LVI-PathNet: Segmentation-classification pipeline for detection of lymphovascular invasion in whole slide images of lung adenocarcinoma.

Lymphovascular invasion (LVI) in lung cancer is a significant prognostic factor that influences treatment and outcomes, yet its reliable detection is challenging due to interobserver variability. This study aims to develop a deep learning model for LVI detection using whole slide images (WSIs) and evaluate its effectiveness within a pathologist's information system. Experienced pathologists annotated blood vessels and invading tumor cells in 162 WSIs of non-mucinous lung adenocarcinoma sourced from two external and one internal datasets. Two models were trained to segment vessels and identify images with LVI features. DeepLabV3+ model achieved an Intersection-over-Union of 0.8840 and an area under the receiver operating characteristic curve (AUC-ROC) of 0.9869 in vessel segmentation. For LVI classification, the ensemble model achieved a F1-score of 0.9683 and an AUC-ROC of 0.9987. The model demonstrated robustness and was unaffected by variations in staining and image quality. The pilot study showed that pathologists' evaluation time for LVI detecting decreased by an average of 16.95%, and by 21.5% in "hard cases". The model facilitated consistent diagnostic assessments, suggesting potential for broader applications in detecting pathological changes in blood vessels and other lung pathologies.

Photoplethysmography-Based Angiography of Skin Tumors in Arbitrary Areas of Human Body.

Noninvasive, rapid, and robust diagnostic techniques for clinical screening of tumors located in arbitrary areas of the human body are in demand. To address this challenge, we analyzed the feasibility of photoplethysmography-based angiography for assessing vascular structures within malignant and benign tumors. The proposed hardware and software were approved in a clinical study involving 30 patients with tumors located in the legs, torso, arms, and head. High-contrast and detailed vessel maps within both benign and malignant tumors were obtained. We demonstrated that capillary maps are consistent and can be interpreted using well-established dermoscopic criteria for vascular morphology. Vessel mapping provides valuable details, which may not be available in dermoscopic images and can aid in determining whether a tumor is benign or malignant. We believe that the proposed approach may become a valuable tool in the preliminary cancer diagnosis and is suitable for large-scale screening.

Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury.

Over the years, advancements in the field of oncology have made remarkable strides in enhancing the efficacy of medical care for patients with cancer. These modernizations have resulted in prolonged survival and improved the quality of life for these patients. However, this progress has also been accompanied by escalation in mortality rates associated with anthracycline chemotherapy. Anthracyclines, which are known for their potent antitumor properties, are notorious for their substantial cardiotoxic potential. Remarkably, even after 6 decades of research, a conclusive solution to protect the cardiovascular system against doxorubicin-induced damage has not yet been established. A comprehensive understanding of the pathophysiological processes driving cardiotoxicity combined with targeted research is crucial for developing innovative cardioprotective strategies. This review seeks to explain the mechanisms responsible for structural and functional alterations in doxorubicin-induced cardiomyopathy.

Morphological Evaluation and Immunohistochemical Analysis of the Reparative Potential of the Buccal Fat Pad.

Background and Objectives: There are many surgical techniques for oroantral communication treatment, one of which is the buccal fat pad. Of particular interest is the high reparative potential of the buccal fat pad, which may be contributed to by the presence of mesenchymal stem cells. The purpose of this work is to evaluate the reparative potential of BFP cells using morphological and immunohistochemical examination. Materials and Methods: 30 BFP samples were provided by the Clinic of Maxillofacial and Plastic Surgery of the Russian University of Medicine (Moscow, Russia) from 28 patients. Morphological examination of 30 BFP samples was performed at the Institute of Clinical Morphology and Digital Pathology of Sechenov University. Hematoxylin-eosin, Masson trichrome staining and immunohistochemical examination were performed to detect MSCs using primary antibodies CD133, CD44 and CD10. Results: During staining with hematoxylin-eosin and Masson's trichrome, we detected adipocytes of white adipose tissue united into lobules separated by connective tissue layers, a large number of vessels of different calibers, as well as the general capsule of BFP. The thin connective tissue layers contained neurovascular bundles. Statistical processing of the results of the IHC examination of the samples using the Mann-Whitney criterion revealed that the total number of samples in which the expression of CD44, CD10 and CD133 antigens was confirmed was statistically significantly higher than the number of samples where the expression was not detected (p < 0.05). Conclusions: During the morphological study of the BFP samples, we revealed statistically significant signs of MSCs presence (p < 0.05), including in the brown fat tissue, which proves the high reparative potential of this type of tissue and can make the BFP a choice option among other autogenous donor materials when eliminating OAC and other surgical interventions in the maxillofacial region.

Methotrexate & rheumatoid arthritis associated atherosclerosis: A narrative review of multidisciplinary approach for risk modification by the international board of experts.

Rheumatoid arthritis (RA) is an idiopathic, autoimmune connective tissue disorder that primarily affects the synovial joints, causing symmetric, erosive-deforming polyarthritis. It is also associated with extra-articular manifestations, particularly cardiovascular (CV) diseases (CVD). CV risk modification in RA remains unsolved despite recent advances in the management of RA. RA is an independent risk factor for atherosclerosis. RA and atherosclerosis share similar pathophysiological features (such as the pro-inflammatory cascade activation including interleukin-6) and risk factors (such as microflora dysbacteriosis and smoking). Patients with RA experience an exacerbation of atherogenesis, with atheromas destabilization, endothelial dysfunction, vasculitis, and hypercytokinemia. Consequently, the inflammatory response associated with RA is the basis for CVD development. The treat-to-target strategy not only improved RA control but also had a favorable effect on the morpho-functional state of the CV system in patients living with RA. Thus, disease-modifying antirheumatic drugs (DMARDs) - in particular methotrexate - may have a beneficial effect on the prevention of CV events in RA. It must be mentioned that RA is a serious multi-system disease, not only because of a window period during which the course of RA can be reversed, but also due to early damage to the heart and blood vessels. For this reason, a thorough cardiological assessment must be performed for all patients with RA, regardless of sex, age, disease stage, and disease activity score.

Photodynamic therapy of lung cancer with photosensitizers based on polycationic derivatives of synthetic bacteriochlorin (experimental study).

BACKGROUND: One of the tasks of anticancer photodynamic therapy is increasing the efficacy of treatment of cancer nodes with large (clinically relevant) sizes using near-infrared photosensitizers (PS). METHODS: The anticancer efficacy and mechanisms of the photodynamic action of PS based on polycationic derivatives of synthetic bacteriochlorin against Lewis lung carcinoma were studied in vitro and in vivo. RESULTS: It was found that studied PS have high phototoxicity against Lewis lung carcinoma cells: the IC50 values were about 0.8 µM for tetracationic PS and 0.5 µM for octacationic PS. In vivo studies have shown that these PS provide effective inhibition of the tumor growth with an increase in the lifespan of mice in the group by more than 130%, and more than 50% survival of mice in the group. CONCLUSIONS: Photosensitizers based on polycationic derivatives of synthetic bacteriochlorin have high photodynamic efficacy caused by the induction of necrosis and apoptosis of cancer cells, including cancer stem cells, and a sharp decrease of mitotic and proliferative activity. Studied polycationic photosensitizers are much more effective at destroying cancer stem cells and newly formed cancer vessels in comparison with anionic photosensitizers, and ensure the cessation of tumor blood flow without hemorrhages and thrombosis.

Digital twin concept: Healthcare, education, research.

Introducing the concept of digital twins in healthcare, medical education, and research is a complex multistage challenge requiring participation of multidisciplinary teams. In pursuing this goal, we have created a validated database of scans of colorectal tumor slides associated with relevant clinical and histological information. This database is also linked to the blood bank, which opens a wide range of opportunities for further research. Herein, we present our experience within the scope of the digital twins initiative.

Analysis of the three-year work of a digital pathomorphological laboratory built from the ground.

Digital pathology is a new stage in the development of pathomorphological diagnostics. This topic was most widespread during the COVID-19 pandemic. The advantages of digitization of diagnostics include the possibility of remote work of a pathologist, remote asynchronous consultation, and automation of business processes. They provide an increase in diagnostic quality and speed up the diagnosis process. These benefits are only a small part of what digital cancer diagnostics can provide. This article is written on our own experience of Russia's first fully digital pathomorphological laboratory UNIM. All advantages and disadvantages of digitization, peculiarities of using technology, differences from the conventional approach to diagnostics, the economics of the process, the importance of integration with LIS (laboratory information system) and MIS (medical information system), errors and principles of their solution, payback will be discussed, and every stage of laboratory work will be considered in detail: from logistics and registration to diagnosis and archiving. Due to the fact that all data has been digitized over several years, we will present a comprehensive analysis of statistics and observations on how to organize processes in a fully digital laboratory. A key feature of our experience is the high cost-effectiveness of the platform and approach, which allowed us to win the competition in the market. The result of the survey of doctors' attitudes towards digital pathology will also be presented.

On the mechanisms of photodynamic action of photosensitizers based on polycationic derivatives of synthetic bacteriochlorin against human lung cancer cells A549 (in vitro study).

BACKGROUND: One of the tasks of anticancer photodynamic therapy is increasing the efficacy of treatment of cancer nodes with large (clinically relevant) sizes using near-infrared photosensitizers (PS). We study the photodynamic action against A549 human lung cancer cells using PS based on polycationic derivatives of synthetic bacteriochlorin. METHODS: The efficacy and mechanisms of the photodynamic action of PS based on polycationic derivatives of synthetic bacteriochlorin against A549 lung cancer cells were studied in vitro using immunocytochemical and morphological methods. RESULTS: It was found that PS based on tetracationic and octacationic derivatives of synthetic bacteriochlorin induce necrosis, apoptosis, decreasing of proliferative and mitotic activity, as well as reducing the number of ALDH1-positive cancer cells with signs of stem cells in A549 human lung cancer cell culture. The IC50 values (concentration of a PS that reduces cells survival by 50%) were about 0.69 µM for tetracationic PS and 0.57 µM for octacationic PS under irradiation at 30 J/cm2 while in the "dark" control they were higher than 100 µM for both PSs. CONCLUSIONS: Photosensitizers based on polycationic derivatives of synthetic bacteriochlorin have high phototoxicity against A549 cancer cells caused by the induction of necrosis and apoptosis of cancer cells, including cells with signs of stemness, and a sharp decrease of mitotic and proliferative activity.

Prognostic Role of FGFR3 Expression Status and Tumor-Related MicroRNAs Level in Association with PD-L1 Expression in Primary Luminal Non-Muscular Invasive Bladder Carcinoma.

BACKGROUND: bladder cancer is one of the most common urinary tract malignancies. Establishment of robust predictors of disease progression and outcome is important for personalizing treatment of non-muscular invasive bladder carcinoma (NMIBC). In this study we evaluated association of PD-L1 expression with other prognostic biomarkers, such as expression of miRNA-145 and miRNA-200a, FGFR3 gene expression, and mutation status in tissue specimens of the luminal subtype of newly diagnosed high and low grade NMIBC. METHODS: twenty patients with primary luminal NMIBC were enrolled in the study. Tumor grade and risk level were determined in accordance with European Organization for Research and Treatment of Cancer (EORTC) guidelines and World Health Organization (WHO) classification. Neoplasm molecular subtype and PD-L1 expression level were assessed by immunohistochemistry. We used real-time PCR to evaluate the expression of microRNAs and FGFR3. We detected FGFR3 hotspot mutations in codons 248 and 249 by Sanger sequencing. RESULTS: high grade primary luminal NMIBC showed comparatively higher expression of PD-L1 and microRNA-145 than a low grade tumor, whereas the latter had a higher FGFR3 expression and hotspot mutation rate. The tumor grade (HR = 571.72 [11.03-2.96] p = 0.002), PD-L1 expression (HR = 2.33 [0.92-1.92] p = 0.012), and FGFR3 expression (HR = 0.08 [0.17-0.42] p = 0.003) were associated with relapse-free survival. CONCLUSIONS: tumor grade in association with PD-L1 and FGFR3 expression can be considered as a complex predictor for primary luminal NMIBC progression.

Patient-Derived Non-Muscular Invasive Bladder Cancer Xenografts of Main Molecular Subtypes of the Tumor for Anti-Pd-l1 Treatment Assessment.

BACKGROUND: Establishment of heterotopic patient-derived xenografts of primary and relapsed non-muscular invasive bladder cancer (NMIBC) to explore the biological property of PD-L1 signaling that may impact bladder tumor growth in humanized animals. METHODS: Tumor cells of luminal, basal, and p53 subtypes of primary and relapsed NMIBC were engrafted to irradiated (3.5 Gy) NOG/SCID female mice along with intraperitoneal transplantation of human lymphocytes (5 × 107 cells/mouse); a role of PD-L1 signaling pathway inhibition for bladder cancer growth was assessed in humanized animals that carried PD-L1-expressing main molecular subtypes of bladder carcinoma patient-derived xenografts (PDX) and provided with selective anti-PD-L1 treatment. We used two-tailed Student's t test to explore differences between main and control subgroups. Significance of intergroup comparison was measured with one-way ANOVA followed by the Tukey's or Newman-Keul's criterion. Survival curves were analyzed with the Gehan's criterion with the Yate's correction. The Spearman's correlation was used to assess the link between CD8+ expression and sPD-L1 serum level. Differences were considered statistically significant at p < 0.05. RESULTS: Heterotopic primary and relapsed luminal, basal, and p53 subtypes of NMIBC PDXs were established. More than 25% of counted tumor cells of all PDX specimens expressed PD-L1, so the tumors were ranged as PD-L1 positive. Anti-PD-L1 intervention increased survival of the animals that carried both primary and relapsed luminal noninvasive, muscular invasive, and relapsed luminal bladder cancer xenografts. There was significant retardation of tumor volume duplication time in aforementioned subgroups correlated with PD-L1 expression. Bad response of p53 mutant subtypes of NMIBC on specific anti-PD-L1 treatment may be associated with low CD8+ cells representation into the tumors tissue. CONCLUSIONS: Established PD-L1-positive NMIBC PDXs differently replied on anti-PD-L1 treatment due to both NMIBC molecular subtype and tumor T-suppressors population. The results may have major implications for further clinical investigations.

Structural, immunohistochemical and molecular features of placentas and placental sites after in vitro fertilization with donor eggs (surrogate motherhood).

OBJECTIVE: to identify structural, immunohistochemical and molecular features of placentas and placental sites afterin vitro fertilization (IVF) with donor eggs (surrogate motherhood). STUDY DESIGN: morphological and immunohistochemical studies were performed on placental material obtained after delivery by caesarean section. The study included 26 women patients whose pregnancy resulted from IVF with a donor egg (IVF-SM group). The comparison group included 13 women patients whose pregnancy occurred after IVF with their own eggs (IVF-OE). Immunohistochemistry of biopsy material was performed using mouse antibodies to total cytokeratin (clone AE1/AE3) and murine antibodies to HLA-DR (clone TAL.1B5). Molecular studies were performed on DNA samples isolated from venous blood. HLA-DNA-TEH reagent kits and polymerase chain reaction were used for genotyping the main human histocompatibility complex class II (DQA1, DQB1 and DRB1). RESULTS: Histological examination of placenta in IVF-SM group showed a high incidence of central ischemic infarctions (69% of cases), dissociated cotyledon development (61%), pathological villus immaturity (46%) and massive perivillous fibrin deposition (73%). This group also had a pronounced lymphoplasmacytic deciduitis, which was 2 times higher than in the control group, and an expressed inflammatory process in the placental sites. Remodeling of the spiral arteries was incomplete in more than 40% of cases, and 30% of spiral arteries had no gestational changes. In comparison group, a complete gestational adjustment was found in more than 90% of spiral arteries. A focal lymphohistiocytic infiltration in perivascular regions, and a decrease in the number of multinucleated cells as compared with the control were also observed. For seven female surrogate mothers and their children, allelic polymorphisms of genes of HLA II class were studied. CONCLUSION: Placental material of women from IVF-SM group is characterized by complex immune response in sites of tight contact between maternal and fetal tissues. The immune pathogenesis is associated with an increase in the number of HLA-DR positive cells, defects in remodeling of the spiral arteries, development of areas of chronic inflammation in perivascular regions, and a decrease in the number of multinucleated cells. Genetic incompatibility between alleles of HLA II genes can be a molecular predictor of impaired immune tolerance.