Citations

AbstractLearning ObjectivesAfter completing this course, the reader will be able to: Describe the potential therapeutic advantages of tyrosine kinase inhibitors (TKIs) over antibody mediated inhibition with trastuzumab, such as oral bioavailability and ability to cross the blood–brain barrier.Explain the ability of TKIs to overcome resistance to and synergize with trastuzumab.Discuss the multiple tyrosine kinase inhibitors currently in development and their spectrum of targets and toxicities.This article is available for continuing medical education credit at CME.TheOncologist.com.HER-2 is a transmembrane, tyrosine kinase (TK) receptor whose overexpression is associated with adverse prognosis in breast cancer. The biological effects of HER-2 are mediated by kinase activity causing phosphorylation of tyrosine residues in the cytoplasmic domain of the receptor molecule, leading to activation of downstream growth-promoting pathways. Antibody-mediated inhibition by trastuzumab as well as TK inhibition are clinically effective anti–HER-2 strategies. Kinase inhibitors offer some potential therapeutic advantages over antibody-based therapies. Being small molecules, TK inhibitors (TKIs) have oral bioavailability and ability to cross the blood–brain barrier. Because of their different mode of action, TKIs may be able to overcome some of the mechanisms of trastuzumab resistance. Preclinical, and limited clinical data also suggest that TKIs and trastuzumab have synergistic activity. Lapatinib is the only TKI available for clinical use at present, but several molecules with anti–HER-2 activity have been identified and are undergoing evaluation. These differ in the spectrum of kinases that they inhibit, potency of HER-2 inhibition, pharmacokinetic properties, and toxicity profiles, and are at various stages of clinical development. In this article we summarize selected HER-2 TKIs approved for clinical use or in development for which clinical data are available.

PurposeThe purpose of this systematic review was to examine the current evidence for the use of oral motor exercises (OMEs) on speech (i.e., speech physiology, speech production, and functional speech outcomes) as a means of supporting further research and clinicians' use of evidence-based practice.MethodThe peer-reviewed literature from 1960 to 2007 was searched for articles examining the use of OMEs to affect speech physiology, production, or functional outcomes (i.e., intelligibility). Articles that met selection criteria were appraised by 2 reviewers and vetted by a 3rd for methodological quality, then characterized as efficacy or exploratory studies.ResultsFifteen studies met inclusion criteria; of these, 8 included data relevant to the effects of OMEs on speech physiology, 8 on speech production, and 8 on functional speech outcomes. Considerable variation was noted in the participants, interventions, and treatment schedules. The critical appraisals identified significant weaknesses in almost all studies.ConclusionsInsufficient evidence to support or refute the use of OMEs to produce effects on speech was found in the research literature. Discussion is largely confined to a consideration of the need for more well-designed studies using well-described participant groups and alternative bases for evidence-based practice.

Summary Natural antibodies are produced by B lymphocytes in the absence of external antigen stimulation. With their ability to recognize self, altered self and foreign antigens, they comprise an important first-line defence against invading pathogens, but are also important for tissue homeostasis. By recognizing oligosaccharides expressed on tumour cells and modified cell surface structures accompanying necrosis, natural antibodies have an important anti-tumorigenic function. IVIg contains a wide spectrum of specificities presented in normal plasma including natural antibodies and has been shown to exert inhibitory effects on tumour cells through a subfraction of anti-vascular endothelial growth factor immunoglobulin (Ig)G antibodies with anti-angiogenic properties. IgA antibodies also have potent immunomodulatory properties, being able to both induce and suppress immune responses. IgA-mediated inhibitory function is able to inhibit several inflammatory diseases including asthma and glomerulonephritis. Autoantibodies of the IgM type, on the other hand, have shown promising results in the treatment of multiple sclerosis. These autoantibodies promote remyelination rather than modulating inflammation. Oxidation-specific epitopes, as found in atherosclerotic lesions and on apoptotic cells, comprise one important target of natural antibodies. By recognizing these epitopes, natural antibodies neutralize proinflammatory responses and mediate atheroprotection.

Recent clinical and experimental evidence has challenged the traditional concept of the venous system as a “passive” element in the genesis and evolution of intracranial vascular malformations. The authors review the clinical and experimental evidence linking the venous system and its anomalies to the genesis of various intracranial vascular malformations, including dural arteriovenous fistulas, cavernous malformations, parenchymal arteriovenous malformations, and capillary telangiectasia. They also describe the potential significance of different associations of these vascular anomalies.