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Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease (CAD) underlies most cases of myocardial infarction (MI), causing or at least contributing to oxygen supply–demand mismatch and myocardial injury, so a careful and reliable evaluation of the main coronary arteries and large branches is a key moment of autopsy in order to establish the cause of death. The aim of this study is to evaluate the application of digital image analysis in the assessment of coronary artery sub-occlusions. Methods: A total of 50 coronary sections sampled during 11 consecutive autopsies, regardless of the cause of death, were analyzed. The ideal lumen and the percentage of the residual lumen were evaluated by digital pathology using QuPath v 4.3 and by an expert pathologist. The evaluations performed were compared using Lin's concordance correlation coefficient. Results: The Lin agreement index between the two evaluation methods for all measurements showed an excellent agreement rate [0.923, with confidence interval (0.866, 0.956)]. However, in the case of critical stenosis, from 60% to 80% and from 65% to 75%, the Lin agreement index between the two evaluation methods was, respectively, 0.798 [0.603, 0.904], corresponding to good agreement, and 0.516 [0.071, 0.725], corresponding to slight agreement. The digital system has superior performance in cases where lumen occlusion falls between 60% and 80% and provides an objective assessment of the residual lumen area. Conclusions: According to the widespread availability and ease of use of these technologies, we suggest that image analysis should be considered a routine tool and established as the diagnostic gold standard in this field. [ABSTRACT FROM AUTHOR]

Several types of B-cell lymphomas, including both primary cutaneous lymphomas and systemic lymphomas, may affect the skin, with partially overlapping clinical, morphological and immunohistochemical features. Currently, the World Health Organization (WHO) classification of primary cutaneous B-cell lymphomas does not include diffuse large B-cell lymphomas (DLBCL) and considers leg-type DLBCL the only primary cutaneous DLBCL. Here we report the case of a 72-year-old white woman with a primary cutaneous neoplasm comprised of large cells with round nuclei, irregularly clumped chromatin and one or more inconspicuous nucleoli. The immunohistochemistry demonstrated positivity for CD20 and MUM1, with no significant genetic translocations detected by fluorescence in-situ hybridization. After staging, we considered this neoplasm a primary cutaneous DLBCL with a non-germinal center phenotype, not otherwise specified, inconsistent with a leg-type DLBCL. Because of this view, we underscore the need for greater knowledge of the molecular landscape of B-cell lymphomas in order to reconsider the classification of such neoplasms in the skin.

Context.--Fine-needle aspiration cytology (FNAC) of pulmonary nodules is usually guided by computed tomography (CT), whereas ultrasonography (US) is generally considered not applicable for such purposes. Objective.--To evaluate the clinical applicability and diagnostic utility of US-guided transthoracic FNAC of peripheral pulmonary nodules. Design.--Ultrasonography-guided transthoracic FNAC was obtained from 40 selected patients with peripheral, subpleural, and paravertebral pulmonary nodules. Airdried and Diff-Quik-stained smears were used for rapid on-site evaluation; additional smears were alcohol fixed for Papanicolaou staining. Cell blocks were set up for immunocytochemical and molecular studies; in 2 cases, a flow cytometry evaluation was also performed. The series was compared to 40 CT-guided pulmonary FNAC samples from patients with pleural, peripheral, and paravertebral pulmonary nodules, to evaluate differences in terms of diagnostic rate, time of execution, safety, and cost. Results.--The US-guided FNAC samples had results that were adequate and representative in 95% of cases. No significant differences were observed between the 2 groups in terms of diagnostic rate, number of passes, and cellularity of both smears and cell blocks. The mean time needed for the execution of US-guided FNAC was 13.1 minutes, whereas the mean time for CT-guided FNAC was 23.6 minutes. Thus, US-guided FNAC was significantly more rapid than CT-guided pulmonary FNAC. Because pneumothorax occurred in 1 individual who underwent US-guided FNAC and in 9 who underwent CT-guided FNAC, we might conclude that US-guided FNAC is a significantly safer procedure. Finally, comparing the costs of both procedures, US-guided FNAC is less expensive. Conclusions.--Our experience showed an elevated clinical applicability and diagnostic utility of US-guided transthoracic FNAC for selected pulmonary nodules. (Arch Pathol Lab Med. 2020;144:361-369; doi: 10.5858/arpa.2018-0346-OA), The diagnostic evaluation of peripheral pulmonary lesions is currently based on an integrated approach that includes imaging and direct sampling techniques. In this setting, computed tomography (CT) has taken the [...]

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.

Synovial sarcomas are soft tissue tumours of uncertain origin, most commonly found in the upper or lower extremities. They are characterised by distinctive chromosomal rearrangements involving the gene SS18. Synovial sarcomas can occasionally arise also in visceral sites, but retroperitoneal SSs are very unusual. Among them, a few primary renal synovial sarcomas have been described in the scientific literature. Primary renal synovial sarcomas tend to be monophasic and often show cystic changes. Histologically, they can closely resemble other primary kidney tumours, mainly paediatric tumours such as nephroblastoma and clear cell sarcoma of the kidney. In the current work, a primary synovial sarcoma of the kidney with unusual morphological features (extensively myxoid stroma and immunohistochemical positivity for BCOR) is described. Molecular analysis, through targeted RNA sequencing, was of invaluable help in reaching the correct diagnosis. Despite locally advanced disease at presentation, the patient showed an unexpectedly brilliant response to chemotherapy. [ABSTRACT FROM AUTHOR]

Patients with COVID-19 have coagulation and platelet disorders, with platelet alterations and thrombocytopenia representing negative prognostic parameters associated with severe forms of the disease and increased lethality. Methods: The aim of this study was to study the expression of platelet glycoprotein IIIa (CD61), playing a critical role in platelet aggregation, together with TRL-2 as a marker of innate immune activation. Results: A total of 25 patients were investigated, with the majority (24/25, 96%) having co-morbidities and dying from a fatal form of SARS-CoV-2(+) infection (COVID-19+), with 13 men and 12 females ranging in age from 45 to 80 years. When compared to a control group of SARS-CoV-2 (−) negative lungs (COVID-19−), TLR-2 expression was up-regulated in a subset of patients with deadly COVID-19 fatal lung illness. The proportion of Spike-1 (+) patients found by PCR and ISH correlates to the proportion of Spike-S1-positive cases as detected by digital pathology examination. Furthermore, CD61 expression was considerably higher in the lungs of deceased patients. In conclusion, we demonstrate that innate immune prolonged hyperactivation is related to platelet/megakaryocyte over-expression in the lung. Conclusions: Microthrombosis in deadly COVID-19+ lung disease is associated with an increase in the number of CD61+ platelets and megakaryocytes in the pulmonary interstitium, as well as their functional activation; this phenomenon is associated with increased expression of innate immunity TLR2+ cells, which binds the SARS-CoV-2 E protein, and significantly with the persistence of the Spike-S1 viral sequence. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, artificial intelligence has been used increasingly in medical practice. Technological progress has made it possible to digitize the slides of histological preparations, allowing the use of image processing and AI technologies in surgical pathology. This potentially reduces variability and improves the uniformity of some histological evaluations, such as cellularity assessment in bone marrow biopsies, which is traditionally performed visually by expert human observers, resulting in inter-observer and intra-observer variability. In this work, we developed an accurate AI-based tool for the automated quantification of cellularity in BMB histology and compared its performances with cellularity estimates from five expert hematopathologists. Our results showed the robustness of our model across users and two different scanners for digitized image generation. The cellularity assessment in bone marrow biopsies (BMBs) for the diagnosis of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is a key diagnostic feature and is usually performed by the human eyes through an optical microscope with consequent inter-observer and intra-observer variability. Thus, the use of an automated tool may reduce variability, improving the uniformity of the evaluation. The aim of this work is to develop an accurate AI-based tool for the automated quantification of cellularity in BMB histology. A total of 55 BMB histological slides, diagnosed as Ph- MPN between January 2018 and June 2023 from the archives of the Pathology Unit of University "Luigi Vanvitelli" in Naples (Italy), were scanned on Ventana DP200 or Epredia P1000 and exported as whole-slide images (WSIs). Fifteen BMBs were randomly selected to obtain a training set of AI-based tools. An expert pathologist and a trained resident performed annotations of hematopoietic tissue and adipose tissue, and annotations were exported as.tiff images and.png labels with two colors (black for hematopoietic tissue and yellow for adipose tissue). Subsequently, we developed a semantic segmentation model for hematopoietic tissue and adipose tissue. The remaining 40 BMBs were used for model verification. The performance of our model was compared with an evaluation of the cellularity of five expert hematopathologists and three trainees; we obtained an optimal concordance between our model and the expert pathologists' evaluation, with poorer concordance for trainees. There were no significant differences in cellularity assessments between two different scanners. [ABSTRACT FROM AUTHOR]