Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubicin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. PATIENTS AND METHODS: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (I.V.) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in at least two patients per dose level of paclitaxel (175 up to 225 mg/m2). RESULTS: The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 micromol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 +/- 9.4 to 37.9 +/- 7.5 ng/mL in patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the threshold level of 0.05 micromol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92%) were observed, and nine (18%) of these were complete. CONCLUSION: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.

Activity and safety of epirubicin plus paclitaxel in advanced breast cancer.

We performed a dose-escalation study to evaluate the maximum tolerated dose (MTD) of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus a fixed dose of epirubicin. Epirubicin was administered as a 90 mg/m2 bolus immediately followed by a 3-hour infusion of paclitaxel starting at 135 mg/m2 and escalating by 20mg/m2 for each triplet of patients as long as no dose-limiting toxicity had occurred; courses were repeated every 3 weeks. The MTD was defined as that at which any of the following toxicities occurred in at least two of six patients: absolute neutrophil count less than 500/microliter for more that 7 days or less than 100/microliter for more than 3 days; any episode of febrile neutropenia requiring intravenous antibiotics and hospitalization; grade 4 thrombocytopenia requiring platelet transfusion; failure to recover absolute neutrophil count to > or = 1,500/microliter and/or platelets to > or = 100,000/microliter by day 28; and any grade > or = 3 nonhematologic toxicity. Two MTDs were defined: the first without granulocyte colony-stimulating factor (MTD 1) and the second with granulocyte colony-stimulating factor given either to accelerate recovery of grade 4 neutropenia lasting more than 72 hours or immediately in case of febrile neutropenia (MTD 2); granulocyte colony-stimulating factor was never used prophylactically. To date, 22 patients have been entered into the study; the median patient age was 55 years (age range, 30 to 66 years). Nineteen (86%) patients had received adjuvant chemotherapy that included anthracyclines in 12 cases (55%). The viscera were the dominant sites of disease in 55% of patients. Median baseline ventricular ejection fraction was 58% (range, 53% to 67%). Short-lasting grade 4 neutropenia occurred in 61% of courses; however, only four episodes of febrile neutropenia were recorded. Grade 4 thrombocytopenia was reported in 8% and grade 3 anemia in 3% of courses; four patients experienced peripheral neuropathy (three patients grade 1, one patient grade 2); complete alopecia was universal. The cardiac effects of the combination were surprisingly low: median ejection fraction at study entry was 58%, and after a cumulative dose 1,080 mg/m2 it was 56%. Three complete responses and 12 partial responses have been documented for an overall response rate of 83.3% (95% confidence interval, 58% to 96%). In conclusion, neutropenia is the most frequent toxicity of this novel combination. However, the MTD has not yet been reached. The combination of epirubicin plus paclitaxel is highly active, and no signs of cumulative myocardiopathy have been observed.

High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast cancer: a dose finding study.

Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4, epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to 732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete cross-resistance between the two drugs.

Cardiopulmonary exercise testing in patients with 21mm St. Jude Medical aortic prosthesis.

BACKGROUND AND AIM OF THE STUDY: Small-sized prostheses may be associated with high transprosthetic gradients, particularly in patients with a body surface area (BSA) >1.70m2, affecting left ventricular mass regression, symptom improvement and long-term survival. However, the influence of such gradients on exercise tolerance has not been clearly defined. The study aim was to verify the utility of cardiopulmonary exercise testing (CPX) in detecting patient-prosthesis mismatch, and to identify the clinical and echocardiographic data that predict exercise tolerance at CPX in patients with a 21mm St. Jude Medical (SJM) aortic prosthesis. METHODS: Twenty patients (one male, 19 females; mean age 66 +/- 9 years) with a 21 mm SJM prosthesis were evaluated by means of 2D echocardiography and CPX at 36 +/- 10 months after operation. Patients were divided into groups on the basis of a BSA of <1.70 m2 (group 1, n = 12) or > or =1.70 m2 (group 2, n = 8). RESULTS: At echocardiography, left ventricular mass reduction was 16 +/- 10% versus 9 +/- 6% in groups 1 and 2, respectively, mean gradient (MG) was 15 +/- 6 versus 17 +/- 4 mmHg (p = NS), effective orifice area index (EOAi) 0.86 +/- 0.10 versus 0.79 +/- 0.09 cm2/m2 (p = 0.05). At CPX, group 2 patients showed a significantly lower exercise duration (p = 0.02), maximum workload (p = 0.02), peak O2 uptake (p = 0.01), anaerobic threshold (AT) (p = 0.03), ventilatory equivalent for CO2 at AT (p = 0.007), and O2 cost of work (p = 0.03). Group 1 patients showed a ventilatory origin for their effort dyspnea, while group 2 patients showed a significant circulatory component. At multivariate analysis, BSA, age, EOAi and MG were independent predictors of CPX results. CONCLUSIONS: In patients with a 21 mm aortic SJM prosthesis and a BSA > or =1.70m2, CPX allows detection of patient-prosthesis mismatch, in terms of impaired exercise tolerance due to circulatory causes. CPX results can be anticipated on the basis of the patient's BSA, age, EOAi and MG. In these patients, technical solutions allowing implantation of a larger prosthesis should be considered whenever an active lifestyle is anticipated after aortic valve replacement.

Relation between dobutamine trans-thoracic echocardiography, 99Tcm-MIBI and 18FDG uptake in chronic coronary artery disease.

The relationships between rest conditions of myocardial asynergy, response to dobutamine administration, perfusion and glucose metabolism were examined in 12 patients with chronic coronary artery disease and left ventricular dysfunction. We evaluated (1) rest and stress myocardial perfusion by 99Tcm-methoxyisobutylisonitrile (MIBI) and single photon emission tomography (SPET), (2) rest myocardial segmental wall motion by trans-thoracic echocardiography and low-dose dobutamine, and (3) myocardial metabolism by [18F]-2-fluoro-2-deoxy-D-glucose (18-FDG) and positron emission tomography (PET), in the fasting state. The analysis was carried out on 16 left ventricular myocardial segments. The SPET studies were analysed semi-quantitatively by normalization to the peak activity. Wall motion was assessed by a visual score. An 18FDG index was determined as the tissue/blood pool radioactivity ratio in each segment. The results showed: (1) remarkably good agreement between the number of dobutamine responsive segments and 18FDG positive segments among those that were only moderately hypoperfused and hypokinetic; (2) a smaller number of dobutamine responsive segments than 18FDG positive segments among those that were hypoperfused and akinetic; and (3) the presence of 18FDG in 50% of the segments that were severely hypoperfused and akinetic or dyskinetic and without improvement with dobutamine. These results indicate that in severely hypoperfused and akinetic or dyskinetic segments, trans-thoracic echocardiography under inotropic stimulation provides little additional information compared with that obtained with rest echocardiography and perfusion studies; the assessment of 18FDG uptake provides information that is complementary to that obtained by perfusion assessment, rest and dobutamine trans-thoracic echocardiography.

Asynergy and left ventricular performance in dilative cardiomyopathy.

The purpose of this work was to evaluate the presence and importance of asynergy in dilative cardiomyopathy. A semiautomatized analysis of left ventriculograms was performed in 18 cases, the morphology of longitudinal and transverse axes time-length curves was evaluated, and mathematical indices of asynchrony and hypokinesis were defined. Ten normal subjects and 9 patients affected by aortic regurgitation were used as controls. In dilative cardiomyopathy, anomalous (polyphasic) time-length curves were present in 55% of the cases, while they were absent in aortic regurgitation and in all normal subjects but one. In addition, the asynchrony index was slightly increased and the hypokinesis index significantly increased (28.8 +/- 7.2% vs. 17.8 +/- 7.1%, p less than 0.001). A negative correlation existed between the asynchrony index and the ejection fraction (r = -0.483, p less than 0.05) and both the ejection fraction and the maximum normalized velocity of contraction were reduced in the patients with the anomalous curves (29.7 +/- 6.9% vs. 46.0 +/- 11.5%, p less than 0.01; 1.66 +/- 0.52 s-1 vs. 2.86 +/- 1.33 s-1, p less than 0.02). It was concluded that asynergy, and especially asynchrony, is frequent in dilative cardiomyopathy and it is strongly associated with a major impairment of overall left ventricular function.

Acute-phase reactants in acute myocardial infarction: impact on 5-year prognosis.

BACKGROUND: Acute-phase reactants have recently been shown to have a short-term and possibly long-term prognostic value in acute coronary syndromes. The aim of the present study was to retrospectively verify whether serum levels of inflammation markers can predict the occurrence of early and late cardiac events after myocardial infarction. METHODS: We reevaluated 58 consecutive patients (43 men and 15 women, mean age 66 +/- 12 years) admitted to our Center during 1993 with a first myocardial infarction. Patients with non-cardiac causes of inflammation were excluded, as well as patients with a left ventricular ejection fraction <40%. From the first blood sample obtained at admission, we evaluated C-reactive protein (CRP) and alpha1-acid glycoprotein (alpha1-AGP) serum levels, the erythrocyte sedimentation rate (ESR), fibrinogen levels, and the white blood cell (WBC) count. We also evaluated the highest level of serum cardiac markers. Follow-up data were collected for 55 patients in June 1999. RESULTS: Five in-hospital and 13 delayed cardiac deaths occurred. The mean follow-up of current survivors was 5.9 +/- 0.4 years. Patients in whom cardiac death occurred had significantly higher CRP (7.4 +/- 4.1 vs 3.0 +/- 2.4 mg/dl, p < 0.001) and alpha1-AGP levels (160 +/- 38 vs 113 +/- 24 mg/dl, p < 0.001), ESR (63 +/- 30 vs 37 +/- 25 mm/hour, p < 0.001), and WBC count (13,727 +/- 3,853 vs 10,936 +/- 3,358/mm3, p = 0.004). At multivariate analysis, higher alpha1-AGP (p < 0.001) and CRP serum levels (p = 0.02) were independent predictors of cardiac death. Patients in whom cardiac events occurred during follow-up showed higher CRP (5.7 +/- 3.7 vs 1.6 +/- 1.5 mg/dl, p < 0.001) and alpha1-AGP levels (140 +/- 36 vs 101 +/- 23 mg/dl, p < 0.001) and ESR (50 +/- 30 vs 34 +/- 26 mm/hour, p = 0.06). Higher alpha1-AGP (p < 0.001) and CRP serum levels (p = 0.03) were independent predictors of the occurrence of cardiac events. CONCLUSIONS: The present study shows that CRP and alpha1-AGP have an independent prognostic value in patients presenting with a first, uncomplicated myocardial infarction. Assays of these markers may help to better stratify patients hospitalized for acute coronary syndromes.

Cardiopulmonary exercise test in young women affected by anorexia nervosa.

BACKGROUND: The aim of this study was to evaluate exercise performance in patients affected by anorexia nervosa. METHODS: We studied 19 patients (all females, mean age 23.1 +/- 5.2 years) affected by anorexia nervosa (mean weight 37.3 kg, body mass index 14.04 +/- 1.4 kg/m2) and 20 constitutionally thin women, matched for age, height and physical activity, with a body mass index < 19 kg/m2. All these women underwent clinical examination, standard ECG and a cardiopulmonary stress test. RESULTS: Patients affected by anorexia nervosa showed a lower heart rate and systolic blood pressure at peak exercise (148.8 +/- 13.8 vs 171 +/- 9.2 b/min, p < 0.001, and 130 +/- 9.5 vs 152 +/- 11.2 mmHg, p < 0.001), work load (85.5 +/- 15.1 vs 117.2 +/- 20.3 W, p < 0.001), rate-pressure product (19 371 +/- 2391 vs 25,986 +/- 2218 b/min/mmHg, p < 0.001), oxygen uptake (VO2) at rest and maximum VO2 (5.4 +/- 1.7 vs 7.1 +/- 1.1 ml/kg/min, p < 0.001, and 28.08 +/- 6.3 vs 40.2 +/- 7.1 ml/kg/min, p < 0.001), anaerobic threshold (15.7 +/- 1.9 vs 20.4 +/- 2.1 ml/kg/min, p < 0.001), VO2 during exercise (9.5 +/- 1.2 vs 12.8 +/- 1.3 ml/min/W, p < 0.001), maximum minute ventilation (34.5 +/- 9.9 vs 48.4 +/- 10.3 /min, p < 0.001), and oxygen pulse (7.2 +/- 2 vs 10.9 +/- 2.4 ml/b, p < 0.001). CONCLUSIONS: These data show an abnormal working capacity and cardiovascular responses to exercise in patients affected by anorexia nervosa. The low VO2, both at rest and during exercise, allows them to maintain a relatively high level of physical activity, which contributes to increase the energy expenditure needed for weight loss.

Smoking and cardiovascular system: cellular features of the damage.

Two morphological features may be seen as a main result of the cardiovascular cell damage caused by cigarette smoking: myocardial cell necrosis and smoke cardiomyopathy that, however, can lead to cell necrosis in case of chronic prolonged exposure to tobacco smoke. Both these pathological patterns recognise hypoxia as the basic mechanism. Cardiovascular cell damage may involve either myocardial cell or coronary artery wall determining a varied but a wide spectrum of alterations. Necrosis may be well defined as a result of those morphological changes which follow cell death in a living tissue or organ with partial or total loss in their function. All infarcts of the heart muscle belong to the group of necrotic lesions, but not all cardiac necroses are necessarily infarcts. Coronarogenic, or non-coronarogenic mechanism following a direct action of tobacco compounds on myocardial cells may induce myocardial cell necrosis. Smoke cardiomyopathy is probably the most typical evidence of cellular damage induced by cigarette smoking on the myocardium. The term cardiomyopathy is used to describe all those forms of degenerative myocardial lesions caused directly by toxics or metabolic substances and, indirectly, by changes in blood flow which are able to induce chronic hypoxia. Initially, smoke cardiomyopathy is not characterised by necrotic phenomena but, instead, by alterations of those intracellular structures RNA- related like mitochondria and ribosomes, which are primarily deputed to carry out metabolic and respiratory pathways of myocardial cells, the function of which strongly depends on oxygen availability. Experimental findings documented undoubtedly either the type of cellular changes or their reproducibility after both acute or chronic exposure to cigarette smoke.

[Coronary disease in patients operated on for valvulopathy]. / Coronaropatia negli operati per valvulopatia.

In order to evaluate the influence of a significant coronary artery disease in patients with valvular heart disease or with prosthetic valves, we reviewed literature and our own experience. The incidence of coronary artery disease in valvulopathies has been diffusely studied and reported and, in a consecutive series of our hemodynamic studies, resulted 11%. The influence of a coronary artery disease on early and late results of a surgical procedure is different whether the coronary artery disease is operated or not. In particular, the combined surgery shows a higher early mortality, but a much better long-term prognosis. In addition, sometimes surgery introduces rare causes of coronary artery disease. Finally, it seems that coronary artery disease arises very rarely in patients undergone valvular surgery or, at least, patients rarely complain anginal symptoms in the post-surgical follow-up. In our experience on 529 patients only 6 complained typical angina and only 2 showed a coronary artery disease not present at the time of operation.

Silent pericardial effusion in a sample of anorexic patients.

Mortality in anorexic patients is mainly due to suicide or cardiac failure. The aim of this study was to investigate structural and functional cardiovascular alterations further by means of echocardiography in a sample of 15 medication-free patients with DSM-IV anorexia nervosa (AN) (BMI < 17.5 kg/m2) and without any known cardiovascular disease and/or a family history of deafness or sudden death, and correlate the findings with clinical variables. The controls consisted of a sample of 10 constitutionally thin women (BMI < 19 kg/m2), of comparable age, height and degree of physical activity. All of the subjects underwent Doppler echocardiography (ECHO), and the patients were also administered the Diagnostic Schedule for Eating Disorders (DSED) in order to assess the features and course of the eating disorder. ECHO revealed silent pericardial effusion in 71.4% of the patients vs. 10% of the controls (p < 0.05); among the patients, the separation of pericardial leaflets was more frequent in those with a shorter duration of illness (p < 0.05). Mitral valve motion abnormalities were more frequent among the patients than the controls (69.2% vs. 10%, p < 0.005), and the left ventricular mass/body surface area was lower (54.8% vs. 59%, p < 0.001). Isovolumetric relaxation time was longer in the patients (98.4 vs. 65 msec, p < 0.01), but there were no significant differences in left ventricular ejection fraction (53.8% vs. 59%) or early diastolic deceleration time (146 vs. 155 msec). The results of this study support the association between AN and demonstrable anatomic and functional cardiac abnormalities, such as a reduced ventricular mass and mitral valve abnormalities. The ECHO findings provide evidence for clinically silent pericardial effusion in AN, which may be an early sign of cardiovascular involvement.

Identification of hibernating myocardium: a comparison between dobutamine echocardiography and study of perfusion and metabolism in patients with severe left ventricular dysfunction.

The distinction between fibrotic and viable myocardium is a key issue in patients with coronary artery disease and left ventricular dysfunction. Metabolic imaging with positron emission tomography (PET) and labeled tracers, along with the study of myocardial perfusion, is now available to identify hibernating myocardium. However, PET imaging of myocardial metabolism is a high-cost and time-consuming technique, and requires an on-site cyclotron. The aim of this study is to test the reliability of dobutamine echocardiography (DE) compared with PET imaging, for the identification of hibernating myocardium. In 16 patients, scheduled for myocardial revascularization, left ventricular shapes were divided in eight segments both for echocardiographic and nuclear study evaluation. All patients underwent a technetium 99m MIBI single-photon emission tomography stress-rest study of perfusion, a fluorine-18-labeled deoxyglucose (FDG(/PET study of metabolism, and a DE test (baseline, at a 5 micrograms/kg/min infusion of dobutamine for 8 minutes and at a 10 micrograms/kg/min dose for additional 8 minutes). Neither myocardial ischemia nor arrhythmia occurred during the DE test. Baseline echocardiograms showed 90 segments with wall motion abnormalities: wall motion impairment was decreased or reversed in 33 of 90 segments; it remained unchanged in 57 of 90 segments. In 32 of 33 segments considered viable on the basis of DE and in 21 of 57 segments with unchanged kinesis, some degree of FDG was detected. Thus, sensitivity and specificity of DE compared with nuclear studies was 60% and 97% respectively. Moreover, a good correlation and agreement (kappa = 0.51) between DE and the presence of FDG were found. We conclude that DE is a safe and reliable test for the screening of hibernating myocardium in patients with chronic coronary artery disease and left ventricular dysfunction.

Mutation and transcription analysis of transthyretin gene in Italian families with hereditary amyloidosis: a putative novel hot spot' in codon 47.

Transthyretin gene mutations are associated with autosomal dominant familial amyloidosis. The commonest phenotype in the patients is peripheral neuropathy, but restrictive cardiomyopathy is also a frequent sign. More than 70 different mutations in the gene have been described. Although these mutations are randomly distributed, some hot spots have also been reported notably at position 6, 30, 33, 58, 109, 119 and 122. A few of these codons contain a CpG dinucleotide. We describe an additional 'hot spot' occurring at codon 47, in which we report one novel and two previously described mutations. This codon, however, does not contain a CpG dinucleotide, suggesting that other mechanisms might be responsible for the allelic heterogeneity. All the reported mutations in codon 47 are located in the exon 2 consensus sequence and are potentially involved in splicing. We performed transcription analysis on two livers obtained from transplanted patients carrying the Ala47 mutation. These livers showed a normally spliced message, indicating that this mutation does not affect splicing.