Tumor proliferation speed, most commonly assessed by counting of mitotic figures in histological slide preparations, is an important biomarker for breast cancer. Although mitosis counting is ...routinely performed by pathologists, it is a tedious and subjective task with poor reproducibility, particularly among non-experts. Inter- and intraobserver reproducibility of mitosis counting can be improved when a strict protocol is defined and followed. Previous studies have examined only the agreement in terms of the mitotic count or the mitotic activity score. Studies of the observer agreement at the level of individual objects, which can provide more insight into the procedure, have not been performed thus far.
The development of automatic mitosis detection methods has received large interest in recent years. Automatic image analysis is viewed as a solution for the problem of subjectivity of mitosis counting by pathologists. In this paper we describe the results from an interobserver agreement study between three human observers and an automatic method, and make two unique contributions. For the first time, we present an analysis of the object-level interobserver agreement on mitosis counting. Furthermore, we train an automatic mitosis detection method that is robust with respect to staining appearance variability and compare it with the performance of expert observers on an "external" dataset, i.e. on histopathology images that originate from pathology labs other than the pathology lab that provided the training data for the automatic method.
The object-level interobserver study revealed that pathologists often do not agree on individual objects, even if this is not reflected in the mitotic count. The disagreement is larger for objects from smaller size, which suggests that adding a size constraint in the mitosis counting protocol can improve reproducibility. The automatic mitosis detection method can perform mitosis counting in an unbiased way, with substantial agreement with human experts.
Extremely dense breast tissue is a risk factor for breast cancer and limits the detection of cancer with mammography. Data are needed on the use of supplemental magnetic resonance imaging (MRI) to ...improve early detection and reduce interval breast cancers in such patients.
In this multicenter, randomized, controlled trial in the Netherlands, we assigned 40,373 women between the ages of 50 and 75 years with extremely dense breast tissue and normal results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The groups were assigned in a 1:4 ratio, with 8061 in the MRI-invitation group and 32,312 in the mammography-only group. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
The interval-cancer rate was 2.5 per 1000 screenings in the MRI-invitation group and 5.0 per 1000 screenings in the mammography-only group, for a difference of 2.5 per 1000 screenings (95% confidence interval CI, 1.0 to 3.7; P<0.001). Of the women who were invited to undergo MRI, 59% accepted the invitation. Of the 20 interval cancers that were diagnosed in the MRI-invitation group, 4 were diagnosed in the women who actually underwent MRI (0.8 per 1000 screenings) and 16 in those who did not accept the invitation (4.9 per 1000 screenings). The MRI cancer-detection rate among the women who actually underwent MRI screening was 16.5 per 1000 screenings (95% CI, 13.3 to 20.5). The positive predictive value was 17.4% (95% CI, 14.2 to 21.2) for recall for additional testing and 26.3% (95% CI, 21.7 to 31.6) for biopsy. The false positive rate was 79.8 per 1000 screenings. Among the women who underwent MRI, 0.1% had either an adverse event or a serious adverse event during or immediately after the screening.
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography resulted in the diagnosis of significantly fewer interval cancers than mammography alone during a 2-year screening period. (Funded by the University Medical Center Utrecht and others; DENSE ClinicalTrials.gov number, NCT01315015.).
The introduction of fast digital slide scanners that provide whole slide images has led to a revival of interest in image analysis applications in pathology. Segmentation of cells and nuclei is an ...important first step towards automatic analysis of digitized microscopy images. We therefore developed an automated nuclei segmentation method that works with hematoxylin and eosin (H&E) stained breast cancer histopathology images, which represent regions of whole digital slides. The procedure can be divided into four main steps: 1) pre-processing with color unmixing and morphological operators, 2) marker-controlled watershed segmentation at multiple scales and with different markers, 3) post-processing for rejection of false regions and 4) merging of the results from multiple scales. The procedure was developed on a set of 21 breast cancer cases (subset A) and tested on a separate validation set of 18 cases (subset B). The evaluation was done in terms of both detection accuracy (sensitivity and positive predictive value) and segmentation accuracy (Dice coefficient). The mean estimated sensitivity for subset A was 0.875 (±0.092) and for subset B 0.853 (±0.077). The mean estimated positive predictive value was 0.904 (±0.075) and 0.886 (±0.069) for subsets A and B, respectively. For both subsets, the distribution of the Dice coefficients had a high peak around 0.9, with the vast majority of segmentations having values larger than 0.8.
Transsexual people receive cross-sex hormones as part of their treatment, potentially inducing hormone-sensitive malignancies.
To examine the occurrence of breast cancer in a large cohort of Dutch ...male and female transsexual persons, also evaluating whether the epidemiology accords with the natal sex or the new sex.
Number of people with breast cancer between 1975 and 2011.
We researched the occurrence of breast cancer among transsexual persons 18–80 years with an exposure to cross-sex hormones between 5 to >30 years. Our study included 2,307 male-to-female (MtF) transsexual persons undergoing androgen deprivation and estrogen administration (52,370 person-years of exposure), and 795 female-to-male (FtM) subjects receiving testosterone (15,974 total years of exposure).
Among MtF individuals one case was encountered, as well as a probable but not proven second case. The estimated rate of 4.1 per 100,000 person-years (95% confidence interval CI: 0.8–13.0) was lower than expected if these two cases are regarded as female breast cancer, but within expectations if viewed as male breast cancer. In FtM subjects, who were younger and had shorter exposure to cross-sex hormones compared with the MtF group, one breast cancer case occurred. This translated into a rate of 5.9 per 100,000 person-years (95% CI: 0.5–27.4), again lower than expected for female breast cancer but within expected norms for male breast cancer.
The number of people studied and duration of hormone exposure are limited but it would appear that cross-sex hormone administration does not increase the risk of breast cancer development, in either MtF or FtM transsexual individuals. Breast carcinoma incidences in both groups are comparable to male breast cancers. Cross-sex hormone treatment of transsexual subjects does not seem to be associated with an increased risk of malignant breast development. Gooren LJ, van Trotsenburg MAA, Giltay EJ, and van Diest PJ. Breast cancer development in transsexual subjects receiving cross-sex hormone treatment. J Sex Med 2013;10:3129–3134.
Abstract
Background
In metastatic breast cancer, hormone and/or human epidermal growth factor receptor 2 (HER2)–targeted therapy decision-making is still largely based on tissue characteristics of ...the primary tumor. However, a change of estrogen receptor alpha (ERα), progesterone receptor (PR), and HER2 status in distant metastases has frequently been reported. The actual incidence of this phenomenon has been debated.
Methods
We performed a meta-analysis including 39 studies assessing receptor conversion from primary breast tumors to paired distant breast cancer metastases. We noted the direction of change (positive to negative or vice versa) and performed subgroup analyses for different thresholds for positivity, the type of test used to assess HER2 receptor status, and metastasis location–specific differences (two-sided tests).
Results
Overall, the incidence of receptor conversion varied largely between studies. For ERα, PR, and HER2, we found that random effects pooled positive to negative conversion percentages of 22.5% (95% confidence interval CI = 16.4% to 30.0%), 49.4% (95% CI = 40.5% to 58.2%), and 21.3% (95% CI = 14.3% to 30.5%), respectively. Negative to positive conversion percentages were 21.5% (95% CI = 18.1% to 25.5%), 15.9% (95% CI = 11.3% to 22.0%), and 9.5% (95% CI = 7.4% to 12.1%). Furthermore, ERα discordance was statistically significantly higher in the central nervous system and bone compared with liver metastases (20.8%, 95% CI = 15.0% to 28.0%, and 29.3%, 95% CI = 13.0% to 53.5%, vs 14.3%, 95% CI = 11.3% to 18.1, P = .008 and P < .001, respectively), and PR discordance was higher in bone (42.7%, 95% CI = 35.1% to 50.6%, P < .001) and liver metastases (47.0%, 95% CI = 41.0% to 53.0%, P < .001) compared with central nervous system metastases (23.3%, 95% CI = 16.0% to 32.6%).
Conclusions
Receptor conversion for ERα, PR, and HER2 occurs frequently in the course of disease progression in breast cancer. Large prospective studies assessing the impact of receptor conversion on treatment efficacy and survival are needed. Meanwhile, reassessing receptor status in metastases is strongly encouraged.
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•We organized a challenge on mitosis detection in breast cancer histopathology images.•The challenge dataset consisted of 23 cases with more than 1000 annotated mitoses.•Eleven ...proposed algorithms were evaluated and compared.•The top scoring method had a performance comparable to expert observers.
The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues.
In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists.
This paper presents an overview of methods that have been proposed for the analysis of breast cancer histopathology images. This research area has become particularly relevant with the advent of ...whole slide imaging (WSI) scanners, which can perform cost-effective and high-throughput histopathology slide digitization, and which aim at replacing the optical microscope as the primary tool used by pathologist. Breast cancer is the most prevalent form of cancers among women, and image analysis methods that target this disease have a huge potential to reduce the workload in a typical pathology lab and to improve the quality of the interpretation. This paper is meant as an introduction for nonexperts. It starts with an overview of the tissue preparation, staining and slide digitization processes followed by a discussion of the different image processing techniques and applications, ranging from analysis of tissue staining to computer-aided diagnosis, and prognosis of breast cancer patients.
Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which ...leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has pre-clinically improved tumor selectivity. However, antibodies have long half-lives and relatively poor tissue penetration, which could limit therapeutic efficacy and lead to long photosensitivity. Here, in this feasibility study, we evaluate at the pre-clinical level a recently introduced format of targeted PDT, which employs nanobodies as targeting agents and a water-soluble PS (IRDye700DX) that is traceable through optical imaging. In vitro, the PS solely binds to cells and induces phototoxicity on cells overexpressing the epidermal growth factor receptor (EGFR), when conjugated to the EGFR targeted nanobodies. To investigate whether this new format of targeted PDT is capable of inducing selective tumor cell death in vivo, PDT was applied on an orthotopic mouse tumor model with illumination at 1h post-injection of the nanobody–PS conjugates, as selected from quantitative fluorescence spectroscopy measurements. In parallel, and as a reference, PDT was applied with an antibody–PS conjugate, with illumination performed 24h post-injection. Importantly, EGFR targeted nanobody–PS conjugates led to extensive tumor necrosis (approx. 90%) and almost no toxicity in healthy tissues, as observed through histology 24h after PDT. Overall, results show that these EGFR targeted nanobody–PS conjugates are selective and able to induce tumor cell death in vivo. Additional studies are now needed to assess the full potential of this approach to improving PDT.
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Background
The benefits of digital pathology for workflow improvement and thereby cost savings in pathology, at least partly outweighing investment costs, are being increasingly recognised. ...Successful implementations in a variety of scenarios have started to demonstrate the cost benefits of digital pathology for both research and routine diagnosis, contributing to a sound business case encouraging further adoption. To further support new adopters, there is still a need for detailed assessment of the impact that this technology has on the relevant pathology workflows, with an emphasis on time‐saving.
Aims
To assess the impact of digital pathology adoption on logistic laboratory tasks (i.e. not including pathologists’ time for diagnosis‐making) in the Laboratorium Pathologie Oost Nederland, a large regional pathology laboratory in The Netherlands.
Methods and results
To quantify the benefits of digitisation, we analysed the differences between the traditional analogue and new digital workflows, carried out detailed measurements of all relevant steps in key analogue and digital processes, and compared the time spent. We modelled and assessed the logistic savings in five workflows: (i) routine diagnosis; (ii) multidisciplinary meeting; (iii) external revision requests; (iv) extra stainings; and (v) external consultation. On average, >19 working hours were saved on a typical day by working digitally, with the highest savings in routine diagnosis and multidisciplinary meeting workflows.
Conclusions
By working digitally, a significant amount of time could be saved in a large regional pathology laboratory with a typical case mix. We also present the data in each workflow per task and concrete logistic steps to allow extrapolation to the context and case mix of other laboratories.
Cancer cells are reliant on the cellular translational machinery for both global elevation of protein synthesis and the translation of specific mRNAs that promote tumor cell survival. Targeting ...translational control in cancer is therefore increasingly recognized as a promising therapeutic strategy. In this regard, DEAD/H box RNA helicases are a very interesting group of proteins, with several family members regulating mRNA translation in cancer cells. In this review, we delineate the mechanisms by which DEAD/H box proteins modulate oncogenic translation and how inhibition of these RNA helicases can be exploited for anti-cancer therapeutics.
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