Clinical impact of neutropenia and febrile neutropenia in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab: a pooled analysis of TRIBE and TRIBE2 studies by GONO.

BACKGROUND: TRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. We focused on the incidence and longitudinal dynamics of neutropenia and febrile neutropenia (FN) in the two studies, to evaluate their clinical relevance, the magnitude of impact of FOLFOXIRI/bevacizumab, and the role of risk factors in predicting their occurrence. METHODS: The overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm. FN episodes were assessed by Multinational Association for Supportive Care in Cancer (MASCC) score. RESULTS: Among 1155 patients, 568 (49%) received FOLFOXIRI/bevacizumab. Overall, 410 (35%) experienced G3-4 neutropenia and 70 (6%) FN, 21 (2%) at high risk. FOLFOXIRI/bevacizumab was associated with higher incidence of neutropenia (51% versus 21%, P < 0.001), FN (8% versus 4%, P = 0.02), and high-risk FN [18 (3%) versus 3 (1%), P = 0.015]. No related deaths were observed. The first episode of G3-4 neutropenia and FN occurred mainly in the first 2 months in both arms. Longitudinal analysis showed different patterns of evolution over cycles between the arms (P < 0.001) G3-4 neutropenia being more frequent in the first cycles with FOLFOXIRI/bevacizumab. Older patients (P = 0.01) and females (P < 0.001) had a significantly higher risk of G3-4 neutropenia. No significant interaction effect between arm and analysed risk factors in terms of risk of G3-4 neutropenia or FN was observed. The incidence of FN among older females receiving FOLFOXIRI/bevacizumab was 12%. Neither G3-4 neutropenia nor FN impaired efficacy in terms of overall response rate, progression-free survival, and overall survival. CONCLUSIONS: FOLFOXIRI/bevacizumab has a higher risk of G3-4 neutropenia and FN than doublets/bevacizumab. FN occurred in <10% of patients, mostly as low-risk episodes. A closer monitoring during the first 2 months is recommended; prophylactic use of granulocyte colony-stimulating factor may be considered for older females.

Thrombolysis in refractory unstable angina.

Multiple drug therapy, including nitrates, beta blockers, calcium antagonists, aspirin, and heparin, has been advocated as effective in the treatment of unstable angina, a syndrome with a multifactorial pathogenesis. Recently, plaque rupture and thrombosis have been demonstrated as the most important pathogenetic mechanisms. Nevertheless, clear-cut results on the effects of thrombolytic treatment in unstable angina are still lacking. Some possible explanations why the medical treatment of unstable angina has still not yet been standardized, whereas that of myocardial infarction has, are suggested. A review of randomized and nonrandomized studies published on this topic evaluating the role of different thrombolytic agents in unstable angina is presented. In addition the role of coronary angiography is discussed. In view of the disappointing results of coronary artery bypass surgery performed in the acute phase of the disease, one of the goals of clinical research is to identify subsets of patients at high and low risk and who undergo different types of therapeutic interventions. To support published data suggesting that total myocardial ischemia has a significant impact on prognosis, we present our results of a study carried out on patients with refractory unstable angina treated with thrombolytic therapy and evaluated with continuous electrocardiographic monitoring in the attempt to correlate total myocardial ischemia with short-term prognosis. Data in favor of the prognostic role of continuous electrocardiographic monitoring in unstable angina are also reviewed. Finally, we propose some suggestions that might be useful for future studies.

Insulin-like growth factor-I and angiographically documented coronary artery disease.

In conclusion, we have reported an association between low IGF-I concentrations and CAD in relatively young men. This observation raises the possibility that IGF-I deficiency could be part of the polymetabolic syndrome. Whether a subnormal IGF-I production is due to growth hormone secretory abnormalities or to other metabolic reasons (e.g., insulin resistance or fat distribution, or both) is still unknown.

Perfusional and metabolic effects of nisoldipine as shown by positron emission tomography after acute myocardial infarction.

After myocardial infarction, regional dysfunction can occur in viable myocardial regions because of the presence of baseline hypoperfusion. Recent evidence suggests that these areas may maintain a residual perfusion reserve. The aim of the present study was to evaluate whether oral nisoldipine can increase regional myocardial blood flow (MBF) in dyssynergic but viable myocardium after myocardial infarction. Patients with isolated left anterior descending coronary stenosis were studied 1 month after the first myocardial infarction. Patients underwent [18F]fluorodeoxyglucose imaging, and MBF was measured, using positron emission tomography and [13N]ammonia, at baseline and following dobutamine administration (10 micrograms/kg/min over 5 minutes). MBF measurements were repeated 24 hours after nisoldipine (10 mg twice daily). Preliminary results suggest that necrotic areas showed the largest reduction in baseline MBF. Dyssynergic-viable regions showed a reduced resting MBF but maintained a residual perfusion reserve in response to inotropic stimulation. Thus, nisoldipine selectively improved basal perfusion in dyssynergic-viable myocardium.

Effectiveness and safety of a single intravenous bolus injection of tissue-type plasminogen activator in acute myocardial infarction. Bolus Dose-Escalation Study of Tissue-Type Plasminogen Activator (BEST) Investigators.

The efficacy of multiple intravenous bolus injections of tissue-type plasminogen activator (t-PA) in inducing rapid coronary recanalization in patients with acute myocardial infarction was previously demonstrated. In this Bolus Dose-Escalation Study of Tissue-Type Plasminogen Activator (BEST), the efficacy of 3 different doses of a single rapid intravenous bolus injection of t-PA (dute-plase, Wellcome Foundation, London) in inducing coronary patency (Thrombolysis In Myocardial Infarction perfusion grade 2 or 3) in 64 patients with acute myocardial infarction presenting less than 6 hours after onset of symptoms was investigated. At 60 minutes after administration of t-PA, the infarct-related coronary artery was patent in 9 of 17 patients (53%; 95% confidence interval [CI] 28 to 77%) after 0.3 MU/kg, in 14 of 23 (61%; 95% CI 39 to 80%) after 0.45 MU/kg and in 10 of 14 (71%; 95% CI 42 to 92%) after 0.6 MU/kg. At 90 minutes after t-PA, coronary patency was present in 9 of 17 cases (53%; 95% CI 28 to 77%) after 0.3 MU/kg, in 12 of 24 (50%; 95% CI 29 to 71%) after 0.45 MU/kg and in 10 of 13 (77%; 95% CI 46 to 95%) after 0.6 MU/kg. One patient in each dose group had a silent reoccluded infarct-related artery by 24 hours, and there were 2 clinical reinfarctions before discharge. No major bleeding events were observed. There were 5 hospital deaths, all unrelated to t-PA. A single intravenous bolus injection of 0.6 MU/kg of t-PA appears to be effective in inducing rapid coronary patency and to be safe in patients with acute myocardial infarction.

Recognition and treatment of unstable angina.

Despite the growing number of patients discharged from hospital with a diagnosis of unstable angina, the diagnostic procedures and treatment of unstable angina are still greatly debated, as they have been for patients with myocardial infarction. In recent years the definition and classification of the clinical syndrome of unstable angina has been subjected to numerous proposals by distinguished cardiologists. An attempt to clarify and redefine practical guidelines for different subgroups of patients has been developed and carried out by the US Agency for Health Care Policy and Research (AHCPR). The current medical approach to treatment of patients with unstable angina is discussed in detail, analysing the role of antiplatelet medications, beta-blockers, nitrates, heparin and calcium antagonists. The small subgroup of patients with refractory unstable angina should undergo urgent coronary angiography and revascularisation. Previous and current research on medical treatment with thrombolytic therapy, GPIIb/IIIa platelet receptor blockers and direct thrombin inhibitors is outlined, keeping in mind one of the main aspects of pathophysiology of the disease, that is ongoing thrombus formation. In the future, a more aggressive strategy aimed at normalising the atherogenic lipid profile in this very high risk group of patients should be carried out, based on the positive results of lipid-lowering drug trials both in primary and secondary prevention.

Right-sided valvular endocarditis supported by an unexpected intracardiac foreign body.

One case of tricuspid valve endocarditis due to a catheter fragment inside the right chambers of the heart is described. The symptoms were fever, cardiac failure, splenomegaly and relapsing pneumonia. Blood culture was positive, revealing Staphylococcus aureus. A two-dimensional echocardiogram demonstrated a large vegetation on the tricuspid valve. The percutaneous removal of the foreign body allowed complete recovery in a few weeks.

Cerebral blood flow reserve in patients with syndrome X.

BACKGROUND: Patients with syndrome X frequently show disorders of oesophageal motility, bronchial reactivity or impaired vasodilator capacity of peripheral vascular beds. For these reasons, it has been suggested that syndrome X may represent a generalized abnormality of vascular and non-vascular smooth muscle function, rather than an isolated coronary problem. OBJECTIVE: To measure the cerebral blood flow and cerebrovascular vasodilator reserve in syndrome X patients and in controls. METHODS: We measured the cerebral blood flow and cerebrovascular reserve in 16 patients with syndrome X [11 women, aged 59.5 +/- 10.8 years (mean +/- SD)] and in 16 age-matched healthy volunteers. No patients had evidence of stenoses of carotid and vertebral arteries on Doppler sonography. Cerebral blood flow was measured by the 133Xe inhalation method, using the initial slope index as the cerebral blood flow index. After a baseline measurement, a second cerebral blood flow measurement was performed 20 min after administration of 10 mg/kg acetazolamide intravenously. Acetazolamide is known to be a potent cerebral vasodilator. The percentage increase in cerebral blood flow after acetazolamide administration was considered an index of cerebrovascular vasodilator reserve. RESULTS: Under basal conditions, both regional and global cerebral blood flow were nearly identical in the control group and in the patient group (initial slope index 50.2 +/- 3.8 versus 50.3 +/-6.2, NS). After acetazolamide administration, the cerebral blood flow increase was 29.0 +/- 14% in the patient group and 29.5 +/- 11% in the control group (NS). CONCLUSIONS: Our data show that cerebral blood flow and cerebrovascular vasodilator reserve were preserved in a series of patients with syndrome X. These results are not consistent with the hypothesis of a diffuse smooth muscle disorder.

Thalassemic cardiomyopathy: echocardiographic difference between major and intermediate thalassemia at rest and during isometric effort: yearly follow-up.

Left ventricular (LV) performance was studied in young patients with severe chronic anemia due to beta-thalassemia major, intermedia, and in healthy control subjects. M-mode echocardiograms were recorded in each patient and semiautomatic computerized analysis of the tracings provided data relating to LV performance. Then a statistical analysis of the difference between each specific thalassemic group and the normal subjects was made using Student's t-test for unpaired data. The study showed that cardiac dysfunction is more serious in major than in intermediate beta thalassemia. A follow-up one year later showed a progressive deterioration of the cardiac indices, in spite of treatment with desferrioxamine. A handgrip test was performed in the follow-up study, which permitted us to distinguish different groups relative to the changes in LV performance indices. Our findings indicate that echocardiography provides a simple noninvasive means for assessing changes in the cardiac structure and function, which should also prove useful in the serial evaluation of patients at risk of developing myocardial iron deposition.

Thrombolytic therapy in refractory unstable angina: the role of Holter monitoring.

We tested the safety and the usefulness of intravenous urokinase (2 million units administered over 30 min) in 44 patients with refractory unstable angina, defined as persistence of ischemic episodes during 48-h Holter monitoring (Phase 1) despite maximal medical therapy. After thrombolysis, recurrence of ischemia was observed during a week of observation in the CCU, including two 24-h Holter monitorings at the beginning and the end of the week (Phase 2). Seventeen patients completed the observation period without either symptomatic or asymptomatic ischemic episodes (Group A); the remaining 27 continued to manifest ischemia (Group B). No bleeding complications occurred. Within a 6-month follow-up, 2 patients of Group A had recurrence of unstable angina while in Group B, 19 patients had refractory angina or a major cardiac event [10 patients underwent coronary artery bypass surgery (CABG) or percutaneous transluminal coronary angioplasty (PTCA) for refractory angina (p less than 0.001), 6 other patients with refractory angina continued medical therapy, one patient had a myocardial infarction, and two patients died]. In Phase 1 the duration of total ischemia (min/24 h) was a relevant prognostic marker: higher duration correlated with adverse clinical outcome (p less than 0.01). In comparison to Phase 1, duration of total ischemia in Phase 2 was significantly reduced in both groups (16.9 +/- 19.6 vs. 25.4 +/- 17.7; p less than .001). A percent value expressing this variation was calculated for each patient: the variation thus obtained again gave information on the clinical outcome--the greater the reduction, the lower the risk of cardiac events (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Ergonovine maleate test detects anginal patients with poorly reproducible exercise tests.

The aim of the study is to evaluate the reproducibility of exercise testing and to determine whether there is any correlation between the reproducibility of exercise test and response to the ergonovine maleate test. Thirty-eight patients with mixed angina and documented coronary artery disease underwent an ergonovine maleate test and four exercise tests on consecutive days in the same basal conditions. The ergonovine test was positive in 20 patients (Group I) and negative in 18 patients (Group II). There were no significant differences in the clinical and angiographic data of the two groups. All 152 exercise tests were positive. The variability of the response of the repeated tests was assessed by means of an analysis of the following parameters: heart rate, blood pressure, rate-pressure product, watts, and minutes were recorded at the onset of ischemia (ST decreases greater than or equal to 0.1 mV). Range (maximal-minimal obtained value), ratio between range and maximal obtained value, and coefficient of variation (standard deviation/mean of the four parameters) were calculated for each patient. The analysis of these values demonstrated that while the test was reproducible in some patients, a high individual variability was present in others. Moreover, the individual variability results were higher in Group I than in Group II, with a statistically significant difference for all considered parameters. In conclusion, it is possible to have a poorly reproducible exercise test in patients with mixed angina. The correlation between a positive ergonovine test and a poorly reproducible exercise test suggests that abnormal coronary vasomotion may sometimes be present during exercise and may affect the reproducibility of the test.

Lipoprotein (a) is increased in acute coronary syndromes (unstable angina pectoris and myocardial infarction), but it is not predictive of the severity of coronary lesions.

Lipoprotein (a) [Lp(a)] concentrations were determined in 365 patients undergoing coronary angiography for stable angina (n = 159), unstable angina (n = 99), recent myocardial infarction (n = 45), and nonischemic heart disease (cardiomyopathy or valvular disease, n = 62, non-IHD). Mean +/- SD and median Lp(a) concentrations in stable angina (29.9 +/- 29.2;22 mg/dl) did not differ from those in non-IHD (26.9 +/- 26.3; 17), but were significantly lower than in patients with unstable angina (52.7 +/- 36.6; 58) and myocardial infarction (44.8 +/- 36.4; 34) (p < 0.01). Coronary angiography revealed that 261 patients, including 4 patients in the non-IHD group, had significant (> or = 50%) coronary lesions. Lp(a) was higher in patients with (41 +/- 35; 32) than in those without (28 +/- 27; 19) angiographic evidence of significant coronary stenosis (p < 0.05) and showed a weak univariate correlation with the angiographic index (Total Score) of the severity of the disease (r = 0.106;p < 0.05). However, in the subgroup of 303 patients with stable/unstable angina or myocardial infarction, Lp(a) was predictive neither of angiographic presence nor of severity of coronary disease. Patients were then ranked according to the Total Score values. Among patients with comparable angiographic severity of coronary artery disease, Lp(a) appeared to be remarkably higher in patients with acute ischemic syndromes (unstable angina, myocardial infarction) than in patients with stable angina. In conclusion, Lp(a) was roughly twice as high in acute (unstable angina, myocardial infarction) than in chronic (stable angina) ischemic syndromes, but there was no difference between chronic stable angina and non-IHD.(ABSTRACT TRUNCATED AT 250 WORDS)

[Primary malignant cardiac tumors]. / Tumori cardiaci maligni primitivi.

Primary tumours of the heart are extremely rare, occurring in only 0.0017 to 0.28 per cent of large postmortem series. About only one-forth of all cardiac tumors are malignant. Modern techniques of diagnosis and surgical treatment have changed the benign cardiac tumor from a curiosity found at postmortem examination to an almost uniformly curable form of heart disease. Unfortunately, the same cannot be said for malignant cardiac tumors, which are both rare and almost always fatal. We reviewed the medical literature to summarize all cases of primary malignant tumors of the heart. Recently it has been pointed out that better survival in this group of patients could be a result of prompt diagnosis and treatment. Surgical intervention is rarely of benefit except for establishing a tissue diagnosis. On the contrary, survival may be enhanced by irradiation and probably by chemotherapy (sometimes as postoperative procedures).

[Arterial hypertension and cardiovascular risk. Epidemiological studies, trials and therapeutic implications]. / Ipertensione arteriosa e rischio cardiovascolare. Gli studi epidemiologici, i trial e le implicazioni terapeutiche.

From the analysis of the epidemiological observational studies, among which one of the most famous is the Framingham study that has lasted for more than 30 years, it is evident that the risk of cardiac events and strokes is closely related to the levels of arterial systolic and diastolic blood pressure. Nevertheless, the link between hypertension and cardiovascular risk has very often been discussed, due to the results of therapeutic intervention trials, which have proved satisfactory for cardiovascular risk reduction but disappointing results for coronary disease reduction risk. Possible explanations for these poor results of antihypertensive therapy on coronary disease are different and very numerous. According to many Authors, the blood pressure was not reduced to the programmed levels in all trials and the drug used (diuretics, beta-blockers) possibly had negative effects on the lipid profile. Therefore, waiting data for new trials, will perhaps produce better results in the future taking into consideration all risks of our patient, monitoring a rigorous and steady blood pressure reduction and selecting drugs like calcium-channel blockers and ACE-inhibitors which contain characteristics similar to those ideal for the modern antihypertensive agent.

[Echocardiographic findings in interatrial septal aneurysm, Chiari's network and tricuspid valve prolapse. An unusual association]. / Riscontro ecocardiografico di aneurisma del setto interatriale, rete di Chiari e prolasso della valvola tricuspide. Una associazione originale.

In this report we discuss the case of a 55-year-old female who underwent echocardiographic and Doppler studies for the presence of systolic murmur at physical examination, in which echocardiography showed the concomitant presence of an atrial septal aneurysm, a Chiari network and a tricuspid valve prolapse, a hypothetic association not previously described. The association of atrial septal aneurysm, tricuspid valve prolapse and Chiari network suggests the possibility of a connective disorder involving fibrous tissue of the heart and a concomitant anomalous development of the valves of the sinus venosus.

[The Study Group of Quinapril in Arterial Hypertension. The Steering Committee]. / Gruppo di studio del quinapril nell'ipertensione arteriosa. Steering Committee.

The efficacy and safety of the treatment of arterial hypertension with the ACE-inhibitor quinapril, were evaluated in a multicentre study conducted in Italy. The study, lasting 14 weeks, after a preliminary wash-out period, allowed response-based titration of quinapril dose from 10 mg to 40 mg once a day, with provision to combine additional hydrochlorothiazide (12.5 to 25 mg), in case of persistently high diastolic pressure levels. The efficacy sample included 1267 patients: at therapy week 14, 78.6% of patients were treated with quinapril alone. Global response rate (intent-to-treat) was 83.3%, with a mean reduction of diastolic pressure of 15.8 mmHg (95% confidence interval from 15.5 to 16.2 mmHg). 91 patients reported 126 associated adverse events (7.0%); the most frequently reported event was cough (2.7%). First-dose hypotension was rarely reported (1.3%), even in elderly and diabetic patients.

[Morphologic and functional evaluation of the left ventricle in patients with acromegaly. An echocardiographic study]. / Valutazione morfologica e funzionale del ventricolo sinistro in pazienti con acromegalia. Studio ecocardiografico.

The aim of our study is to detect morphological and functional aspects of left ventricle with noninvasive M-B-Mode echocardiography in acromegalic patients (pz) with and without high blood pressure. We studied 19 acromegalic pz (group A) and 19 normal pz (group N). All subjects were evaluated for the following parameters: left ventricular mass index (MI); end diastolic volume index (EDVI); end systolic volume index (ESVI); ejection fraction (EF); end systolic stress (ESS). Group A vs group N shows an increase of cardiac mass (p less than 0.01), of EDVI (p less than 0.05) and of ESS (p less than 0.05). We found the asymmetrical septal hypertrophy, considered from other Authors one of the more evident markers of acromegaly, in only one patient. In conclusion, the acromegalic pz show an increase of cardiac mass and preload and a reduced capacity of adaptation to afterload variation independently of blood pressure values and of the duration of disease, even if they have normal indexes of global systolic function.

[Ventricular function in dilated cardiopathy]. / La funzione ventricolare nelle cardiopatie dilatative.

Global and regional systo-diastolic ventricular function evaluation is of primary importance in the study of patients suffering from heart disease. The finding of intact global systolic function in subjects with documented heart disease is not rare. However a variety of cardiovascular diseases can alter, at an early stage, the characteristics of the diastolic function. Functional alterations during the initial diastolic phase can be found in patients with early stage heart disease and with normal regional systolic function suggesting that regional and global diastolic evaluation could be useful in the diagnostic approach to patients with still normal global and regional systolic function.

[A comparison between amlodipine and nifedipine retard in patients with essential arterial hypertension]. / Confronto tra amlodipina e nifedipina ritardo in pazienti con ipertensione arteriosa essenziale.

Amlodipine, a novel dihydropyridine calcium-antagonist, was compared to slow-release nifedipine in a short-term study on 40 patients with mild to moderate essential hypertension, in order to assess the efficacy and tolerability of two different dihydropyridine calcium-antagonists with short and long half-life. After a two-week single-blind placebo period, patients were given, in a randomized sequence, amlodipine (5 or 10 mg/day od, 20 patients) or nifedipine s.r. (20 or 40 mg BID, 20 patients). At the end of treatment (12 weeks) a significant lowering of arterial pressure was obtained after 24h from the administration of amlodipin (-34/-17 mmHg) and after 12h from the administration of nifedipine s.r. (-33/-16 mmHg). Furthermore, with both drugs, no significant changes in heart rate and ECG have been reported. Amlodipine was better tolerated than nifedipine, as shown by the lower incidence of side effects. Therefore amlodipine proved to be an effective and well tolerated drug in the therapy of mild to moderate hypertension.