Summary Background Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting ...fluorouracil with the oral prodrug capecitabine. Methods This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II–III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m2 days 1–14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 days 1–38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m2 days 1–5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m2 daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m2 daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m2 per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m2 days 1–5 and 29–33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m2 for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov , number NCT01500993. Findings Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41–72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% 95% CI 67–82 vs 67% 58–74; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68–81) in the capecitabine group and 67% (59–73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 6% in the capecitabine group vs 14 7% in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 19% vs 54 28%; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 53% patients in the capecitabine group vs 85 44% in the fluorouracil group; grade 3–4: 17 9% vs four 2%). Patients in the capecitabine group had more hand-foot skin reactions (62 31% any grade, four 2% grade 3–4 vs three 2% any grade, no grade 3–4), fatigue (55 28% any grade, no grade 3–4 vs 29 15%, two 1% grade 3–4), and proctitis (31 16% any grade, one <1% grade 3–4 vs ten 5%, one <1% grade 3–4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 35% any grade, 16 8% grade 3–4 vs 50 25% any grade, three 2% grade 3–4). Interpretation Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer. Funding Roche Pharma AG (Grenzach-Wyhlen, Germany).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Extracorporeal shock wave therapy may enhance revascularization and repair of healing soft tissue. Methods Between January 2006, and September 2007, 28 patients with acute traumatic wounds ...and burns requiring skin grafting were randomly assigned in a 1:1 fashion to receive standard topical therapy (nonadherent silicone mesh Mepitel, Mölnlycke Health Care and antiseptic gel polyhexanide/octenidine) to graft donor sites with (n = 13) or without (n = 15) defocused extracorporeal shock wave therapy (ESWT, 100 impulses/cm2 at 0.1 mJ/mm2 ) applied once to the donor site, immediately after skin harvest. The randomization sequence was computer generated, and the patients were blinded to treatment allocation. The primary endpoint was time to complete donor site epithelialization and was determined by an independent blinded observer. Results Statistical tests indicated no unbalanced distribution of subject characteristics across the two study groups. Mean times to complete graft donor site epithelialization for patients who did and did not undergo ESWT were 13.9 ± 2.0 days and 16.7 ± 2.0 days, respectively (p = 0.0001). Conclusions For centers that apply nonadherent gauze dressings and topical antiseptics to skin graft donor sites, application of a single defocused shock wave treatment immediately after skin graft harvest can significantly accelerate donor site epithelialization.
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GEOZS, NUK, OILJ, SBJE, UL, UPUK
Highlights • The rate of rare sellar lesions is higher than expected. • Radiological findings and distinct clinical features facilitate differential diagnosis. • Individualised diagnostic and ...treatment regimen are mandatory
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile ...enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis. Objectives This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome. Methods This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation. Results During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval CI: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively. Conclusions PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In postinfarction left ventricular aneurysm, abnormal geometry and desynchronized wall motion may cause a highly inefficient pump function. The traditional endoventricular patch plasty according to ...the Dor technique might result in a truncated and restrictive left ventricular cavity in small adults. We report a modified technique of left ventricular anteroapical aneurysm repair by using a semispherical reshaping patch to restore the left ventricular geometry.
Abstract Background Endothelial dysfunction plays a major role in cardiovascular diseases, including acute myocardial infarction (AMI). However, its quantification has not been available as a ...clinical tool. Methods In a prospective international multicentre study, we analyzed the diagnostic and prognostic utility of endothelial dysfunction as quantified by C-terminal proendothelin-1 (CT-proET-1) in 658 consecutive patients presenting with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long-term for mortality. Results The adjudicated final diagnosis was AMI in 145 patients (22%). The diagnostic performance of CT-proET-1 for AMI was moderate; its area under the receiver operating characteristic (ROC) curve amounted to 0.66 (95% confidence interval CI, 0.61-0.72; P < 0.001). There was no significant increase in the AUC when CT-proET-1 was added to either cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT). Seventy four percent of patients who died during the first 24 months (n = 50) were in the fourth quartile of the CT-proET-1 presentation value (>82 pmol/L). The prognostic accuracy of CT-proET-1 regarding mortality was tantamount to that of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and outperformed cTnT and hs-cTnT both in patients with AMI and in patients without acute coronary syndrome. CT-proET-1 at presentation yielded high prognostic accuracy that was similar to that of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score could be significantly improved by adding CT-proET-1 (integrated discriminatory improvement IDI of 0.074 P = 0.004). Conclusions Use of CT-proET-1 improves risk stratification of unselected patients with suspected AMI. CT-proET-1 did not provide additional diagnostic value.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives The aim of this study was to determine the prognostic utility of midregion proadrenomedullin (MR-proADM) in all patients, cardiac and noncardiac, presenting with acute shortness of breath. ...Background The recently published BACH (Biomarkers in Acute Heart Failure) study demonstrated that MR-proADM had superior accuracy for predicting 90-day mortality compared with B-type natriuretic peptide (area under the curve: 0.674 vs. 0.606, respectively, p < 0.001) in acute heart failure. Methods The BACH trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. Using this dataset, the prognostic accuracy of MR-proADM was evaluated in all patients enrolled for predicting 90-day mortality with respect to other biomarkers, the added value in addition to clinical variables, as well as the added value of additional measurements during hospital admission. Results Compared with B-type natriuretic peptide or troponin, MR-proADM was superior for predicting 90-day all-cause mortality in patients presenting with acute dyspnea (c index = 0.755, p < 0.0001). Furthermore, MR-proADM added significantly to all clinical variables (all adjusted hazard ratios: >3.28), and it was also superior to all other biomarkers. MR-proADM added significantly to the best clinical model (bootstrap-corrected c index increase: 0.775 to 0.807; adjusted standardized hazard ratio: 2.59; 95% confidence interval: 1.91 to 3.50; p < 0.0001). Within the model, MR-proADM was the biggest contributor to the predictive performance, with a net reclassification improvement of 8.9%. Serial evaluation of MR-proADM performed in patients admitted provided a significant added value compared with a model with admission values only (p = 0.0005). More than one-third of patients originally at high risk could be identified by the biomarker evaluation at discharge as low-risk patients. Conclusions MR-proADM identifies patients with high 90-day mortality and adds prognostic value to natriuretic peptides in patients presenting with acute shortness of breath. Serial measurement of this biomarker may also prove useful for monitoring, although further studies will be required. (Biomarkers in Acute Heart Failure BACH; NCT00537628 )
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives The purpose of this study was to assess the impact of atrial fibrillation (AF) on the performance of mid-region amino terminal pro-atrial natriuretic peptide (MR-proANP) in comparison with ...the B-type peptides (BNP and NT-proBNP) for diagnosis of acute heart failure (HF) in dyspneic patients. Background The effects of AF on the diagnostic and prognostic performance of MR-proANP in comparison with the B type natriuretic peptides have not been previously reported. Methods A total of 1,445 patients attending the emergency department with acute dyspnea had measurements taken of MR-proANP, BNP, and NT-proBNP values on enrollment to the BACH trial and were grouped according to presence or absence of AF and HF. Results AF was present in 242 patients. Plasma concentrations of all three peptides were lowest in those with neither AF nor HF and AF without HF was associated with markedly increased levels (p < 0.00001). HF with or without AF was associated with a significant further increment (p < 0.00001 for all three markers). Areas under receiver operator characteristic curves (AUCs) for discrimination of acute HF were similar and powerful for all peptides without AF (0.893 to 0.912; all p < 0.001) with substantial and similar reductions (0.701 to 0.757) in the presence of AF. All 3 peptides were independently prognostic but there was no interaction between any peptide and AF for prediction of all-cause mortality. Conclusions AF is associated with increased plasma natriuretic peptide (MR-proANP, BNP and NT-proBNP) levels in the absence of HF. The diagnostic performance of all three peptides is impaired by AF. This warrants consideration of adjusted peptide thresholds for diagnostic use in AF and mandates the continued search for markers free of confounding by AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is currently no promising interventional solution for in-stent stenosis in previously stented bifurcation lesions, even with drug-eluting stents. Rather than being restricted to stent struts, ...catheter-based local antiproliferative therapy offers the advantage of homogenous drug transfer to the whole vessel wall, and thereby allows for intracoronary pharmacotherapy without adding additional layers of metal into an already stented lesion. The newly developed GENIE catheter (Acrostak Corp, Switzerland), applied in the kissing balloon technique, allows for delivery of liquid paclitaxel into whole bifurcation lesions without repeat stent implantation. After conventional percutaneous transluminal coronary angioplasty, local delivery of paclitaxel using two GENIE catheters in the kissing balloon technique was performed in three patients (left anterior descending, left circumflex and right coronary arteries) with highly symptomatic in-stent bifurcation stenoses. The intervention was feasible and safe in all coronary arteries. Final angiography and control angiography after six months showed good results. No major adverse cardiac events occurred 30 days and six months after intervention. The patients, who represent a group at high risk of recurrent instent restenosis, remained asymptomatic since the local drug delivery. They did not require insertion of a drug-eluting stent or crossover to coronary artery bypass surgery. In conclusion, this new treatment strategy proved to be safe and effective in this first human experience and offers a promising alternative to surgery or implantation of additional stents in these patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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