Observational study of trastuzumab-related cardiotoxicity in early and metastatic breast cancer.

Introduction Trastuzumab-related cardiotoxicity has been a major concern in clinical practice, since observational studies have shown higher incidences than that reported in clinical trials. We aim to measure the incidence of trastuzumab-related cardiotoxicity in patients with early and metastatic breast cancer in the south of Brazil. Methods Multicenter prospective observational study, which included 109 patients with early or metastatic HER-2+ breast cancer undergoing any trastuzumab-based regimen. Cardiac events were measured by transthoracic echocardiography assessments and by signs and symptoms of heart failure. Results Trastuzumab-related cardiotoxicity was observed in 58 patients (53.2%). Emergency and hospitalization admissions were necessary in seven and three patients, respectively, due to symptoms of heart failure. One patient died in consequence of trastuzumab-related cardiotoxicity. In total, trastuzumab was discontinued in 31.2% of patients, of which almost a third could not return to treatment. In this study, no risk factors were significantly associated with the development of cardiotoxicity. Discussion The incidence of TRC and trastuzumab's early discontinuation observed was significantly higher in comparison with other studies. These findings endorse the fact that trastuzumab-related cardiotoxicity is a relevant adverse reaction, and therefore, cardiac dysfunction's monitoring must be highlighted in order to allow a safe use of trastuzumab in this population.

The management of Gaucher disease in developing countries: a successful experience in Southern Brazil.

OBJECTIVE: Gaucher disease (GD) is a genetic disease caused by glucocerebrosidase deficiency. GD is treated by enzyme replacement therapy (ERT) with imiglucerase, a high-cost drug provided by the Brazilian Ministry of Health (BMH). This study reports the implementation of the BMH guidelines for GD in the southernmost state of the country. METHODS: We review the clinical and laboratorial data for patients seen at the reference center for GD from Rio Grande do Sul, Brazil (July 2003 to June 2006). RESULTS: Twenty-five patients were included in this study. At baseline, 19/20 were on ERT (mean dosage of imiglucerase = 51.8 U/kg/infusion), 3/17 presented anemia, and 5/16 thrombocytopenia. The amount of imiglucerase prescribed to these patients was adjusted according to the guidelines in July 2003; out of them, 18 were receiving ERT in the reference center at month 36 (mean dosage of imiglucerase = 27.5 U/kg/infusion), 2/18 presented anemia, and 4/18 presented thrombocytopenia. The analysis of the liver, spleen, and bone data presented some limitations, but the available information suggests that patients did not deteriorate. GD patients who initiated ERT after July 2003 (n = 5) received lower dosage of imiglucerase since the beginning of the treatment; most of them demonstrated clinical and laboratorial response. From baseline to month 36, the consumption of imiglucerase by the reference center showed a significant reduction, which represented savings of USD 3 million to the public health system. CONCLUSIONS: The model of care of GD patients suggested by the BMH guidelines appears to be cost-effective and could be an example for management of rare diseases in underdeveloped countries.

Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil.

PURPOSE: To determine the frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions (ADRs), anti-tuberculosis (TB) drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity in a population from Brazil. METHODS: Two hundred and fifty-four Brazilian TB patients using isoniazid (INH), rifampicin (RMP), and pirazinamide (PZA) were tested in a prospective cohort study. NAT2 genotyping was performed by direct PCR sequencing. The association between gastrointestinal ADRs/hepatotoxicity and the NAT2 profile genotype was evaluated by univariate analysis and multiple logistic regression. RESULTS: Of the 254 patients analyzed, 69 (27.2%) were slow acetylators and 185 (72.8%) were fast acetylators. Sixty-five (25.6%) patients were human immunodeficiency virus (HIV)-positive. Thirty-three (13%) and 14 (5.5%) patients developed gastrointestinal ADR and hepatotoxicity, respectively. Of the 14 hepatotoxicity patients, nine (64.3%) were slow acetylators and five (35.7%) were fast acetylators. Sex, age, presence of hepatitis C virus, alcohol abuse, and baseline aminotransferases were not found to be risk factors for hepatotoxicity. However, logistic regression analysis revealed that slow acetylator status and the presence of HIV (p < 0.05) were independent risk factors for hepatotoxicity. CONCLUSIONS: Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs.

Atherosclerosis and acute arterial thrombosis in rabbits: a model using balloon desendothelization without dietary intervention.

Acute thrombosis can be induced in rabbits by a triggering protocol using Russell's viper venom and histamine given after 8 months of a 1% cholesterol diet and balloon desendothelization. In the present study, we tested the hypothesis that aortic desendothelization performed 4 months before the triggering protocol without a high cholesterol diet is a highly effective and less expensive way of producing arterial atherosclerosis and thrombosis. Nineteen male New Zealand white rabbits on a normal diet were studied. The control group (N = 9) received no intervention during the 4-month observation period, while the other group (N = 10) was submitted to aortic balloon desendothelization using a 4F Fogarty catheter. At the end of this period, all animals were killed 48 h after receiving the first dose of the triggering treatment. Eight of 10 rabbits (80%) in the balloon-trauma group presented platelet-rich arterial thrombosis while none of the animals in the control group had thrombus formation (P < 0.01). Thus, this model, using balloon desendothelization without dietary manipulation, induces arterial atherosclerosis and thrombosis and may provide possibilities to test new therapeutic approaches.

Atherosclerosis and acute arterial thrombosis in rabbits: a model using ballon desendothelization without dietary intervention

Acute thrombosis can be induced in rabbits by a triggering protocol using Russell's viper venom and histamine given after 8 months of a 1 per cent cholesterol diet and balloon desendothelization. In the present study, we tested the hypothesis that aortic desendothelization performed 4 months before the triggering protocol without a high cholesterol diet is a highly effective and less expensive way of producing arterial atherosclerosis and thrombosis. Nineteen male New Zealand white rabbits on a normal diet were studied. The control group (N = 9) received no intervention during the 4-month observation period, while the other group (N = 10) was submitted to aortic balloon desendothelization using a 4F Fogarty catheter. At the end of this period, all animals were killed 48 h after receiving the first dose of the triggering treatment. Eight of 10 rabbits (80 per cent) in the balloon-trauma group presented platelet-rich arterial thrombosis while none of the animals in the control group had thrombus formation (P<0.01). Thus, this model, using balloon desendothelization without dietary manipulation, induces arterial atherosclerosis and thrombosis and may provide possibilities to test new therapeutic approaches.

Triggering of plaque disruption and arterial thrombosis in an atherosclerotic rabbit model.

BACKGROUND: It is now recognized that plaque disruption and thrombosis, a process often triggered by activities of the patient, is generally the cause of the onset of acute coronary syndromes. Understanding of disease onset could be greatly enhanced by the availability of a suitable animal model of plaque disruption and thrombosis. The aim of this study was to replicate and further characterize an atherosclerotic rabbit model of triggering of arterial thrombosis that was introduced by Constantinides and Chakravarti more than 30 years ago but not subsequently used. Aortic plaques were induced by a high-cholesterol diet, by mechanical balloon injury of the artery, or by a combination of the two. Triggering was attempted by injection of Russell's viper venom (RVV), which is a proteolytic procoagulant, and histamine. METHODS AND RESULTS: A total of 53 New Zealand White rabbits were exposed to one of four preparatory regimens: rabbits in group I (n = 9) were fed a regular diet for 8 months; rabbits in group II (n = 13) were fed a diet of 1% cholesterol for 2 months alternated with 2 months of a regular diet for a total of 8 months; rabbits in group III (n = 5) underwent balloon-induced arterial wall injury, then were given a regular diet for 8 months; and rabbits in group IV (n = 14) underwent balloon-induced arterial wall injury, then were given a diet of 1% cholesterol for 2 months followed by a regular diet for 2 months for a total of 4 months. After completion of the preparatory regimen, triggering of plaque disruption and thrombosis was attempted by injection of RVV (0.15 mg/kg IP) and histamine (0.02 mg/kg IV). In group I, normal control rabbits without atherosclerosis, only one small thrombus was noted in 1 of 9 rabbits. In group II, cholesterol-fed rabbits, thrombosis occurred in 3 of 13 rabbits. Thrombus occurred in all rabbits in group III (5 of 5) and in 10 of 14 rabbits in group IV. Although the frequency of thrombosis was not significantly different between groups I and II, possibly due to a small sample size, it was significantly different among all four groups (P < .001). Also, the frequency and amount of thrombus formation were significantly different among all four groups (P < .001; P < .0001) but not between groups I and II. Rabbits with atherosclerosis (those in groups II and IV) demonstrated plaque disruption and overlying platelet-rich thrombus formation similar to that observed in patients with acute coronary syndromes. The surface area covered by thrombus was 2 mm2 in group I, 15.3 +/- 19.2 mm2 in group II, 223 +/- 119 mm2 in group III, and 263 +/- 222 mm2 in group IV. Rabbits in groups III and IV had the greatest amount of thrombus, and this amount was significantly greater than in rabbits in groups I and II (P < .001 and P < .03, respectively). CONCLUSIONS: A suitable animal model is available for the study of plaque disruption and arterial thrombosis. Hypercholesterolemia and mechanical arterial wall injury seemed to produce plaques vulnerable to triggering of disruption and thrombosis, whereas normal arteries were relatively resistant to triggering. This model provides a method to evaluate agents that might decrease the occurrence of vulnerable plaques or the amount of thrombus formed after triggering. Most important, the model can be used to identify the features of vulnerable plaques and the pharmacological stressors that trigger plaque disruption and thrombus formation.

Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results.

Seventy-five patients with hemoptysis were treated with bronchial artery embolization (BAE). The procedure was performed with Hexabrix (sodium methylglucamine ioxaglate), Mikaelson catheters, and Gelfoam particles. Angiographic evaluation of the bronchial artery anatomy revealed ten different configurations, which are described. The embolization attempt failed in three cases (4%); eight additional patients (10.7%) were excluded from the series because of inadequate data. In the remaining 64 patients, 41 underwent BAE alone and 23 underwent either chemotherapy or surgery in addition to embolization. Immediate control of hemoptysis was achieved in 49 of 64 patients (76.6%). Long-term control of hemoptysis was achieved in 46 of the 56 patients included in the long-term follow-up (82.1%). Eight of the 64 patients were lost to follow-up, which ranged from one to 47 months (mean 24.8 months). Hemoptysis recurred in 12 of 56 patients (severe in 10, mild in 2) (21.4%). Twelve patients died (21.4%), five of them due to hemoptysis (8.9%). None of the patients who died of hemoptysis had responded to initial BAE. It is concluded that BAE is an effective treatment for immediate control of life-threatening hemoptysis, allowing long-term control of bleeding in the majority of patients.

Management of massive hemoptysis by bronchial artery embolization.

Massive hemoptysis is a major clinical and surgical problem with a mortality of 80%, which is most often related to asphyxiation. Thirty-three patients with massive hemoptysis underwent selective bronchial arteriography and treatment by embolization or surgery. Lasting control of hemoptysis was achieved in 27 of 33 patients (81.8%) at follow-up ranging from one to 24 months. Hemoptysis recurred in six of 33 patients (18.2%). Mortality related to hemoptysis was three of 33 patients (9.0%), and overall mortality was six of 33 patients (18.2%). Seven patients underwent surgical treatment in addition to bronchial artery embolization. Patients with mycetoma suffered the highest relapse of bleeding and the highest mortality in this series. In these patients, bronchial artery embolization may be effective in the control of acute bleeding, but permanent control of hemoptysis is achieved only by later surgery. Bronchial artery embolization is an effective way to control massive hemoptysis with a low recurrence rate and reduced mortality among severely ill patients. Although we have had no unfavorable sequelae, reports of neurological damage following bronchial angiography indicate care in avoiding obstruction of the artery of Adamkiewicz.

Oxalosis associated with an aspergillus niger fungus ball. Report of a case.

During a seventeen day period an A. niger fungus ball evolved within a healed tuberculous cavity of a patient. Symptoms were a cough with a chocolate brown expectoration and dyspnea. The patient died and necropsy was performed. Crystals of calcium oxalate were deposited in the cavity lining and in the adjacent tissue of the lung. Fibrosis, mononuclear infiltration and intraalveolar purulent exudate were seen in these tissues. Some small vessels presented recent thrombosis and deposition of calcium oxalate. The bronchus connected with the cavity presented a disrupted epithelial layer, edema, polymorphonuclear infiltration and birefringent crystals. Scattered areas of tubular atrophy, glomerular sclerosis and lymphoid infiltration were seen in the cortex of the kidney. Oxalate crystals were also seen within the renal tubuli.