Cardiac safety, efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study.

PURPOSE: Cardiotoxicity is a side effect of trastuzumab. We assessed efficacy and cardiac safety of CMF with trastuzumab (CMF+T) in HER2-positive metastatic breast cancer patients (MBC). METHODS: In this phase II study, centrally confirmed, previously treated HER2-positive MBC patients with measurable disease (per RECIST v 1.0) were enrolled. Initially, patients were randomized between 8 CMF cycles alone or combined with trastuzumab during chemotherapy, followed by 3-weekly trastuzumab maintenance till progression. A protocol amendment dropped the CMF arm and thereafter all patients received CMF+T. Translational research for prediction of treatment benefit was performed through serial serum HER2-shed antigen assessments. RESULTS: Ninety patients (CMF: 19; CMF+T: 71) were enrolled between 2002 and 2006. Median age was 54 years. 42 patients had prior chemotherapy (33 with anthracyclines) and 41/71 patients who received CMF+T continued trastuzumab monotherapy for a median duration of 40 weeks. Overall response rate was 50% for CMF+T (35/70) and 32% for CMF (6/19). Median duration of response was 10.3 months and 5.4 months, respectively. Median progression-free survival was 9.4 months (95% CI 8.1-11.6) and 4.8 months (95% CI 2.8-7.9), respectively. In the CMF+T arm, 13(18%) patients had an absolute LVEF decline, including 3 patients developing any grade of New York Heart Association cardiac dysfunction. Patients with an increase of 30% over baseline shed antigen had a higher progression risk (95% CI 7.6, 3.9-14.8). CONCLUSIONS: CMF+T is effective, with an acceptable cardiotoxicity profile. LVEF declines were mostly asymptomatic and occurred irrespective of previous anthracycline exposure. CMF+T can be considered for these patients, if other cytotoxics are contraindicated.

First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients.

BACKGROUND: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice. PATIENTS AND METHODS: Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point. RESULTS: Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9). CONCLUSIONS: The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials.

Alveolar soft-part sarcoma responding to interferon alpha-2b.

A 23-year-old woman with an alveolar soft-part sarcoma of her calf with pulmonary metastases unresponsive to chemotherapy is described. Interferon (IFN) alpha-2b induced an impressive tumour response still ongoing after IFN treatment had to be stopped because of a psychosis. An explanation of this effect is still speculative.

[A gastric signet ring cell carcinoma as the first expression of a breast carcinoma]. / Een zegelringcelcarcinoom van de maag als eerste uiting van een mammacarcinoom.

A 73-year-old woman presented with dull pain in the epigastric region, a rapid feeling of fullness upon eating and a weight loss of 10 kg in 6 months. Further examination showed linitis plastica due to a signet ring cell carcinoma in the stomach, multiple bone metastases, and an occult, small breast tumour. Immunohistochemical comparison of the tumours strongly suggested that all cases involved a metastasised breast carcinoma. At check-up after one year of tamoxifen treatment, the complaints had disappeared and the activity of the tumour marker had dropped. Gastric metastases from breast carcinoma are rare. Nevertheless, this possibility should be kept in mind in women presenting with malignancies of the stomach and mastopathy. Hormonal treatment and chemotherapy may result in reasonable palliation.

[Non-traumatic myositis ossificans circumscripta in the teres major muscle]. / Niet-traumatisch ontstane myositis ossificans circumscripta in de M. teres major.

A 49-year-old male presented with a painful progressive swelling in his right axillar region, without further complaints, which had been present for 2 weeks. On radiological examination a peripheral circumferential zone of mineralisation was seen in the right teres major muscle. An incision biopsy specimen showed a lesion of fibroblastic tissue in which areas of osteoid and fragmented lamellar bone tissue, without signs of malignancy. The diagnosis was myositis ossificans circumscripta. This is a rare benign ossifying lesion in skeletal muscles, mostly caused by a trauma and with an average age of occurrence between 20 and 30 years old. It must be differentiated from extra-skeletal osteosarcoma. The pathogenesis is unknown. Because it is a benign and self-limiting disorder, surgical excision is only necessary in case of mechanical hindrance. The patient's swelling partially regressed and he had no further complaints.

Iron does not bind to the Apo-B protein of low-density lipoprotein.

BACKGROUND: Epidemiological and experimental evidence suggests that (nontransferrin-bound) iron plays an important role in atherogenesis by catalysing peroxidation of low-density lipoprotein (LDL). However, the mechanism of the interaction of iron and LDL is unclear. Iron has to be in the closest vicinity of LDL in order to catalyse the formation of the short-lived hydroxyl. In this study we investigated whether iron can bind to LDL in order to facilitate LDL peroxidation. METHODS: LDL and [(59)Fe]ferric citrate were incubated at 37 degrees C and pH 7.4 for 30 min. Unbound [(59)Fe]ferric citrate was separated from LDL using a Sephadex G25-M column. Activity of [59Fe]ferric citrate was measured in the collected fractions. A control experiment was performed using albumin instead of LDL. RESULTS AND CONCLUSION: No binding was observed between iron, as a low molecular weight Fe(III) complex, and LDL. As a control albumin was able to bind iron, it seems evident that interaction of iron with LDL will involve other iron complexes.

Biochemical expression of heterozygous hereditary hemochromatosis.

Background: Hereditary hemochromatosis (HH) is a common autosomal recessive disease caused by an iron overload. Two mutations (C282Y and H63D) on the responsible HFE gene have been described. HH heterozygotes may have a slight iron overload that does not cause clinical disease. Compound heterozygosity may be associated with higher iron stores than C282Y heterozygosity. We studied biochemical iron parameters in HH C282Y and compound heterozygotes without a clinically significant iron overload. Methods: Data on hemoglobin, hematocrit, mean corpuscular volume, serum ferritin, serum iron, transferrin, and transferrin saturation were obtained from 40 C282 wild type controls (irrespective of H63D genotype), 61 C282Y heterozygotes, and 18 compound (C282Y/H63D) heterozygotes without clinical iron overload disease. Results: Serum ferritin levels were significantly higher in female HH heterozygotes, particularly in compound heterozygotes, than in normal women. In male heterozygotes, no difference in serum ferritin was found. We found higher mean serum iron and transferrin saturation levels in male and female HH heterozygotes than in normal controls, the highest in the group of compound heterozygotes. Conclusions: Mean serum ferritin (only in women), serum iron, and transferrin saturation are highest in compound heterozygotes and lowest in controls. C282Y heterozygotes seem to be an intermediate group between compound heterozygotes and the normal population.

Non-transferrin-bound iron is present in serum of hereditary haemochromatosis heterozygotes.

BACKGROUND: Hereditary haemochromatosis (HH) is a common autosomal recessive disease. Recently, HH heterozygosity has been identified as an independent risk factor for myocardial infarction and cardiovascular mortality. Iron may play an important role in atherogenesis by catalyzing peroxidation of low-density-lipoprotein (LDL), an essential step in atherogenesis. In iron overload conditions, non-transferrin-bound iron (NTBI) is found in serum, which can catalyze lipid peroxidation. We investigated whether sera of HH heterozygotes contain more NTBI than sera of normal controls. METHODS: In 27 treated HH homozygotes, 22 HH heterozygotes and 17 healthy control subjects, conventional parameters of iron status (serum iron, transferrin saturation, serum ferritin) were measured. NTBI was detected using HPLC after addition of nitrilotriacetic acid and pretreatment with cobalt. RESULTS: The conventional parameters of iron status were similar in the HH heterozygous group and the control group. NTBI was significantly higher in homozygotes compared to heterozygotes (1.79 micromol L-1 vs. 0.51 micromol L-1, 95% CI of the difference = 0.6-1.95, P < 0.001), and controls (1.79 micromol L-1 vs. - 0.3 micromol L-1, 95% CI of the difference = 1.36-2.81, P < 0.001). The difference in NTBI between the heterozygous subjects and control subjects was also significant (0.51 micromol L-1 vs. - 0. 3 micromol L-1, 95% CI of the difference = 0.05-1.57, P < 0.05). CONCLUSION: Phlebotomy treated HH homozygotes maintain a high and potentially harmful serum NTBI. HH heterozygotes have a higher serum NTBI than normal controls. The reported increased risk of cardiovascular events in heterozygous haemochromatosis may be explained by NTBI-catalyzed LDL peroxidation.

Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women.

Background-The genetic background of hereditary hemochromatosis (HH) is homozygosity for a cysteine-to-tyrosine transition at position 282 in the HFE gene. Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death. Methods and Results-We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12 239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182 976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3. 5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3. 3%, 8.8%, and 4.0%, respectively. In addition, we found evidence for effect modification by hypertension and smoking. Conclusions-We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors.

Iron, atherosclerosis, and ischemic heart disease.

OBJECTIVE: To review the epidemiological and experimental data concerning iron and the development of atherosclerosis and ischemic heart disease. DATA SOURCES: The English-language literature was searched from 1981 through 1998 manually and using MEDLINE and Current Contents. Important references in the articles that were found were also included in this review. RESULTS: There is growing epidemiological evidence for a relationship between iron levels and cardiovascular disease. Some experimental data support the role of iron in the process of lipid peroxidation, the first step in the formation of atherosclerotic lesions. Macrophages and endothelial cells are involved in this process, but the exact mechanism and the sites of the interactions between these cells, iron, and low-density lipoprotein are still unknown. CONCLUSIONS: Strong epidemiological evidence is available that iron is an important factor in the process of atherosclerosis. Epidemiological studies, eg, prospective follow-up studies in blood donors, may clarify the cardiovascular benefits of iron depletion. Knowledge of the molecular mechanism of iron-related cardiovascular disease is still limited. We speculate that catalytically active iron species modify low-density lipoprotein levels to interact with the macrophage oxidized low-density lipoprotein receptor. Both nontransferrin-bound plasma iron and hemoglobin are candidates for such interactions.