Background The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Methods We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). Results The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 ...

Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2

There is convincing evidence that cellular prooxidant states--that is, increased concentrations of active oxygen and organic peroxides and radicals--can promote initiated cells to neoplastic growth. Prooxidant states can be caused by different classes of agents, including hyperbaric oxygen, radiation, xenobiotic metabolites and Fenton-type reagents, modulators of the cytochrome P-450 electron-transport chain, peroxisome proliferators, inhibitors of the antioxidant defense, and membrane-active agents. Many of these agents are promoters or complete carcinogens. They cause chromosomal damage by indirect action, but the role of this damage in carcinogenesis remains unclear. Prooxidant states can be prevented or suppressed by the enzymes of the cellular antioxidant defense and low molecular weight scavenger molecules, and many antioxidants are antipromoters and anticarcinogens. Finally, prooxidant states may modulate the expression of a family of prooxidant genes, which are related to cell growth and differentiation, by inducing alterations in DNA structure or by epigenetic mechanisms, for example, by polyadenosine diphosphate-ribosylation of chromosomal proteins.

https://science.sciencemag.org/content/sci/227/4685/375.full.pdf

Prooxidant states and tumor promotion.

Objectives: To obtain reliable estimates of the effects of neuraxial blockade with epidural or spinal anaesthesia on postoperative morbidity and mortality. Design: Systematic review of all trials with randomisation to intraoperative neuraxial blockade or not. Studies: 141 trials including 9559 patients for which data were available before 1 January 1997. Trials were eligible irrespective of their primary aims, concomitant use of general anaesthesia, publication status, or language. Trials were identified by extensive search methods, and substantial amounts of data were obtained or confirmed by correspondence with trialists. Main outcome measures: All cause mortality, deep vein thrombosis, pulmonary embolism, myocardial infarction, transfusion requirements, pneumonia, other infections, respiratory depression, and renal failure. Results: Overall mortality was reduced by about a third in patients allocated to neuraxial blockade (103 deaths/4871 patients versus 144/4688 patients, odds ratio=0.70, 95% confidence interval 0.54 to 0.90, P=0.006). Neuraxial blockade reduced the odds of deep vein thrombosis by 44%, pulmonary embolism by 55%, transfusion requirements by 50%, pneumonia by 39%, and respiratory depression by 59% (all P Conclusions: Neuraxial blockade reduces postoperative mortality and other serious complications. The size of some of these benefits remains uncertain, and further research is required to determine whether these effects are due solely to benefits of neuraxial blockade or partly to avoidance of general anaesthesia. Nevertheless, these findings support more widespread use of neuraxial blockade.

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Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials.

Antithrombotic therapy for venous thromboembolic disease.

Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABAA receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABAA receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.

https://www.jneurosci.org/content/jneuro/23/3/876.full.pdf

Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits

The potency and anesthetic state produced by nitrous oxide alone were investigated in order to clarify its contribution to the effect of other anesthetic agents. Seven volunteers anesthetized with 1.55 atm absolute N2O in a pressure chamber displayed muscle rigidity with jerking movements, labored and rapid breathing, sweating, and dilated pupils. At 1.1 atm absolute N2O, relaxation and quiescence occurred, sweating ceased, and pupil size decreased. Determination of MAC (using tetanic electrical impulses as the noxious stimulus) produced a mean value of 1.04 +/- 0.10 (SE) atm absolute. All subjects complained of nausea and vomiting after anesthesia.

The minimum alveolar concentration of nitrous oxide in man.

This is a new edition of the short textbook of Anaesthesia aimed at the FCA Part 1 exam and for all equivalents around the world. It covers the whole range of anaesthesia and presents the subject as an integrated development from the basic sciences, incorporating Anatomy, Physiology and Pharmacology of relevance to anaesthetists.

Textbook of Anaesthesia

General anesthesia may predispose patients to aspiration of gastroesophageal contents because of depression of protective reflexes during loss of consciousness. In addition, some patients may be at increased risk of pulmonary aspiration because of retention of gastric contents caused by pain, inadequate starvation, or gastrointestinal pathology resulting in reduced gastric emptying and gastroesophageal reflux. Despite increasing knowledge of the problems associated with aspiration, the relatively small incidence and associated mortality rates in the perioperative period do not appear to have changed markedly over the last few decades. In this review article, the physiological factors associated with an increased risk of gastroesophageal reflux and aspiration are considered together with some of the methods that are used to prevent aspiration. In particular, preoperative starvation, the use of drugs designed to increase gastric pH, recent developments in airway devices, and appropriate application of cricoid pressure are critically appraised.

/pdf/gastroesophageal-reflux-and-aspiration-of-gastric-contents-mn17o9h5zv.pdf

Gastroesophageal reflux and aspiration of gastric contents in anesthetic practice.

The toxicity of oxygen.

The effects of alfentanil (given during induction of anaesthesia) on the haemodynamic and catecholamine responses to tracheal intubation were studied in 44 adult patients who received alfentanil 10 μg kg−1 or 40 μg kg−1, or saline placebo. Alfentanil 10 μg kg−1 and 40 fig kg−1 prevented any increase in heart rate and arterial pressure after tracheal intubation. Alfentanil 40 μg kg−1 produced profound hypotension and bradycardia. The use of alfentanil in both doses was associated with a decrease in plasma adrenaline concentrations after tracheal intubation.

Graham Smith

Papers

The minimum alveolar concentration of nitrous oxide in man.

Textbook of Anaesthesia

Gastroesophageal reflux and aspiration of gastric contents in anesthetic practice.

The toxicity of oxygen.

Effects of alfentanil on the pressor and catecholamine responses to tracheal intubation