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Silvia Antolín,1 Benigno Acea,2 Luis Albaina,2 Ángel Concha,3 Paz Santiago,3 Tomás García-Caballero,4 Joaquín J Mosquera,5 José Ramón Varela,5 Rafaela Soler,5 Lourdes Calvo1 1Medical Oncology Department, Breast Unit, A Coruña University Hospital, A Coruña, Spain; 2Surgery Department, Breast Unit, A Coruña University Hospital, A Coruña, Spain; 3Anatomic Pathology Department, Breast Unit, A Coruña University Hospital, A Coruña, Spain; 4Department of Morphological Sciences, University of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain; 5Radiology Department, Breast Unit, A Coruña University Hospital, A Coruña, Spain Objective: The aim of this study was to evaluate the efficacy, cardiotoxicity profile and long-term benefits of neoadjuvant therapy in human epidermal growth factor receptor 2-positive operable breast cancer patients. Patients and methods: A total of 142 patients diagnosed from 2005 to 2016 were included in the study. The treatment consisted of a sequential regimen of taxanes and anthracyclines plus trastuzumab. The clinical and pathological responses were evaluated and correlated with clinical and biological factors. The cardiotoxicity profile and long-term benefits were analyzed. Results: The median age was 49 years, and 4%, 69% and 27% of patients had stage I, II and III breast cancer, respectively, while 10% had inflammatory breast cancer at diagnosis. Hormone receptor (HR) status was negative in 43%, and 62% had grade III breast cancer. The clinical complete response rate was 49% and 63% as assessed using ultrasound and magnetic resonance imaging, respectively, and this allowed a high rate of conservative surgery (66%). The pathological complete response (pCR) rate was 52%, and it was higher in HR-negative (64%) patients than in HR-positive (41%) patients and in grade III breast cancer (53%) patients than in grade I–II breast cancer (45%) patients. Patients who achieved pCR had longer disease-free survival and a trend toward improved overall survival. A total of 2% of patients showed a 10% decrease in left ventricular ejection fraction to

José Carlos López López,1 Nieves Fernández Alonso,1 Juan Cuevas Álvarez,1,2 Tomás García-Caballero,2 José Carlos Pastor Jimeno3 1Ocular Pathology Laboratory, Instituto Universitario de Oftalmobiología Aplicada (IOBA), University of Valladolid, Valladolid, Spain; 2Department of Pathology, Hospital Clínico Universitario, Santiago de Compostela, Spain; 3Retina Group, Instituto Universitario de Oftalmobiología Aplicada (IOBA), University of Valladolid, Hospital Clínico Universitario, Valladolid, Spain Purpose: We evaluated the expression of the neural markers, neuron-specific enolase, and synaptophysin, as a tool to confirm the diagnosis of retinoblastoma (RB) in undifferentiated and advanced tumors. Additionally, we determined whether the extent of RB-associated protein (pRb) expression is helpful in assessing the prognosis in RB patients. Methods: Conventional whole tissue section and tissue microarray immunohistochemistry for neuron-specific enolase, synaptophysin, and pRb were carried out in a series of 22 RBs. Results: Neuron-specific enolase and synaptophysin were expressed in 75%–100% of the tumor cells, and the staining intensity was strong. Two RBs expressed pRb in 75%–100% of the tumor cells, also with strong staining intensity. Concordance between the immunohistochemical outcomes for whole tissue staining and tissue microarray staining was 76.2% for neuron-specific enolase, 85.7% for synaptophysin, and 80.0% for pRb. Conclusion: Neuron-specific enolase and synaptophysin have the potential to be useful markers for the diagnosis of RBs. Extensive and strong pRb staining is not associated with less aggressive tumor behavior according to the pathologic classification of RBs. Keywords: retinoblastoma, immunohistochemistry, neuron-specific enolase, synaptophysin, pRb

Abstract: Our aim was to assess wounds made by lasers (CO2 and Er,Cr:YSGG) for their epithelial architectural changes and width of damage. We allocated 60 Sprague–Dawley® rats into groups: glossectomy by CO2 laser at 3 different wattages (n =10 in each); glossectomy by Er,Cr:YSGG laser at two different emissions (n =10 in each), and a control group (n =10). Histological examination assessed both prevalence and site of thermal artefacts for each group. Both lasers (CO2 and Er,Cr:YSGG) caused the same type of cytological artefacts. The 3W Er,Cr:YSGG laser produced the fewest cytological artefacts/specimen, and was significantly different from the other experimental groups: 3W CO2 laser (95% CI=0.8 to 1.0); the 6W CO2 laser (95% CI=0.1 to 2.0) and the 10W CO2 laser (95% CI=1.1 to 3.0). CO2 lasers (3–10W) generate epithelial damage that can simulate dysplastic changes with cytological atypia that affects mainly the basal and suprabasal layers. Irradiation with Er,CR:YSGG laser (2–4W) produces significantly fewer cellular artefacts and less epithelial damage, which may be potentially useful for biopsy of oral mucosa. [Copyright &y& Elsevier]

Background: The sequelae of myocardial infarction (MI) require specific pharmacological therapy to minimise the post-MI remodelling, which in many cases evolves into cardiovascular complications. The aim of this study was to analyse the effect of edoxaban, an oral anticoagulant, on cardiac recovery in a rat model of permanent coronary artery ligation., Methods: An experimental method to assess the post-MI remodelling in rats for 4 weeks, based on cardiac magnetic resonance imaging (MRI) and final histological analysis of the hearts was performed. The influence of daily oral treatment with edoxaban (20 mg/kg/day) for 28 days post-MI was analysed in comparison to vehicle., Results: In our model, edoxaban was shown to be safe and bleeding was observed in 1 of 10 animals. General physical recovery of the treated animals was shown by higher body weight recovery compared with non-treated animals (38.6 ± 2.9 vs. 29.9 ± 3.1 g, respectively, after 28 days). There was not a pronounced effect of edoxaban in post-MI cardiac remodelling, but mitigated fibrosis was observed by the reduced expression of vascular endothelial growth factor and tumour growth factor β1 in the peri-infarct zone., Conclusions: Our analysis provided the experimental basis to support the feasibility of MRI to study cardiac function and characterise myocardial scarring in a rat model. Overall data suggested the safety of edoxaban in the model, and compared to placebo, it showed a better post-MI recovery, probably by reducing fibrosis of the heart. Further research on mid-term cardiac recovery with edoxaban after MI is justified., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors declare that this work was supported by Daiichi-Sankyo España, but this did not influence the results or interpretation of this manuscript for any of the authors., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

More than two decades ago, Marmarou published a valid model for producing diffuse axonal injury (DAI) in rats. Since then, both mild and severe injuries have been obtained by researchers using the original method and a weight of 450 g. However, the diffuse brain injuries produced in rats were only similar to those seen in humans when the rats sustained severe brain injuries. In these cases, rat mortality in the original article was around 50%, and the cause of death was prolonged apnea post-impact. Rat survival after impact is critical for studying the progression of DAI. In order to explain the cause of death in human victims with cranial trauma who do not show gross brain injury, testing for the presence of DAI is essential. Thus, in order to minimize local and cervical injuries to increase rat survival, attention should be paid to the following aspects: a wider head protector disc should be used, the head of the rat should be elevated at the time of impact, and the foam bed should be soft enough to allow the movement caused by acceleration. With our modified method, rat survival increased by 30% compared to the original model (80% versus 50%). Moreover, 85.7% of rats demonstrated DAI after 24 h of survival. With these modifications, injuries appear in the same locations as in humans; thus, the method is suitable for the study of traumatic DAI in humans., (© 2023 American Academy of Forensic Sciences.)

Immunohistological patterns of density and distribution of neural tissue in the human penis, including the prepuce, are not fully characterized, and effects of circumcision (partial or total removal of the penile prepuce) on penile sexual sensation are controversial. This study analyzed extra- and intracavernosal innervation patterns on the main penile axes using formalin-fixed, paraffin-embedded human adult and fetal penile tissues, single- and double-staining immunohistochemistry and a variety of neural and non-neural markers, with a special emphasis on the prepuce and potential sexual effects of circumcision. Immunohistochemical profiles of neural structures were determined and the most detailed immunohistological characterizations to date of preputial nerve supply are provided. The penile prepuce has a highly organized, dense, afferent innervation pattern that is manifest early in fetal development. Autonomically, it receives noradrenergic sympathetic and nitrergic parasympathetic innervation. Cholinergic nerves are also present. We observed cutaneous and subcutaneous neural density distribution biases across our specimens towards the ventral prepuce, including a region corresponding in the adult anatomical position (penis erect) to the distal third of the ventral penile aspect. We also describe a concept of innervation gradients across the longitudinal and transverse penile axes. Results are discussed in relation to the specialized literature. An argument is made that neuroanatomic substrates underlying unusual permanent penile sensory disturbances post-circumcision are related to heightened neural levels in the distal third of the ventral penile aspect, which could potentially be compromised by deep incisions during circumcision., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Breast cancers of the luminal B subtype are frequent tumors with high proliferation and poor prognosis. Epigenetic alterations have been found in breast tumors and in biological fluids. We aimed to profile the cell-free DNA (cfDNA) methylome of metastatic luminal B breast cancer (LBBC) patients using an epigenomic approach to discover potential noninvasive biomarkers. Plasma cfDNA was analyzed using the Infinium MethylationEpic array in a cohort of 14 women, including metastatic LBBC patients and nontumor controls. The methylation levels of cfDNA and tissue samples were validated with droplet digital PCR. The methylation and gene expression data of 582 primary luminal breast tumors and 79 nontumor tissues were obtained from The Cancer Genome Atlas (TCGA). We found an episignature of 1,467 differentially methylated CpGs that clearly identified patients with LBBC. Among the genes identified, the promoter hypermethylation of WNT1 was validated in cfDNA, showing an area under the ROC curve (AUC) of 0.86 for the noninvasive detection of metastatic LBBC. Both paired cfDNA and primary/metastatic breast tumor samples showed hypermethylation of WNT1 . TCGA analysis revealed significant WNT1 hypermethylation in the primary tumors of luminal breast cancer patients, with a negative association between WNT1 methylation and gene expression. In this proof-of-principle study, we discovered an episignature associated with metastatic LBBC using a genome-wide cfDNA methylation approach. We also identified the promoter hypermethylation of WNT1 in cfDNA as a potential noninvasive biomarker for luminal breast cancer. Our results support the use of EPIC arrays to identify new epigenetic noninvasive biomarkers in breast cancer., Competing Interests: RL-L has received honoraria for participation in Advisory Boards from Roche, AstraZeneca, Merck, Merck Sharp and; Dohme, Bayer, Bristol-Myers Squibb, Novartis, Janssen, Lilly, Pfizer, and Leo; travel, accommodations, and expenses from PharmaMar, Roche, Bristol-Myers Squibb, and Pierre Fabre; research funding from Roche and Merck; and is co-founder and shareholder in Nasasbiotech, S.L., Mtrap Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodriguez-Casanova, Costa-Fraga, Castro-Carballeira, González-Conde, Abuin, Bao-Caamano, García-Caballero, Brozos-Vazquez, Rodriguez-López, Cebey, Palacios, Cueva, López-López, Costa and Díaz-Lagares.)