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Background HPV cervical cancer screening (CCS) must use validated HPV tests based on the molecular detection of either viral mRNA (Aptima HPV Assay—AHPV) or DNA. AHPV has demonstrated the same cross-sectional and longitudinal sensitivity for the detection of HSIL/CIN2+ lesions but with greater specificity than HPV-DNA tests. The study aimed to estimate the total costs of a CCS with a primary HPV test based on the detection of mRNA compared to DNA in women aged 35–65 years for the National Health System. Methods A decision-tree-based model to estimate the cost of the CCS until the first colposcopy was designed based on Spanish CCS guidelines. The total cost (€, 2019) for CCS with AHPV or DNA tests (HC2 and Cobas) was calculated, including HPV test, liquid-based cytology (LBC) and colposcopy, for a population of 7,263,529 women aged 35–65 years (assuming 70% coverage). Clinical inputs derived from a literature review were validated by a multidisciplinary expert panel. Data from head-to-head studies between different HPV tests were selected. Results The use of AHPV showed reduction of 290,541 (− 35%) and 355,913 (− 40%) LBC compared to HC2 or Cobas, respectively. Furthermore, AHPV avoided 151,699 (− 47%) colposcopies versus HC2 and 151,165 (− 47%) versus Cobas. The total cost of CCS was € 282,747,877 with AHPV, € 322,587,588 with HC2 and € 324,614,490 with Cobas. Therefore, AHPV savings € − 39,839,711 versus HC2 and € − 41,866,613 versus Cobas. Conclusions Assuming that 70% of women from 35 to 65 years attend the CCS programme, the cost of screening up to the first colposcopy using AHPV would provide cost savings of up to € 41.9 million versus DNA tests in Spain.

Background Engineered stone silicosis is an emerging disease in many countries worldwide produced by the inhalation of respirable dust of engineered stone. This silicosis has a high incidence among young workers, with a short latency period and greater aggressiveness than silicosis caused by natural materials. Although the silica content is very high and this is the key factor, it has been postulated that other constituents in engineered stones can influence the aggressiveness of the disease. Different samples of engineered stone countertops (fabricated by workers during the years prior to their diagnoses), as well as seven lung samples from exposed patients, were analyzed by multiple techniques. Results The different countertops were composed of SiO2 in percentages between 87.9 and 99.6%, with variable relationships of quartz and cristobalite depending on the sample. The most abundant metals were Al, Na, Fe, Ca and Ti. The most frequent volatile organic compounds were styrene, toluene and m-xylene, and among the polycyclic aromatic hydrocarbons, phenanthrene and naphthalene were detected in all samples. Patients were all males, between 26 and 46 years-old (average age: 36) at the moment of the diagnosis. They were exposed to the engineered stone an average time of 14 years. At diagnosis, only one patient had progressive massive fibrosis. After a follow-up period of 8 ± 3 years, four patients presented progressive massive fibrosis. Samples obtained from lung biopsies most frequently showed well or ill-defined nodules, composed of histiocytic cells and fibroblasts without central hyalinization. All tissue samples showed high proportion of Si and Al at the center of the nodules, becoming sparser at the periphery. Al to Si content ratios turned out to be higher than 1 in two of the studied cases. Correlation between Si and Al was very high (r = 0.93). Conclusion Some of the volatile organic compounds, polycyclic aromatic hydrocarbons and metals detected in the studied countertop samples have been described as causative of lung inflammation and respiratory disease. Among inorganic constituents, aluminum has been a relevant component within the silicotic nodule, reaching atomic concentrations even higher than silicon in some cases. Such concentrations, both for silicon and aluminum showed a decreasing tendency from the center of the nodule towards its frontier.

To identify subgroups with good progress over an extended period, we used diagnostic screening, tumour palpability, tumour phenotype, and node involvement.We identified patients with good progress by means of a descriptive, observational and retrospective study.Of 746 patients diagnosed with node-negative breast cancer between 2001 and 2015: 110 (14.75%) had non-palpable screening-diagnosed tumours; 88 (80%) were endocrine-sensitive, 10 (9.10%) were triple-negative and 11 (10%) were HER2. Only 3 patients developed metastases, and there were 4 deaths: 2 from breast cancer and 2 from other causes. The distant recurrence-free interval (DRFI) was 95.60%: 100% in 34 endocrine-sensitive histological grade 1 (equivalent to luminal A) tumours, and 94.40% (95% CI 86.76-102.04) in 54 grade 2-3 (luminal B) tumours. In triple-negative and HER2 cases, it was 100%. In tumours1 cm it was 100%, and1 cm it was 95.50% (95% CI 79.42-100.98).Patients with non-palpable tumours detected by mammogram screening have ultralow risk. The good progress in the luminal A, triple-negative, HER2, and less than 1 cm subgroups may explain the efficacy of the treatment but it also makes them candidates to de-escalation of their treatment.

The foremost cause of death of breast cancer (BC) patients is metastasis, and the first site to which BC predominantly metastasizes is the axillary lymph node (ALN). Thus, ALN status is a key prognostic indicator at diagnosis. The immune system has an essential role in cancer progression and dissemination, so its evaluation in ALNs could have significant applications. In the present study we aimed to investigate the association of clinical-pathological and immune variables in the primary tumour and non-metastatic ALNs (ALNsWe analysed the differences in the variables between patients with different outcomes, created univariate and multivariate Cox regression models, validated them by bootstrapping and multiple imputation of missing data techniques, and used Kaplan-Meier survival curves for a 10-years follow-up.We found some clinical-pathological variables at diagnosis (tumour diameter, TNBC molecular profile and presence of ALN metastasis), and the levels of several immune markers in the two studied sites, to be associated with worse CSS and TTP. Nevertheless, only CD68 and CD83 in ALNsThe study identified the importance of macrophage and dendritic cell markers as prognostic factors of relapse for BC. We highlight the importance of studying the immune response in ALNs

Breast cancer (BC) comprises four immunohistochemical surrogate subtypes of which triple-negative breast cancer (TNBC) has the highest risk of mortality. Axillary lymph nodes (ALNs) are the regions where BC cells first establish before distant metastasis, and the presence of tumor cells in the ALN causes an immune tolerance profile that contrasts with that of the nonmetastatic ALN (ALN−). However, few studies have compared the immune components of the ALNs− in BC subtypes. The present study aimed to determine whether differences between immune populations in the primary tumor and ALNs− were associated with the luminal A or TNBC subtype. We evaluated a retrospective cohort of 144 patients using paraffin-embedded biopsies. The TNBC samples tended to have a higher histologic grade and proliferation index and had higher levels of immune markers compared with luminal A in primary tumors and ALNs−. Two methods for validating the multivariate analysis found that histologic grade, intratumoral S100 dendritic cells, and CD8 T lymphocytes and CD57 natural killer cells in the ALNs− were factors associated with TNBC, whereas CD83 dendritic cells in the ALNs− were associated with the luminal A subtype. In conclusion, we found that intratumoral regions and ALNs− of TNBC contained higher concentrations of markers related to immune tolerance than luminal A. This finding partially explains the worse prognosis of patients with TNBC.

The data presented in this article is part of the whole slide imaging (WSI) datasets generated in European project AIDPATH 2 This data is also related to the research paper entitle “Glomerulosclerosis Identification in Whole Slide Images using Semantic Segmentation”, published in Computer Methods and Programs in Biomedicine Journal [1]. In that article, different methods based on deep learning for glomeruli segmentation and their classification into normal and sclerotic glomerulous are presented and discussed. The raw data used is described and provided here. In addition, the detected glomeruli are also provided as individual image files. These data will encourage research on artificial intelligence (AI) methods, create and compare fresh algorithms, and measure their usability in quantitative nephropathology. Keywords: Glomeruli identification, Normal glomerulus, Global sclerotic glomerulus, Whole slide image, Digital pathology

Resumen Introduccion Las recomendaciones del cribado de cancer de cervix en Espana incluyen la participacion en programas de control de calidad externos a los laboratorios de citologia. La Sociedad Espanola de Citologia ha iniciado un programa de control de calidad de la citologia ginecologica. Objetivo Presentar y discutir los resultados de la primera ronda del control de calidad de la Sociedad Espanola de Citologia. Material y metodo Organizacion de los hospitales participantes segun el tipo de citologia. Intercambio de preparaciones de 50 casos entre los participantes: 10 negativos, 20 ASCUS-ASCH, 10 LSIL y 10 HSIL. Estudio de la correlacion diagnostica interobservador. Resultados Trece hospitales participantes: 6 en ThinPrep, 5 en triple toma y 2 en SurePath. La concordancia global media fue del 69,7%. La concordancia media por tipo de lesion fue del 41,7%. La concordancia en negativos fue del 78,1%, en ASCUS del 41,3%, en LSIL de 58,9% y en HSIL del 64,2%. Los casos discordantes se diagnosticaban con mayor frecuencia como negativos, ASCUS y LSIL. Las discordancias severas (HSIL/ASCH versus negativo), alcanzaron un 3,8% de casos. Conclusiones Nuestros resultados son similares a los descritos en la literatura con muy escasas discordancias severas. El metodo de intercambio de laminillas utilizado no permite una formacion continuada posterior, ya que no incluye la revision de los casos con discordancias diagnosticas. Por ello, se contemplan correcciones metodologicas en sucesivas rondas.

Tumor cells can modify the immune response in primary tumors and in the axillary lymph nodes with metastasis (ALN+) in breast cancer (BC), influencing patient outcome. We investigated whether patterns of immune cells in the primary tumor and in the axillary lymph nodes without metastasis (ALN-) differed between patients diagnosed without ALN+ (diagnosed-ALN-) and with ALN+ (diagnosed-ALN+) and the implications for clinical outcome. Eleven immune markers were studied using immunohistochemistry, tissue microarray, and digital image analysis in 141 BC patient samples (75 diagnosed-ALN+ and 66 diagnosed-ALN-). Two logistic regression models were derived to identify the clinical, pathologic, and immunologic variables associated with the presence of ALN+ at diagnosis. There are immune patterns in the ALN- associated with the presence of ALN+ at diagnosis. The regression models revealed a small subgroup of diagnosed-ALN+ with ALN- immune patterns that were more similar to those of the ALN- of the diagnosed-ALN-. This small subgroup also showed similar clinical behavior to that of the diagnosed-ALN-. Another small subgroup of diagnosed-ALN- with ALN- immune patterns was found whose members were more similar to those of the ALN- of the diagnosed-ALN+. This small subgroup had similar clinical behavior to the diagnosed-ALN+. These data suggest that the immune response present in ALN- at diagnosis could influence the clinical outcome of BC patients.

Approximately 1.67 million new cases of breast cancer (BC) are diagnosed annually, and patient survival significantly decreases when the disease metastasizes. The axillary lymph nodes (ALNs) are the main doorway for BC tumoral cell escape, through which cells can disseminate to distant organs. The immune response, which principally develops in the lymph nodes, is linked to cancer progression, and its efficacy at controlling tumoral growth is compromised during the disease. Immunohistochemistry (IHC) is one of the most widely used research techniques for studying the immune response. It allows the measurement of the expression of particular markers related to the immune populations. This review focuses on the role of the immune populations in the primary tumour in the locoregional metastasis of the ALN, and the relationship of the immune response in these regions to distant metastasis. We considered only studies of immune cells using IHC techniques. In particular, lymphocytes, macrophages and dendritic cells all play important roles in BC and have been extensively studied. Although further research is needed, there is much evidence of their role in the invasion of the ALN and distant organs. Their association with tumoral growth or protection has not yet been demonstrated decisively and is very likely to be determined by a combination of factors. Moreover, even though IHC is a widely used technique in cancer diagnosis and research, there is still room for improvement, since its quantification needs to be properly standardized.

A mouse model has been developed to study the effect of dietary fat combined with food deprivation periods on palatable food seeking and on the expression of three potential addiction biomarkers in the nucleus accumbens: fumarate hydratase (FH), ATP synthase subunit alpha (ATP5a1) and transketolase (TKT). Forty C57BL/6 J male mice, four-week old, were fed either with a high-fat (HF) diet or standard diet along the experiment. After 3 weeks of differential feeding, animals underwent a two-week training period of two daily sessions where visual cues were paired either to palatable food (chocolate cereals) or no food at all. This training was prolonged one more week with similar, one daily sessions preceded by 12 hours of food deprivation. A behavioural test was finally conducted where mice were confined for 30 minutes either in food unpaired compartments or in compartments previously paired with cereals, but now with empty food trays. Total activity during this behavioural test and serum corticosterone levels right after it were similar in all experimental groups. Mice tested in food-paired compartments showed a marked preference for the empty food tray that gradually disappeared in standard diet-fed individuals but persisted in HF-fed mice. HF-fed mice also overexpressed FH, ATP5a1 and TKT, which positively correlated with the persistence of preference for the empty food tray. It is suggested that HF diets combined with food deprivation may enhance food seeking behaviours while upregulating FH/ATP5a1/TKT, which are further envisaged as biomarkers of addiction.

Digital technology is progressively changing our vision of the practice of neuropathology. There are a number of facts that support the introduction of digital neuropathology. With the development of wholeslide imaging (WSI) systems the difficulties involved in implementing a neuropathology network have been solved. A relevant difficulty has been image standardization, but an open digital image communication protocol defined by the Digital Imaging and Communications in Medicine (DICOM) standard is already a reality. The neuropathology network should be established in Europe because it is the expected geographic context for relationships among European neuropathologists. There are several limitations in the implementation of a digital neuropathology consultancy network such as financial support, operational costs, legal issues, and technical assistance of clients. All of these items have been considered and should be solved before implementing the proposal. Finally, the authors conclude that a European digital neuropathology network should be created for patients' benefit.

Introduction: A whole slide image (WSI) is typically comprised of a macro image (low-power snapshot of the entire glass slide) and stacked tiles in a pyramid structure (with the lowest resolution thumbnail at the top). The macro image shows the label and all pieces of tissue on the slide. Many whole slide scanner vendors do not readily show the macro overview to pathologists. We demonstrate that failure to do so may result in a serious misdiagnosis. Materials and Methods: Various examples of errors were accumulated that occurred during the digitization of glass slides where the virtual slide differed from the macro image of the original glass slide. Such examples were retrieved from pathology laboratories using different types of scanners in the USA, Canada, Europe, and Asia. Results: The reasons for image errors were categorized into technical problems (e.g., automatic tissue finder failure, image mismatches, and poor scan coverage) and human operator mistakes (e.g., improper manual region of interest selection). These errors were all detected because they were highlighted in the macro image. Conclusion: Our experience indicates that WSI can be subject to inadvertent errors related to glitches in scanning slides, corrupt images, or mistakes made by humans when scanning slides. Displaying the macro image that accompanies WSIs is critical from a quality control perspective in digital pathology practice as this can help detect these serious image-related problems and avoid compromised diagnoses.

As digital pathology systems for clinical diagnostic work applications become mainstream, interoperability between these systems from different vendors becomes critical. For the first time, multiple digital pathology vendors have publicly revealed the use of the digital imaging and communications in medicine (DICOM) standard file format and network protocol to communicate between separate whole slide acquisition, storage, and viewing components. Note the use of DICOM for clinical diagnostic applications is still to be validated in the United States. The successful demonstration shows that the DICOM standard is fundamentally sound, though many lessons were learned. These lessons will be incorporated as incremental improvements in the standard, provide more detailed profiles to constrain variation for specific use cases, and offer educational material for implementers. Future Connectathon events will expand the scope to include more devices and vendors, as well as more ambitious use cases including laboratory information system integration and annotation for image analysis, as well as more geographic diversity. Users should request DICOM features in all purchases and contracts. It is anticipated that the growth of DICOM-compliant manufacturers will likely also ease DICOM for pathology becoming a recognized standard and as such the regulatory pathway for digital pathology products.

Introduction: The optimal management of grade II gliomas (LGGs) remains controversial, and only limited definitive data is available to guide recommendations. Radiation therapy is currently offered to LGG patients with certain combinations of risk factors. However, its benefit on initial tumor control may be outweighed by late toxicities. Mathematical modeling has the potential of helping in selecting patients who may benefit from radiotherapy and in developing optimal fractionation schemes for patient subgroups. Materials and methods: LGG growth was described in-silico using a previously validated mathematical model incorporating accelerated repopulation and growth saturation. Tumor response to radiation and normal tissue toxicity was accounted for by a classical linear-quadratic (LQ) model. An optimization problem was posed to determine the optimal fractionation protocol (dose per fraction, number of doses and time between fractions) delaying the most the tumor’s malignant transformation (MT) while at the same time maintaining the toxicity on or below the level of the standard fractionation (30 daily fractions of 1.8 Gy). Results: The optimal protocols were found to be metronomic with 0.5 Gy/fraction and dose interspacing ranging from one week to one month depending on tumor’s growth rate. The MT was found to be delayed from 1 (fast growing LGGs) to 7 years (slowly growing LGGs). A robust protocol was found to provide a sub-optimal gain for all tumor growth rates. Other non-standard radiotherapy fractionations were found to provide survival advantages: (i) Protracted schemes with 1.8 Gy/fraction and time interval between doses ranging from one to three months (ii) Hypoprotracted schemes with dose per fraction of 3.2 Gy and larger interdose time spacings. In all cases the potential time delay of the MT, was of up to several years with the advantage over metronomic schemes of being more feasible from the practical point of view. Some fractionations were proven to provide a substantial survival advantage while at the same time reducing the toxicity in comparison with the standard fractionation. The concepts are being validated in biomimetic devices (microfluidic chips) and the results will be also reported at the conference. CONCLUSION: A substantial survival benefit could be achieved by using non-standard radiotherapy fractionation schemes together with a reduction in treatment toxicity. Thus, mathematical modelling techniques may complement the use of highly conformal techniques in order to improve treatment efficacy and reduce neurotoxicity.

Background: Oesophagoscopy with biopsy is considered the gold standard for diagnosing and monitoring eosinophilic oesophagitis (EoE). Therefore is important to discover less-invasive diagnostic methods. Methods: Cytology specimens were obtained in patients with active EoE (AEoE) (� 15 eos/hpf) and EoE in remission (EoER) (

This paper describes a specific tool for automatically segmenting and archiving of tissue microarray (TMA) cores in microscopy images at different magnifications. TMA enables researchers to extract the small cylinders of a single tissue (core sections) from histological sections and arrange them in an array on a paraffin block such that hundreds can be analyzed simultaneously. A crucial step to improve the speed and quality of this process is the correct localization of each tissue core in the array. However, usually the tissue cores are not aligned in the microarray, the TMA cores are incomplete and the images are noisy and with distorted colors. We develop a robust framework to handle core sections under these conditions. The algorithms are able to detect, stitch, and archive the TMA cores at different magnifications. Once the TMA cores are segmented they are stored in a relational database allowing their processing for further studies of benign-malignant classification. The method was shown to be reliable for handling the TMA cores and therefore enabling further large-scale molecular pathology research.

Background Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is the best operative treatment currently available for patients with peritoneal carcinomatosis of ovarian origin. The open abdomen technique is the classic technique for hyperthermic intraperitoneal chemotherapy. We developed a closed abdomen model that improves temperature control and increases exposure of peritoneal surfaces to the drug by recirculating the perfusate. Methods We used a porcine model with 12 female, Large White pigs—4 in the open technique group and 8 in the closed technique CO2 group. We performed cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for 60 minutes using paclitaxel (175 mg/m2) at an input temperature of 42°C. Perfusate recirculation was performed under controlled pressure (range, 12–15 mmHg). The infusion of 0.7 L of CO2 via a separate intraperitoneal infusion catheter mixed the perfusate within the peritoneal cavity. Intra-abdominal temperature was assessed using 6 intra-abdominal temperature probes and 2 temperature probes in the inflow and outflow circuits. Drug distribution was assessed using methylene blue staining. Results Intra-abdominal temperatures remained constant and homogeneous in all intra-abdominal quadrants with a constant input temperature of 42°C and a minimum output temperature of 41.4°C. The infused CO2 caused the fluid to bubble and created agitation inside the abdominal cavity to facilitate a homogeneous distribution of the drug-containing perfusate. Conclusion The closed recirculation hyperthermia with intraperitoneal chemotherapy technique developed in this study is safe and feasible, and may provide a more homogeneous delivery of heated chemotherapy to the peritoneal cavity in patients with peritoneal malignancies.

A new method that simplifies the evaluation of the traditional HER2 fluorescence in situ hybridization (FISH) evaluation in breast cancer was proposed. HER2 status was evaluated in digital images (DIs) captured from 423 invasive breast cancer stained sections. All centromeric/CEP17 and HER2 gene signals obtained from separated stacked DIs were manually counted on the screen. The global ratios were compared with the traditional FISH evaluation and the immunohistochemical status. The 2 FISH scores were convergent in 96.93% of cases, showing an “almost perfect” agreement with a weighted k of 0.956 (95% confidence interval, 0.928-0.985). The new method evaluates at least 3 times more nuclei than traditional methods and also has an almost perfect agreement with the immunohistochemical scores. The proposed enhanced method substantially improves HER2 FISH assessment in breast cancer biopsy specimens because the evaluation of HER2/CEP17 copy numbers is more representative, easier, and faster than the conventional method.

Immunohistochemical (IHC) biomarkers in breast tissue microarray (TMA) samples are used daily in pathology departments. In recent years, automatic methods to evaluate positive staining have been investigated since they may save time and reduce errors in the diagnosis. These errors are mostly due to subjective evaluation. The aim of this work is to develop a density tool able to automatically quantify the positive brown IHC stain in breast TMA for different biomarkers. To avoid the problem of colour variation and make a robust tool independent of the staining process, several colour standardization methods have been analysed. Four colour standardization methods have been compared against colour model segmentation. The standardization methods have been compared by means of NBS colour distance. The use of colour standardization helps to reduce noise due to stain and histological sample preparation. However, the most reliable and robust results have been obtained by combining the HSV and RGB colour models for segmentation with the HSB channels. The segmentation provides three outputs based on three saturation values for weak, medium and strong staining. Each output image can be combined according to the type of biomarker staining. The results with 12 biomarkers were evaluated and compared to the segmentation and density calculation done by expert pathologists. The Hausdorff distance, sensitivity and specificity have been used to quantitative validate the results. The tests carried out with 8000 TMA images provided an average of 95.94% accuracy applied to the total tissue cylinder area. Colour standardization was used only when the tissue core had blurring and fading stain and the expert could not evaluate them without a pre-processing.

Digital slides, also called whole-slide images, are being evaluated to replace conventional microscopy, and several guidelines have been published. This paper reviews technical specifications of digital pathology systems that have been included in the guidelines and position papers from the Canadian Association of Pathologists, the College of American Pathologists, the American Telemedicine Association, the Digital Pathology Association, the Food and Drug Administration, the Centers for Medicare and Medicaid Services, the Centers for Disease Control and Prevention, the Society of Toxicologic Pathology, the European Commission, the Spanish Society of Anatomic Pathology, The Royal College of Pathologists and The Royal College of Pathologists of Australasia. In conclusion, most technical aspects are well covered by these guidelines, although they offer limited information regarding image quality and compression, and file formats.

The future paradigm of pathology will be digital. Instead of conventional microscopy, a pathologist will perform a diagnosis through interacting with images on computer screens and performing quantitative analysis. The fourth generation of virtual slide telepathology systems, so-called virtual microscopy and whole-slide imaging (WSI), has allowed for the storage and fast dissemination of image data in pathology and other biomedical areas. These novel digital imaging modalities encompass high-resolution scanning of tissue slides and derived technologies, including automatic digitization and computational processing of whole microscopic slides. Moreover, automated image analysis with WSI can extract specific diagnostic features of diseases and quantify individual components of these features to support diagnoses and provide informative clinical measures of disease. Therefore, the challenge is to apply information technology and image analysis methods to exploit the new and emerging digital pathology technologies effectively in order to process and model all the data and information contained in WSI. The final objective is to support the complex workflow from specimen receipt to anatomic pathology report transmission, that is, to improve diagnosis both in terms of pathologists' efficiency and with new information. This article reviews the main concerns about and novel methods of digital pathology discussed at the latest workshop in the field carried out within the European project AIDPATH (Academia and Industry Collaboration for Digital Pathology).

In this work we present a study for assessing and comparing the fidelity of biopsy and cytology images captured with two different devices, that is optical microscopes and scanners, at 40× magnification in bright field. The devices use different ways to magnify images. Microscopes use a set of lenses while scanners capture light through arrays of micro-photoreceptors. The objective is to carry out a quantitative evaluation to discern which of the two devices provides better image quality in terms of contrast, colour and stain. Since there is no unanimous consensus on quality metrics, we will make use of both an objective metric based on perceptual features, together with a subjective psychophysical test as the International Telecommunications Union (ITU) recommends in ITU-R BT.500 for such type of tests. Both techniques indicate a slight preference for the scanner over the microscope in terms of better image quality, considering defocus as the main problem followed by colour distortions. However, the image quality of both devices is suitable for clinical, educational and research purposes. © 2011 Elsevier Ltd., This work has been carried out with the support of COST ActionIC0604, and the research projects DPI2008-06071, TEC2010-20307, TEC2010-09834-E of the Spanish Research Ministry, PI-2010/040 of the FISCAM and PAI08-0283-9663 of JCCM.

The development of small molecule inhibitors of growth factor receptors, and the discovery of somatic mutations of the thyrosine kinase domain, have resulted in new paradigms for cancer therapy. Digital microscopy is an important tool for surgical pathologists. The achievements in the digital pathology field have modified the workflow of pathomorphology labs, enhanced the pathologist’s role in diagnostics, and increased their contribution to personalized targeted medicine. Digital image analysis is now available in a variety of platforms to improve quantification performance of diagnostic pathology. We here describe the state of digital microscopy as it applies to the field of quantitative immunohistochemistry of biomarkers related to the clinical personalized targeted therapy of breast cancer, non-small lung cancer and colorectal cancer: HER-2, EGFR, KRAS and BRAF genes. The information is derived from the experience of the authors and a review of the literature. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 570–578)

Whole slide imaging (WSI) scanners and automatic image analysis algorithms, in order to be used for clinical applications, including primary diagnosis in pathology, are subject to specific regulatory frameworks in each country. Until May 25, 2018, in the European Union (EU), in vitro diagnostic (IVD) medical devices were regulated by directive 98/79/EC (in vitro diagnostic medical device directive [IVDD]). Main scanner vendors have obtained a Conformité Européenne mark of their products that in Europe were classified as General Class IVDD, so that conformity is only based on a self-declaration of the manufacturer. This contrasts with the initial classification of the US Food and Drug Administration (FDA) of WSI system as Class III medical devices, although the first digital pathology WSI system to be cleared by FDA was classified as Class II, with special controls. Other digital pathology solutions (automated cervical cytology slide reader) are considered of higher risk by US and European regulations. There is also some disparity in the classification of image analysis solutions between Europe and the United States. All IVD-MDs must be approved under the new European regulation (in vitro diagnostic medical device regulation) 2017/746 after May 26, 2024. This means the need of a performance evaluation, including a scientific validity report, an analytical performance report, and a clinical performance report. According to its clinical use (e.g., screening, diagnosis, or staging of cancer), a WSI slide scanner can be now classified as Class C device. A special regulation is applied to companion diagnostics. The new EU regulation 2017/746 contemplates the use of standard unique identifiers for medical devices and the creation of a European database on medical devices (Eudamed). Existing validation studies and clinical guidelines already available in the literature are a sound basis to avoid that this new regulation becomes a barrier for digital pathology development in Europe.