The new ASCO/CAP guidelines on hormone receptor testing in breast cancer recommends standard operating procedures (SOPs) established to confirm or adjudicate estrogen receptor (ER) results with weak or ≤10% staining, and the status of internal controls (ICs) reported for cases with 0% to 10% staining. The aim of this study is to determine the frequency of ER testing with weak or ≤10% staining that may require additional steps following SOPs and to identify any correlation between hormone receptor status of the tumor and the likelihood of finding IC. Breast cancer cases between January 2014 and April 2019 were included to identify negative, low-positive and weak-positive cases. The presence/absence of IC was correlated to tumor type. Following ASCO/CAP guidelines, 29.8% of cases (374/1261) will need additional steps to confirm/adjudicate results due to negative, low, or weak positive ER status. The probability of finding IC is ~50% lower in cases of ER and progesterone receptor (PgR) negative tumors. Repeat testing may be warranted in 13.1% (92/700) of all cases due to lack of IC. In conclusion, the new ASCO/CAP guidelines recommend laboratories to establish and follow SOP to confirm or adjudicate ER results for about 30% of the cases before reporting hormone receptors status. Over 40% of cases with <10% tumor ER positivity lacked IC that may need a comment per the guidelines indicating a repeat testing may be warranted. However, the presence/absence of IC may be related to the subtype of breast cancer and should not necessarily bring into question the validity of the test.

To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment.
ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel\'s review of the evidence from six trials.
The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment.
The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of recurrence risk using established prognostic factors. The Panel noted that the benefits in absolute risk of reduction were modest and that, for lower-risk node-negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate. A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second breast cancers. Shared decision making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of breast cancer recurrence, the prevention of second breast cancers, and the impact of adverse effects of treatment. Additional information can be found at www.asco.org/breast-cancer-guidelines .

BACKGROUND: The present review is part of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biologic therapies.
OBJECTIVE: To review, from an infectious diseases perspective, the safety profile of therapies targeting cell surface receptors and associated signaling pathways among cancer patients and to suggest preventive recommendations.
METHODS: Computer-based Medline searches with MeSH terms pertaining to each agent or therapeutic family.
BACKGROUND: Vascular endothelial growth factor (VEGF)-targeted agents (bevacizumab and aflibercept) are associated with a meaningful increase in the risk of infection, likely due to drug-induced neutropaenia, although no clear benefit is expected from the universal use of anti-infective prophylaxis. VEGF tyrosine kinase inhibitors (i.e. sorafenib or sunitinib) do not seem to significantly affect host\'s susceptibility to infection, and universal anti-infective prophylaxis is not recommended either. Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) induce neutropaenia and secondary skin and soft tissue infection in cases of severe papulopustular rash. Systemic antibiotics (doxycycline or minocycline) should be administered to prevent the latter complication, whereas no recommendation can be established on the benefit from antiviral, antifungal or anti-Pneumocystis prophylaxis. A lower risk of infection is reported for anti-ErbB2/HER2 monoclonal antibodies (trastuzumab and pertuzumab) and ErbB receptor tyrosine kinase inhibitors (including dual-EGFR/ErbB2 inhibitors such as lapatinib or neratinib) compared to conventional chemotherapy, presumably as a result of the decreased occurrence of drug-induced neutropaenia.
CONCLUSIONS: With the exception of VEGF-targeted agents, the overall risk of infection associated with the reviewed therapies seems to be low.

Childhood-onset pulmonary arterial hypertension (PAH) is considered complex and multifactorial, with relatively poor estimates of the natural history of the disease. Strategies allowing earlier detection, establishment of disease aetiology together with more accurate and sensitive biomarkers could enable better estimates of prognosis and individualise therapeutic strategies. Evidence is accumulating that genetic defects play an important role in the pathogenesis of idiopathic and hereditary forms of PAH. Altogether nine genes have been reported so far to be associated with childhood onset PAH suggesting that comprehensive multigene diagnostics can be useful in the assessment. Identification of disease-causing mutations allows estimates of prognosis and forms the most effective way for risk stratification in the family. In addition to genetic determinants the analysis of blood biomarkers are increasingly used in clinical practice to evaluate disease severity and treatment responses. As in genetic diagnostics, a multiplex approach can be helpful, as a single biomarker for PAH is unlikely to meet all requirements. This consensus statement reviews the current evidence for the use of genetic diagnostics and use of blood biomarkers in the assessment of paediatric patients with PAH.

Among patients with chronic heart failure (HF), it is known that soluble concentrations of the interleukin receptor family member ST2 (sST2) are prognostic for adverse outcome, including risk for progression of HF and death. Considerably less was known about the merits of serial testing of sST2 and whether such testing provides incremental information beyond single measurements; additionally, the influence of HF therapies on sST2 concentrations and whether sST2 values predicted benefit of therapy changes remained unclear. Recently, several studies indicate that serial testing for sST2 increases the prognostic information gained compared with a single measurement. When measured in patients with chronic HF, concentrations of sST2 appear to predict worsening left ventricular remodeling, and serial measurements of sST2 appear particularly useful for predicting HF events, such as worsening HF and risk for either hospitalization or death from HF. Values for sST2 are lower in those treated with several HF therapies; in turn, sST2 concentrations may predict benefit from specific HF therapy changes. Using an upper reference limit of 35 ng/ml, serial testing for sST2 in chronic HF thus appears useful. The promising role of sST2 for serial chronic HF therapy monitoring will be discussed.

ST2 is a member of the interleukin 1 receptor family with 2 main isoforms: transmembrane or cellular (ST2L) and soluble or circulating (sST2) forms. ST2 is the receptor of the IL-33, which is an IL-1-like cytokine that can be secreted by living cells in response to cell damage. IL-33 exerts its cellular functions by binding a receptor complex composed of ST2L and IL-1R accessory protein. The IL-33/ST2 system is upregulated in cardiomyocytes and fibroblasts as response to mechanical stimulation or injury. The interaction between IL33 and ST2L has been demonstrated to be cardioprotective: in experimental models, this interaction reduces myocardial fibrosis, prevents cardiomyocyte hypertrophy, reduces apoptosis, and improves myocardial function. The beneficial effects of IL-33 are specifically through the ST2L receptor. sST2 avidly binds IL-33 which results in interruption of the interaction between IL-33/ST2L and consequently eliminates the antiremodeling effects; thus, sST2 is viewed as a decoy receptor. In recent years, knowledge about ST2 role in the pathophysiology of cardiovascular diseases has broadly expanded, with strong links to myocardial dysfunction, fibrosis, and remodeling. Beyond its myocardial role, the IL-33/ST2 system could have an additional role in the development and progression of atherosclerosis. In conclusion, IL-33/ST2L signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which may have therapeutic potential for beneficially regulating the myocardial response to overload and injury. In contrast, sST2 acts as a decoy receptor and, by sequestering IL-33, antagonizes the cardioprotective effects of IL-33/ST2L interaction.

ST2 is a member of the interleukin (IL) 1 receptor family that exists in 2 forms, a transmembrane receptor (ST2L) and a soluble receptor (sST2). The ligand of ST2 is IL-33, known to be involved in reducing tissue fibrosis and myocyte hypertrophy in mechanically strained hearts. Through its ability to act as a decoy receptor, sST2 blocks the beneficial effects that occur when IL-33 attempts to bind to ST2L; experimentally, this leads to cardiac hypertrophy, fibrosis, and ventricular dysfunction. In patients with acutely decompensated heart failure, elevated concentrations of sST2 are strongly associated with the presence and severity of the diagnosis and powerfully predict increased risk of heart failure complications including arrhythmia, pump failure, or death, independent of natriuretic peptides and other established or emerging biomarkers. The role of sST2 measurement in acutely decompensated heart failure evaluation and management will be discussed.

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Receptors are typically characterized via two distinct approaches: (1) the identification and pharmacological characterization of a receptor-mediated response using classical pharmacological and/or radioligand approaches in tissues and animal models using selective agonist and antagonist ligands, and; (2) the cloning and expression of proteins with structural homology to known receptors, the function of which is subsequently established by studying the structure activity relationship (SAR) of receptor-mediated responses. An additional means to characterize receptors proceeded, and evolved, with the structural approach, namely classification in terms of signal transduction mechanisms. The International Union of Pharmacology (IUPHAR) created guidelines and selected working groups for each receptor family to establish a common nomenclature system. Reports from those groups that have reached some degree of consensus have been summarized in this appendix.

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