Marilena Vered

Objectives: To investigate the prognostic value of the systemic inflammation‐related biomarkers of neutrophil‐lymphocyte, albumin‐globulin, lymphocyte‐monocyte, and platelet‐lymphocyte ratios at three perioperative time points, and to explore their association with clinicopathologic features and disease‐specific survival. Methods: In 220 oral squamous cell carcinoma patients undergoing surgery (2012–2023), we assessed risk factors, such as extranodal extension, TNM stage, and biomarker cutoffs (neutrophil‐lymphocyte 5.0; albumin‐globulin 1.21; lymphocyte‐monocyte 3.14; platelet‐lymphocyte 218.9). Disease‐specific survival was analyzed using Kaplan–Meier curves, log‐rank tests, and Cox multivariate models. Significance set at p < 0.05. Results: Biomarkers measured 3 months postoperatively were the strongest predictors. Multivariate analysis identified high neutrophil‐lymphocyte (HR = 2.99, 95% CI 1.44–6.21; p = 0.003), low albumin‐globulin (HR = 0.44, 95% CI 0.21–0.89; p = 0.023) ratios, and extranodal extension (HR = 3.17, 95% CI 1.54–6.52; p = 0.002) as independent predictors of poorer disease‐specific survival. Importantly, neutrophil‐lymphocyte prognostic impact was comparable to that of extranodal extension, a well‐established pathological risk factor. Conclusions: Three months post‐surgery, high neutrophil‐lymphocyte and low albumin‐globulin ratios independently predict worse disease‐specific survival in oral cancer. Neutrophil‐lymphocyte, a simple and widely available biomarker, offers prognostic insight comparable to extranodal extension, supporting its integration into postoperative risk stratification and potentially guiding adjuvant therapy decisions.

Background: Free palatal gingival grafts (FGG) are commonly harvested during mucogingival procedures. The present study investigates age‐related local and systemic early secondary wound healing outcomes, following FGG harvest in a rat model. Methods: A 4.2 mm diameter defect was created in the palate of 24 younger (2 m) and 24 older (6 m) Wistar male rats. They were divided according to experimental days 1–4. Values of complete blood count, chemistry analysis, and inflammatory biomarkers were assessed. Specimens were examined histologically. Results: Wound healing was similar between groups, with a significant de‐epithelized surface reduction from day 1 to day 2 ( p = 0.0007) and day 2 to day 3 ( p = 0.002), without a significant difference between day 3 and day 4 ( p = 0.4). Histological inflammation scores were consistently higher in younger individuals, suggesting a more pronounced local inflammatory response. Picrosirius red staining revealed more dynamic collagen fiber organization in the younger rats, with significant differences at days 2 ( p  = 0.01), 3 ( p  = 0.03), and 4 ( p  = 0.03). Age‐related differences were noted regarding levels of WBC (white blood cells), RBC (red blood cells), HGB (hemoglobin), HCT (hematocrit), MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), platelet counts, creatinine, SGPT (serum glutamic pyruvic transaminase), SGOT (serum glutamic‐oxaloacetic transaminase), and AlkPhos. Younger rats displayed higher MCV, MCH, platelet counts, and a delayed rise in SGPT, creatinine, and AlkPhos over time, whereas older rats presented constantly higher WBC, RBC, HGB, HCT, and creatinine levels. Serum TNF‐α levels were initially higher in the older rats but declined rapidly. In contrast, IL‐6 peaked earlier and was higher in the older rats. IL‐18 peaked earlier in the older (day 2) compared with the younger rats (day 3). Conclusions: Local and systemic early events following surgery of the palatal mucosa revealed age‐related differences. The older rats demonstrated in general a decreased local response vs. an increased systemic response. Plain language summary: Free palatal gingival grafts are commonly harvested during mucogingival procedures around teeth and implants. The present study investigated age‐related local and systemic early phase outcomes following palatal free gingival harvest with a 4.2 mm diameter punch in a rat model. Younger and older Wistar male rats were included and divided into four experimental groups according to experimental days 1–4. Systemic outcome parameters included complete blood count, chemistry analysis, and immunological parameters. Biopsies were examined for local histological‐inflammatory outcome and collagen immunohistochemistry. Wound healing was similar between the older and younger groups. Local inflammation scores were consistently higher in younger rats. Collagen staining revealed more dynamic activity in the younger rats. The older group exhibited higher and more stable serologic levels of WBC, RBC, HGB, HCT, and creatinine. The younger group displayed higher serologic MCV, MCH, platelet counts, and a delayed rise in SGPT, creatinine, and AlkPhos over time. Serum TNF‐α levels were initially higher in the older group but declined rapidly, IL‐6 peaked higher in the older group and IL‐18 peaked earlier in the older group. It can be concluded that local and systemic wound healing early events following surgery of the palatal mucosa reveal age‐related differences. The older group demonstrated in general a decreased local response versus an increased systemic response.

Background: Papilliferous keratoameloblastoma (PKA) is an exceptionally rare variant of conventional ameloblastoma, marked by papilliferous epithelial projections and prominent keratinization within an ameloblastomatous framework. Because of its rarity and overlap with other keratinizing odontogenic tumours, PKA is often overlooked and is not recognised in the current WHO classification. Limited awareness and inconsistent terminology contribute to diagnostic uncertainty and may affect clinical management. Objectives: This review critically analysed all published PKA cases to describe their clinical, radiographic and histopathological features, evaluating whether PKA should be regarded as a distinct clinicopathological entity or a histological subtype of conventional ameloblastoma. Materials and Methods: A comprehensive search of PubMed, Scopus, Web of Science, and Google Scholar was performed to identify all English‐language reports of PKA. Extracted data included demographics, clinical presentation, radiographic findings, histopathology, treatment and outcomes. The information was synthesised and descriptively analysed. Results: Seven cases of PKA were included. Patients ranged from 18 to 76 years (mean age: 50.4 years), with a male predominance. All lesions involved the right mandible. Clinically, most patients presented with slow‐growing mandibular swellings, occasionally accompanied by pain or mucosal changes. Radiographs most often show multilocular radiolucencies with buccolingual expansion or cortical perforation. Histopathology consistently reveals classic ameloblastomatous epithelium with squamous metaplasia, keratin pearl formation, and distinctive papilliferous projections lining cystic spaces. Conclusion: The uniform histopathological pattern observed across reported cases supports recognising PKA as a distinct histopathological subtype of conventional ameloblastoma. Its formal inclusion in odontogenic tumour classification appears justified, although further molecular and clinicopathological studies are needed to better define its biological behaviour.

Background: Accurate diagnosis of oral soft tissue lesions is critical for effective treatment, yet conventional histopathological examination, the gold standard, faces limitations. These include two-dimensional (2D) visualization and malorientation, which can obscure critical diagnostic features, like epithelial-connective tissue interfaces. Micro-computed tomography (µCT) offers a non-destructive, high-resolution three-dimensional (3D) imaging alternative to address these challenges. Still, its use for soft tissue visualization is limited. We tested a method with specific radio-opaque staining and µCT scanning settings to visualize oral soft tissue biopsies as a proof of concept. Methods: Biopsies from 12 patients with different oral mucosa lesions were stained with Lugol’s iodine, scanned at 3µm resolution with 70kV energy, and the resulting volumes were compared to histopathological sections by specialists in oral radiology and oral pathology. Results: µCT produced 2D images with tissue architecture comparable to hematoxylin and eosin (H&E)-stained sections, distinguishing epithelium, connective tissue, and keratin, while 3D reconstructions revealed topographic details, such as ulceration depth and vascular patterns, unattainable in histopathology. Conclusions: These findings highlight µCT potential as a complementary diagnostic tool, enhancing topographic rendering while preserving tissue integrity. Standardized protocols and broader validation, particularly for precancerous and malignant lesions, are essential for clinical adoption, promising improved diagnostic accuracy in oral pathology.

Microscopic images of aggressive and non-aggressive cases of central giant cell granuloma (CGCG) were analyzed by deep learning algorithms in order to assess its potential as a tool in predicting the biological behavior of CGCG. CGCGs with cortical expansion/perforation, tooth resorption/displacement, or recurrence were classified as aggressive (A-group; N = 48), CGCGs without these features as non-aggressive (N-group; N = 39). Data on patient age, gender, and jaw location were collected. Hematoxylin–eosin (H&E)–stained sections were scanned at × 10 magnification, yielding 9982 sections (5236 A-group, 4746 N-group). After excluding artifacts, 4272 sections (2629 A-group, 1643 N-group) were used to train a ResNet-50 model pre-trained on ImageNet. Data augmentation included random rotation, flipping, and zooming. Model was trained for 100 epochs with an 80/20 train/validation split and tested on 100 images (50 A-group, 50 N-group). Receiver Operating Characteristic (ROC) analysis with area under the curve (AUC), sensitivity, and specificity was performed; t-test and chi-square test were used for age and frequency (p < 0.05). AUC was 52%, sensitivity 54%, and specificity 50%. Mean age of patients in A-group was lower than in N-groups (32.6 ± 19.98 years and 42.2 ± 21.58 years, respectively; p = 0.038). F:M ratio was 1:1 in both groups. Mandible was twofold more frequently than maxilla in both groups. This pioneering study to differentiate between aggressive and non-aggressive CGCGs based on whole microscopic sections using a deep machine learning model was not successful, probably due to lack of specific segmentations and technical staining issues. Further investigation with advanced preprocessing is needed to enhance model performance and clinical utility.

Background: Expression of angiotensin-converting enzyme (ACE)-2 and co-factors like furin, play key-roles in entry of SARS-CoV-2 into host cells. Furin is also involved in oral carcinogenesis. We investigated their expression in oral pre-malignant/malignant epithelial pathologies to evaluate whether ACE2 and furin expression might increase susceptibility of patients with these lesions for SARS-CoV-2 infection. Methods: Study included normal oral mucosa (N = 14), epithelial hyperplasia-mild dysplasia (N = 27), moderate-to-severe dysplasia (N = 24), squamous cell carcinoma (SCC, N = 34) and oral lichen planus (N = 51). Evaluation of ACE2/furin membranous/membranous-cytoplasmic immunohistochemical expression was divided by epithelial thirds (basal/middle/upper), on a 5-tier scale (0, 1—weak, 1.5 –weak-to-moderate, 2—moderate, 3—strong). Total score per case was the sum of all epithelial thirds, and the mean staining score per group was calculated. Real time-polymerase chain reaction was performed for ACE2-RNA. Statistical differences were analyzed by One-way ANOVA, significance at p<0.05. Results: All oral mucosa samples were negative for ACE2 immuno-expression and its transcripts. Overall, furin expression was weakly present with total mean expression being higher in moderate-to-severe dysplasia and hyperplasia-mild dysplasia than in normal epithelium (p = 0.01, each) and SCC (p = 0.008, p = 0.009, respectively). Conclusions: Oral mucosa, normal or with epithelial pathologies lacked ACE2 expression. Furin was weak and mainly expressed in dysplastic lesions. Thus, patients with epithelial pathologies do not seem to be at higher risk for SARS-CoV-2 infection. Overall, results show that oral mucosae do not seem to be a major site of SARS-CoV-2 entry and these were discussed vis-à-vis a comprehensive analysis of the literature.

Background: Ameloblastoma is a rare odontogenic neoplasm frequently located in the mandible. Standard treatment involves radical bone resection and immediate reconstruction, causing functional, aesthetic, and psychological impairments. The BRAF V600E mutation is present in approximately 80% of mandible ameloblastomas, and BRAF inhibitors have demonstrated sustained responses in unresectable cases. Methods: We identified ameloblastoma patients planned for ablative surgery and screened them for BRAF V600E mutation. Neoadjuvant BRAF inhibitors were offered to facilitate jaw preservation surgery. Retrospective data collection encompassed treatment regimens, tolerability, tumor response, and conversion to mandible preservation surgery. Results: Between 2017 and 2022, a total of 11 patients received dabrafenib (n = 6) or dabrafenib with trametinib (n = 5). The median age was 19 (range = 10-83) years. Median treatment duration was 10 (range = 3-20) months. All (100%) patients achieved a radiological response. Ten (91%) patients successfully converted to mandible preservation surgery with residual tumor enucleation. One patient attained complete radiological response, and surgery was not performed. Among the 10 surgically treated patients, all exhibited a pathological response, with 4 achieving near complete response and 6 partial response. At a median follow-up of 14 (range = 7-37) months after surgery, 1 case of recurrence was observed. Grade 1-2 adverse effects were reported in 8 (73%) patients, with a single case of grade 3 (hepatitis). Dose modification was necessary for 3 patients, and 4 experienced treatment interruptions, while 1 patient permanently discontinued therapy. Conclusions: Neoadjuvant BRAF inhibition may offer a safe and effective strategy for organ preservation in mandible ameloblastoma treatment.

Aims: The aim of the study was to analyze objective and subjective olfactory/gustatory function in post‐COVID‐19 infection (PCI).Materials and Methods: Patients with past PCR‐confirmed COVID‐19 infection and persistent olfactory/gustatory complaints were investigated. Olfactory threshold and identification, gustatory detection, identification, and magnitude scaling were tested.Results: A total of 42 PCI subjects were compared to 41 age‐ and gender‐matched controls with no COVID‐19 history. All PCI tested had mild COVID‐19 disease. Mean interval between COVID‐19 confirmations to testing was 7.4 ± 3.1 months. PCI subjects complained of combined dysfunction in 85.7%, isolated olfactory or gustatory dysfunction in 7.1% each. Combined complaints were significantly higher in PCI (p < 0.001). Objective testing showed significantly higher prevalence of dysfunction in PCI versus controls for hyposmia (73.8%, 12.2%), anosmia (11.9%, 0%), odor identification (68.5%, 83.0%), hypogeusia (23% and 2.4%, respectively), and impaired magnitude scaling, (p < 0.05). All PCI subjects with hypogeusia had abnormal gustatory magnitude scaling.Conclusions: While most PCI subjects complained of combined gustatory and olfactory dysfunction, objective testing showed in the majority an isolated single sense dysfunction, with a low level of agreement between subjective and objective findings.Abnormal objective results for all olfactory and gustatory functions tested may suggest a central rather than peripheral mechanism, although concomitant mechanisms cannot be excluded.