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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.

Introduction: Integrated care models aim to provide solutions to fragmentation of care by improving coordination. This study will evaluate the effectiveness of a new integrated care model (Salut + Social), which will promote the coordination and communication between social and healthcare services in southern Catalonia (Spain) to improve quality of life, adherence to treatment and access to medical services for patients with chronic conditions, and also to reduce caregiver burden. Additionally, we will evaluate the experience of caregivers, health professionals and social workers with the new model implemented. Methods and analysis: A clinical trial using mixed methodology will be carried out. The intervention consists of improving the coordination between the social and healthcare sectors during a 6-month period, by means of information and communication technology (ICT) tools that operate as an interface for the integrated care model. The study subjects are primary care patients with chronic health and social conditions that can benefit from a collaborative and coordinated approach. A sample size of 141 patients was estimated. Questionnaires that assess quality of life, treatment adherence, medical service and caregiver burden will be used at baseline and at 6, 9, and 12 months after the beginning of the study. The principal variable is quality of life. For statistical analysis, comparisons of means and proportions at different time points will be performed. A discussion group and semi-structured interviews will be conducted with the aim of improving the care model taking into account the opinions of professionals and caregivers. A thematic content analysis will be carried out. Ethics and dissemination: This study protocol has been approved by the Clinical Research Ethics Committee of the Fundació Institut Universitari per a la Recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (code P17/100). Articles will be published in international, peer-reviewed scientific journals. Trial registration: Clinical-Trials.gov: NCT04164160.

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.

Background The axillary lymph nodes (ALNs) in breast cancer patients are the body regions to where tumoral cells most often first disseminate. The tumour immune response is important for breast cancer patient outcome, and some studies have evaluated its involvement in ALN metastasis development. Most studies have focused on the intratumoral immune response, but very few have evaluated the peritumoral immune response. The aim of the present article is to evaluate the immune infiltrates of the peritumoral area and their association with the presence of ALN metastases. Methods The concentration of 11 immune markers in the peritumoral areas was studied in 149 patients diagnosed with invasive breast carcinoma of no special type (half of whom had ALN metastasis at diagnosis) using tissue microarrays, immunohistochemistry and digital image analysis procedures. The differences in the concentration of the immune response of peritumoral areas between patients diagnosed with and without metastasis in their ALNs were evaluated. A multivariate logistic regression model was developed to identify the clinical-pathological variables and the peritumoral immune markers independently associated with having or not having ALN metastases at diagnosis. Results No statistically significant differences were found in the concentrations of the 11 immune markers between patients diagnosed with or without ALN metastases. Patients with metastases in their ALNs had a higher histological grade, more lymphovascular and perineural invasion and larger-diameter tumours. The multivariate analysis, after validation by bootstrap simulation, revealed that only tumour diameter (OR = 1.04; 95% CI [1.00–1.07]; p = 0.026), lymphovascular invasion (OR = 25.42; 95% CI [9.57–67.55]; p p = 0.033) and 3 (OR = 5.18; 95% CI [1.40–19.17]; p = 0.014) were associated with the presence of ALN metastases at diagnosis. This study is one of the first to study the association of the peritumoral immune response with ALN metastasis. We did not find any association of peritumoral immune infiltrates with the presence of ALN metastasis. Nevertheless, this does not rule out the possibility that other peritumoral immune populations are associated with ALN metastasis. This matter needs to be examined in greater depth, broadening the types of peritumoral immune cells studied, and including new peritumoral areas, such as the germinal centres of the peritumoral tertiary lymphoid structures found in extensively infiltrated neoplastic lesions.

Introduction : In June 2014 an innovative experience that made it possible to carry out a health and social monitoring of the patients was initiated in Amposta. It is a coordination project with the help of the application Salut+Social [Health+Social] created to establish a quick and fluid communication between the Amposta primary care centre from the Institut Catala de la Salut and the social services (SS) from the Amposta City Council. This project was born out of the common concern of the primary care professionals from the CAP and the municipal social services, both from Amposta, with the intention to provide and integrated, efficient and high-quality attention to the patients with the need of complex social and medical cares: complex chronic patients (CCP), advanced chronic disease (ACD), home health care (HHC), patients with a 2nd or 3rd dependence degree or with home care services (HCS). Brief description : The objectives of the project are to guarantee the continuity of the healings, strengthen the patients and their families autonomy, improve the assistance, reducing its variability and increasing its quality, establish a fluid and bidirectional communication, avoid duplicating efforts, coordinate the actions between the professionals, establish an interaction through an instant e-mail messaging service and integrate the social and medical services. After several meetings between the SS professionals from the Amposta City Council and those from the CAP and being aware of the importance of both assistance levels, an interdisciplinary team was created. This team, together with the IT department from the Terres de l'Ebre unit, created the ICT tool SALUT+SOCIAL. The initiative has gone ahead thanks to an agreement between the ICS and the Amposta City Council in order to share information through the tool. The app, after the user sign up, lets the professionals to share its information and changes made after each visit always respecting the data confidentiality. Conclusions : Speeding up of the procedures, communication and coordination improvement, IT app, in-person sessions, joint effort, framework updating, integration of the social professionals in the CAP once a week, fluid communication, improvement of the accessibility for the user. The tool has been the salutary lesson because with it we have been able to build an integration project, the social professionals from the City Council go to the CAP once a week in order to meet the rest of professionals and talk about each of the cases from the app and other ones that may need a specific work too. 934 users are included in the application and 983 movements (messages) have been carried out in order to treat 134 users in collaboration between both services. The social professionals from the reference hospitals and the case manager, who work with the app and go to the coordination meetings to follow up the cases, have been incorporated to the project too. Lessons learnt : The concept of services integration makes the attention to the user from a global vision possible. The joint effort allowed the long term consolidation of both teams coordination. It is necessary to move forward the integration of the medical and social systems in order to address the chronicity. While the project was progressing, we have been presented with new challenges that we are now developing. We have incorporated the possibility of making the common interventions with the patients that do not comply with the usual requirements (CCP, HHC, HCS, etc.), but that they need it because they are complex care or social cases not known. We have achieved the maximum integration of the health and social services for the benefit of the patient and also the updating of the public services. We have made a great dissemination of our task presenting the project to different territories, conferences and congresses. We are now adapting the health professional schedules for the coordination of the social services. We have developed the app for tablets and we are on the implementation phase in order to go to the patient home and directly registering the data. We have implemented the tool Business Intelligent: Pentaho in order to work with the data and establish an analysis and treatment, and we are developing the evaluation indicators. The project Salut+Social is included in the second line of action of the Health plan referring to the treatment of chronic patients using the new technologies and communication systems in order to create an innovative and accessible attention system for the chronic patients through an interdepartmental vision. Other frameworks are the governmental agreement from the Interdepartmental plan for the health and social attention and interaction.

The Joint Photographic Experts Group (JPEG) standard format is one of the most widely used in image compression technologies. More recently, JPEG2000 format has emerged as a state-of-the-art technology that provides substantial improvements in picture quality at higher compression ratios. However, there has been no attempt to date to determine which of the two compression formats produces less variability in the automated evaluation of immunohistochemically stained digital images in agreement with their compression rates and complexity degrees. The evaluation of Ki67 and FOXP3 immunohistochemical nuclear markers was performed in a total of 329 digital images: 47 were captured in uncompressed Tagged Image File Format (TIFF), 141 were converted to three JPEG compressed formats (47 each with 1:3, 1:23 and 1:46 compression) and 141 were converted to three JPEG2000 compressed formats (47 each with 1:3, 1:23 and 1:46 compression). The count differences between images in TIFF versus JPEG formats were compared with those obtained between images in TIFF versus JPEG2000 formats at the three levels of compression. It was found that, using JPEG2000 compression, the results of the stained nuclei count are close enough to the results obtained with uncompressed images, especially in highly complex images at minimum and medium compression. Otherwise, in images of low complexity, JPEG and JPEG2000 had similar count efficiency to that of the original TIFF images at all compression levels. These data suggest that JPEG2000 could give rise to an efficient means of storage, reducing file size and storage capacity, without compromise on the immunohistochemical analytical quality.

The volume of digital image (DI) storage continues to be an important problem in computer-assisted pathology. DI compression enables the size of files to be reduced but with the disadvantage of loss of quality. Previous results indicated that the efficiency of computer-assisted quantification of immunohistochemically stained cell nuclei may be significantly reduced when compressed DIs are used. This study attempts to show, with respect to immunohistochemically stained nuclei, which morphometric parameters may be altered by the different levels of JPEG compression, and the implications of these alterations for automated nuclear counts, and further, develops a method for correcting this discrepancy in the nuclear count. For this purpose, 47 DIs from different tissues were captured in uncompressed TIFF format and converted to 1:3, 1:23 and 1:46 compression JPEG images. Sixty-five positive objects were selected from these images, and six morphological parameters were measured and compared for each object in TIFF images and those of the different compression levels using a set of previously developed and tested macros. Roundness proved to be the only morphological parameter that was significantly affected by image compression. Factors to correct the discrepancy in the roundness estimate were derived from linear regression models for each compression level, thereby eliminating the statistically significant differences between measurements in the equivalent images. These correction factors were incorporated in the automated macros, where they reduced the nuclear quantification differences arising from image compression. Our results demonstrate that it is possible to carry out unbiased automated immunohistochemical nuclear quantification in compressed DIs with a methodology that could be easily incorporated in different systems of digital image analysis.

Introduction Lymph nodes are one of the main sites where an effective immune response develops. Normally, axillary nodes are the first place where breast cancer produces metastases. Several studies have demonstrated the importance of immune cells, especially dendritic cells, in the evolution of breast cancer. The goal of the project is to identify differences in the patterns of immune infiltrates, with particular emphasis on dendritic cells, in tumour and axillary node biopsies between patients with and without metastases in the axillary nodes at the time of diagnosis. It is expected that these differences will be able to explain differences in survival, relapse and clinicopathological variables between the two groups. Methods and analysis The study will involve 100 patients diagnosed with invasive breast cancer between 2000 and 2007, 50% of whom have metastases in the axillary lymph node at diagnosis. In selected patients, two cylinders from biopsies of representative areas of tumour and axillary nodes (with and without metastasis) will be selected and organised in tissue microarrays. Samples will be stained using immunohistochemical techniques for different markers of immune response and dendritic cells. Two images of each cylinder will be captured under standardised conditions for each marker. Each marker will be quantified automatically by digital image procedures using Image-Pro Plus and Image-J software. Associations of survival, relapse and other clinicopathological variables with the automatically quantified levels of immune infiltrates in patients with and without axillary node metastasis will be sought. Ethics and dissemination The present project has been approved by the Clinical Research Ethics Committee of the Hospital Universitari Joan XXIII (Ref: 22p/2011). Those patients whose biopsies and clinical data are to be used will give their signed informed consent. Results will be published in peer-reviewed journals.

The “removal” of background from digital images (DIs) to identify only the objects of interest is difficult due to the overlapping color values of pixels of the nuclei and background. We outline a new automated procedure to quantify only immunohistochemically stained nuclear markers, despite the similar color of the background. This procedure was compared with the gold standard manual method and a previous method developed for low-background DIs.

Manual quantification of immunohistochemically stained nuclear markers is still laborious and subjective and the use of computerized systems for digital image analysis have not yet resolved the problems of nuclear clustering. In this study, we designed a new automatic procedure for quantifying various immunohistochemical nuclear markers with variable clustering complexity. This procedure consisted of two combined macros. The first, developed with a commercial software, enabled the analysis of the digital images using color and morphological segmentation including a masking process. All information extracted with this first macro was automatically exported to an Excel datasheet, where a second macro composed of four different algorithms analyzed all the information and calculated the definitive number of positive nuclei for each image. One hundred and eighteen images with different levels of clustering complexity was analyzed and compared with the manual quantification obtained by a trained observer. Statistical analysis indicated a great reliability (intra-class correlation coefficient > 0.950) and no significant differences between the two methods. Bland–Altman plot and Kaplan–Meier curves indicated that the results of both methods were concordant around 90% of analyzed images. In conclusion, this new automated procedure is an objective, faster and reproducible method that has an excellent level of accuracy, even with digital images with a high complexity.