Clinical experience with gefitinib: an update

Gefitinib is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways involved in cell proliferation. This drug demonstrated impressive and durable responses in patients with heavily pretreated non-small cell lung cancer (NSCLC). In two large phase II trials, responses were observed in 9-19% of unselected patients, along with symptom improvement and benefit in quality of life. Biological mechanisms underlying TKI sensitivity have recently been discovered. There is evidence that specific EGFR gene mutations and/or amplification confer a particularly sensitive phenotype, especially in individuals with tumors demonstrating activation of the anti-apoptotic protein Akt. However, in all so far conducted clinical trials, no patient selection has been made, providing a logical explanation for the negative results observed in large phase III studies. In the present review, we will summarize the results observed in clinical trials with gefitinib. We will present results obtained in NSCLC and in other solid tumor, focusing on biological and clinical markers predicting drug sensitivity.     

Actin polymerization in neutrophils from donors of peripheral blood stem cells: divergent effects of glycosylated and nonglycosylated recombinant human granulocyte colony-stimulating factor

Neutrophil functions can be modified by Recombinant human G-CSF (rhG-CSF) treatment, with divergent effects on phagocytosis, motility, bactericidal activity, and surface molecule expression. Neutrophil morphology is modified by treatment with filgrastim (the nonglycosylated form of rhG-CSF), while it is not affected by lenograstim (the glycosylated type of rhG-CSF). Little information is available about actin polymerization in neutrophils from subjects treated with the two types of rhG-CSF. In the current paper we evaluated two groups of donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. Ten subjects were treated with filgrastim and 10 with lenograstim to mobilize PBSC; 15 blood donors were evaluated as a control group. Actin polymerization (both spontaneous and fMLP-stimulated) was studied by a flow cytometric assay. A microscopic fluorescent assay was also carried out to evaluate F-actin distribution in neutrophils. We found that filgrastim induced an increased F-actin content in resting neutrophils, along with morphologic evidence for increased actin polymerization distributed principally at the cell membrane and frequently polarized in focal areas; in addition, fMLP was not able to induce further actin polymerization. On the contrary, treatment with lenograstim was associated with F-actin content, distribution, and polymerization kinetics indistinguishable from those displayed by control neutrophils. Such experimental results show that filgrastim and lenograstim display divergent effects also on neutrophil actin polymerization and provide further explanation for previous experimental findings.     

Giant congenital aortic aneurysm with cleft sternum in a neonate: pathological and surgical considerations for optimal management

We report a rare case of a neonate with congenital giant aortic aneurysm associated to cleft sternum, who underwent surgical repair. The patient died on postoperative Day 5 from cardiac arrest. Autopsy revealed a circumferential subendocardial myocardial infarction and misdiagnosed coronary ostial anomalies. A critical analysis of this unfortunate case may help optimal surgical planning in similar patients in the future.     

Mutant p53 proteins: between loss and gain of function

Cancer might result from both the aberrant activation of genes, whose physiological tuning is essential for the life of a normal cell, and the inactivation of tumor suppressor genes, whose main job is to preserve the integrity of cell genome. Among the latter, p53 is considered a key tumor suppressor gene that is inactivated mainly by missense mutations in half of human cancers. It is becoming increasingly clear that the resulting mutant p53 proteins gain oncogenic properties favoring the insurgence, the maintenance, and the spreading of malignant tumors. In this review, we mainly discuss the molecular mechanisms underlying gain of function of human tumor-derived p53 mutants, their impact on the chemoresistance and the prognosis of human tumors, with a special focus on head and neck cancers, and the perspectives of treating tumors through the manipulation of mutant p53 proteins.     

Tension-free vaginal tape versus transobturator tape as surgery for stress urinary incontinence: results of a multicentre randomised trial

OBJECTIVES: This prospective, multicentre, randomised study compared the safety and success rate of tension-free vaginal tape (TVT) and transobturator tape (TOT) in treatment of female stress urinary incontinence. METHODS: Of 148 women, 73 were randomised to TVT and 75 to TOT. Preoperative workups included case history, clinical examination, Urogenital Distress Inventory and Impact Incontinence Quality of life questionnaires, 1-h pad test, pelvic ultrasound, and urodynamics. Intra- and postoperative complications were the primary end point; subjective and objective changes in SUI, and postoperative voiding dysfunctions were secondary end points. Patients were classified into two main categories: dry (no leakage during clinical and/or stress test and/or reported by patients) versus wet. Patients who referred being wet were separated into "improved" or "failure" on subjective analysis. Other outcome variables were quality of life questionnaires and VAS scale. Clinical checkups were conducted at 3, 6, 12 mo, and then annually. RESULTS: Both techniques are safe and no significant differences emerged in intra- and postoperative complications. At a mean follow-up of 31 mo, the overall objective cure (dry) was 71.4% for TVT and 77.3% for TOT (p=ns). When one considered "dry" plus "wet but improved," these values increased to 90% and 90.6%, respectively (p=ns). Median satisfaction rate was 9 (range: 1-10) for both procedures. Postoperative storage symptoms are a controversial issue; they persisted in 44% of patients in TVT group versus 24% in TOT group (p<0.053). CONCLUSIONS: TOT appears as safe and effective as TVT in surgery for female SUI, with minimal complications at mean follow-up of 31 mo.     

Recent advances in the medical management of breast cancer: highlights from the 29th San Antonio Breast Cancer Conference San Antonio, TX, USA, 14-17 December 2007

The 29th edition of the San Antonio Breast Cancer Symposium was attended by a total of > 8000 basic scientists, translational researchers, clinical investigators and physicians gathering from approximately 80 countries worldwide. This is the largest meeting focusing on breast cancer, encompassing a wide array of topics from prevention, aetiology and diagnosis to molecular biology and treatment. From the main presentations at the meeting, it seems clear that combined efforts at prevention and treatment of this disease have translated into small, but significant, achievements. Much of the research in the area is focused on improving the therapeutic ratio of available treatments by better selection of patients.     

Evaluation of Liberase, a purified enzyme blend, for the isolation of human primordial and primary ovarian follicles

BACKGROUND: The purpose of this study is to evaluate the effectiveness of a standardized mixture of purified enzymes (Liberase), for the isolation of human ovarian follicles. METHODS: This is an experimental prospective study. Ovarian biopsies were obtained from eight young women undergoing laparoscopy for benign gynaecological disease. Follicles were isolated by Liberase or collagenase enzymatic digestion. Follicle quality was assessed by evaluating their general morphology and viability after fluorescent staining, and the ultrastructure by electron microscopy. RESULTS: The number of fully isolated follicles recovered from the Liberase-treated group was lower than from the collagenase group (156 versus 263) despite equal-sized biopsies being taken. A high proportion of follicles (98.6%, 70/71) were viable after Liberase isolation and most follicles were of good morphology with a complete granulosa cell layer (70.4%, 31/44). Ultrastructural studies indicated that Liberase-isolated follicles showed signs of atresia only occasionally and that the oolemma-follicular cell interface was well preserved. CONCLUSIONS: Liberase treatment allows the isolation of highly viable follicles from human ovarian tissue, with an unaltered morphology and ultrastructure. This purified endotoxin-free enzyme preparation is a promising alternative to impure collagenase preparations for the reproducible isolation of intact primordial and primary follicles for culture and grafting purposes.