There is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer. We initially conducted a randomized, phase 2 study involving 86 patients to ...compare cisplatin plus gemcitabine with gemcitabine alone. After we found an improvement in progression-free survival, the trial was extended to the phase 3 trial reported here.
We randomly assigned 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter on days 1 and 8, every 3 weeks for eight cycles) or gemcitabine alone (1000 mg per square meter on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks. The primary end point was overall survival.
After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin-gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P<0.001). The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group (P<0.001). In addition, the rate of tumor control among patients in the cisplatin-gemcitabine group was significantly increased (81.4% vs. 71.8%, P=0.049). Adverse events were similar in the two groups, with the exception of more neutropenia in the cisplatin-gemcitabine group; the number of neutropenia-associated infections was similar in the two groups.
As compared with gemcitabine alone, cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer. (ClinicalTrials.gov number, NCT00262769.)
Cardiovascular magnetic resonance is the gold-standard technique for the assessment of ventricular function. Although left ventricular volumes and ejection fraction are strong predictors of outcome ...in dilated cardiomyopathy (DCM), there are limited data regarding the prognostic significance of right ventricular (RV) systolic dysfunction (RVSD). We investigated whether cardiovascular magnetic resonance assessment of RV function has prognostic value in DCM.
We prospectively studied 250 consecutive DCM patients with the use of cardiovascular magnetic resonance. RVSD, defined by RV ejection fraction≤45%, was present in 86 (34%) patients. During a median follow-up period of 6.8 years, there were 52 deaths, and 7 patients underwent cardiac transplantation. The primary end point of all-cause mortality or cardiac transplantation was reached by 42 of 86 patients with RVSD and 17 of 164 patients without RVSD (49% versus 10%; hazard ratio, 5.90; 95% confidence interval CI, 3.35-10.37; P<0.001). On multivariable analysis, RVSD remained a significant independent predictor of the primary end point (hazard ratio, 3.90; 95% CI, 2.16-7.04; P<0.001), as well as secondary outcomes of cardiovascular mortality or cardiac transplantation (hazard ratio, 3.35; 95% CI, 1.76-6.39; P<0.001), and heart failure death, heart failure hospitalization, or cardiac transplantation (hazard ratio, 2.70; 95% CI, 1.32-5.51; P=0.006). Assessment of RVSD improved risk stratification for all-cause mortality or cardiac transplantation (net reclassification improvement, 0.31; 95% CI 0.10-0.53; P=0.001).
RVSD is a powerful, independent predictor of transplant-free survival and adverse heart failure outcomes in DCM. Cardiovascular magnetic resonance assessment of RV function is important in the evaluation and risk stratification of DCM patients.
On T2 magnetic resonance and cardiac iron Carpenter, John-Paul; He, Taigang; Kirk, Paul ...
Circulation (New York, N.Y.),
04/2011, Letnik:
123, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically ...via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited.
Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean ± SD global myocardial iron causing severe heart failure in 10 patients was 5.98 ± 2.42 mg/g dry weight (range, 3.19 to 9.50 mg/g), but in 1 outlier case of heart failure was 25.9 mg/g dry weight. Myocardial lnR2* was strongly linearly correlated with lnFe (R²=0.910, P<0.001), leading to Fe=45.0×(T2*)⁻¹·²² for the clinical calibration equation with Fe in milligrams per gram dry weight and T2* in milliseconds. Midventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron.
These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration. The iron values are of considerable interest in terms of the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in vivo by cardiovascular magnetic resonance of the midseptum.
Objectives We investigated the significance of fibrosis detected by late gadolinium enhancement cardiovascular magnetic resonance for the prediction of major clinical events in hypertrophic ...cardiomyopathy (HCM). Background The role of myocardial fibrosis in the prediction of sudden death and heart failure in HCM is unclear with a lack of prospective data. Methods We assessed the presence and amount of myocardial fibrosis in HCM patients and prospectively followed them for the development of morbidity and mortality in patients over 3.1 ± 1.7 years. Results Of 217 consecutive HCM patients, 136 (63%) showed fibrosis. Thirty-four of the 136 patients (25%) in the fibrosis group but only 6 of 81 (7.4%) patients without fibrosis reached the combined primary end point of cardiovascular death, unplanned cardiovascular admission, sustained ventricular tachycardia or ventricular fibrillation, or appropriate implantable cardioverter-defibrillator discharge (hazard ratio HR: 3.4, p = 0.006). In the fibrosis group, overall risk increased with the extent of fibrosis (HR: 1.18/5% increase, p = 0.008). The risk of unplanned heart failure admissions, deterioration to New York Heart Association functional class III or IV, or heart failure-related death was greater in the fibrosis group (HR: 2.5, p = 0.021), and this risk increased as the extent of fibrosis increased (HR: 1.16/5% increase, p = 0.017). All relationships remained significant after multivariate analysis. The extent of fibrosis and nonsustained ventricular tachycardia were univariate predictors for arrhythmic end points (sustained ventricular tachycardia or ventricular fibrillation, appropriate implantable cardioverter-defibrillator discharge, sudden cardiac death) (HR: 1.30, p = 0.014). Nonsustained ventricular tachycardia remained an independent predictor of arrhythmic end points after multivariate analysis, but the extent of fibrosis did not. Conclusions In patients with HCM, myocardial fibrosis as measured by late gadolinium enhancement cardiovascular magnetic resonance is an independent predictor of adverse outcome. (The Prognostic Significance of Fibrosis Detection in Cardiomyopathy; NCT00930735 )
Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients With Symptomatic Chronic Heart Failure and Iron Deficiency: FERRIC-HF: A Randomized, Controlled, ...Observer-Blinded Trial Darlington O. Okonko, Agnieszka Grzeslo, Tomasz Witkowski, Amit K. J. Mandal, Robert M. Slater, Michael Roughton, Gabor Foldes, Thomas Thum, Jacek Majda, Waldemar Banasiak, Constantinos G. Missouris, Philip A. Poole-Wilson, Stefan D. Anker, Piotr Ponikowski The FERRIC-HF (Ferric Iron Sucrose in Heart Failure) trial randomized 35 (18 anemic and 17 nonanemic) patients with symptomatic chronic heart failure and abnormal iron metabolism to 16 weeks of intravenous iron sucrose or no treatment. Iron therapy was well tolerated and improved exercise capacity and symptoms. Benefits were more evident in anemic patients. Increments in peak oxygen consumption related only to increments in transferrin saturation, a putative marker of circulating iron status. Such outcomes, if replicated in larger and longer studies, suggest that iron may be a legitimate therapeutic treatment in selected patients with chronic heart failure and anemia and possibly even in those without anemia.
Left atrial (LA) size is related to cardiovascular morbidity and mortality. Cardiovascular magnetic resonance (CMR) provides high quality images of the left atrium with high temporal resolution ...steady state free precession (SSFP) cine sequences. We used SSFP cines to define normal ranges for LA volumes and dimensions relative to gender, age and body surface area (BSA), and examine the relative value of 2D atrial imaging techniques in patients.For definition of normal ranges of LA volume we studied 120 healthy subjects after careful exclusion of cardiovascular abnormality (60 men, 60 women; 20 subjects per age decile from 20 to 80 years). Data were generated from 3-dimensional modeling, including tracking of the atrioventricular ring motion and time-volume curves analysis. For definition of the best 2D images-derived predictors of LA enlargement, we studied 120 patients (60 men, 60 women; age range 20 to 80 years) with a clinical indication for CMR.
In the healthy subjects, age was associated with LA 4-chamber transverse and 3-chamber anteroposterior diameters, but not with LA volume. Gender was an independent predictor of most absolute LA dimensions and volume, but following normalization to BSA, some associations became non-significant. CMR normal ranges were modeled and are tabled for clinical use with normalization, where appropriate, for BSA and gender and display of parameter variation with age. The best 2D predictors of LA volume were the 2-chamber area and 3-chamber area (both r = 0.90, p < 0.001).
These CMR data show that LA dimensions and volume in healthy, individuals vary significantly by BSA, with lesser effects of age and gender.
Prenatal diagnosis of aortic coarctation suffers from high false-negative rates at screening and poor specificity.
This retrospective study tested the applicability of published aortic arch and ...ductal Z scores (measured just before the descending aorta in the 3-vessel and tracheal view) and their ratio on 200 consecutive normal controls at a median of 22+/-0 gestational weeks (range, 15+/-4 to 38+/-4 weeks). Second, this study tested the ability of serial Z scores to distinguish fetuses with coarctation within a cohort with ventricular and/or great arterial disproportion detected at screening or fetal echocardiography. Third, it evaluated the diagnostic significance of associated cardiac lesions, coarctation shelf, and isthmal flow disturbance. We studied 44 fetuses with suspected coarctation at 24+/-0 weeks (range, 17+/-3 to 37+/-4 weeks). Receiver-operating characteristic curves were created. Logistic regression tested the association between z scores, additional cardiac diagnoses, and coarctation. Good separation was found of isthmal Z scores for cases requiring surgery from controls and false-positive cases, and receiver-operating characteristic curves showed an excellent area under the curve for isthmal Z score (0.963) and isthmal-to-ductal ratio (0.969). Serial isthmal Z scores improved to >-2 in suspected cases with normal outcomes; those requiring surveillance or surgery remained <-2. Minor lesions did not increase the diagnostic specificity of coarctation, but isthmal flow disturbance increased the odds ratio of true coarctation versus arch hypoplasia 16-fold.
Isthmal Z scores and isthmal-to-ductal ratio are sensitive indicators of fetal coarctation. Serial measurements and abnormal isthmal flow patterns improve diagnostic specificity and may reduce false positives.
The Cancer Research UK "Over 50s" trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years.
Between 1987 and 1997, 3,449 ...patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were randomly assigned to either stop or continue for an additional 3 years, if they were alive and recurrence free. Data on recurrences, new tumors, deaths, and cardiovascular events were obtained (April 2010).
There were 1,103 recurrences, 755 deaths as a result of breast cancer, 621 cardiovascular (CV) events, and 236 deaths as a result of CV events. Fifteen years after starting treatment, for every 100 women who received tamoxifen for 5 years, 5.8 fewer experienced recurrence, compared with those who received tamoxifen for 2 years. The risk of contralateral breast cancer was significantly reduced (hazard ratio, 0.70; 95% CI, 0.48 to 1.00). Among women age 50 to 59 years, there was a 35% reduction in CV events (P = .005) and 59% reduction in death as a result of a CV event (P = .02); in older women, the effect was much smaller and not statistically significant.
Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment. It also lowers the risk of CV disease and death as a result of a CV event, particularly among those age 50 to 59 years. Women should therefore be encouraged to complete the full course. Although aromatase inhibitors improve disease-free survival, tamoxifen remains a cheap and highly effective alternative, particularly in developing countries.
Objectives
Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long‐acting pasireotide during a ...long‐term extension study in patients with CD.
Design
Open‐label extension to a 12‐month Phase III study of long‐acting pasireotide in CD (N = 150; NCT01374906).
Patients
Patients with mean urinary free cortisol (mUFC) ≤ upper limit of normal (ULN) or receiving clinical benefit at core study end could continue long‐acting pasireotide during the extension.
Results
Eighty‐one of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received ≥ 12 months’ treatment during the extension and could transit to a separate pasireotide safety study). mUFC was ≤ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median late‐night salivary cortisol was 2.6 × ULN at core baseline and 1.3 × ULN at M36. Clinical improvements were sustained over time. Forty‐two (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemia‐related AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA1c) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixty‐six (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA1c ≥ 6.5%, FPG ≥ 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment.
Conclusions
Long‐acting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective long‐term therapy for CD.
Cardiac involvement is common in amyloidosis and associated with a variably adverse outcome. We have previously shown that cardiovascular magnetic resonance (CMR) can assess deposition of amyloid ...protein in the myocardial interstitium. In this study we assessed the prognostic value of late gadolinium enhancement (LGE) and gadolinium kinetics in cardiac amyloidosis in a prospective longitudinal study.
The pre-defined study end point was all-cause mortality. We prospectively followed a cohort of 29 patients with proven cardiac amyloidosis. All patients underwent biopsy, 2D-echocardiography and Doppler studies, 123I-SAP scintigraphy, serum NT pro BNP assay, and CMR with a T1 mapping method and late gadolinium enhancement (LGE).
Patients with were followed for a median of 623 days (IQ range 221, 1436), during which 17 (58%) patients died. The presence of myocardial LGE by itself was not a significant predictor of mortality. However, death was predicted by gadolinium kinetics, with the 2 minute post-gadolinium intramyocardial T1 difference between subepicardium and subendocardium predicting mortality with 85% accuracy at a threshold value of 23 ms (the lower the difference the worse the prognosis). Intramyocardial T1 gradient was a better predictor of survival than FLC response to chemotherapy (Kaplan Meier analysis P = 0.049) or diastolic function (Kaplan-Meier analysis P = 0.205).
In cardiac amyloidosis, CMR provides unique information relating to risk of mortality based on gadolinium kinetics which reflects the severity of the cardiac amyloid burden.
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