This study sought to compare long-term survival after off- and on-pump coronary artery bypass grafting (CABG).
Although several large-scale clinical trials have compared the surgical outcomes between ...off- and on-pump CABG, the long-term survival has not been compared between the 2 surgical strategies in a reasonably sized cohort.
We evaluated long-term survival data in 5,203 patients (age 62.9 ± 9.1 years, 1,340 females) who underwent elective isolated CABG (off-pump: n = 2,333; on-pump: n = 2,870) from 1989 through 2012. Vital statuses were validated using the Korean National Registry of Vital Statistics. Long-term survival was compared with the use of propensity scores and inverse probability weighting to adjust selection bias.
Patients undergoing on-pump CABG had a higher number of distal anastomoses than those undergoing off-pump CABG (3.7 ± 1.2 vs. 3.0 ± 1.1; p < 0.001). Survival data were complete in 5,167 patients (99.3%), with a median follow-up duration of 6.4 years (interquartile range: 3.7 to 10.5 years; maximum 23.1 years). During follow-up, 1,181 patients (22.7%) died. After adjustment, both groups of patients showed a similar risk of death at 30 days (odds ratio: 0.70; 95% confidence interval CI: 0.35 to 1.40; p = 0.31) and up to 1 year (hazard ratio HR: 1.11; 95% CI: 0.74 to 1.65; p = 0.62). For overall mortality, however, patients undergoing off-pump CABG were at a significantly higher risk of death (HR: 1.43; 95% CI: 1.19 to 1.71; p < 0.0001) compared with those undergoing on-pump CABG. In subgroup analyses, on-pump CABG conferred survival benefits in most demographic, clinical, and anatomic subgroups compared with off-pump CABG.
In patients undergoing elective isolated CABG, on-pump strategy conferred a long-term survival advantage compared with off-pump strategy.
In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related ...signaling pathways, four different microarray experiments were reanalyzed before radiotherapy.
Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1) was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2). Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM) and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway.
Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that integrin signaling via adhesion molecules could be a target for radiosensitization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Heparin is the main anticoagulant used during extracorporeal membrane oxygenation (ECMO) support. Nafamostat mesilate, a synthetic serine protease inhibitor, has seen increased use as a ...substitute for heparin in patients undergoing ECMO because of its short half-life. We aimed to compare these 2 anticoagulants with respect to bleeding and thromboembolic complications during ECMO support. Methods From January 2005 to November 2014, 320 patients who underwent venoarterial ECMO support were retrospectively reviewed. The primary end point was thromboembolic or bleeding complications during ECMO support. Propensity score matching was used to compare the 2 groups. Univariate and multivariate analyses were performed for risk factor analysis. Results The mean duration of support was 111 ± 101 hours in all the study participants. Among them, ECMO was weaned successfully in 59 (48.4%) patients. Heparin was used in 201 patients, whereas nafamostat was used in 119 patients. Bleeding complications were significantly higher in the nafamostat group in both the unmatched and matched cohorts ( p = 0.03), whereas thromboembolic events were comparable. Regarding risk factor analysis, nafamostat use was the only significant risk factor for bleeding (hazard ratio HR, 2.4; 95% confidence interval CI, 1.07–5.36; p = 0.032), whereas only old age was a risk factor for thromboembolic complications (HR, 1.06; 95% CI, 1.01–1.11; p = 0.03) regardless of the type of anticoagulant used. Conclusions Nafamostat mesilate was found to increase the bleeding risk in patients receiving venoarterial ECMO. Regarding thromboembolic complications, there was no significant difference between heparin and nafamostat. Only old age increased the thromboembolic risk.
More evidence is required with respect to the comparative effectiveness of percutaneous coronary intervention (PCI) with second-generation drug-eluting stents (DESs) versus coronary artery bypass ...grafting (CABG) in contemporary clinical practice. This prospective observational registry–based study compared the outcomes of 6,647 patients with multivessel disease who underwent PCI with second-generation DES (n = 3,858) or CABG (n = 2,789) between January 2006 and June 2018 and for whom follow-up data were available for at least 2 to 13 years (median 4.8). The primary outcome was a composite of death, spontaneous myocardial infarction, or stroke. Baseline differences were adjusted using propensity scores and inverse probability weighting. In the overall cohort, there were no significant between-group differences in the adjusted risks for the primary composite outcome (hazard ratio HR for PCI vs CABG 1.03, 95% confidence interval CI 0.86 to 1.25, p = 0.73) and all-cause mortality (HR 0.95, 95% CI 0.76 to 1.20, p = 0.68). This relative treatment effect on the primary outcome was similar in patients with diabetes (HR 1.15, 95% CI 0.91 to 1.46, p = 0.25) and without diabetes (HR 0.95, 95% CI 0.73 to 1.22, p = 0.67) (p for interaction = 0.24). The adjusted risk of the primary outcome was significantly greater after PCI than after CABG in patients with left main involvement (HR 1.39, 95% CI 1.01 to 1.90, p = 0.044), but not in those without left main involvement (HR 0.94, 95% CI 0.76 to 1.16, p = 0.56) (p = 0.03 for interaction). In this prospective real-world long-term registry, we observed that the risk for the primary composite of death, spontaneous myocardial infarction, or stroke was similar between PCI with contemporary DES and CABG.
Background
Nivolumab showed improvement in overall survival (OS) in ATTRACTION-2, the first phase 3 study in patients with gastric/gastroesophageal junction (G/GEJ) cancer treated with ≥ 2 ...chemotherapy regimens. The 2-year follow-up results of ATTRACTION-2 are presented herein.
Methods
ATTRACTION-2 was a randomized, double-blind, placebo-controlled, phase 3 trial (49 sites; Japan, South Korea, and Taiwan). The median (min–max) follow-up period was 27.3 (24.1–36.3) months. The primary endpoint was OS. A subanalysis of OS was performed based on best overall response and tumor-programmed death ligand-1 (PD-L1) expression status.
Results
Overall, 493 of 601 screened patients were randomized (2:1) to receive nivolumab (330) or placebo (163). OS (median 95% confidence interval; CI) was significantly longer in the nivolumab group (5.26 4.60–6.37 vs 4.14 3.42–4.86 months in placebo group) at the 2-year follow-up (hazard ratio 95% CI, 0.62 0.51–0.76;
P
< 0.0001). A higher OS rate was observed in the nivolumab vs placebo group at 1 (27.3% vs 11.6%) and 2 years (10.6% vs 3.2%). The OS benefit was observed regardless of tumor PD-L1 expression. Among patients with a complete or partial response (CR or PR) in the nivolumab group, the median OS (95% CI) was 26.6 (21.65—not applicable) months; the OS rates at 1 and 2 years were 87.1% and 61.3%, respectively. No new safety signals were identified.
Conclusions
Nivolumab treatment resulted in clinically meaningful long-term improvements in OS in patients with previously treated G/GEJ cancer. The long-term survival benefit of nivolumab was most evident in patients with a CR or PR.
Abstract
In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for ...unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval CI: 61.4–88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival.
Post hoc
analyses of pretreatment tumor specimens via targeted sequencing indicated that
ERBB2
amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.
Purpose
Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association ...between CK2 activation and paclitaxel resistance in a gastric cancer (GC).
Experimental design
CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model.
Results
Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%,
p
= 0.017) and shorter progression-free survival (2.8 vs. 4.8 months,
p
= 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities.
Conclusions
These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
Objectives We aimed to define the relationship between cerebral atherosclerosis and stroke after coronary artery bypass grafting (CABG). Background Although cerebral atherosclerosis may play a ...crucial role in the advent of post-CABG stroke, only extracranial carotid artery disease has been extensively studied, and the effects of atherosclerosis on the mechanisms underlying post-CABG stroke remain unclear. Methods Pre-operative magnetic resonance angiography was performed on 1,367 consecutive CABG patients to assess intracranial and extracranial cerebral atherosclerosis. Disease severity was evaluated by atherosclerosis score, as determined by the number of steno-occlusions of cerebral arteries and the degree thereof. Post-CABG strokes (within 14 days) were classified as atherosclerotic (strokes attributable to pre-defined atherosclerosis) or other (strokes caused by other mechanisms). Associations between post-CABG stroke and each type of atherosclerotic disease (extracranial carotid artery disease, intracranial, extracranial, or extracranial and/or intracranial cerebral atherosclerosis), differentiated according to the involved arteries, were analyzed. Results Stroke occurred in 33 patients, and the atherosclerosis score was independently associated with stroke development (odds ratio: 1.35; 95% confidence interval: 1.16 to 1.56). Atherosclerotic stroke was defined in 15 (45%), and constituted >40% of both immediate (within 24 h) and delayed strokes. Intracranial, extracranial, and extracranial and/or intracranial cerebral atherosclerosis were significantly associated with stroke. Conclusions Cerebral atherosclerosis was closely related to the occurrence of post-CABG stroke, being both an independent risk factor for and the cause of a significant proportion of strokes. Pre-operative evaluation of intracranial and extracranial cerebral arteries, apart from the extracranial carotid artery, may be useful to predict the likelihood of post-CABG stroke.
Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel. This single arm, multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM in ...patients with histologically confirmed metastatic breast cancer (MBC). Forty-one women received Genexol-PM by intravenous infusion at 300 mg/m
2
over 3 h every 3 weeks without premedication until disease progression or intolerability. A total of 331 chemotherapy cycles were administered, with a median of 8 cycles per patient (range, 1–16). Overall response rate was 58.5% (95% CI: 43.5–72.3) with 5 complete responses and 19 partial responses. Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5–73.7), and two responses were reported in four patients treated in the second-line setting for their metastatic disease. The median time to progression (TTP) for all patients was 9.0 months (range, 1.0–17.0+ months). Grade 3 non-hematologic toxicities included sensory peripheral neuropathy (51.2%), and myalgia (2.4%). Eight patients (19.5%) experienced hypersensitivity reactions, with grade 3 in two patients. Hematologic toxicities were grade 3 and 4 neutropenia (51.2 and 17.1%, respectively), and grade 1 and 2 thrombocytopenia (22.0%). Notably, no febrile neutropenia was observed. Genexol-PM appears a promising new paclitaxel in view of significant efficacies. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted.
Sarcopenia, known as physical frailty, is highly prevalent in older patients and is related to adverse outcomes after cardiac surgery. However whether sarcopenia assessment can reclassify an ...individual patient’s risk, which is estimated by Society of Thoracic Surgeons–predicted risk of mortality scores in patients who undergo surgical aortic valve replacement, is unclear.
This retrospective, single-center, cohort study comprised 874 patients aged ≥65 years who underwent surgical aortic valve replacement between 2009 and 2016. Total skeletal muscle area was calculated using height squared (cm2/m2) and was measured by preoperative computed tomography at the third lumbar vertebra inferior border using machine learning–based analysis. Sex-specific Z-scores were calculated, and patients in the lowest Z-score tertile were considered to have sarcopenia. The primary endpoint was 30-day mortality, and secondary endpoints were in-hospital events, 1-year mortality, and long-term mortality.
Thirty-day mortality, 30-day in-hospital events, and 1-year mortality rates were 4.7%, 17.6%, and 8.0%, respectively. As the Z-score decreased, the odds of an early adverse event showed a stepwise increase. Sarcopenia was independently associated with higher 30-day mortality, 30-day in-hospital events, and 1-year mortality. Reclassification analyses showed improvements in the ability to predict early adverse events after adding the Z-scores over and above The Society of Thoracic Surgeons–predicted risk of mortality scores (all P < .005).
Sarcopenic patients had significantly higher risks of early adverse events and long-term mortality after undergoing surgical aortic valve replacement than nonsarcopenic patients. Sarcopenia determined by preoperative computed tomography can enhance the prediction of postoperative outcome risk.
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