Prognostic significance of proliferative activity, DNA-ploidy, p53 and Ki-ras point mutations in colorectal liver metastases

Paired colorectal liver metastases (CLM) and normal tissue samples from a consecutive series of 36 patients were studied prospectively. MIB-1 expression was studied by immunohistochemistry on paraffin-embedded sections. DNA ploidy and S-phase fraction (SPF) measurements were performed by flow cytometry on frozen tissues. Mutations within the p53 (exons 5-8) and c- Ki-ras (codons 12 and 13) genes were detected by PCR single-strand conformation polymorphism analysis followed by sequencing. A high correlation was observed between the MIB-1 LI and SPF value (rho=0.81; P <0.01). Moreover, p53 gene mutations were associated with either high MIB-1 LI and high SPF. In univariate analysis, SPF and MIB-1 levels were related to risk of death. The association between overall survival and DNA-ploidy or p53 mutations did not reach statistical significance, but a slightly better survival was observed for patients either with DNA-diploid tumours or without mutations ( P =0.05 and P =0.06, respectively). SPF was shown by multivariate Cox model analysis to be an independent prognostic variable and thus it might be a useful prognostic factor in patients with CLM.     

Hemostasis During Urologic Surgery: Fibrin Sealant Compared With Absorbable Hemostat

In the United States, fibrin sealants have been used to achieve hemostasis for nearly two decades. Although their clinical utility was first demonstrated in cardiac surgery, their effectiveness and safety have since been demonstrated to extend to a wide array of procedures. Fibrin sealants typically contain two components—fibrinogen and thrombin—that are combined and delivered simultaneously to a target bleeding site in order to achieve hemostasis. However, many commercial formulations contain other additional components, such as antifibrinolytic agents, that have been associated with adverse outcomes. This subanalysis compares the safety and effectiveness of a fibrin sealant versus an absorbable hemostat for achieving hemostasis during urologic procedures with mild to moderate bleeding.Key words: Hemostasis, Hemostatics, Fibrin tissue adhesive, Urologic surgical procedures, Surgical techniqueIn the United States, fibrin sealants have been used to achieve hemostasis for nearly two decades. Although their clinical utility was first demonstrated in cardiac surgery,¹ their effectiveness and safety have since been demonstrated to extend to a wide array of procedures, including cardiovascular, gastrointestinal, pneumothoracic, neurologic, urologic, otolaryngologic, dental, and reconstructive surgeries.^2,3 Within the field of urology, fibrin sealants have been used to manage bleeding from renal trauma,⁴ as well as to facilitate hemostasis during renal surgeries, including partial nephrectomies.^5–7Fibrin sealants typically contain two components—fibrinogen and thrombin—that are combined and delivered simultaneously to a target bleeding site (TBS) in order to achieve hemostasis.³ Many commercial formulations contain other additional components, such as antifibrinolytic agents, that have been associated with adverse outcomes. For example, in an observational study (N = 4374), the antifibrinolytic aprotinin was associated with an increased risk of long-term mortality within 5 years following coronary artery bypass graft surgery.⁸ Furthermore, repeated exposure to aprotinin may lead to allergic or potentially fatal anaphylactic reactions.^9–11 For this reason, the US Food and Drug Administration (FDA) issued an alert in 2006 indicating that caution should be used when using aprotinin in patients with a history of previous exposure to the product.¹² Tranexamic acid, another antifibrinolytic present in some commercial fibrin sealants, has been associated with alterations in neural tissue growth and adherence.¹³ Because of the risk of cerebral neurologic toxicity, fibrin sealants containing tranexamic acid are contraindicated for use in neurosurgery or in surgical procedures during which contact with cerebrospinal fluid or dura mater may occur.¹⁴In a phase III, randomized, single-blind, parallel-group, multicenter study,¹⁵ the fibrin sealant CROSSEAL™ (Ethicon, Inc., Somerville, NJ) significantly reduced the time to hemostasis during liver resection surgery compared with conventional hemostatic techniques. EVICEL® Fibrin Sealant (Human) (Ethicon, Inc.), the successor of CROSSEAL, requires no antifibrinolytic additive and is therefore both aprotinin and tranexamic acid free, and achieves hemostasis using exclusively human components.¹⁶ The effectiveness and safety of this fibrin sealant for hemostasis in soft tissue during elective retroperitoneal or intra-abdominal surgery were compared with an absorbable hemostat (SURGICEL® Absorbable Hemostat; Ethicon, Inc.) in a randomized, active-controlled, multicenter study.¹⁷ This article describes a subanalysis of data from the largest patient subgroup from that study, and evaluates the effectiveness and safety of a fibrin sealant versus an absorbable hemostat for patients who underwent urologic surgical procedures.     

Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases

The text describes a preventive clinical trial with drug treatment in a very rare neurodegenerative disease (Fatal familial Insomnia, FFI) designed with the help of individuals at genetic risk of developing the disease, asymptomatic carriers, who have agreed to be exposed over a 10-year period to doxycycline, an antibiotic with anti-prion activity. At least 10 carriers of the FFI mutation over 42 y old will be treated with doxycycline (100 mg/die) and the incidence of the disease will be compared to that of an historical dataset. For ethical reasons a randomized, double-blind, placebo-controlled trial was not feasible, however the study design and the statistical analysis ensure the scientific value of the results. This approach might represent an important breakthrough in terms of potential therapy and knowledge of rare diseases that could give some hopes to these neglected patients.     

Association of urinary 15-F2t-isoprostane level with oxygen desaturation and carotid intima–media thickness in nonobese sleep apnea patients

Obstructive sleep apnea (OSA) is characterized by recurrent apnea during sleep that may unbalance oxidative stress, increasing atherosclerosis. Among oxidative stress markers, 15-F_2t-isoprostane is considered one of the most sensitive and specific metabolites of lipid peroxidation. To explore the relationship between urinary 15-F_2t-isoprostane with sleep apnea severity and carotid modifications in nonobese OSA patients, 31 nonobese sleep apnea patients were studied, along with 10 lean subjects without OSA. Patients were assessed by polysomnography, blood pressure measurement, and ultrasonography to determine the carotid intima–media thickness (IMT). Urinary 15-F_2t-isoprostanes were measured by liquid chromatography–tandem mass spectrometry. Urinary 15-F_2t-isoprostane concentrations were increased in severe OSA patients compared to control subjects (20.2 ± 7.3 vs 12.3 ± 2.8 ng/mmol creatinine; P = 0.020). Mean carotid IMT was correlated with 15-F_2t-isoprostane (r = 0.532; P < 0.001) and with the apnea–hypopnea index (r = 0.345; P = 0.029). 15-F_2t-Isoprostane level was related to the night time spent at SaO₂ < 90% (r = 0.478; P = 0.002), the apnea–hypopnea index (r = 0.465; P = 0.003), and the mean nocturnal SaO₂ (r = ? 0.424; P = 0.007). These results showed a relationship between lipid peroxidation, carotid intima–media thickness, and intermittent hypoxia in nonobese OSA patients, thus reinforcing the hypothesis that oxidative stress could be involved in the early atherosclerotic process.     

Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling

Gene expression profiling technology is expected to advance our understanding of genotoxic mechanisms involving direct or indirect interaction with DNA. We exposed human lymphoblastoid TK6 cells to 14 anticancer drugs (vincristine, paclitaxel, etoposide, daunorubicin, camptothecin, amsacrine, cytosine arabinoside, hydroxyurea, methotrexate, 5-fluorouracil, cisplatin, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), and bleomycin) for 4-h and examined them immediately or after a 20-h recovery period. Cytotoxicity and genotoxicity, respectively, were evaluated by cell counting and by in vitro micronucleus assay at 24h. Effects on the cell cycle were determined by flow cytometry at 4 and 24h. Gene expression was profiled at both sampling times by using human Affymetrix U133A GeneChips (22K). Bioanalysis was done with Resolver/Rosetta software and an in-house annotation program. Cell cycle analysis and gene expression profiling allowed us to classify the drugs according to their mechanisms of action. The molecular signature is composed of 28 marker genes mainly involved in signal transduction and cell cycle pathways. Our results suggest that these marker genes could be used as a predictive model to classify genotoxins according to their direct or indirect interaction with DNA.     

The ethics of cesarean section on maternal request: a feminist critique of the American College of Obstetricians and Gynecologists' position on patient-choice surgery

In recent years, the medical establishment has been speaking in favor of women's autonomy in childbirth by advocating cesarean delivery on maternal request (CDMR). This paper offers to look at the ethical dimension of CDMR through a feminist critique of the medicalization of childbirth and its influence on present-day medical ethics. I claim that the medicalization of childbirth reflects a sexist bias with regard to conceptions of the body and needs to be used with caution when applied to women's reproductive health. I then use this perspective to critically analyze the position of the American College of Obstetricians and Gynecologists (ACOG) on the ethics of decision-making in patient-choice surgery. I claim that informed consent cannot be meaningfully exercised unless women are made aware of the sexist underpinnings of the medical model of childbirth and its influence on the ethical reasoning of the American College of Obstetricians and Gynecologists. I also express concern about the effects of normalizing patient-choice cesarean sections on the choices available to pregnant women using as examples the institutional rules on mandatory cesarean sections for women with a previous cesarean delivery or breech presentation. I conclude with a call for more research into the real cost of convenience in CDMR, particularly as our increasingly strained publicly funded healthcare system would greatly benefit from the de-medicalization of normal body functions rather than an increased dependence on costly surgical technology.