Malignancy Rate and Malignancy Risk Assessment in Different Lesions of Uncertain Malignant Potential in the Breast (B3 Lesions): An Analysis of 192 Cases from a Single Institution

BackgroundThe question of how to deal with B3 lesions is of emerging interest.MethodsIn the breast diagnostics of 192 patients between 2009 and 2016, a minimally invasive biopsy revealed a B3 lesion with subsequent resection. This study investigates the malignancy rate of different B3 subgroups and the risk factors that play a role in obtaining a malignant finding.ResultsThe distribution of B3 lesions after minimally invasive biopsy was as follows: atypical ductal hyperplasia (ADH), 7.3%; flat epithelial atypia (FEA), 7.8%; lobular neoplasia (LN), 7.8%; papilloma (Pa), 49.5%; phylloidal tumour (PT), 8.9%; radial sclerosing scar (RS), 3.1%; mixed findings, 10.4%; and other B3 lesions, 5.2%. Most B3 lesions were detected by stereotactic vacuum-assisted biopsy (44.3%), 36.5% by ultrasound-assisted biopsy, and 19.3% by magnetic resonance imaging-assisted biopsy. Most B3 lesions (55.2%) were verified by surgical resection, whereas 30.7% were downgraded to a benign lesion. About 14.1% of the cases were upgraded to malignant lesions, 9.4% to ductal carcinoma in situ and 4.7% to invasive carcinoma. In relation to individual B3 lesions, the following malignancy rates were found: 28.6% (ADH), 13.3% (FEA), 33.3% (LN), 12.6% (Pa), 5.9% (PT), and 0% (RS). The most important risk factor was increasing age. Postmenopausal status was considered an increased risk for an upgrade (p = 0.015). A known malignancy in the ipsilateral breast was a significant risk factor for a malignant upgrade (p = 0.003).ConclusionIncreasing knowledge about B3 lesions allows us to develop a “lesion-specific” therapy approach in the heterogeneous group of B3 lesions, with follow-up imaging for some lesions with less malignant potential and concordance with imaging or further surgical resection in cases of disconcordance with imaging or higher malignant potential.     

Risk-Adjusted Cancer Screening and Prevention (RiskAP): Complementing Screening for Early Disease Detection by a Learning Screening Based on Risk Factors

BackgroundRisk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action.SummaryTherefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.     

Non-arteritic anterior ischemic optic neuropathy (NA-AION) after intravitreal injection of bevacizumab (Avastin®) for treatment of angoid streaks in pseudoxanthoma elasticum

Background

To report a case of nonarteritic anterior ischemic optic neuropathy (NA-AION) following intravitreal injection of bevacizumab (Avastin®).

Methods

Interventional case report with an 18-month follow-up.

Results

A 51-year-old male with pseudoxanthoma elasticum presented with NA-AION 2 weeks after treatment with intravitreal of bevazicumab (Avastin®) for choroidal neovascularisation secondary to angioid streaks. Except from a small optic disc without cupping he did not show further risk factors.

Discussion

Risk of NA-AION should be taken into consideration when deciding for intravitreal application of drugs including anti-vascular endothelial growth factors (VEGF) agents like bevacizumab (Avastin®) in the treatment of retinal vascular diseases.

     

LOH at 6q and 10q in fractionated circulating DNA of ovarian cancer patients is predictive for tumor cell spread and overall survival

ABSTRACT: BACKGROUND: We recently showed that LOH proximal to M6P/IGF2R locus (D6S1581) in primary ovarian tumors is predictive for the presence of disseminated tumor cells (DTC) in the bone marrow (BM). For therapy-monitoring, it would be highly desirable to establish a blood-based biomarker. Therefore, we quantified circulating DNA (cirDNA) in sera of 63 ovarian cancer patients before surgery and after chemotherapy, measured incidence of LOH at four cancer-relevant chromosomal loci, correlated LOH with tumor cell spread to the BM and evaluated prognostic significance of LOH. Patients and Methods: cirDNA was fractionated into high- and low molecular-weight fraction (HMWF, LMWF) for LOH-profiling, utilizing PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. RESULTS: cirDNA levels in the HMWF before surgery were predictive for residual tumor load (p=0.017). After chemotherapy, we observed a significant decline of cirDNA in the LMWF (p=0.0001) but not in the HMWF. LOH was prevalently detected in the LMWF with an overall frequency of 67 %, only moderately ablating after chemotherapy (45 %). Before surgery, LOH in the LMWF at marker D10S1765 and D13S218 significantly correlated with tumor grading and FIGO stage (p=0.033, p=0.004, respectively). In both combined fractions, LOH at D6S1581 additionally associated with overall survival (OS) (p=0.030). Moreover, solely LOH at D10S1765 in LMWF after therapy correlated with DTC in BM after therapy (p=0.017). CONCLUSION: We demonstrate the applicability and necessity of DNA-fractionation prior to analyzing circulating LOH and identify LOH at D10S1765 and D6S1581 as novel blood-based biomarkers for ovarian cancer, being relevant for therapy-monitoring.     

Prognostic impact of circulating tumor cells assessed with the CellSearch System? and AdnaTest Breast? in metastatic breast cancer patients: the DETECT study

Introduction

There is a multitude of assays for the detection of circulating tumor cells (CTCs) but a very limited number of studies comparing the clinical relevance of results obtained with different test methods. The DETECT trial for metastatic breast cancer patients was designed to directly compare the prognostic impact of two commercially available CTC assays that are prominent representatives of immunocytochemical and RT-PCR based technologies.

Methods

In total, 254 metastatic breast cancer patients were enrolled in this prospective multicenter trial. CTCs were assessed using both the AdnaTest Breast Cancer and the CellSearch system according to the manufacturers' instructions.

Results

With the CellSearch system, 116 of 221 (50%) evaluable patients were CTC-positive based on a cut-off level at 5 or more CTCs. The median overall survival (OS) was 18.1 months in CTC-positive patients. (95%-CI: 15.1-22.1 months) compared to 27 months in CTC-negative patients (23.5-30.7 months; p<0.001). This prognostic impact for OS was also significant in the subgroups of patients with triple negative, HER2-positive and hormone receptor-positive/HER2-negative primary tumors. The progression free survival (PFS) was not correlated with CTC status in our cohort receiving different types and lines of systemic treatment (p = 0.197). In multivariate analysis, the presence of CTCs was an independent predictor for OS (HR: 2.7, 95%-CI: 1.6-4.2). When the AdnaTest Breast was performed, 88 of 221 (40%) patients were CTC-positive. CTC-positivity assessed by the AdnaTest Breast had no association with PFS or OS.

Conclusions

The prognostic relevance of CTC detection in metastatic breast cancer patients depends on the test method. The present results indicate that the CellSearch system is superior to the AdnaTest Breast Cancer in predicting clinical outcome in advanced breast cancer.

Trial registration

Current Controlled Trials Registry number ISRCTN59722891.     

Blastocyst development after sperm selection at high magnification is associated with size and number of nuclear vacuoles

Spermatozoa selection at high magnification before intracytoplasmic sperm injection seems to be positively associated with pregnancy rates after day 3 embryo transfers. The aim was to demonstrate an association between the presence of vacuoles in sperm nuclei and the competence of embryos to develop to day 5. Grading of spermatozoa at x 6000-x 12,500 magnification: grade I, no vacuoles; grade II, or=1 large vacuole; grade IV, large vacuoles with other abnormalities. The outcome of embryo development in a group of 25 patients after sibling oocyte injection with the four different grades of spermatozoa showed no significant difference in embryo quality up to day 3. However, the occurrence of blastocyst formation was 56.3 and 61.4% with grade I and II spermatozoa respectively, compared with 5.1% with grade III and 0% with grade IV respectively (P < 0.001). Spermatozoa selection at high magnification using Nomarski interference contrast is useful to identify more precisely the size and the number of nuclear vacuoles that greatly exert a negative effect on embryo development to the blastocyst stage. These observations confirm previous studies pointing to possible 'early and late paternal effects', both of which may have an impact on early embryonic development.     

Selective visualization of the Fallopian tube with magnetic resonance imaging

At present, X-ray hysterosalpingography is used commonly as a screening method for testing Fallopian tube patency, but the results are often unreliable due to mucous plugs or muscular contractions. Selective catheterization of the tubes under X-ray control is feasible, but is rarely used due to exposure of young individuals aiming for pregnancy to a high ionizing dose. Here, a case is described of a patient whose Fallopian tubes were selectively catheterized and visualized three-dimensionally under contrast-enhanced magnetic resonance imaging (MRI) guidance using a high-viscous gadoteric acid solution (Dotarem). In this patient, bilateral peritubal adhesions caused a blockage of the fimbrial part of the tube leading to transuterine spilling of tubal fluid. Laparoscopy followed by bilateral salpingectomy was then performed, which confirmed the three-dimensional MRI images, and the excised specimens were examined histologically. The advantages of this novel technique include the avoidance of ionizing damage to the gonads and the potential for development of more elaborate interventional methods, such as ballooning and stenting. It is intended to develop contrast MRI further, both for improved non-invasive visualization and for manipulative technology of the Fallopian tubes.     

Comparison of the efficiency of various methods for the synthesis of models of metabolites: example of 4a-methylhexahydronaphtalenones

In order to examine the biotransformations of xenobiotics, it is essential to realize studies of metabolism of drugs in living animals. It is generally difficult to extract quantitatively the metabolites from biological media or excreta. Alternative methods have then been developed. Application of such techniques to 4a-methylhexahydronaphthalenones, which constitute starting material for the stereospecific synthesis of terpenoids or steroids, is particularly demonstrative. By biosynthetical ways, it was not possible to access with good yields to all the metabolites obtained in vivo. A novel methodology, based on the use of a manganoporphyrin catalyst, allowed to synthesize large amounts of several models of metabolites corresponding to those which had been isolated in living rats. Only one of the metabolites obtained in vivo could not be synthesized by this biomimetic system. This proved that alternative methods are precious to obtain models with good yields, but need to be validated by controls in living animals.