Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM)

Abstract Biomarkers play an essential role in the management of patients with invasive breast cancer. For selecting patients likely to respond to endocrine therapy, both oestrogen receptors (ERs) and progesterone receptors (PRs) should be measured on all newly diagnosed invasive breast cancers. On the other hand, for selecting likely response to all forms of anti-HER2 therapy (trastuzumab, pertuzumab, lapatinib or ado-trastuzumab emtansine), determination of HER2 expression or gene copy number is mandatory. Where feasible, measurement of ER, PR and HER2 should be performed on recurrent lesions and the primary invasive tumour. Although methodological problems exist in the determination of Ki67, because of its clearly established clinical value, wide availability and low costs relative to the available multianalyte signatures, Ki67 may be used for determining prognosis, especially if values are low or high. In oestrogen receptor (ER)-positive, HER2-negative, lymph node–negative patients, multianalyte tests such as urokinase plasminogen activator (uPA)-PAI-1, Oncotype DX, MammaPrint, EndoPredict, Breast Cancer Index (BCI) and Prosigna (PAM50) may be used to predict outcome and aid adjunct therapy decision-making. Oncotype DX, MammaPrint, EndoPredict and Prosigna may be similarly used in patients with 1–3 metastatic lymph nodes. All laboratories measuring biomarkers for patient management should use analytically and clinically validated assays, participate in external quality assurance programs, have established assay acceptance and rejection criteria, perform regular audits and be accredited by an appropriate organisation

Health state utilities for infertility and subfertility

Background: Health state utility values allow for comparison of treatments across different diseases. Utility values for fertility-impaired health states are currently unavailable. Such values are necessary in order to determine the relative costs-effectiveness of fertility treatments. Methods: This study aimed to determine utility weights for infertile and subfertile health states. In addition, it explored the Dutch general population’s opinions regarding the inclusion of infertility treatments in the Dutch health insurers’ basic benefit package. An online questionnaire was designed to determine the health-related quality of life values of six fertility-impaired health states. The study population consisted of a representative sample of the Dutch adult population. Respondents were asked to evaluate the health states through direct health valuation methods, i.e. the Visual Analogue Scale (VAS) and the Time Trade-Off (TTO) method. In addition, respondents were asked about their opinions regarding reimbursement of fertility-related treatments. Results: The respondents’ (n = 767) VAS scores ranged from 0.640 to 0.796. TTO utility values ranged from 0.792 to 0.868. Primary infertility and subfertility was valued lower than secondary infertility and subfertility. In total, 92% of the respondents stated that fertility treatments should be fully or partially reimbursed by the health insurance basic benefit package. Conclusions: Having fertility problems results in substantial disutilities according to the viewpoint of the Dutch general population. The results make it possible to compare the value for money of infertility treatment to that of treatments in other disease areas. There is strong support among the general population for reimbursing fertility treatments through the Dutch basic benefit package

Genomic Organization, Splice Variants and Expression of CGMl, a CD66-related Member of the Carcinoembryonic Antigen Gene Family

The tumor marker carcinoembryonic antigen (CEA) belongs to a family of proteins which are composed of one immunogiobulin variable domain and a varying number of immunoglobulin constant-like domains. Most of the membrane-bound members, which are anchored either by a glycosylphosphatidylinositol moiety or a transmembrane domain, have been shown to convey cell adhesion in vitro. Here we describe two splice variants of CGMI. a transmembrane member of the CEA family without immunoglobulin constant.like domains. CGM1a and CGM1c contain cytopiasmic domains of 71 and 31 amino acids, respectively, The cytoplasmic region of CGM1a is encoded by four exons (Cyt1-Cyt4). Differential splicing of the Cyt1 exon (53 bp)..

Recovery of myocardial perfusion after percutaneous coronary intervention of chronic total occlusions is comparable to hemodynamically significant non-occlusive lesions.

BACKGROUND: The benefits of chronic coronary total occlusion (CTO) percutaneous coronary intervention (PCI) are being questioned. The aim of this study was to assess the effects of CTO PCI on absolute myocardial perfusion, as compared with PCI of hemodynamically significant non-CTO lesions. METHODS: Consecutive patients with a preserved left ventricular ejection fraction (≥50%) and a CTO or non-CTO lesion, in whom [15 O]H2 O positron emission tomography was performed prior and after successful PCI, were included. Change in quantitative (hyperemic) myocardial blood flow (MBF), coronary flow reserve (CFR) and perfusion defect size (in myocardial segments) were compared between CTOs and non-CTO lesions. RESULTS: In total 92 patients with a CTO and 31 patients with a non-CTO lesion were included. CTOs induced larger perfusion defect sizes (4.51 ± 1.69 vs. 3.23 ± 2.38 segments, P < 0.01) with lower hyperemic MBF (1.30 ± 0.37 vs. 1.58 ± 0.62 mL·min-1 ·g-1 , P < 0.01) and similarly impaired CFR (1.66 ± 0.75 vs. 1.89 ± 0.77, P = 0.17) compared with non-CTO lesions. After PCI both hyperemic MBF and CFR increased similarly between groups (P = 0.57 and 0.35) to normal ranges with higher hyperemic MBF values in non-CTO compared with CTO (2.89 ± 0.94 vs. 2.48 ± 0.73 mL·min-1 ·g-1 , P = 0.03). Perfusion defect sizes decreased similarly after CTO PCI and non-CTO PCI (P = 0.14), leading to small residual defect sizes in both groups (1.15 ± 1.44 vs. 0.61 ± 1.45 segments, P = 0.054). CONCLUSIONS: Myocardial perfusion findings are slightly more hampered in patients with a CTO before and after PCI. Percutaneous revascularization of CTOs, however, improves absolute myocardial perfusion similarly to PCI of hemodynamically significant non-CTO lesions, leading to satisfying results

Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Weak Segregation Theory and Non-Conventional Morphologies in the Ternary ABC Triblock Copolymers

The Leibler weak segregation theory in molten diblock copolymers is generalized with due regard for the 2nd shell harmonics contributions defined in the paper and the phase diagrams are built for the linear and miktoarm ternary ABC triblock copolymers. The symmetric linear copolymers with the middle block non-selective with respect to the side ones are shown to undergo the continuous ODT not only into the lamellar phase but also into various non-conventional cubic phases (depending on the middle block composition it could be the simple cubic, face-centered cubic or non-centrosymmetric phase revealing the symmetry of space group No.214 first predicted to appear in molten block copolymers). For asymmetric linear ABC copolymers a region of compositions is found where the weakly segregated gyroid (double gyroid) phase exists between the planar hexagonal and lamellar or one of the non-conventional cubic phases up to the very critical point. In contrast, the miktoarm ABC block copolymers with one of its arm non-selective with respect to the two others are shown to reveal a pronounced tendency towards strong segregation, which is preceded by increase of stability of the conventional BCC phase and a peculiar weakly segregated BCC phase (BCC3), where the dominant harmonics belong to the 3rd co-ordination sphere of the reciprocal lattice. The validity region of the developed theory is discussed and outlined in the composition triangles both for linear and miktoarm copolymers.Comment: 61 pages, 12 figure

Towards Endometriosis Diagnosis by Gadofosveset-Trisodium Enhanced Magnetic Resonance Imaging

Endometriosis is defined as the presence of endometrial tissue outside the uterus. It affects 10–15% of women during reproductive age and has a big personal and social impact due to chronic pelvic pain, subfertility, loss of work-hours and medical costs. Such conditions are exacerbated by the fact that the correct diagnosis is made as late as 8–11 years after symptom presentation. This is due to the lack of a reliable non-invasive diagnostic test and the fact that the reference diagnostic standard is laparoscopy (invasive, expensive and not without risks). High-molecular weight gadofosveset-trisodium is used as contrast agent in Magnetic Resonance Imaging (MRI). Since it extravasates from hyperpermeable vessels more easily than from mature blood vessels, this contrast agent detects angiogenesis efficiently. Endometriosis has high angiogenic activity. Therefore, we have tested the possibility to detect endometriosis non-invasively using Dynamic Contrast-Enhanced MRI (DCE-MRI) and gadofosveset-trisodium as a contrast agent in a mouse model. Endometriotic lesions were surgically induced in nine mice by autologous transplantation. Three weeks after lesion induction, mice were scanned by DCE-MRI. Dynamic image analysis showed that the rates of uptake (inwash), persistence and outwash of the contrast agent were different between endometriosis and control tissues (large blood vessels and back muscle). Due to the extensive angiogenesis in induced lesions, the contrast agent persisted longer in endometriotic than control tissues, thus enhancing the MRI signal intensity. DCE-MRI was repeated five weeks after lesion induction, and contrast enhancement was similar to that observed three weeks after endometriosis induction. The endothelial-cell marker CD31 and the pericyte marker α-smooth-muscle-actin (mature vessels) were detected with immunohistochemistry and confirmed that endometriotic lesions had significantly higher prevalence of new vessels (CD31 only positive) than the uterus and control tissues. The diagnostic value of gadofosveset-trisodium to detect endometriosis should be tested in human settings

Neurovasculature of high and low tie ligation of the inferior mesenteric artery

PURPOSE: Controversy exists as to whether a high or low tie ligation of the inferior mesenteric artery (IMA) is the preferred technique in surgeries of the left colon and rectum. This study aims to contribute to the discussion as to which is the more beneficial technique by investigating the neurovasculature at each site. METHODS: Ten embalmed cadaveric donors underwent division of the inferior mesenteric artery at the level of the low tie. The artery was subsequently ligated at the root to render a section of tissue for histological analysis of the proximal (high tie), mid and distal (low tie) segments. RESULTS: Ganglia observed in the proximal end of seven specimens in the sample imply that there would be disruption to the innervation in a high tie procedure. CONCLUSION: This study suggests that a high tie should be avoided if the low tie is oncologically viable