Breast cancer highlights: key findings from the San Antonio Breast Cancer Symposium: a U.S. perspective

The San Antonio Breast Cancer Symposium has become one of the leading forums for communication of important discoveries in breast cancer research. Over the past couple of years, seminal, practice-changing results have been presented at this meeting. The aromatase inhibitors represent the most effective endocrine interventions for postmenopausal women with hormone receptor-positive breast cancer. Their introduction into the adjuvant therapy of primary breast cancer was prompted by evidence from the ATAC trial. Progress in adjuvant chemotherapy included the introduction to taxanes, and more recently, the demonstration that the dose-dense administration of paclitaxel in association with doxorubicin and cyclophosphamide resulted in significant improvements in relapse-free and overall survival rates. Molecular targets have become accepted as rational targets, and targeted therapies are proceeding through clinical trials. The success of trastuzumab elicited much excitement, but a number of theoretical and practical hurdles must be overcome before other molecularly targeted agents are incorporated into standard therapy of primary and metastatic breast cancer.     

Hepatitis C virus infection associated with liver-kidney microsomal antibody type 1 (LKM1) autoantibodies in children

OBJECTIVE: To evaluate the clinical pattern and evolution of chronic hepatitis C in children with liver/kidney microsomal antibody type 1 autoantibodies (LKM1). STUDY DESIGN: A multicenter, retrospective study, including the following groups of children with hepatitis C virus infection: (1). 21 consecutive LKM1-positive patients, (2). 42 age- and sex- matched LKM1-negative patients, and (3). 4 interferon-induced LKM1-positive cases. LKM1 reactivity to human microsomes and recombinant cytochrome P450IID6 (CYP2D6) was assayed by immunoblotting. RESULTS: Clinical and biochemical features overlapped in LKM1-positive and LKM1-negative children, but a fibrosis score >3 (range 0-6) was significantly more frequent (P =.04) in the former. Reactivity to microsomal protein and CYP2D6 was significantly (P =.02) associated with LKM1 titers >or=1:320 and was found in 39% of patients, including severe cases and both children (of 4 treated) who achieved a sustained alanine aminotransferase (ALT) normalization after steroid treatment. Five of 7 LKM1-positive children treated with interferon had an ALT exacerbation. CONCLUSIONS: LKM1-positive hepatitis C in children is characterized by a wide spectrum of biochemical, serologic, and histologic features. Whether autoimmunity may contribute to liver damage in a subgroup of patients with more severe liver disease, high LKM1 titers, and reactivity to CYP2D6 is a question deserving further investigation.     

Nitric oxide produced by the enterocyte is involved in the cellular regulation of ion transport

The role of nitric oxide (NO) in the intestinal basal ion transport and under conditions of enterotoxin-induced ion secretion is controversial. Namely it is not clear whether NO enhances or counteracts intestinal ion secretion and whether the effects on transport result from a direct interaction with the enterocyte. The cell origin of NO is also unclear. We have tested the hypothesis that NO produced by the enterocyte directly regulates ion transport processes either in basal condition or in response to cholera toxin-induced secretion. Electrical variables reflecting transepithelial ion transport were measured in Caco-2 cell monolayers mounted in Ussing chambers exposed to the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester, in the presence or absence of cholera toxin. cAMP concentrations were also measured. NO release was determined by nitrite-nitrate concentration. NO synthase activities were assayed by Western blot analysis. Nomega-nitro-l-arginine methyl ester had a secretory effect, as judged by increased basal short-circuit current and cAMP concentration. It also increased cholera toxin-induced electrical response and cAMP production. Either cholera toxin or the cAMP analog 8-bromo-cAMP induced a rapidly progressive and Ca2+-dependent increase in NO concentration, suggesting a homeostatic up-regulation of the constitutive form of NO synthase. Western blot analysis showed an increase in constitutive NO synthase enzyme isoform. These results indicate that the enterocyte regulates its own ion transport processes, either in basal condition or in the presence of active secretion, through the activation of a constitutive NO synthase-NO pathway, functioning as a braking force of cAMP-induced ion secretion.     

Blood withdrawal and infusion via umbilical catheters: effect on cerebral perfusion and influence of ibuprofen

Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preterm infants. We compared the effects on cerebral perfusion of 3 ml/kg blood withdrawal and infusion via umbilical arterial (UAC) and venous (UVC) catheters in 16 infants < or =32 weeks gestation, age <24 h, on mechanical ventilation. Near infrared spectroscopy was used to monitor changes in cerebral oxy- and deoxyhemoglobin, total cerebral hemoglobin (an index of cerebral blood volume; CBV) and HbD (an index of cerebral intravascular oxygenation). In 10 infants the study was repeated 1 h after intravenous administration of 10 mg/kg ibuprofen as prophylaxis against PDA. Withdrawal and infusion via the UVC caused significant MABP and concordant HbD and CBV changes. Smaller modifications were seen following blood withdrawal and infusion via the UAC. Ibuprofen attenuated cerebral hemodynamic changes associated with withdrawal, but not infusion, from UAC and UVC.     

Fetal cricotracheal manipulation: effects on airway healing,cricoid growth and lung development

The last decade has seen significant advance in the surgical management of pediatric subglottic stenosis, which remains one of the most fascinating problems of the laryngotracheal complex (LTC). Refined techniques for operating on these fragile structures should reduce cricotracheal scarring to a minimum, thus avoiding a lot of severe postoperative complications in a tricky moment of laryngeal's growing up. Experimental works indicates that the LTC growth is variously affected by longitudinal anterior, posterior or lateral incisions and actually the indications for laringotracheoplasty or cricotracheal resection in children with subglottic stenosis are still unclear. Reports on fetal manipulation of cricotracheal tissues are lacking as well as early effects on airway healing, LTC growth and lung development. The aim of this study was to evaluate if the airway mucosal healing is regenerative and scarless after cricotracheal manipulation in fetuses of New Zealand White Rabbits (NZWRFs). The consequences of fetal incisions on the cricoid growth and lung development are also examined, in a group of 12 NZWRFs, manipulated at 25±1 days of gestational age. The does underwent halothane anesthesia and all received a bilateral longitudinal cricoidotracheotomy. Twenty sham-operated fetuses were submitted to a limited cervicotomy (control's group). At the time of retrieval (31±0.5 days), en bloc laryngotracheobronchial tree and lungs were collected and processed for histological and morphometric analysis. Parameters recorded included: 1)histological full-thicknes examinations focusing on inflammation, foreign body reaction, fibrosis, neochondrogenesis; 2)morphometric analysis, including the fetal Subglottic Diameter (FSD), the fetal Subglottic Area (FSA), the Radial Alveolar Count (rAC) and Computer Assisted Morphometric Colorimetry (CAmc); 3)analysis of lung hypoplasia (LH) by means of lung weight/body weight (LW/BW) ratio, protein and DNA indexes; 4)finally, different fractions of lung tissue phospholipids for lung maturity assessment were studied. Student's t test, when indicated, was performed for statistical analysis (p <0.05 = significant). There was no maternal mortality in this study. Ten fetuses were available for a final evaluation (16.6% mortality). In one case only, an incomplete closure of the fetal cricoidotomy was seen and could be probably due to a technical mistake. Mean fetal subglottic diameter and area were respectively 0.13±0.05 mm and 3.15±0.45 mm2 in both groups. As well as in fetal dermal repair, regeneration of the airway cartilage and mucosa were complete and scarless. LW/BW ratio, DNA content and analysis of different fractions of phospholipids were similar in experimental vs. the control group. These findings suggest that the healing processes were fibrosis-free and without evidence of scars. A complete closure of the incisions was achieved without stenosis of the fetal subglottic region. In addition, it seems that the fetal cricoidotracheotomy doesn't interfere with the laryngeal function which coordinate the amount of liquid leaving the lungs via the trachea. In addition, only a small leakage of amniotic fluid is shown and this could be responsible for normal and mature lungs.     

Bronchiolar columnar cell dysplasia—genetic analysis of a novel preneoplastic lesion of peripheral lung

Atypical adenomatous hyperplasia is the only known precursor lesion of lung adenocarcinomas (ACs) so far. Here, we describe a new dysplastic lesion in the bronchioles of peripheral lung for which we propose the name bronchiolar columnar cell dysplasia (BCCD). Eight of fourteen BCCDs were successfully analyzed by means of comparative genomic hybridization (CGH). The average number of chromosomal aberrations was 2.6 in BCCD and 14.7 in concomitant AC. Among the aberrations were losses of 3p, 9, 13, 14 and gains of 1q, 17, 19q and 20q. Summarizing our data from morphological and genetic analysis, we conclude that BCCD is a preneoplasia of the bronchiolar epithelium and most probably represents an additional precursor lesion of lung adenocarcinomas.     

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1) is an autosomal dominant disorder characterised by progressive degeneration of right ventricular myocardium, arrhythmias and risk of sudden death. By linkage analysis, we previously mapped the involved gene to chromosome 14q24.3. In the present study we report on linkage analysis of one additional and unrelated family, which enabled to confirm previous locus assignment. Another family is reported, in which genetic and clinical data suggest linkage to the same locus. Direct sequencing of DNA from individuals belonging to established ARVD1 families failed to detect causative mutations in exonic sequences of four genes (POMT2, TGFbeta3, KIAAA1036 and KIAA0759) expressed in the heart and which defects could possibly induce plasma membrane instability or apoptosis, key features of ARVD pathogenesis.