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Section:ChooseTop of pageAbstract <<INFLAMMATION IN COPDPROINFLAMMATORY CYTOKINEST-CELL CYTOKINESGROWTH FACTORSCHEMOKINESANTI-INFLAMMATORY CYTOKIN...THERAPEUTIC IMPLICATIONSFUTURE DIRECTIONSReferencesCITING ARTICLES

No abstract is provided for this article.

Abstract The efficacy of trastuzumab in the treatment of primary breast cancer has mandated accurate and timely testing of all patients with a new diagnosis of breast cancer. Testing is centralized in designated laboratories across Canada with adherence to guidelines and mandatory participation in quality assurance programs. The Canadian testing algorithm recommends starting with immunohistochemistry (IHC) followed by in situ hybridization (ISH) for equivocal cases. Early HER2 testing showed that approximately 25–30% of invasive breast cancer is HER2 positive. Recent data shows that the HER2/neu positive rate in breast cancer in Canada is 17.6%. Design: The study was designed to assess the rate of false-negative HER2 tests based on the IHC-first algorithm used in 8 pathology centres across Canada. Surgical excisions with invasive carcinoma were tested using the standardized local methodology for both IHC and ISH. The cases were scored by the local breast pathologist and in 2 of 8 centers image analysis was used in the evaluation of ISH. We compared consecutive HER2-negative IHC results (score 0/1+) to the corresponding ISH (either silver or fluorescence) result. False negative cases were defined as a negative IHC with an ISH ratio of≥ 2, since these patients are eligible for trastuzumab therapy. Results: 715 cases were analyzed by IHC using Ventana 4B5 (287), HercepTest (253), or SP3 (175), and by ISH kits: Vysis FISH (303), Ventana SISH (412). The HER2 and CEP17 counts were available in all cases. There were 4 cases with an ISH score ≥2 (4B5: 2/4, HercepTest 1/4, SP3 1/4). In 3 additional cases the absolute HER2 copy number was ≥6 but the HER2/CEP17 amplification ratio was &amp;lt;2 due to an increased number of CEP 17 signal (“polysomy 17”) or amplification of the pericentromeric region. The overall rate of false negative cases was 0.98% (7/715). These cases had a low level of amplification (ratio 2 to 2.45) or an absolute HER2 count of 6–8. Conclusion: Our observation confirms that IHC is an adequate test to predict negative HER2 status in primary breast cancer in surgical excision specimens, even when different antibodies and IHC platforms are used. The study supports and justifies the Canadian algorithm of IHC followed by ISH in equivocal cases in view of the extremely low percentage of false negative cases observed. This reflects the strict adherence to internal protocols and mandatory participation in quality assurance programs. These results provide further confirmation that the vast majority of patients eligible for trastuzumab are not deprived from an effective treatment by using this algorithm. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-09.

Luminal renarrowing (restenosis) is the major limitation of percutaneous transluminal coronary angioplasty (PTCA), and the search for a 'magic bullet' to prevent this apparent biological healing response to vessel injury has thus far been unsuccessful. Large clinical trials using serial quantitative coronary angiography have, however, provided some valuable insight into this area. In particular, the restenosis process may be measured as the loss in minimal luminal diameter from post-PTCA to follow-up angiography, and is essentially ubiquitous and normally distributed. The angiographic outcome of clinical trials can thus be appropriately evaluated using a continuous rather than a categorical approach, which also considerably reduces the number of patients required. Fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been shown experimentally to reduce the neointimal proliferative response after PTCA, independent of its lipid-lowering action. The FLuvastatin Angioplasty REstenosis trial was designed to evaluate whether fluvastatin 40 mg twice daily, commencing at least 2 weeks before planned PTCA, can reduce luminal loss by 30% from successful PTCA to follow-up angiography at 26 +/- 2 weeks in 730 evaluable patients.

No abstract is provided for this article.

The direct traumatic effects of coronary artery bypass surgery may counter-balance the expected improvement of myocardial function in the early postoperative period. In 55 patients, the regional shortening fraction was measured over 12 months using radiopaque epicardial markers pairs implanted during surgery in the newly perfused regions. The time course of cardiothoracic ratio, heart rate and cuff blood pressure was documented. All patients were catheterized before surgery and 1 year afterwards. There is an initial depression in myocardial function lasting up to 3 months after surgery which is not directionally related to changes in loading conditions or chronotropic state, but most likely to recovery of the myocardium from perioperative injury. At 1 year after surgery the overall ventricular function is unchanged. The evaluation of ventricular function after coronary artery bypass grafting should be performed no sooner than 3 months after surgery to avoid this transient period of depressed myocardial performance.

Objectives The aim of this study was to assess 10-year all-cause mortality in patients with heavily calcified lesions (HCLs) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Background Limited data are available on very long term outcomes in patients with HCLs according to the mode of revascularization. Methods This substudy of the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study assessed 10-year all-cause mortality according to the presence of HCLs within lesions with >50% diameter stenosis and identified during the calculation of the anatomical SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score among 1,800 patients with the 3-vessel disease and/or left main disease randomized to PCI or CABG in the SYNTAX trial. Patients with HCLs were further stratified according to disease type (3-vessel disease or left main disease) and assigned treatment (PCI or CABG). Results The 532 patients with ≥1 HCL had a higher crude mortality rate at 10 years than those without (36.4% vs 22.3%; HR: 1.79; 95% CI: 1.49-2.16; P < 0.001). After adjustment, an HCL remained an independent predictor of 10-year mortality (HR: 1.36; 95% CI: 1.09-1.69; P = 0.006). There was a significant interaction in mortality between treatment effect (PCI and CABG) and the presence or absence of HCLs (P interaction = 0.005). In patients without HCLs, mortality was significantly higher after PCI than after CABG (26.0% vs 18.8%; HR: 1.44; 95% CI: 0.97-1.41; P = 0.003), whereas in those with HCLs, there was no significant difference (34.0% vs 39.0%; HR: 0.85; 95% CI: 0.64-1.13; P = 0.264). Conclusions At 10 years, the presence of an HCL was an independent predictor of mortality, with a similar prognosis following PCI or CABG. Whether HCLs require special consideration when deciding the mode of revascularization beyond their current contribution to the anatomical SYNTAX score deserves further evaluation. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES], NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX], NCT00114972)

Corticosteroids are by far the most effective treatment available for the control of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. Their beneficial effects are mainly mediated through multiple anti-inflammatory mechanisms (1). One of the most important actions of corticosteroids in suppressing allergic inflammation is the repression of genes encoding the multiple inflammatory cytokines and chemokines that are important in amplifying and perpetuating allergic inflammation. The molecular mechanisms of suppression of inflammatory genes involve an interaction of glucocorticoid receptors (GRs) activated by corticosteroids interacting with transcription factors that have been activated by inflammatory stimuli. This does not involve binding of GR to DNA recognition sequences, since anti-inflammatory effects of corticosteroids are preserved in mutant forms of GR that do not dimerize and that therefore fail to bind to glucocorticoid-response elements (GREs) in the upstream promoter regions of inflammatory genes (2). Inflammatory stimuli activate transcription factors, such as NF-κB and activator protein-1 (AP-1), that bind to and activate coactivator proteins at the start site of transcription, resulting in acetylation of core histones and increased transcription of inflammatory genes. Corticosteroids suppress the transcription of these inflammatory genes by reversing histone acetylation, in part by recruiting histone deacetylases to the transcription start site, thus repressing inflammatory genes (3). This mechanism accounts for many of the therapeutic effects of corticosteroids in the treatment of allergic diseases. But although corticosteroids are highly effective in clinical management of allergic diseases, they have some cellular and molecular effects that are difficult to reconcile with this beneficial effect. In atopy there is a switch from the characteristic predominance of Th1 lymphocytes toward Th2 lymphocytes that characteristically secrete IL-4 and IL-5. IL-4, together with the related cytokine IL-13, is important for isotype switching of B lymphocytes to secrete IgE, the characteristic antibody that underlies atopy. IL-5 is critical for eosinophilic inflammation in allergic disease, as recently demonstrated by the profound fall in circulating eosinophils after administration of an anti–IL-5 antibody in atopic asthmatic patients (4). Corticosteroids inhibit the transcription of IL-4, IL-5, and IL-13 genes, and it is likely that switching off these key cytokines contributes importantly to their efficacy in controlling allergic diseases. Curiously, corticosteroids tip the balance toward Th2-cell predominance, through an effect that may be due to suppression of IFN-γ, which normally inhibits Th2 differentiation in response to IL-4 (5), and suppression of IL-12 receptors that result in increased differentiation of Th1 cells (6). Corticosteroids also suppress IL-12 production, while having little effect on the anti-inflammatory cytokine IL-10 (7). While this suggests that corticosteroids would be detrimental in the treatment by further polarizing the immune response toward a Th2 pattern, the inhibitory effects of corticosteroids on the secretion of IL-4, IL-5, and IL-13 override this detrimental effect. In addition, corticosteroids decrease the survival of T cells and eosinophils by increasing apoptosis, contributing to their suppression of chronic allergic inflammation. Another effect of corticosteroids that appears to be detrimental to the allergic process is an increased production of IgE from B lymphocytes stimulated with IL-4 (8). This has also been demonstrated in vivo in asthmatic patients after 1 week of treatment with oral prednisolone, when there is a small, but significant, rise in polyclonal IgE in asthmatic patients (9). This explains why treatment with corticosteroids, even at high systemic doses, does not inhibit skin prick tests to common allergens. The molecular mechanisms underlying this paradoxical effect of corticosteroids are further elucidated by the study of Jabara et al. in this issue of the JCI (10). They have demonstrated that corticosteroid-induced IgE synthesis, in the presence of IL-4, is dependent on increased expression of the costimulatory molecule CD40 ligand (CD40L), a transmembrane glycoprotein that belongs to the TNF superfamily. CD40L is normally expressed on activated T lymphocytes and interacts with CD40, a surface glycoprotein related to TNF receptors that is expressed on all B lymphocytes (Figure ​(Figure1).1). The interaction between CD40L and CD40 is critical to the induction of IgE synthesis by IL-4 and IL-13 (11). The gene for CD40L maps to the X chromosome, and patients with X-linked hyper-IgM syndrome have low levels of Ig’s, as well as dysfunctional mutations of the CD40L gene, with defective expression of CD40L (12). In patients with X-linked hyper-IgM syndrome, corticosteroids fail to induce any IgE synthesis, and a blocking CD40-Ig fusion protein inhibits the effects of hydrocortisone in vitro (10). The effect of corticosteroids on CD40L is mediated by GR, as it is blocked by the GR antagonist mifepristone (RU486). It is likely to involve DNA binding, resulting in increased gene transcription and expression of CD40L on the cell surface of T lymphocytes but also on B lymphocytes that do not normally express CD40L. These B cells may then interact with other B cells that express CD40. Figure 1 Interaction of T and B lymphocytes. The left panel shows interaction of a CD4+ Th2 cell with a B lymphocyte. The release of cytokines IL-4 and IL-13 and interaction of CD40L and CD40 result in IgE synthesis and the sensitization of mast cells, ... The 5′-upstream promoter region of CD40L has several potential GRE sites. The molecular mechanism for increasing transcription involves interaction of GR with coactivators and subsequent acetylation of core histones, leading to increased gene transcription (3). By contrast, a previous study showed that corticosteroids inhibit CD40L expression in human peripheral blood CD4+ lymphocytes (13), so that the response to steroids may differ between cell types and in different conditions, such as the absence or presence of IL-4. Although corticosteroids increase CD40L in B lymphocytes, other studies show that in the same cells they suppress the expression of CD40, which acts as a receptor for CD40L, thus potentially diminishing any functional effect of corticosteroids on IgE production (14). Furthermore, as noted above, corticosteroids suppress the synthesis of IL-4 and IL-13, which are necessary for IgE production. The suppressive effects of corticosteroids on inflammatory genes, such as IL-4 and CD40, are seen at lower concentrations than the effects that involve increased transcription, such as the increase in CD40L. The clinical implications of these findings are not yet clear. Corticosteroids may induce CD40L in T lymphocytes, which may also activate other CD40-expressing inflammatory cells, such as macrophages and eosinophils. This would paradoxically increase inflammation in the short-term, although presumably corticosteroids may suppress expression of CD40 in these other cells. Corticosteroids, while very effective at suppressing chronic allergic inflammation, are less effective against acute allergic events that are mediated via interaction of allergen with IgE bound to mast cells. However, there is no clinical evidence that IgE-mediated responses are worsened by corticosteroid treatment. In part, this may be because of counteracting beneficial effects of corticosteroids on these acute responses, as treatment with topical steroids reduces the number of mast cells in the mucosa, so that allergen is less able to activate these cells (15). With respect to therapy, this apparent adverse effect of corticosteroids on the acute allergic response suggests that therapies that deal with the increased IgE levels may be complementary to the effects of corticosteroids. A humanized monoclonal antibody to IgE, which profoundly reduces circulating IgE concentrations (16), has recently been found to provide surprising benefit in patients with severe steroid-dependent asthma, reducing the requirement for oral corticosteroids and allowing some patients to discontinue oral steroids completely (17). These findings can now be understood, as the high doses of systemic corticosteroid therapy may maintain high IgE levels, via the mechanisms described by Jabara and colleagues (10). This effect can be overcome by anti-IgE therapy, which appears to be of greater benefit in patients with more severe disease who are steroid-dependent.