknemers met een tijdelijk contract zonder uitzicht op vast, uitzend- en oproepkrachten scoren lager op productiviteit dan vaste werknemers, (deels) door hun hogere baanonzekerheid. HR-professionals kunnen een rol spelen om de positie van flexwerkers op de arbeidsmarkt te versterken.
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Shah, Manish A., Jae Yong Cho, Iain Tan Bee Huat, Niall C. Tebbutt, Chia-Jui Yen, Alice Kang, David S. Shames, Lilian Bu, and Yoon-Koo Kang. "Randomized phase II study of FOLFOX +/- MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC)." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 2. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.2.
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2 Background: Aberrant up-regulation of the MET/HGF pathway is associated with poor prognosis in multiple malignancies, including GEC. Onartuzumab (O) is a fully humanized, monovalent anti-MET antibody that inhibits HGF binding and receptor activation. We examined the efficacy and safety of mFOLFOX6 and O in the first-line setting for metastatic, HER2-negative GEC. Methods: This was a double-blind, placebo controlled phase II study in which patients were randomized 1:1 to mFOLFOX6 + O 10 mg/kg. Eligibility included no prior treatment for metastatic disease, age >18, ECOG 0-1, retained organ function, HER2-negative, and evaluable disease. The primary objectives were to detect a meaningful improvement in progression free survival (PFS) in the ITT population or the MET-positive (≥ 50% of tumor with moderate-strong intensity staining by IHC based on central review) subgroup. With 120 patients enrolled and 84 PFS events observed, the target HR was 0.7 in the ITT population, and 0.6 in the MET-positive subgroup (estimated 50% of total). Results: 123 patients (83 Asia/Pacific, 40 US) from 25 sites were from 7/2012-5/2013. The treatment arms were well balanced: median age (57 placebo (P), 58.5 O), male (n=36 (59%) P, n=40 (65%) O), and MET-positive (n=19 (33%) P, n=16 (28%) O). Serious adverse events were more frequent with O (55%) vs placebo (40%). Selected grade 3-5 adverse events observed at least 5% more commonly with O included neutropenia (58% vs 45%), thrombocytopenia (10% vs 3%), peripheral edema (10% vs 0), and pulmonary embolism (7% vs 2%). At data cutoff (29 Jan 2014), 96 patients had PFS events (n=46 (74%) O, n=50 (82%) P), with median PFS of 6.77 and 6.97 months, respectively (HR 1.08, 95% CI 0.71-1.63). In the MET-positive subgroup, median PFS was 5.95 months for O and 6.8 months for placebo (HR 1.38 [0.60-3.20]). No difference in efficacy was noted with alternate MET-positive definitions (50% vs 90% MET staining, and 1, 2, or 3+ intensity). Conclusions: The addition of O to mFOLFOX6 in metastatic GEC did not improve PFS in either an unselected population or in MET-positive patients as defined by IHC. Additional biomarker analyses are ongoing to identify patients that may benefit from MET inhibition. Clinical trial information: NCT01662869.
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Kamiya, Kentaro, Takashi Masuda, Atsuhiko Matsunaga, Masahiko Kimura, Mari Kawano, Yumi Takahashi, Chiharu Noda, and Tohru Izumi. "Delta-HR/delta-MET at submaximal exercise reflects exercise capacity in patients with ischemic heart disease." Journal of Cardiac Failure 14, no. 7 (September 2008): S152. http://dx.doi.org/10.1016/j.cardfail.2008.07.095.
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Rivera-Brown, Anita M., Miguel A. Rivera, and Walter R. Frontera. "Applicability of Criteria for V̇O2max in Active Adolescents." Pediatric Exercise Science 4, no. 4 (November 1992): 331–39. http://dx.doi.org/10.1123/pes.4.4.331.
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This study examined the applicability of criteria for maximal oxygen consumption (V̇O2max) in adolescents. Active females (n=38) and males (n=196) who were students at a sports-technical junior high school performed a treadmill Bruce protocol to volitional fatigue. The criteria for V̇O2max were R ≥1.0, HR ≥95% of predicted maximal for age, and an increase in V̇O2 ≤2.1 ml·kg−1·min−1 with an increase in workload. The first criterion was met by 97% of the females and 93% of the males, while 81% of the females and 75% of the males met the second criterion. Only 8% of the females and 13% of the males met the third criterion. Those who achieved a plateau showed higher HR at peak exercise compared to those who did not (204 ±7.0 vs. 200.6 ±7.2, P≤0.05). Our data indicate that a high proportion of adolescents exhibit subjective and objective indicators of maximal performance without showing a plateau in V̇O2. Age-specific criteria for V̇O2max should be developed.
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Zinsmeister, Joop, Daniel van Middelkoop, and Marcel van Maanen. "Naar een duurzame toekomst? Het belang van vakmanschap van (oudere) werknemers bij de transitie naar een meer duurzame industrie." Tijdschrift voor HRM 23, no. 2 (June 1, 2020): 1–23. http://dx.doi.org/10.5117/thrm2020.2.zins.
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Economische sectoren als landbouw, transport en industrie staan voor de opgave om te verduurzamen. Deze opgave zorgt voor andere banen en stelt andere eisen aan mensen die werkzaam zijn in deze sectoren. In dit artikel verkennen we de vraagstukken rond werk, vakmanschap en oudere werknemers die ontstaan vanwege deze transitie, en de rol die HR hierin speelt. Om hier inzicht in te krijgen, deden we een jaar lang onderzoek bij een groot industrieel bedrijf, waar we spraken met vakmensen, HR-medewerkers en leidinggevenden over de gevolgen voor het werk van de transitie van grijze naar groene productiemethoden. In deze casus bleek dat de schoksgewijs verlopende transitie het vakmanschap van (oudere) werknemers onder druk zet. De onzekerheid die de transitie voor de komende jaren met zich meebrengt leidt op organisatieniveau tot spanningsvelden. HR zou de eigen rol kunnen invullen door de concretisering van de duurzame productie in de toekomst samen met de werknemers en de leidinggevenden proactief vorm te geven.Economic sectors like agriculture, transport and industry face the challenge to become more sustainable. This challenge impacts the jobs available and changes the skills which people need to work in those sectors. In this article, we explore questions concerning work, craftmanship and older employees which arise because of this transition as well as the potential role of HR in addressing these questions. In order to gain insight in these questions, we conducted research for over a year in a large industrial company, during which we spoke with craftsmen, HR professionals and managers. We spoke with them about the consequences of the transition to more sustainable production methods, now and in the near future. In this case, it became clear that the transition puts pressure on the craftmanship of employees, especially the older employees. The insecurity that emerged as a result of the transition also leads to various tensions on the organizational level. HR could play an important role by proactively shaping the concretization of the envisioned sustainable future of the company together with the craftsmen and the managers.
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Friedenreich, Christine M., Linda S. Cook, Qinggang Wang, Renée L. Kokts-Porietis, Jessica McNeil, Charlotte Ryder-Burbidge, and Kerry S. Courneya. "Prospective Cohort Study of Pre- and Postdiagnosis Physical Activity and Endometrial Cancer Survival." Journal of Clinical Oncology 38, no. 34 (December 1, 2020): 4107–17. http://dx.doi.org/10.1200/jco.20.01336.
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PURPOSE The aim of this study was to evaluate associations between pre- and postdiagnosis physical activity and survival in survivors of endometrial cancer by physical activity domain, intensity, dose (metabolic-equivalent task [MET]-hours/week/year), and change from pre- to postdiagnosis. METHODS We conducted a prospective cohort study in Alberta, Canada, of 425 women who were diagnosed with histologically confirmed invasive endometrial cancer between 2002 and 2006 and observed to 2019. The interviewer-administered Lifetime Total Physical Activity Questionnaire recorded prediagnosis (assessed at a median of 4.4 months after diagnosis) and postdiagnosis physical activity (assessed at a median of 3.4 years after diagnosis). Associations between physical activity and overall and disease-free survival were assessed using Cox proportional hazards models adjusted for age, stage, grade, treatments, body mass index, menopausal status, hormone therapy use, family history of cancer, and comorbidities. RESULTS After a median follow-up of 14.5 years, there were 60 deaths, including 18 endometrial cancer deaths, and 80 disease-free survival events. Higher prediagnosis recreational physical activity was statistically significantly associated with improved disease-free survival (> 14 v ≤ 8 MET-hours/week/year; hazard ratio [HR], 0.54; 95% CI, 0.30 to 0.96; Ptrend = .04), but not overall survival (HR, 0.56; 95% CI, 0.29 to 1.07; Ptrend = .06). Higher postdiagnosis recreational physical activity (> 13 v ≤ 5 MET-hours/week/year) was strongly associated with both improved disease-free survival (HR, 0.33; 95% CI, 0.17 to 0.64; Ptrend = .001) and overall survival (HR, 0.33; 95% CI, 0.15 to 0.75; Ptrend = .007). Participants who maintained high recreational physical activity levels from pre- to postdiagnosis also had improved disease-free survival (HR, 0.35; 95% CI, 0.18 to 0.69) and overall survival (HR, 0.43; 95% CI, 0.20 to 0.94) compared with those who maintained low physical activity levels. CONCLUSION Recreational physical activity, especially postdiagnosis, is associated with improved survival in survivors of endometrial cancer.
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Folprecht, Gunnar, Eric Van Cutsem, Carsten Bokemeyer, Michael Schlichting, Steffen Heeger, and Claus-Henning Kohne. "First-line chemotherapy plus cetuximab in patients grouped according to prognostic risk factors: Analysis of the CRYSTAL and OPUS studies." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3591. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3591.
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3591 Background: Analysis of randomized trials has shown that mCRC patients (pts) can be divided into prognostic risk groups according to baseline clinical parameters including ECOG performance status, white blood cell count (WBC), alkaline phosphatase (ALP) and number of metastatic (met) sites (Köhne C, et al. Ann Oncol 2002;13:308-17). The effect of adding cetuximab to first-line chemotherapy (CT) on overall survival (OS) in these groups of KRAS wild-type mCRC pts was investigated in the CRYSTAL and OPUS studies. Methods: Pt risk groups were: low-risk (LRG= ECOG 0/1, 1 met site) intermediate-risk (IRG= ECOG <1, >1 met site, ALP <300 U/L or, ECOG>1, low WBC, 1 met site) and high-risk (HRG= ECOG<1, >1 met site, ALP>300 U/L or ECOG>1, high WBC, or ECOG>1, low WBC and >2 met sites). Exploratory analyses comprised estimates of effects using Cox‘s proportional hazards model for OS on individual pt data and comparison of treatment arms by log-rank test. Results: Data are shown in the table. In the pooled analyses, in both treatment arms OS was longest in LRG pts and shortest in HRG pts. Adding cetuximab to CT led to marked improvements in OS in the HRG (Hazard ratio [HR] 0.765, 95% CI 0.506–1.157, p=0.203) and IRG (HR 0.781, 95% CI 0.622–0.981, p=0.033), while improvements in LRG pts (HR 0.869, 95% CI 0.672–1.124, p=0.287) were observed only after prolonged follow up. Data were similar in the separate CRYSTAL and OPUS studies. Conclusions: The analysis confirms the concept of prognostic risk groups for OS according to baseline clinical parameters in pts with KRAS wt mCRC. Benefit from the addition of cetuximab to first-line CT in terms of OS appears to be more pronounced in the IRG and HRG. [Table: see text]
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Tong, Wilson P., Michele Azada, and Sai-Hong Ignatius Ou. "Should crizotinib be dosed to sinus bradycardia (SB) (HR < 55)? A single institution, retrospective analysis of heart rate (HR) changes and tumor response in crizotinib treated NSCLC patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e18140-e18140. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e18140.
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e18140 Background: Crizotinib can result in SB as a part of its dose-dependent pharmacodynamic property. We analyzed the correlation between SB and tumor response in ALK or MET+ NSCLC patients (pts). Methods: Single institution retrospectively analysis of SB incidence (HR < 55) of ALK or MET+ NSCLC patients enrolled in 2 phase II crizotinib trials. Comparison performed between pt characteristics, HR changes, treatment duration, tumor response and shrinkage according to SB status. Results: 42 ALK or MET+ NSCLC pts (30 from A8081001, 12 from PROFILE1005) rx’d with crizotinib 250 mg po bid were analyzed. 90% of pts had a HR decrease of > 10 beats per minutes (bpm). 19 (45%) patients developed at least 1 SB episode at anytime during crizotinib treatment including 8 (19%) pts with profound SB (HR =< 45). All pts with SB were asymptomatic. There was no difference in the median age of diagnosis between pts (57.6 yrs [SB] vs. 49.7 yrs [no SB]; p = 0.073) by SB status. Median time to SB was 3 wks (mean: 7.2 wks, range 2-32 wks). There was significant difference in the mean pre-Rx baseline HR by SB status (74.5 bpm [SB] vs. 92.6 bpm [no SB]; p = 0.005), Rx duration (57.3 wks [SB] vs. 33.3 wks [no SB]; p = 0.021). The average maximum HR decrease (MHRD) from baseline for all pts were 26.3 bpm. There was no significant difference in the mean MHRD from baseline according to SB status (28.2 bpm [SB] vs. 24.7 bpm [no SB]; p = 0.598). 68% (13/19) of SB pts compared to 35% (8/23) of pts without SB achieved a CR/PR (p = 0.030). The mean maximum decrease in tumor measurements (MDTM) (RECIST) was 46.2% for pts with SB compared to 32.0% for pts without SB (p = 0.095). There was no difference in the mean MDTM in pts who achieved CR/PR without SB (62.5%) and with SB (63.5%) (p = 0.913) nor the mean response duration (RD) in CR/PR pts by SB status (43.3 wks [SB] vs. 51.5 wks [no SB]; p = 0.426). Conclusions: HR decrease is common in pts treated with crizotinib. Pts who developed asymptomatic SB had significantly lower pre-Rx baseline HR, longer Rx duration, higher response rates. However there was no difference in the mean MDTM or RD between pts who achieved CR/PR by SB status.
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Engel-Nitz, Nicole M., Yanni Hao, Jaqueline Willemann Rogerio, James D. Turnbull, Gabriel Gomez Rey, Jane Sullivan, and Arthur H. Rossof. "Hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer: Sequencing of chemotherapy and endocrine therapy." Journal of Clinical Oncology 31, no. 26_suppl (September 10, 2013): 164. http://dx.doi.org/10.1200/jco.2013.31.26_suppl.164.
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164 Background: National Comprehensive Cancer Network breast cancer guidelines suggest sequencing of systemic therapy. This study examined sequencing of endocrine and chemotherapy treatments to better understand real-world treatment patterns for HR+/HER2- advanced breast cancer. Methods: A proprietary clinical cancer database with physician-reported clinical data on patients with breast cancer was linked to medical and pharmacy claims (2008-2012) from a national US health plan. Study patients had HR+ and HER2- status. Advanced cancer cohorts were defined: stage III (SIII) or IV (SIV) at initial diagnosis, or developed metastases following initial diagnosis (MET). Index date was the first date of advanced cancer diagnosis or date of metastases following initial diagnosis. Health plan enrollment for 3 months pre- and ≥ 3-months post- index date was required; patients who died within 3 months after index date and were continuously enrolled were retained. A 3-month baseline period assessed prior treatment; a variable follow-up (until disenrollment or 31 Oct 2012) assessed patterns of endocrine and chemotherapy treatments following index date. Results: A total of 954 breast cancer patients met study inclusion criteria and were HR+/HER2- with ≥ 3 months of continuous enrollment after index date, with 369 of the 954 (38.68%) SIII, 117 (12.26%) SIV, and 469 (49.16%) MET patients. In the study population, 83.65% were treated with endocrine therapy, starting an average of 179 days after index date. A total of 80.29% were treated with chemotherapy, starting an average of 53 days following the index date; 65% of patients initiated chemotherapy after index date without prior endocrine treatment. Rates varied by cohort: 90% of SIII, 57% of SIV, and 48% of MET patients had no evidence of endocrine treatment prior to initiating chemotherapy. Conclusions: This study found large proportions of HR+/HER2- advanced breast cancer patients initiated chemotherapy without prior endocrine therapy. Further investigation of patient characteristics and outcomes by therapy sequencing patterns will help illuminate the extent to which patterns adhere to NCCN guidelines.
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Carpentier, Marieke, Sara Stockman, and Greet Van Hoye. "Rekrutering via Sociale MediaEen Kwalitatief Onderzoek Bij Hr-managers En Medewerkers." Tijdschrift voor HRM 21, no. 4 (December 1, 2018): 32–55. http://dx.doi.org/10.5117/thrm2018.4.carp.
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De meerderheid van de werkzoekenden is actief op sociale media. Deze platformen zijn daarom veelbelovende tools voor rekrutering en employer branding. Organisaties kunnen sociale media aanwenden om huidige vacatures in te vullen, maar ook om een aantrekkelijk employer brand te creëren met het oog op toekomstige aanwervingen. Ondanks dat meer en meer organisaties sociale media gebruiken voor rekrutering, is er nog weinig onderzoek over hoe en waarom sociale media worden gebruikt in een rekruteringscontext en welke problemen zich hierbij kunnen stellen. Deze kwalitatieve studie onderzoekt de ervaringen van HR-managers en medewerkers. Hierbij ligt enerzijds de focus op sociale media als rekruteringstool in het algemeen. Anderzijds wordt gekeken naar één specifieke manier waarop sociale media als rekruteringstool kunnen worden ingezet, met name via het betrekken van medewerkers. Op basis van de resultaten adviseren wij HR-professionals in de praktijk om een systematische samenwerking met de departementen marketing en communicatie uit te bouwen, en om te investeren in HR-metrics. Ook strekt het tot de aanbeveling om medewerkers meer te informeren over wat ze kunnen doen met sociale media gericht op rekrutering, en daarbij beter in te spelen op wat medewerkers motiveert om positieve informatie over hun werkgever te verspreiden. Tenslotte wijzen we op het belang van een lange termijn strategie voor rekrutering waarop alle activiteiten worden afgestemd.Due to the widespread use of social media, these platforms are promising tools for recruitment and employer branding. Organizations can employ social media not only for filling in vacancies, but also to create an attractive employer brand to serve future needs. However, almost no research has investigated recruiting through social media. Hence, this qualitative study examines the experiences of both HR managers and employees to understand why and how social media are used in a recruitment context and which problems occur. We focus on social media as recruitment tools in general and on how and why employees are stimulated to share vacancies and messages on these platforms as well. Based on the study results, we recommend that organizations set up a collaboration between the different departments involved in the use of social media, invest in HR metrics and analytics, improve the communication to employees with regard to what they can do, how and why, understand why employees want to share information about the organization as an employer and create communication to trigger these motives, and, finally, invest in a long term strategy and align all recruitment activities with this strategy.
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Graziano, Francesco, Nadia Galluccio, Paola Lorenzini, Annamaria Ruzzo, Emanuele Canestrari, Silvia D'Emidio, Vincenzo Catalano, et al. "Genetic Activation of the MET Pathway and Prognosis of Patients With High-Risk, Radically Resected Gastric Cancer." Journal of Clinical Oncology 29, no. 36 (December 20, 2011): 4789–95. http://dx.doi.org/10.1200/jco.2011.36.7706.
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Purpose To investigate whether prognosis of patients with high-risk gastric cancer may depend on MET copy number gain (CNG) or an activating truncation within a deoxyadenosine tract element (DATE) in the promoter region of the MET ligand HGF. Patients and Methods A single-institution cohort of 230 patients with stage II/III gastric cancer was studied. Formalin-fixed paraffin-embedded tumor specimens were used for DNA extraction. Quantitative polymerase chain reaction (qPCR) for MET CNG and sequencing for HGF DATE truncation (< 25 deoxyadenosines instead of 30) were used. Results were analyzed for association with disease-free survival (DFS) and overall survival (OS). To assess the reliability of the qPCR measurement, a random sample of cases was reanalyzed using an alternative assay (fluorescent in situ hybridization [FISH]) with calculation of the intracorrelation coefficient (ICC). Results In 216 assessable patients, MET CNG five or more copies and homozygous HGF-truncated DATE occurred in 21 patients (10%) and 30 patients (13%), respectively. Patients with MET CNG five or more copies (MET-positive) showed significantly worse prognosis with multivariate hazard ratio (HR) of 3.02 (95% CI, 1.71 to 5.33; P < .001) for DFS and multivariate HR of 2.91 (95% CI, 1.65 to 5.11; P < .001) for OS. The agreement between qPCR and FISH was high, with ICC = 0.9% (95% CI, 0.81% to 0.95%; the closer the ICC is to 1, the greater is the agreement). HGF-truncated DATE did not show relevant prognostic effect. Conclusion In this study, qPCR revealed approximately 10% of white patients with gastric cancer harboring MET CNG of five or more copies. This marker was significantly associated with unfavorable prognosis. This information is relevant to the current clinical development of anti-MET compounds.
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Des Guetz, Gaetan, Bernard Uzzan, Thierry Bouillet, Patrick Nicolas, Kader Chouahnia, Laurent Zelek, and Jean-François Morere. "Impact of Physical Activity on Cancer-Specific and Overall Survival of Patients with Colorectal Cancer." Gastroenterology Research and Practice 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/340851.
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Background. Physical activity (PA) reduces incidence of colorectal cancer (CRC). Its influence on cancer-specific (CSS) and overall survival (OS) is controversial.Methods. We performed a literature-based meta-analysis (MA) of observational studies, using keywords “colorectal cancer, physical activity, and survival” in PubMed and EMBASE. No dedicated MA was found in the Cochrane Library. References were cross-checked. Pre- and postdiagnosis PA levels were assessed by MET. Usually, “high” PA was higher than 17 MET hour/week. Hazard ratios (HRs) for OS and CSS were calculated, with their 95% confidence interval. We used more conservative adjusted HRs, since variables of adjustment were similar between studies. When higher PA was associated with improved survival, HRs for detrimental events were set to <1. We used EasyMA software and fixed effect model whenever possible.Results. Seven studies (8056 participants) were included, representing 3762 men and 4256 women, 5210 colon and 1745 rectum cancers. Mean age was 67 years. HR CSS for postdiagnosis PA (higher PA versus lower) was 0.61 (0.44–0.86). The corresponding HR OS was 0.62 (0.54–0.71). HR CSS for prediagnosis PA was 0.75 (0.62–0.91). The corresponding HR OS was 0.74 (0.62–0.89).Conclusion. Higher PA predicted a better CSS. Sustained PA should be advised for CRC. OS also improved (reduced cardiovascular risk).
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Manabe, Osamu, Shigeru Yamaguchi, Kenji Hirata, Kentaro Kobayashi, Hiroyuki Kobayashi, Shunsuke Terasaka, Takuya Toyonaga, et al. "Preoperative Texture Analysis Using 11C-Methionine Positron Emission Tomography Predicts Survival after Surgery for Glioma." Diagnostics 11, no. 2 (January 28, 2021): 189. http://dx.doi.org/10.3390/diagnostics11020189.
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Background: Positron emission tomography with 11C-methionine (MET) is well established in the diagnostic work-up of malignant brain tumors. Texture analysis is a novel technique for extracting information regarding relationships among surrounding voxels, in order to quantify their inhomogeneity. This study evaluated whether the texture analysis of MET uptake has prognostic value for patients with glioma. Methods: We retrospectively analyzed adults with glioma who had undergone preoperative metabolic imaging at a single center. Tumors were delineated using a threshold of 1.3-fold of the mean standardized uptake value for the contralateral cortex, and then processed to calculate the texture features in glioma. Results: The study included 42 patients (median age: 56 years). The World Health Organization classifications were grade II (7 patients), grade III (17 patients), and grade IV (18 patients). Sixteen (16.1%) all-cause deaths were recorded during the median follow-up of 18.8 months. The univariate analyses revealed that overall survival (OS) was associated with age (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01–1.08, p = 0.0093), tumor grade (HR 3.64, 95% CI 1.63–9.63, p = 0.0010), genetic status (p < 0.0001), low gray-level run emphasis (LGRE, calculated from the gray-level run-length matrix) (HR 2.30 × 1011, 95% CI 737.11–4.23 × 1019, p = 0.0096), and correlation (calculated from the gray-level co-occurrence matrix) (HR 5.17, 95% CI 1.07–20.93, p = 0.041). The multivariate analyses revealed OS was independently associated with LGRE and correlation. The survival curves were also significantly different (both log-rank p < 0.05). Conclusion: Textural features obtained using preoperative MET positron emission tomography may compliment the semi-quantitative assessment for prognostication in glioma cases.
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Scagliotti, Giorgio, Joachim von Pawel, Silvia Novello, Rodryg Ramlau, Adolfo Favaretto, Fabrice Barlesi, Wallace Akerley, et al. "Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 33, no. 24 (August 20, 2015): 2667–74. http://dx.doi.org/10.1200/jco.2014.60.7317.
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Purpose Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety. Results The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%). Conclusion E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
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Chabot, Thomas, Alain Defontaine, Damien Marquis, Axelle Renodon-Corniere, Emmanuelle Courtois, Fabrice Fleury, and Yvonnick Cheraud. "New Phosphorylation Sites of Rad51 by c-Met Modulates Presynaptic Filament Stability." Cancers 11, no. 3 (March 23, 2019): 413. http://dx.doi.org/10.3390/cancers11030413.
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Genomic instability through deregulation of DNA repair pathways can initiate cancer and subsequently result in resistance to chemo and radiotherapy. Understanding these biological mechanisms is therefore essential to overcome cancer. RAD51 is the central protein of the Homologous Recombination (HR) DNA repair pathway, which leads to faithful DNA repair of DSBs. The recombinase activity of RAD51 requires nucleofilament formation and is regulated by post-translational modifications such as phosphorylation. In the last decade, studies have suggested the existence of a relationship between receptor tyrosine kinases (RTK) and Homologous Recombination DNA repair. Among these RTK the c-MET receptor is often overexpressed or constitutively activated in many cancer types and its inhibition induces the decrease of HR. In this study, we show for the first time that c-MET is able to phosphorylate the RAD51 protein. We demonstrate in vitro that c-MET phosphorylates four tyrosine residues localized mainly in the subunit-subunit interface of RAD51. Whereas these post-translational modifications do not affect the presynaptic filament formation, they strengthen its stability against the inhibitor effect of the BRC peptide obtained from BRCA2. Taken together, these results confirm the role of these modifications in the regulation of the BRCA2-RAD51 interaction and underline the importance of c-MET in DNA damage response.
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Ratner, M. I., D. E. Lebach, I. I. Shapiro, N. Bartel, M. F. Bietenholz, R. R. Ransom, and J. F. Lestrade. "Progress in VLBI Stellar Astrometry for the NASA/Stanford Relativity Mission (Gravity Probe B)." International Astronomical Union Colloquium 164 (1998): 385–86. http://dx.doi.org/10.1017/s0252921100046054.
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AbstractThe NASA/Stanford Relativity Mission (Gravity Probe B) is to test the unverified “frame-dragging” prediction of general relativity through measurements of the precessions of orbiting gyroscopes. For mission accuracy goals to be met, the proper motion of a “guide star,” whose position will be used as an inertial reference, must be determined in an extragalactic reference frame with a standard error less than 0.5 mas/yr. We discuss our VLBI observations of the current guide-star candidates (radio stars HR 1099, HR 5110, and HR 8703) and our techniques for obtaining differential astrometric positions with the needed accuracy.
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Benedikova, Andrea, Josef Srovnal, Jiri Klein, Pavel Skalicky, Marek Szkorupa, Karel Cwiertka, Lenka Radova, and Marian Hajduch. "Clinical importance of circulating tumor cells in lung cancer patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22109-e22109. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22109.
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e22109 Background: Assessment of the circulating tumor cells (CTCs) in lung cancer patients could prevent burdensome surgery in understaged cases. Therefore we have tested the hypothesis that the presence of CTCs is a negative prognostic factor in these patients and correlates with poor survival. Methods: This was a prospective study to test the presence of CTCs in peripheral blood, pulmonary blood and bone marrow in 108 lung cancer patients (75 males, 33 females; mean age 66.2 years, ranging from 29 to 82 years) at the time of surgery using real-time RT-PCR for carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), lung-specific X protein (LUNX) and hepatocyte growth factor receptor (c-met). Results: We found a statistically significant association between c-met expression level in the pulmonary blood and clinical stage (p<0.044) and lymph node involvement (p<0.0023). C-met marker also showed significantly higher positivity ratio in the peripheral (p<0.034) and pulmonary (p<0.04) blood in patients with histologically proven lymphatic metastases than in patients with negative lymph nodes. The positivity of CTCs in peripheral blood or bone marrow using c-met was independent of clinical stage, age, sex and grading using Cox regression analysis (p=0.006, resp. 0.001). 82 patients followed up for more than 1 year were involved into the overall survival (OS) analysis. 27 of them (32.9 %) died, the OS median was 19.8 months. The patients with the presence of CTCs in the peripheral blood or the bone marrow using c-met had significantly shorter OS and higher hazard ratio (p<0.024; HR=4.39 [95% CI: 1.58-12.22], resp. p<0.008; HR=5.08 [95% CI: 1.79-14.43]). In addition, patients with the presence of CTCs detected in bone marrow using CEA and/or c-met had significantly shorter OS (p<0.025; HR=3.08 [95% CI: 1.26-7.5]). Conclusions: Our study demonstrates that the presence of CTCs is independent negative prognostic factor in lung cancer patients. The analysis of CTCs is clinically feasible, reproducible and further studies focused on early clinical stages should demonstrate its applicability in individualization of adjuvant therapy in lung cancer patients and identification of individuals who would not benefit from extensive lung surgery.
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Seo, Seyoung, Seong Joon Park, Sook Ryun Park, Min-Hee Ryu, Baek-Yeol Ryoo, Young Soo Park, Young-Soon Na, Chae-Won Lee, Ju-Kyung Lee, and Yoon-Koo Kang. "Clinical significance of MET amplification in metastatic or locally advanced gastric cancer treated with first-line fluoropyrimidine and platinum (FP) combination chemotherapy." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 69. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.69.
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69 Background: Amplification of the MET proto-oncogene has been reported in a subset of gastric cancer (GC). However, clinical information of MET amplified GC is limited, especially in the metastatic setting. We investigated the clinical significance of MET amplification in GC patients treated with palliative chemotherapy. Methods: MET amplification was analyzed in formalin-fixed, paraffin-embedded GC tissues by a quantitative PCR-based copy number assay, using advanced GC cohorts between 2008 and 2014 in Asan Medical Center (AMC), Seoul, Korea. A total of 327 patients with tumor portion ≥ 70% were analyzed for clinical features and among them, 260 patients treated with first-line FP were analyzed for survival. MET amplification was defined as > 5 copy number. Results: Twenty one out of 327 patients (6.4%) were classified as harboring MET amplification. Clinical characteristics were compared between patients with or without MET amplification (AMP vs. no AMP group). The AMP group was related with ECOG performance status ≥ 2 (33.3% vs. 10.5% p = 0.007), peritoneal metastasis (76.2% vs. 46.2%, p = 0.008) and poor risk category (47.6% vs. 14.2%, p = 0.001) by AMC prognostic model (Koo et al. Cancer Chemother Pharmacol 2011, 68:913-921). A total of 174 patients had measurable lesions from 260 patients treated with FP and 80 patients (51.4%) obtained objective responses. There were no significant differences in response rate between two groups (61.5% vs. 52.2%, p = 0.518). With a median follow-up of 27.8 months (range, 8.2-68.5), median overall survival (OS) and progression-free survival (PFS) were 12.7 and 5.8 months, respectively. In univariate analysis, neither PFS nor OS was different between two groups (hazard ratio [HR] = 0.677, 95% confidence interval [CI] 0.347-1.322, p = 0.254 for PFS; HR = 0.676, 95% CI 0.347-1.318, p = 0.251 for OS). Conclusions: In advanced GC, MET amplification was associated with poor performance status, peritoneal metastasis, and poor risk category. However, MET amplification was not an independent prognostic predictor in patients with metastatic or locally advanced GC treated with palliative FP chemotherapy.
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van der Togt, Jorrit, and Thomas Hedegaard Rasmussen. "Toward evidence-based HR." Journal of Organizational Effectiveness: People and Performance 4, no. 2 (June 5, 2017): 127–32. http://dx.doi.org/10.1108/joepp-02-2017-0013.
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Purpose Sharing a practitioner perspective on the current value, challenges and future direction of HR analytics, from experience in a Fortune 500 company, to contribute to the development of the field in practice and academia. The paper aims to discuss this issue. Design/methodology/approach Perspective/position paper with practical findings. Findings HR analytics – i.e., applied management/OE science – clearly adds value when a number of pre-conditions are met. The value goes beyond talent outcomes, and applies to profits, cyber security, safety, and other outcomes. Practical implications HR/OE practitioners and academia should continue to work together, and consider both clear monetary value and change management when working toward evidence-based HR and evidence-based management. Social implications The approach increases the impact of for- and non-profit organizations, giving higher impact at lower cost, via more efficient and effective use of human capital and also removes biases present in approaches that are not evidence-based. Originality/value Few very large companies have shared their experiences building up HR analytics, and this paper does exactly that from a large company that has invested heavily in HR analytics and is considered a front-runner globally (Shell). This showcases to practitioners and researchers what HR analytics can be, provided proper investments are made, and practitioners and researchers work together – i.e., what the impact of HR analytics is and what the challenges and pitfalls are.
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Stewart, Paul, Phillip S. Blanchette, Prakesh S. Shah, Xiang Y. Ye, R. Gabriel Boldt, Ricardo Fernandes, Theodore A. Vandenberg, and Jacques Raphael. "Do all patients with HER2-positive breast cancer require one year of adjuvant trastuzumab?: A systematic review and meta-analysis." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 522. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.522.
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522 Background: One year of adjuvant trastuzumab (T) remains the standard treatment for patients with HER2 positive breast cancer. Results from randomized trials with diverse non-inferiority margins comparing one year to a shorter duration of adjuvant T were not consistent, particularly with the PERSEPHONE and the final PHARE and Short-HER trials’ results. Our objective was to conduct a systematic review and meta-analysis of randomized trials in patients with HER2 positive breast cancer to assess whether a shorter duration of adjuvant T was non-inferior to one year of treatment. Methods: PubMed, EMBASE and The Cochrane Library were searched for eligible randomized trials. Hazard ratios (HR) for disease free and overall survival (DFS, OS) were weighted using generic inverse variance and pooled in a meta-analysis using random-effects models. The median of non-inferiority margins derived from each trial was calculated to set a non-inferiority margin of 1.29 for the pooled analysis. Subgroup analyses compared survival outcomes by estrogen receptor (ER) status, nodal status, length and timing of trastuzumab treatment. Results: Data of 11,376 patients from 5 trials were analyzed. A shorter duration of T was non-inferior to one year of therapy for DFS (HR 1.13, 95%CI 1.03-1.24) but worse for OS (HR 1.16, 95%CI 1.01-1.32). In addition, the non-inferiority for DFS was met for patients with ER positive disease (HR 1.1, 95%CI 0.95-1.28) and patients treated with 6 months (HR 1.09, 95%CI 0.98-1.22) or sequential T (HR 0.97, 95%CI 0.75-1.27). Conversely, the non-inferiority for DFS was not met for patients with ER negative disease (HR 1.22, 95%CI 1.06-1.41), patients treated with 9 weeks (HR 1.26, 95%CI 1.02-1.55) or concomitant T (HR 1.25, 95%CI 1.07-1.45) and patients with node negative (HR 1.12, 95% 0.93-1.35) or positive (HR 1.16, 95%CI 0.99-1.36) disease. Conclusions: Within the limitations of the available data and the different non-inferiority margins used in randomized trials, a shorter duration of adjuvant T is non-inferior to one year of therapy for DFS in patients with HER2 positive breast cancer, particularly in patients with ER positive disease. Further trials with appropriately chosen non-inferiority margins are needed to confirm the optimal duration of T in patients with low-risk disease.