Pío del Río-Hortega : A Visionary in the Pathology of Central Nervous System Tumors

Fondo de Investigaciones Sanitarias (11/00185), Redes Temáticasde Investigación Cooperativa en Salud (Ref. RD06/0020/1020).The last 140 years have seen considerable advances in knowledge of central nervous system tumors. However, the main tumor types had already been described during the early years of the twentieth century. The studies of Dr. Pío del Río Hortega have been ones of the most exhaustive histology and cytology-based studies of nervous system tumors. Río Hortega's work was performed using silver staining methods, which require a high level of practical skill and were therefore difficult to standardize. His technical aptitude and interest in nervous system tumors played a key role in the establishment of his classification, which was based on cell lineage and embryonic development. Río Hortega's approach was controversial when he proposed it. Current classifications are not only based on cell type and embryonic lineage, as well as on clinical characteristics, anatomical site, and age

Interplay Between ncRNAs and Cellular Communication: A Proposal for Understanding Cell-Specific Signaling Pathways

Cancer; Cell signaling; EpigeneticsCàncer; Comunicació cel·lular; EpigenèticaCáncer; Comunicación celular; EpigenéticaIntercellular communication is essential for the development of specialized cells, tissues, and organs and is critical in a variety of diseases including cancer. Current knowledge states that different cell types communicate by ligand-receptor interactions: hormones, growth factors, and cytokines are released into the extracellular space and act on receptors, which are often expressed in a cell-type-specific manner. Non-coding RNAs (ncRNAs) are emerging as newly identified communicating factors in both physiological and pathological states. This class of RNA encompasses microRNAs (miRNAs, well-studied post-transcriptional regulators of gene expression), long non-coding RNAs (lncRNAs) and other ncRNAs. lncRNAs are diverse in length, sequence, and structure (linear or circular), and their functions are described as transcriptional regulation, induction of epigenetic changes and even direct regulation of protein activity. They have also been reported to act as miRNA sponges, interacting with miRNA and modulating its availability to endogenous mRNA targets. Importantly, lncRNAs may have a cell-type-specific expression pattern. In this paper, we propose that lncRNA-miRNA interactions, analogous to receptor-ligand interactions, are responsible for cell-type-specific outcomes. Specific binding of miRNAs to lncRNAs may drive cell-type-specific signaling cascades and modulate biochemical feedback loops that ultimately determine cell identity and response to stress factors

Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications

Bioluminescence; Radioiodine therapy; TransdifferentiationBioluminiscencia; Terapia con yodo radiactivo; TransdiferenciaciónBioluminescència; Teràpia amb iode radioactiu; TransdiferenciacióDue to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer.This research was supported by Instituto de Salud Carlos III (ISCIII) (PI19/01007 and DTS21/00130) and by Fondo Europeo de Desarrollo Regional (Feder) “Una manera de hacer Europa”. We also thank CIBER-BBN and CIBERONC an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III (ISCIII) with the assistance of the European Regional Development Fund. This study was also partially funded by the Aragon Government (Ph.D. Grant No.r B054/12) and cofounded by Aragon/FEDER 2014–2020 “Building Europe from Aragon”. This research was funded by Spanish Ministerio de Economía y Competitividad and European Regional Development Fund (FEDER) SAF2015-69964-R, RTI2018-099343-B-100 and from the CiberOnc by Instituto de Salud Carlos III (to ADlV)

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future

COVID-19; Bioseguretat; PatologiaCOVID-19; Bioseguridad; PatologíaCOVID-19; Biosafety; PathologyBackground: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. Materials and methods: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. Results: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. Conclusions: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe

Clearance of ctDNA in triple-negative and HER2-positive breast cancer patients during neoadjuvant treatment is correlated with pathologic complete response

Breast cancer; Liquid biopsy; Neoadjuvant therapyCàncer de mama; Biòpsia líquida; Teràpia neoadjuvantCáncer de mama; Biopsia líquida; Terapia neoadyuvanteBackground: Although the standard of care is to perform surgery of primary breast cancer (BC) after neoadjuvant chemotherapy (NAC), for certain patients achieving clinical complete response (cCR) and pathologic complete response (pCR), omission of surgical treatment may be an option. Levels of circulating tumor DNA (ctDNA) during and after therapy could identify patients achieving minimal residual disease. In this study, we evaluated whether ctDNA clearance during NAC could be a correlate to effective response in human epidermal growth factor receptor 2 positive (HER2+) and triple-negative (TN) BC patients. Methods: A prospective study was conducted to identify patient-specific PIK3CA and TP53 mutations in tissue using next-generation sequencing, which could then be used to track the presence/absence of mutations prior to, during, and following NAC using Sysmex SafeSEQ technology. All patients underwent a surgical excision after NAC, and pCR was assessed. Results: A total of 29 TN and HER2+ BC patients were examined and 20 that carried mutations in the PIK3CA and/or TP53 genes were recruited. Overall, 19 of these 20 patients harbored at least one tumor-specific mutation in their plasma at baseline. After NAC, 15 patients (75.0%) achieved pCR according to the histopathologic evaluation of the surgical specimen, and 15 patients (75.0%) had a cCR; 18 of 20 patients (90.0%) had concordant pCR and cCR. The status of ‘no mutation detected’ (NMD) following NAC in cCR patients correctly identified the pCR in 14 of 15 patients (93.33%), as well as correctly ruled out pCR in three patients, with an accuracy of 89.47%. During the 12-month follow-up after surgery, 40 plasma samples collected from 15 patients all showed no detectable ctDNA (NMD), and no patient recurred. Conclusion: These findings prompt further research of the value of ctDNA for non-invasive prediction of clinical/pathological response, raising the possibility of sparing surgery following NAC in selected BC patients.The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from Sysmex Inostics, Inc. The sponsor coordinated data collection from study centers, and funded the statistical analysis and medical writing assistance

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma

Perfils epigenètics; Matriu extracel·lular; Cèl·lules immunesPerfiles epigenéticos; Matriz extracelular; Células inmunesEpigenetic profiles; Extracellular matrix; Immune cellsThe invasive tumor front (the tumor–host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.This research was supported by grants from the ISCIII and ERDF (PI17/01558 and PI20/01107), by the CIBERONC (contracts CB16/12/00484, CB16/12/0328, CB16/12/00363, CB16/12/00364, CB16/12/00481, and CB16/12/00231) and Grupos Coordinados Estables from the Asociación Española Contra el Cáncer (AECC). ÁD-L was funded by a contract “Juan Rodés” from the ISCIII (JR17/00016). The funders had no involvement in the research process nor in the preparation and submission of the article

Brain ApoA-I, ApoJ and ApoE Immunodetection in Cerebral Amyloid Angiopathy

ApoA-I; ApoE; Cerebral amyloid angiopathyApoA-I; ApoE; Angiopatía amiloide cerebralApoA-I; ApoE; Angiopatia amiloide cerebralCerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage (ICH) in elderly individuals and it is the result of the cerebrovascular deposition of beta-amyloid (Aβ) protein. CAA is frequently found in patients with Alzheimer's disease (AD), although it has an independent contribution to the cognitive deterioration associated with age. Specific apolipoproteins (Apo) have been associated with Aβ fibrillization and clearance from the brain. In this regard, in the present study, we analyzed the brain levels of ApoE, ApoA-I, and ApoJ/clusterin in autopsy brains from 20 post-mortem cases with CAA type I, CAA type II, with parenchymal Aβ deposits or without Aβ deposits. Our objective was to find a possible differential pattern of apolipoproteins distribution in the brain depending on the CAA pathological presentation. The protein expression levels were adjusted by the APOE genotype of the patients included in the study. We found that ApoE and ApoJ were abundantly present in meningeal, cortical, and capillary vessels of the brains with vascular Aβ accumulation. ApoE and ApoJ also deposited extracellularly in the parenchyma, especially in cases presenting Aβ diffuse and neuritic parenchymal deposits. In contrast, ApoA-I staining was only relevant in capillary walls in CAA type I cases. On the other hand, ICH was the principal cause of death among CAA patients in our cohort. We found that CAA patients with ICH more commonly had APOEε2 compared with CAA patients without ICH. In addition, patients who suffered an ICH presented higher vascular ApoE levels in brain. However, higher ApoE presence in cortical arteries was the only independent predictor of suffering an ICH in our cohort after adjusting by age and APOE genotype. In conclusion, while ApoE and ApoJ appear to be involved in both vascular and parenchymal Aβ pathology, ApoA-I seems to be mainly associated with CAA, especially in CAA type I pathology. We consider that our study helps to molecularly characterize the distribution subtypes of Aβ deposition within the brain

DigiPatICS: Digital Pathology Transformation of the Catalan Health Institute Network of 8 Hospitals—Planification, Implementation, and Preliminary Results

Artificial intelligence; Digital pathology; ImplementationInteligencia artificial; Patología digital; ImplementaciónIntel·ligència artificial; Patologia digital; ImplementacióComplete digital pathology transformation for primary histopathological diagnosis is a challenging yet rewarding endeavor. Its advantages are clear with more efficient workflows, but there are many technical and functional difficulties to be faced. The Catalan Health Institute (ICS) has started its DigiPatICS project, aiming to deploy digital pathology in an integrative, holistic, and comprehensive way within a network of 8 hospitals, over 168 pathologists, and over 1 million slides each year. We describe the bidding process and the careful planning that was required, followed by swift implementation in stages. The purpose of the DigiPatICS project is to increase patient safety and quality of care, improving diagnosis and the efficiency of processes in the pathological anatomy departments of the ICS through process improvement, digital pathology, and artificial intelligence tools.This project was funded by European Regional Development Funds, Programa operatiu FEDER de Catalunya 2014–2020 and SA18-014623 DIGIPATICS. UPC activity in this project was partially supported by PID2020-116907RB-I00 and funded by MCIN/AEI/10.13039/501100011033

Dissecting Breast Cancer Circulating Tumor Cells Competence via Modelling Metastasis in Zebrafish

Cáncer de mama; Metástasis; Pez cebraCàncer de mama; Metàstasi; Peix zebraBreast cancer; Metastasis; ZebrafishBackground: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear. Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms. Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes. Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.This work was supported by Roche-Chus Joint Unit (IN853B 2018/03) funded by Axencia Galega de Innovación (GAIN), Consellería de Economía, Emprego e Industria. I.M.-P. is funded by the Training Program for Academic Staff fellowship (FPU16/01018), from the Ministry of Education and Vocational Training, Spanish Government. P.H. is funded by a Predoctoral fellowship (IN606A-2018/019) from Axencia Galega de Innovación (GAIN, Xunta de Galicia). N.C.-U. is funded by Axudas Predoutorais do IDIS (Instituto de Investigación Sanitaria de Santiago)