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To investigate whether a radiomic machine learning (ML) approach employing texture-analysis (TA) features extracted from primary tumor lesions (PTLs) is able to predict tumor grade (TG) and nodal status (NS) in patients with oropharyngeal (OP) and oral cavity (OC) squamous-cell carcinoma (SCC). Contrast-enhanced CT images of 40 patients with OP and OC SCC were post-processed to extract TA features from PTLs. A feature selection method and different ML algorithms were applied to find the most accurate subset of features to predict TG and NS. For the prediction of TG, the best accuracy (92.9%) was achieved by Naïve Bayes (NB), bagging of NB and K Nearest Neighbor (KNN). For the prediction of NS, J48, NB, bagging of NB and boosting of J48 overcame the accuracy of 90%. A radiomic ML approach applied to PTLs is able to predict TG and NS in patients with OC and OP SCC.

Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC. The invasion of epithelial tumours often depends on the epithelial-mesenchymal transition. Here, the authors report that intracellular activation of thyroid hormone by the D2 deiodinase enzyme promotes invasion and progression of squamous cell carcinoma by transcriptionally up-regulating ZEB-1.

Human papillomavirus (HPV) plays a crucial role in the pathogenesis of oropharyngeal squamous cell carcinomas (OPSCC). Accurate HPV status classification is essential for therapeutic stratification. While p16 immunohistochemistry (IHC) is the clinical surrogate marker, it has limited specificity. In this study, we implemented a weakly supervised deep learning approach using the Clustering-constrained Attention Multiple-Instance Learning (CLAM) framework to directly predict HPV status from hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) of OPSCC. A total of 123 WSIs from two cohorts (The Cancer Genome Atlas (TCGA) cohort and OPSCC cohort from the University of Naples Federico II (OPSCC-UNINA)) were used. Attention heatmaps revealed that the model predominantly focused on tumor-rich regions. Errors were primarily observed in slides with conflicting p16/in situ hybridization (ISH) status or suboptimal quality. Morphological analysis of high-attention patches confirmed that cellular features extracted from correctly classified slides align with HPV status, with a Random Forest classifier achieving 83% accuracy at the cell level. This work supports the feasibility of deep learning-based HPV prediction from routine H&E slides, with potential clinical implications for streamlined, cost-effective diagnostics.

Background The muscle invasive form of urothelial bladder cancer (UBC) is a deadly disease. Currently, the therapeutic approach of UBC is mostly based on surgery and standard chemotherapy. Biomarkers to establish appropriate drugs usage are missing. Deficiency of the tumor suppressor CCDC6 determines PARP-inhibitor sensitivity. The CCDC6 levels are modulated by the deubiquitinase USP7. In this work we scored CCDC6 and USP7 expression levels in primary UBC and we evaluated the expression levels of CCDC6 in correlation with the effects of the PARP-inhibitors combined with the USP7 inhibitor, P5091, in vitro. Since PARP-inhibitors could be enhanced by conventional chemotherapy or DNA damage inducers, we tested the new agent RRx-001, able to induce DNA damage, to prove the benefit of combined treatments in bladder cancer cells. Methods The J82, T24, 5637 and KU-19-19 bladder cancer cells were exposed to USP7 inhibitor P5091 in presence of cycloheximide to analyse the CCDC6 stability. Upon the CCDC6 degradation induced by P5091, the cells sensitivity to PARP-inhibitor was evaluated by cell viability assays. The ability of the DNA damage inducer RRx-001 to modulate CCDC6 protein levels and H2AX phosphorylation was detected at immunoblot. The combination of USP7 inhibitor plus RRx-001 enhanced the PARP-inhibitor sensitivity, as evaluated by cell viability assays. The results of the scores and correlation of CCDC6 and USP7 expression levels obtained by UBC primary biopsies staining were used to cluster patients by a K-mean cluster analysis. Results P5091 determining CCDC6 degradation promoted bladder cancer cells sensitivity to PARP-inhibitor drugs. RRx-001, by inducing DNA damage, enhanced the effects of the combined treatment. The immunohistochemical staining of both CCDC6 and USP7 proteins allowed to cluster the high grade (G3) UBC patients, on the basis of CCDC6 expression levels. Conclusions In high grade UBC the identification of two clusters of patients based on CCDC6 and USP7 expession can possibly indicate the use of PARP-inhibitor drugs, in combination with USP7 inhibitor in addition to the DNA damage inducer RRx-001, that also acts as an immunomodulatory agent, offering novel therapeutic strategy for personalized medicine in bladder cancer patients.

Epiretinal traction is not responsible only for epiretinal but also intraretinal changes. This study aims to describe structural and vascular intraretinal changes after macular peeling in idiopathic (iERM) vs diabetic ERM (dERM). We conducted a prospective interventional study on forty-two eyes, 23 with iERMs and 19 with dERMs, undergoing ERM-ILM peeling. We performed SD-OCT preoperatively, 1 and 6 months postoperatively to assess central macular thickness (CMT), intraretinal cysts (IC) and/or continuous ectopic inner foveal layers (CEIFL), superficial and deep capillary free zone (CFZ) area on OCT-A. Glial fibrillary acidic protein (GFAP), as a Müller cells marker, was detected immunohistochemically on ILM specimens, to assess Müller cells iatrogenic damage. The CEIFLs were significantly more common in iERMs (12 (52.2%) in iERMs vs 2 (10.5%) in dERMs, p = 0.004), whereas ICs in dERMs (6 (26.1%) in iERMs vs 17 (89.5%) in dERMs, p<0.001). Median preoperative and postoperative BCVA was 20/50 [20/40-20/66] and 20/33 [20/25-20/40] in iERMs and 20/100 [20/66-20/200] and 20/50 [20/50-20/66] in dERMs, respectively. Median preoperative and postoperative CMT was 423 [370-488] and 364 [329-382] μm in iERM group and 465 [447-503] and 378 [359-433] μm in dERM group, respectively. The BCVA improvement and reduction of CMT thickness were significant in both groups (p<0.001). The presence of CEIFL was associated with lower BCVA in iERMs. Deep CFZ network significantly increased only in dERMs, passing from 0.34 [0.29-0.42] mm2 preoperatively to 0.56 [0.46-0.6] mm2 at 6-month follow-up (p<0.001). The GFAP expression was significantly higher in dERMs (p = 0.001). The intraretinal changes are different in iERMs and dERMs, as increased expression of CEIFLs in iERMs vs ICs in dERMs. The CEIFLs are associated with worse anatomical and functional outcomes in iERMs, whereas GFAP espression in peeled ILMs is higher in dERMs.

Mycosis fungoides (MF) represents the most common type of cutaneous lymphoma. In the majority of patients, the disease has a slow evolution and a protracted course; however, a subset of patients shows poor oncologic outcomes. Unfortunately, there are no reliable prognostic markers for MF, and the currently available treatments are only effective in a minority of patients. This study aimed to evaluate the expression and clinical significance of PARP-1 and CAF-1/p60 in MF. Sixty-four MF representatives of the different stages of disease were assessed by immunohistochemistry for PARP-1 and CAF-1/p60. The association of PARP-1 and CAF-1/p60 with the MF stage and outcome was assessed by using Fisher’s exact test and Kaplan-Meier survival analysis with the Log-rank test; a p value < 0.05 was considered significant. PARP-1 was overexpressed in 57.9% of MF and was significantly associated with a MF stage > II (p = 0.034) but not with the risk of death (p = 0.237). CAF-1/p60 was overexpressed in 26.8% of MF and was significantly associated with decreased overall survival (p < 0.001) but not with the MF stage (p = 1). A significant association was found between PARP-1 overexpression and CAF-1/p60 overexpression (p = 0.0025). Simultaneous overexpression of PARP-1 and CAF-1/p60 was significantly associated with decreased overall survival (p < 0.001), although less strongly than CAF-1/p60 alone (χ2 = 14.916 vs 21.729, respectively). In MF, PARP-1 is overexpressed in advanced stages, while CAF-1/p60 is overexpressed in the cases with shorter overall survival, appearing as a significant prognostic marker. A role for PARP-1 inhibitors and anti-CAF-1/p60 targeted therapy may be reasonably hypothesized in MF.

Background/Objectives: Oral cavity carcinomas (OCCs) represent roughly 50% of all head and neck cancers. The risk of occult neck metastases for early-stage OCCs ranges from 15 to 35%, thus the need to develop tools that can support the diagnosis detecting these neck metastases. Inflammatory biomarkers and perineural and lympho-vascular invasion are emerging as effective in this field. The aim of this study is to demonstrate the effectiveness of these parameters to detect occult neck metastases in early-stage (T1-T2/N0) OCCs. Methods: A retrospective analysis was conducted on 81 patients surgically treated for early-stage OCC. For all patients, data regarding TNM, pN status after the histopathological examination, inflammatory biomarkers, and perineural and lympho-vascular invasion have been obtained. A statistical analysis was performed using the receiver operating characteristic (ROC) curve to calculate the optimal cutoff values for SII, SIRI, PLR, and NLR. Results: Fifty-eight patients confirmed N0 status after surgery, while twenty-three resulted pN+. The best cut-off to detect occult neck metastases were PLR 249.30, NLR 13.10, MLR 0.439, SII 1043.12, and SIRI 1.85. The accuracy to detect occult neck metastases was PLR 75%, NLR 81%, MLR 74%, SII 73%, SIRI 70%, perineural invasion 70%, and lympho-vascular invasion 83%. Conclusions: Our results confirm that inflammatory biomarkers and perineural and lympho-vascular invasion are effective in detecting occult neck metastases in early-stage OCCs. The clinical relevance of this study is that these parameters could be used routinely as preoperative tools to support diagnosis and to help surgeons in the decision-making process, particularly regarding surgical indications for neck lymph nodes treatment.

Oral squamous cell carcinoma is the most common oral cancer. In this paper, we present a performance analysis of four different deep learning-based pixel-wise methods for lesion segmentation on oral carcinoma images. Two diverse image datasets, one for training and another one for testing, are used to generate and evaluate the models used for segmenting the images, thus allowing to assess the generalization capability of the considered deep network architectures. An important contribution of this work is the creation of the Oral Cancer Annotated (ORCA) dataset, containing ground-truth data derived from the well-known Cancer Genome Atlas (TCGA) dataset.

Background To date, very few studies on clinical-histopathological correlations of cutaneous disorders associated with COVID-19 have been conducted. Case presentation The Case 1 was a 90-year-old man, who tested positive for SARS-CoV-2 from a nasopharyngeal swab. Two days later, he was hospitalized and after eleven days transferred to Intensive Care Unit. A chest CT showed bilateral ground-glass opacities. Just that day, an erythematous maculo-papular rash appeared on trunk, shoulders and neck, becoming purpuric after few days. Histological evaluations revealed a chronic superficial dermatitis with purpuric aspects. The superficial and papillary dermis appeared edematous, with a perivascular lympho-granulocytic infiltrate and erythrocytic extravasation. At intraepithelial level, spongiosis and a granulocyte infiltrate were detected. Arterioles, capillaries and post-capillary venules showed endothelial swelling and appeared ectatic. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Regrettably, due to severe lung impairment, he died. The Case 2 was a 85-year-old man, admitted to Intensive Care Unit, where he was intubated. He had tested positive for SARS-CoV-2 from a nasopharyngeal swab two days before. A chest RX showed bilateral atypical pneumonia. After seven days, a cutaneous reddening involving trunk, upper limbs, neck and face developed, configuring a sub-erythroderma. Histological evaluations displayed edema in the papillary and superficial reticular dermis, and a perivascular lymphocytic infiltrate in the superficial dermis. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Sub-erythroderma as well as respiratory symptoms gradually improved until healing. Conclusions The endothelial swelling detected in the Case 1 could be a morphological expression of SARS-CoV-2-induced endothelial dysfunction. We hypothesize that cutaneous damage could be initiated by endothelial dysfunction, caused by SARS-CoV-2 infection of endothelial cells or induced by immune system activation. The disruption of endothelial integrity could enhance microvascular permeability, extravasation of inflammatory cells and cytokines, with cutaneous injury. The Case 2 developed a sub-erythroderma associated with COVID-19, and a non-specific chronic dermatitis was detected at histological level. We speculate that a purpuric rash could represent the cutaneous sign of a more severe coagulopathy, as highlighted histologically by vascular abnormalities, while a sub-erythroderma could be expression of viral hematogenous spreading, inducing a non-specific chronic dermatitis.

Abstract Objectives To assess the prevalence of Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia trachomatis in ocular adnexa lymphoma (OAL) determined by molecular testing in different countries and the potential association of Chlamydia infection with mucosa-associated lymphoid tissue (MALT) histotype by performing a systematic review and meta-analysis. Methods Electronic databases were searched for studies assessing the presence of Chlamydia in OAL. Pooled prevalence of the three Chlamydia species was calculated in each country. An odds ratio was calculated for the association between Chlamydia and MALT histotype, with a significant P < .05. Results Thirty-seven studies with 1,188 OALs were included. Pooled prevalence of C psittaci, C pneumoniae, and C trachomatis by country was done. Chlamydia infection was significantly associated with MALT histotype (odds ratio, 2.183; P = .027). Conclusions The involvement of C psittaci in OAL is highly variable, with the highest prevalence in Italy and Korea. Chlamydia is associated with MALT histotype.