Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas.

PURPOSE: We conducted a randomized trial to evaluate primarily the cardioprotective effect of dexrazoxane (DEX) in patients with advanced breast cancer and soft tissue sarcomas (STS) treated with high-dose epirubicin (EPI). We wished also to determine the value of radioimmunoscintigraphy (RIS) in the assessment of anthracycline cardiotoxicity. PATIENTS AND METHODS: Patients with breast cancer (n = 95) or STS (n = 34) received EPI 160 mg/m2 by intravenous (I.V.) bolus every 3 weeks with or without DEX 1,000 mg/m2 I.V. Cardiac monitoring included multigated radionuclide (MUGA) scans with determination of resting left ventricular ejection fraction (LVEF), and RIS with indium 111 antimyosin monoclonal antibodies. RESULTS: In either disease, antitumor response rates, time to progression, and survival did not significantly differ between the two arms. There was little difference in noncardiac toxicity for the two treatment groups. All methods of cardiac evaluation clearly documented the cardioprotective effect of DEX. Four patients developed congestive heart failure (CHF), all in the EPI arm. The decrease in LVEF from baseline was significantly greater in the control group. An abnormal antimyosin uptake was observed early in both arms and progressively increased during treatment. However, this increase was significantly higher in the EPI group (P = .004). CONCLUSION: DEX significantly protects against the development of cardiotoxicity when high single doses of EPI are used. Apparently, there was no evidence of an adverse impact of DEX on antitumor activity. Although RIS is a sensitive technique in detecting anthracycline cardiac damage, its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment.

Myocardial 123I-MIBG kinetics in acutely hypothyroid patients with differentiated thyroid carcinoma.

Marked changes in cardiac function have been noted in patients with hyperthyroidism or hypothyroidism due both to changes in sympathetic system function and to biochemical modifications of myocardial tissue. Metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, can be used to evaluate myocardial sympathetic tone. Here, we report myocardial 123I-MIBG kinetics in patients with differentiated thyroid carcinoma undergoing acute hypothyroidism followed by hormonal replacement as part of their routine clinical follow-up. Ten patients with differentiated thyroid carcinoma in acute hypothyroidism (A) and on hormonal replacement with thyroxine (150 micrograms.day-1) and triiodothyronine (20 micrograms.day-1) (B) underwent scintigraphic imaging 20 min and 4 h after injection of 111 MBq of ultra-high specific activity 123I-MIBG. No patient had cardiac disease or was taking medications that could interfere with cardiac or autonomic system function. Cardiac MIBG kinetics (heart-to-mediastinum, H/M, ratio and myocardial washout rate), serum norepinephrine, T3, T4, FT3, FT4, TSH, CPK, CPK-MB, blood pressure and ECG were evaluated. Systolic and diastolic blood pressure did not differ significantly between state A and state B. In the acute hypothyroid state (A), the prevalence of non-specific ST-T abnormalities was 70% and heart rate was significantly different (P < 0.001) than in state B. Norepinephrine and CPK-MB levels were higher during hypothyroidism, but this did not reach statistical significance. A positive correlation between early H/M and delayed H/M in the hypothyroid state (r = 0.57) and an even higher positive correlation between early H/M and delayed H/M in the euthyroid state (r = 0.91) were seen. The myocardial and mediastinal MIBG washout rates were significantly different between the hypothyroid and euthyroid states (P < 0.05), whereas the lung washout rate did not differ significantly between the two metabolic states. We conclude that the myocardial washout rate during hypothyroidism is clearly increased (P < 0.005) with a subclinical derangement of myocardial adrenergic innervation, which is rapidly reversed with hormonal therapy.

Somatostatin receptor imaging in CNS tumours using 111In-octreotide.

This study evaluates the in vivo visualization of somatostatin (SS) receptors in central nervous system (CNS) tumours using 111In-octreotide imaging and discusses the clinical implications. Ninety-five patients with histologically confirmed diagnosis of CNS tumours were imaged 2-4 and 24 h after the intravenous injection of 111-185 MBq of 111In-octreotide. An uptake index was computed using tumour/non-tumour ratios evaluated using a standard region-of-interest method. Semi-quantitative immunohistochemical studies of SS binding sites were performed on frozen tumour sections. All meningiomas, most pituitary adenomas and many glial tumours showed a positive scan, whereas all neurinomas, craniopharingiomas and ependymomas had negative receptor scans. Radio-octreotide uptake varied among the SS receptor positive CNS tumours: very intense in meningioma, intermediate in pituitary adenoma and of a low grade in glioma. The results of immunohistochemical studies confirmed the scintigraphic findings in all cases. We believe 111In-octreotide is a suitable radiopharmaceutical for characterizing CNS tumours in vivo as SS receptor positive or negative. This new neuronuclear imaging technique may be useful for differential diagnosis in selected cases, for post-surgical follow-up and in the assessment of differentiation in glial tumours.

Dexrazoxane cardioprotection in advanced breast cancer patients undergoing high-dose epirubicin treatment.

PURPOSE: We performed a randomized trial to evaluate the cardioprotective effect of dexrazoxane (DEX) in advanced breast cancer patients (ABC) treated with high single-dose epirubicin (EPI). A secondary objective was to determine the role of radioimmunoscintigraphy (RIS) in the assessment of epirubicin cardiotoxicity. PATIENTS AND METHODS: Ninety-five patients with ABC were treated with EPI 160 mg/m2 by i.v. bolus every 3 weeks with or without DEX, 1,000 mg/m2 i.v. Cardiac monitoring included multigated radionuclide (MUGA) scan with determination of resting left ventricular ejection fraction (LVEF), and RIS with 111-Indium antimyosin monoclonal antibodies. RESULTS: The overall response rate was 69% in the EPI arm and 67% in the EPI + DEX arm; median time to response and median time to progression were identical in both arms, being 2 and 8 months, respectively. Median survival was 19 months versus 29 months (p 0.21), respectively. DEX did not appear to contribute to extracardiac EPI toxicity. Congestive heart failure occurred only in the EPI arm (2 instances). LVEF significantly decreased from baseline only in the EPI group. An abnormal tracer uptake at RIS was observed early in both arms, but the increase in heart to lung ratio was much more evident in the control group. CONCLUSIONS: DEX significantly protects against the development of high dose epirubicin cardiotoxicity apparently without evidence of an adverse impact on antitumor activity and non cardiac toxicity. RIS is a very sensitive technique in detecting anthracycline cardiac damage, but its specificity is low and cannot be considered alone a primary test for guiding anthracycline treatment.

Platinum compounds as radiosensitizers in strontium-89 metabolic radiotherapy.

PURPOSE: Strontium-89 is currently used for the treatment of painful bone metastases. This study reports on two preliminary experiences with low-dose platinum compounds, carboplatin and cisplatin, as radiosensitizers in 89Sr therapy. PATIENTS AND METHODS: 30 patients entered the carboplatin study: 15 patients (Group A) were treated with 148 MBq 89Sr followed by carboplatin (100 mg/m2 at 7 and 21 days) and 15 patients (Group B) were treated with 89Sr alone. 12 patients entered the cisplatin study: six patients (Arm 1) received 148 Mq 89Sr plus cisplatin (50 mg/m2) in two administrations (immediately before and 10 days after 89Sr injection) and six patients (Arm 2) received 89Sr plus two placebo administrations. Pain response was assessed 8 weeks after the therapy on the Wisconsin score modifications. RESULTS: No clinically significant adverse effects or myelosuppression by platinum compounds were observed. In carboplatin study a pain response was observed in 20 of 27 (74%) evaluable patients, 13/15 in group A and 7/12 in group B. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). In cisplatin study a pain response was observed in 10 of 12 (83%) evaluable patients, 5/6 in Arm 1 and 4/6 in Arm 2. CONCLUSIONS: Low-dose platinum compounds seem to enhance the effects of 89Sr radioisotope therapy on pain from bone metastases without relevant hematological toxicity.

[Idiopathic dilated cardiomyopathy: clinical and prognostic significance of the morpho-functional involvement of the right heart]. / Cardiomiopatia dilatativa idiopatica: significato clinico e prognostico della compromissione morfo-funzionale del cuore destro.

Aim of this study was to evaluate whether different severity of clinical and functional impairment of right heart in patients with idiopathic dilated cardiomyopathy (IDC) might condition distinct clinical features and prognosis. From 104 consecutive patients with hemodynamically assessed diagnosis of IDC studied between 1977 and 1987 in our Institute, 39 patients (28 males and 11 females, mean age 41 +/- 14 years) were selected on the basis of ejection fraction ranging from 35 to 50%, left ventricular end-diastolic pressure ranging from 13 to 20 mmHg and left ventricular end diastolic volume less than or equal to 150 ml/m2. A significant involvement of right heart (diagnosed according to a mean right atrial pressure greater than or equal to 9 mmHg, a right ventricular end-diastolic pressure greater than or equal to 9 mmHg and a right ventricular end-diastolic diameter greater than or equal to 30 mm) was assessed in 16 patients (41%), 11 males and 5 females, aged 40 +/- 15 years (Group A). On the contrary the remaining 23 patients (59%), 17 males and 6 females, aged 42 +/- 12 years, had a normal right heart (Group B). At entry into the study, clinical features appeared similar in the 2 groups of patients whereas patients of Group A had significantly higher incidence of atrial fibrillation (25% vs 4%, p less than 0.01) and complex ventricular arrhythmia (greater than or equal to 4 Lown class) (25% vs 4%, p less than 0.01) compared with patients of Group B. With respect to conduction defects no difference was found between Group A and Group B.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of slow-release isosorbide-5-mononitrate on ergometric parameters and cardiac output in stable effort angina pectoris: a double-blind randomized placebo study]. / Effetti dell'isosorbide-5-mononitrato in formulazione retard sui parametri ergometrici e sulla portata cardiaca nell'angina da sforzo stabile: studio in doppio cieco, randomizzato con placebo.

The effects of a single oral dose of 60 mg of sustained release (R) isosorbide-5-mononitrate (ISM) administered in 9 male patients (mean age: 53 +/- 7 years) with stable exercise-induced angina pectoris were studied in a randomized, double blind, cross-over study. The effectiveness of the drug was evaluated by concomitant ergometer exercise stress test and cardiac output determination (bioimpedance method, Bomed Med-Ltd) performed 1 hour before and 1, 4, 10 and 24 hours after acute administration of placebo (P) and ISM-R. After P, all patients showed a positive exercise test, whereas 3 patients during ISM-R treatment had a negative exercise stress test 1 and 4 hours after ISM-R administration. Compared with P, ISM-R produced a statistically significant improvement of exercise stress test parameters at peak exercise (maximum work load, heart rate, systolic and diastolic blood pressures and double product) up to 10 hours after drug administration. On the other hand, cardiac output did not significantly differ at any time after ISM-R compared with both control conditions and P treatment. Moreover, no side effect was detected in any patient during the study. In conclusion, a single oral dose of 60 mg of sustained-release ISM-R seems to be an effective drug in the treatment of effort angina, its effectiveness lasting more than 10 hours without side effects.

Clinical relevance of 111In-octreotide scans in CNS tumors.

Sixty-six patients with a clinical and neuroradiological diagnosis of CNS tumors were evaluated by 111In-octreotide scintigraphy. Planar images were acquired at 2-4 and 24 hours after the injection of 111-185 MBq of 111In-octreotide (Octreoscan, Byk-Gulden). In the positive scans the tumor/non-tumor ratio was evaluated using a standard ROI method, and an uptake index (U.I.) of the lesion was determined. In vitro binding assays were performed on frozen sections from surgical specimens from 17 patients. All 32 meningiomas demonstrated a positive 111In-octreotide scan with a high U.I. Only 13 of 21 gliomas showed a positive scan, but the U.I. was significantly lower (p < 0.001 by "t"-test); one lymphoma showed a faint tracer uptake. All the other histotypes evaluated yielded negative scans. In all cases the receptorial pattern shown by the immunohistochemical staining technique was concordant with the scintigraphic results. 111In-octreotide scintigraphy allowed a differential diagnosis of meningioma versus other CNS tumors in 6 patients (4 neurinomas, 1 brain metastasis of melanoma, 1 lymphoma). In conclusion, 111In-octreotide scintigraphy is a promising tool to evaluate the SS receptorial pattern of CNS tumors and to increase the diagnostic specificity of conventional imaging providing useful information in selected cases for the therapeutic strategy.

111In-octreotide scintigraphy in small cell lung cancer.

Somatostatin receptors have been identified on the cellular surface of a subset of patients with small cell lung cancer (SCLC) and may be associated with a less aggressive evolution of the tumor. Moreover, medical therapy with somatostatin analogues holds promise for neoplastic growth control. We performed planar imaging in 22 patients with histologically proven SCLC at 2-4 and 24 hours after the injection of 111-185 MBq of 111In-DTPA-octreotide (Octreoscan, Byk-Gulden). Tumor uptake was observed in 19 patients in both early and late scans, while 2 patients previously treated with chemotherapy showed negative early and late scans. One patient had a positive early scan and a negative late scan. All the scintigraphic studies showed more extensive disease than expected by CT. No significant modification in tumor uptake of radiooctreotide was observed in three patients studied before and after chemotherapy. In conclusion, 111In-octreotide is a suitable radiopharmaceutical for the in vivo evaluation of the somatostatin receptors of small lung cancer. The prognostic and therapeutical implications of this nuclear technique must be further investigated, however.

Clinical relevance of radionuclide angiography and antimyosin immunoscintigraphy for risk assessment in epirubicin cardiotoxicity.

BACKGROUND: Cardiotoxicity is the major limiting factor in anthracycline chemotherapy of advanced neoplastic disease. Epirubicin shows a more favorable therapeutic index than does doxorubicin, but it is still cardiotoxic. Limited data regarding epirubicin cardiotoxicity are available, and suggested guidelines for doxorubicin with left ventricular ejection fraction (LVEF) measurement may not be empirically useful for epirubicin therapy. This study evaluates the diagnostic role of antimyosin immunoscintigraphy for early identification of patients at risk for late pump dysfunction from cardiotoxicity induced by high-dose administration of epirubicin up to high cumulative dosages. METHODS AND RESULTS: Chemotherapy with epirubicin was administered to 36 patients with cancer at a dosing rate of 160 mg/m2 as a bolus injection every 21 days to a cumulative dosage of 960 mg/m2. Radionuclide angiography (LVEF) and antimyosin immunoscintigraphy with heart-lung ratio (HLR) measurements were performed before chemotherapy, at intermediate cumulative epirubicin dosages, at the end of treatment, and during the follow-up. LVEF decreased significantly at the end of the treatment and after therapy discontinuation. HLR values were significantly increased at intermediate epirubicin dosage levels and continued to increase to the end of the treatment but thereafter remained substantially unmodified for 3 to 6 months after therapy discontinuation. A value of HLR >1.85 at intermediate epirubicin dosage level showed a sensitivity of 95% and a specificity of 57% as a predictor of late LVEF impairment. CONCLUSIONS: LVEF appears more useful at high cumulative dosages and during follow-up to monitor late pump dysfunction, whereas HLR may be effective during the early phase of the therapy in determining which patients are at risk for development of late cardiac dysfunction.

[Winging effect in interatrial defect after transseptal mitral valvuloplasty: an anatomical study]. / Effetto winging nel difetto interatriale post-valvuloplastica mitralica transettale: studio anatomico.

In the balloon catheters the redundancy of the deflated balloon produces 2 or 3 sort of thin wings. The presence of wings can reduce the catheter "pushability" or, in certain conditions, can determine tissue lesion (winging effect). Simulating a transeptal valvuloplasty of the mitral valve by technique of the 2 balloon in human fresh heart, we studied the winging effect over the interatrial septum in 12 hearts; in the first 6 the atrial septum was dilated with a 6 mm balloon (Group A), in the second 6 the atrial septum was dilated with a 10 mm balloon (Group B). The procedure was completed introducing consecutively 2 bigger balloons (15 + 20 mm). We suppose that the winging effect of the 2 bigger balloons (15 + 20 mm) could counter balance the theoretical advantage of a small balloon (6 mm). The atrial septal defect (ASD) after septal dilatation was 5.0 +/- 0.59 mm x 1.56 +/- 0.25 mm (long axis x short axis) in Group A and 6.53 +/- 0.35 x 2.16 +/- 0.39 mm in Group B (p less than 0.01). The final ASD (after introducing the 2 bigger balloons) was 7.04 +/- 1.06 x 2.36 +/- 0.57 mm in Group A and 7.03 +/- 0.18 x 2.16 +/- 0.32 mm in Group B (NS). Our data show that the winging effect can determine biological negative effects.

[Primary pulmonary hypertension: a retrospective study of 13 patients]. / Ipertensione polmonare primitiva: studio retrospettivo di 13 pazienti.

Twenty-four patients (9M and 15F, mean age 28 years) with primary pulmonary hypertension underwent cardiac catheterization in our institution from 1955 to 1989. The prevalence of the disease in our population was lower (0.2%) than that reported by other Authors (1%). Thirteen of these patients (4 M and 9 F, mean age 32 years) evaluated between January 1979 and December 1989, were followed. Five were alive after 52 +/- 30 months (Group A) while 8 died after 11 +/- 9 months (Group B). In Group B mean pulmonary pressure was significantly higher than in Group A (66.7 +/- 17.2 vs 41.2 +/- 19.0 mmHg, p less than 0.05, respectively). Cardiac index and systolic volume index were lower in Group B than in Group A (2.07 +/- 0.85 vs 3.72 +/- 1.32 l/min/m2, p less than 0.01 and 24.43 +/- 10.25 vs 41.08 +/- 16.97 ml/m2, p less than 0.05, respectively). Pulmonary resistance index and systemic resistance index were higher in Group B than in Group A (3039 +/- 1519 vs 1181 +/- 1236 dyne x s x cm-5/m2, p less than 0.01; 4277 +/- 1794 vs 2309 +/- 1238 dyne x s x cm-5/m2, p less than 0.01). One patient underwent repeated cardiac catheterization after 2 years. This patient showed a deterioration of the hemodynamic parameters, consistent with the worsening of the clinical conditions. In conclusion, in our population of patients with primary pulmonary hypertension, an increase in pulmonary artery pressure and pulmonary resistances, as well as a decrease in cardiac index, are associated with a reduced life expectancy. On the other hand, right atrial pressure does not affect mortality.

Docetaxel in patients with anthracycline-resistant advanced breast cancer.

OBJECTIVE: To better determine docetaxel activity in patients with well-defined anthracycline-resistant breast cancer. METHODS: From October 1996, we carried out a phase II trial in 69 heavily pretreated patients with advanced breast cancer with docetaxel 100 mg/m(2) by a 1-hour infusion on day 1, with cycles repeated every 3 weeks. Patients were classified as having primary anthracycline resistance (n = 32), secondary anthracycline resistance (n = 7), anthracycline pretreatment (n = 22) or no anthracycline pretreatment (n = 8). RESULTS: Among 68 evaluable patients, we observed 6 (9%) complete responses and 27 (40%) partial responses, for an overall response rate of 49% (95% confidence interval 37-61%); the disease remained stable in 17 patients (25%). Responses according to the above subgroups were as follows: primary anthracycline resistance 41%, secondary anthracycline resistance 43%, anthracycline pretreatment 64% and no anthracycline pretreatment 43%. The median time to response, median time to progression and median overall survival were 2, 7 and 10 months, respectively. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia occurring in 47% of the patients and neutropenic fever in 12%. G-CSF was added in the case of grade 4 febrile neutropenia; a 25% reduction in the dose of docetaxel was required in 4 patients. Other side effects were mild. CONCLUSIONS: The results of the present trial confirm the high activity of docetaxel in heavily pretreated patients with advanced breast cancer, including those with strictly defined anthracycline resistance.

[Relations between ACE inhibition with captopril and atrial natriuretic factor during an acute hemodynamic study]. / Relazione tra ACE-inibizione con captopril e fattore natriuretico atriale durante studio emodinamico acuto.

Aim of this study was to evaluate if captopril treatment may directly alter the trial natriuretic factor (ANF) concentration. Six patients (2 male and 4 female) aged 53 +/- 11 years, with mitral stenosis, and atrial fibrillation, underwent cardiac catheterization in our Institution. The following parameters were evaluated: heart rate, right atrial and pulmonary capillary wedge pressure, aortic and pulmonary pressure, cardiac index, pulmonary and systemic resistances and ANF concentration in coronary sinus, pulmonary, artery, aorta, peripheral vein. All these parameters were measured before and 30 and 60 min after captopril administration (50 mg orally). No hemodynamic changes occurred after captopril administration. No changes in ANF concentration occurred in comparison with baseline levels, after 30 and 60 min in coronary sinus (199.8 +/- 151.5 vs 181.9 +/- 102.5 fmol/ml; 178.4 +/- 95.2 vs 181.9 +/- 102.5 fmol/ml), in pulmonary artery (58.3 +/- 36.6 vs 51.4 +/- 48.8 fmol/ml; 35.5 +/- 16.9 vs 51.4 +/- 48.8 fmol/ml), in aorta (29.7 +/- 22.7 vs 37.5 +/- 26.3 fmol/ml; 25.2 +/- 9.8 vs 37.5 +/- 26.3 fmol/ml); and in peripheral vein (14.6 +/- 7.9 vs 17.3 +/- 9.7 fmol/ml; 16.2 +/- 12.2 vs 17.3 +/- 9.7 fmol/ml). In conclusion our data show that, providing no hemodynamic changes occur, captopril administration does not alter ANF concentration.