ROMANIAN JOURNAL of MORPHOLOGY and EMBRYOLOGY

Vol. 67 No. 1, January-March 2026

1. Alcohol-induced structural and cellular brain alterations: molecular and histopathological mechanisms

Iulia Balutoiu, Sorin Nicolae Dinescu, Andrei Gresita, Lucretiu Radu, Citto Iulian Taisescu, Alexandra-Daniela Rotaru-Zavaleanu, Madalina Aldea, Mihai Andrei Ruscu, Rossy Vladut Teica, Marian Valentin Zorila, Mircea-Sebastian Serbanescu

Chronic alcohol consumption is a leading cause of acquired neurodegeneration with well-documented structural and ultrastructural brain alterations. This review analyzes the cellular and molecular mechanisms underlying alcohol neurotoxicity, integrating findings from animal models, human post-mortem studies, and neuroimaging investigations. Ethanol crosses the blood-brain barrier and generates toxic metabolites including acetaldehyde and reactive oxygen species, triggering oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Chronic exposure induces glutamatergic and gamma-aminobutyric acid (GABA)ergic adaptations leading to excitotoxicity during withdrawal. Cell death occurs through apoptotic, necrotic, and necroptotic pathways, while microglial and astrocytic activation perpetuates neuroinflammation. Histopathological (HP) changes include selective neuronal loss in the prefrontal cortex, hippocampus, and cerebellum, dendritic simplification, and synaptic alterations. White matter pathology manifests as demyelination and axonal degeneration. Associated thiamine deficiency produces characteristic lesions in the mammillary bodies, thalamus, and cerebellar vermis. Neuroimaging techniques provide valuable HP correlates and biomarkers for disease monitoring. While some changes demonstrate partial reversibility with abstinence through remyelination and synaptic plasticity, extensive neuronal loss remains irreversible. Understanding these mechanisms is essential for developing neuroprotective therapeutic strategies.

Corresponding author: Radu Lucretiu, Associate Professor, MD, PhD; e-mail: radu.lucretiu@umfcv.ro; Citto Iulian Taisescu, Professor, MD, PhD; e-mail: citto.taisescu@umfcv.ro

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2. Primary cutaneous extraskeletal Ewing sarcoma of the plantar region: clinicopathological features and review of the literature

Laurentiu Augustus Barbu, Gabriel Florin Razvan Mogos, Nicolae Dragos Margaritescu, Daniela Marinescu, Stelian Stefanita Mogoanta, Liviu Vasile, Liliana Cercelaru, Valentina Caluianu, Ioana Alexia Tenea-Cojan, Tiberiu Stefanita Tenea-Cojan

Background/Objectives: Primary cutaneous extraskeletal Ewing sarcoma (pcEES) is an exceptionally rare malignant small round cell tumor, with limited cases reported and challenging diagnosis due to overlapping clinicopathological features. We aimed to review its diagnostic and therapeutic aspects and present a rare plantar case. Study selection for review: A PubMed search was performed to evaluate current data regarding the epidemiology, diagnosis, differential diagnosis, and management of pcEES. Case presentation: A 62-year-old woman with recurrent pcEES of the left plantar region presented with severe pain, ulceration, superinfection, inguinal lymph node involvement, and suspected osseous invasion. Histopathology and immunohistochemistry supported the diagnosis. Due to advanced locoregional disease, left transfemoral amputation was performed. Conclusions: pcEES is a rare and diagnostically demanding malignancy that may show aggressive behavior despite superficial location. Early diagnosis and multidisciplinary management are essential.

Corresponding author: Gabriel Florin Razvan Mogos, Lecturer, MD, PhD; e-mail: gabriel.mogos@umfcv.ro; Nicolae Dragos Margaritescu, Lecturer, MD, PhD; e-mail: dmargaritescu@yahoo.com

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3. Primary gallbladder melanoma - a rare entity or a diagnostic pitfall?

Radu Gheorghe Dan, Gabriel Veniamin Cozma, Adrian Iosif Moldoveanu, Diana Maria Orzata, Ovidiu Alexandru Mederle, Emil Florin Hut

Primary gastrointestinal (GI) melanoma is an exceptionally rare and controversial diagnostic entity. Because the mucosa of the gallbladder, stomach, small bowel, and large bowel is not considered a common site of melanocytic proliferation, most GI melanomas are regarded as metastatic lesions originating from a primary cutaneous melanoma. Whether some of these tumors may truly arise primarily in GI sites remains a matter of debate. The diagnosis is further complicated by the possibility of occult, clinically subtle, or amelanotic cutaneous melanomas that may remain unrecognized until advanced metastatic disease becomes symptomatic. In addition, spontaneous regression of the primary cutaneous lesion may lead to complete or partial disappearance of the original tumor, creating further diagnostic uncertainty. We performed a literature review focused on GI and gallbladder melanoma, with emphasis on the distinction between primary and metastatic lesions and the role of spontaneous regression. In addition, we analyzed all cases of GI and gallbladder melanoma diagnosed in our department during the last five years. Three cases were identified: one gallbladder melanoma and two small bowel melanomas. These cases illustrated distinct clinical scenarios, including GI bleeding associated with gallbladder involvement, amelanotic ileal melanoma, and intussusception caused by metastatic melanoma from a known cutaneous primary lesion. Our findings support the need for cautious interpretation when diagnosing primary GI melanoma. Metastatic disease from occult, regressed, or previously undiagnosed cutaneous melanoma should always be carefully excluded through multidisciplinary clinicopathological evaluation.

Corresponding author: Adrian Iosif Moldoveanu, Assistant Professor, MD, PhD Student; e-mail: adrian.moldoveanu@umft.ro

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4. Short histological kaleidoscope - recent findings in histology. Part VI. Kupffer cells, hepatic stellate cells, enteroendocrine cells, and telocytes

Lavinia Patricia Mocan, Carmen Mihaela Mihu, Anne-Marie Constantin, Rada Teodora Sufletel, Ingrid Anamaria Paunescu, Tudor Andrei Ilie, Alina Simona Sovrea

The liver, intestinal epithelium, and nervous system harbor specialized cell populations whose biology has been fundamentally redefined by contemporary histological and molecular methodologies. This review synthesizes recent advances across four such populations: Kupffer cells (KCs), hepatic stellate cells (HSCs; Ito cells), enteroendocrine cells (EECs), and telocytes (TCs). KCs are now understood as ontogenetically heterogeneous, yolk sac-derived populations maintained by local self-renewal and shaped by durable epigenomic reprogramming. Their molecular identity, anchored to species-specific markers including C-type lectin domain family 4 member F (CLEC4F), T-cell immunoglobulin and mucin domain-containing protein 4 (TIM4), V-set and immunoglobulin domain-containing protein 4 (VSIG4), and the human-specific succinate receptor 1 (SUCNR1), is dynamically regulated by sinusoidal niche signals and underlies central roles in metabolic liver disease, fibrosis, viral hepatitis, and hepatocellular carcinoma. HSCs exhibit a tightly regulated functional continuum spanning quiescence, activation, senescence, and apoptosis, with single-cell transcriptomics revealing spatially restricted subpopulations and novel cytoskeletal markers - syncoilin, synemin, and cytoglobin - adding molecular resolution to the activation-quiescence axis. EECs, though representing only 1% of intestinal epithelial cells, operate as multifunctional neuroepithelial transducers: their neuropod-mediated gut-brain connectivity, microbiota-driven epigenetic regulation, and vesicle-mediated mucosal immune modulation challenge the classical view of these cells as simple hormone-secreting units. TCs, defined by their moniliform cytoplasmic extensions termed telopodes, constitute an emerging stromal population within peripheral and central nervous system compartments, with putative roles in intercellular scaffolding, post-lesional regeneration, and tumor microenvironment organization. Collectively, these findings redefine each population as a dynamic, context-responsive entity with significant implications for the understanding and treatment of metabolic, inflammatory, fibrotic, and neoplastic diseases.

Corresponding author: Anne-Marie Constantin, Lecturer, MD, PhD; e-mail: annemarie_chindris@yahoo.com

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5. Cleft lip/palate. From embryology to developmental pathogenesis

Marcello Guarino

Cleft of the lip associated with or unassociated with cleft of the palate and cleft palate (CLP) represent frequent birth defects, and the mechanisms by which they occur are not completely clear. On the other hand, knowledge of the normal mechanisms underlying lip development and palatogenesis is still incomplete, and therefore a better understanding and consolidation of our knowledge in this field could help to study these deformities. Upper lip and secondary palate formation are complex processes, involving the subtle integration of several biological events, the disruption of which causes the clefting phenotype. Indeed, these developmental events imply a series of morphogenetic changes involving concerted cell survival, migration, growth, pattern generation, modulation of adhesiveness, death and differentiation. In recent years, genetically engineered animal models and in vitro palate cultures have greatly advanced our knowledge of the cellular and molecular pathways underlying normal orofacial morphogenesis, and abnormally developed CLP as well. Indeed, most of the morphogenetic events of craniofacial development are highly conserved amongst vertebrates, therefore animal models have revealed major insights into the mechanisms that take place in human orofacial development. Given their complexity, it is easy to imagine that the failure of the highly coordinated processes that guide the union of the lip and palate causes various forms of clefts. This article provides an overview of the embryological development of the lip and secondary palate, as well as the mechanisms underlying deviant development resulting in CLP, concentrating on the cellular and molecular characteristics.

Corresponding author: Marcello Guarino, MD; e-mail: marcello.guarino@gmail.com

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6. Formaldehyde in pathology services: from molecular toxicity to histopathological change and occupational risk

Mircea-Sebastian Serbanescu, Alexandra-Daniela Rotaru-Zavaleanu, Lucretiu Radu

Background and Objective: Formaldehyde (FA), classified as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC), constitutes a significant occupational hazard within hospital pathology service, where it remains the “gold standard” fixative for tissue preservation. Despite widespread recognition of its toxicological properties, the specific carcinogenic and non-carcinogenic health risks confronting pathology personnel subjected to chronic, low-level, and intermittent exposures remain incompletely characterized. This review synthesizes the current body of evidence regarding the cellular and molecular mechanisms of FA toxicity, histopathological (HP) alterations in target tissues, and associated occupational health risks among pathology staff. Study selection for review: A comprehensive literature search was conducted across PubMed/MEDLINE, Web of Science, and Scopus databases, encompassing publications through December 2025. Studies were selected based on relevance to FA toxicity mechanisms, HP effects, and occupational exposure in pathology settings. Given the heterogeneity of study designs and outcomes, a narrative synthesis approach was adopted. Evidence synthesis: The synthesized evidence demonstrates that pathology personnel are routinely exposed to FA concentrations exceeding recommended occupational exposure limits (OELs). At the cellular level, FA exerts toxicity through deoxyribonucleic acid (DNA)-protein crosslink formation, oxidative stress induction, and inflammatory pathway activation. HP examination of exposed individuals reveals a characteristic progression from ciliary loss and goblet cell hyperplasia through squamous metaplasia to epithelial dysplasia in the nasal mucosa. Non-carcinogenic health effects, including respiratory symptoms and genotoxicity biomarker elevation, are highly prevalent. However, direct epidemiological evidence substantiating elevated cancer risk within this specific occupational cohort remains limited, mainly due to improper (occupational medicine) reporting. Conclusions: This review confirms substantial non-carcinogenic health effects among pathology personnel, with documented HP alterations representing preneoplastic changes at the portal of entry. The mechanistic evidence supports biological plausibility for carcinogenic risk, though epidemiological confirmation specific to this workforce remains lacking, highlighting a critical research gap.

Corresponding author: Alexandra-Daniela Rotaru-Zavaleanu, MD; e-mail: alexandra.rotaru@umfcv.ro

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7. Clinicopathological and immunohistochemical profile of breast lesions diagnosed by core needle biopsy: a retrospective study from Sf. Ioan Hospital, Bucharest, Romania

Iulia Bistriceanu, Razvan-Andrei Stoica, Niculae Iordache, Claudiu-Octavian Ungureanu, Carmen Giuglea, Valentin Titus Grigorean, Maria-Alexandra Paunescu, Ileana-Adela Vacaroiu, Mara Mardare, Bogdan Cosmin Tanase, Daniela Roca, Octav Ginghina

Background: Breast cancer (BC) is the most frequently type of cancer diagnosed among women worldwide, according to current epidemiological data. It represents also a leading cause of cancer-related mortality and there are many disparities in stage at diagnosis due to differences among patients education and access to care. Accurate tissue diagnosis is mandatory to provide best treatment decisions. The positive diagnosis is provided by image-guided core needle biopsy (CNB) that offers adequate tissue for both histopathological (HP) and immunohistochemical (IHC) analysis. The examination of the tissue remains fundamental for establishing tumor subtype and appropriate treatment. Objective: The study evaluates HP and IHC characteristics of BC tumors obtained by CNB in a tertiary care hospital in Bucharest, Romania. Patients, Materials and Methods: We conducted a retrospective analysis of 39 patients diagnosed with breast tumors at Sf. Ioan Hospital, in Bucharest, between January 2024 and December 2024. Data extracted included tumor laterality, quadrant location, histological type and hormone receptor status. This included estrogen receptor (ER), progesterone receptor (PR), as well as human epidermal growth factor receptor 2 (HER2) status, and the Ki-67 proliferation index (PI). Cases were classified into molecular subtypes. All biopsies were performed on clinically palpable lesions. Results: Among the 39 biopsies, invasive BC of no special type (NST) represented the predominant malignant subtype. Most tumors were ER-positive and/or PR-positive, with HER2-negative expression being the leading phenotype. Ki-67 PI values were frequently >=20%, indicating a high-proliferation profile in a substantial proportion of cases. Conclusions: This single-center retrospective study provides insight into the distribution of key pathological and molecular features among newly diagnosed BC patients in a Romanian clinic. Our findings highlight the importance of accurate biopsy-based profiling in guiding treatment strategies.

Corresponding author: Razvan-Andrei Stoica, Assistant Lecturer, MD, PhD; e-mail: andrei.stoica@umfcd.ro; Niculae Iordache, Professor, MD, PhD; e-mail: niculae.iordache@umfcd.ro

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8. Neurological symptoms observed in patients with COVID-19

Roberta Andreea Cercel, Florin Ionut Buibas, Mircea-Sebastian Serbanescu, George Popescu, Ionica Pirici, Nina Ionovici, Laurentiu Mogoanta

Infection with the novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) has triggered the largest pandemic of the early 21st century. The disease primarily affects the respiratory system and may present as a common respiratory viral infection, but more severe cases can progress to acute pneumonia or acute respiratory distress syndrome, with heart and kidney failure, digestive symptoms, liver failure, and sometimes death. In SARS-CoV-2 infection, respiratory symptoms are frequently accompanied by neurological manifestations ranging from headaches, dizziness, anosmia, and asthenia to severe complications such as ataxia, seizures, and strokes. A study was conducted on a cohort of 5649 patients clinically and paraclinically diagnosed with coronavirus disease 2019 (COVID-19), admitted to the Victor Babes Clinical Hospital for Infectious Diseases and Pneumophthisiology, Craiova, Romania, between 2020 and 2022, to identify the most common signs of neurological involvement. The most common signs of neurological involvement in COVID-19 were asthenia, headache, and myalgia. The most severe complications in COVID-19 were strokes.

Corresponding author: Nina Ionovici, Associate Professor, MD, PhD; e-mail: nina.ionovici@umfcv.ro

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9. Remodeling of muscular component of the myocardial tissue depending on age, sex and cause of death

Laura Elena Camenita, Cristina Florescu, Iancu Emil Plesea, Mircea-Sebastian Serbanescu, Razvan Mihail Plesea, Adriana-Roxana Lazarovici, Liviu Martin

Aim: Ageing process, as well as different pathological conditions, can induce morphological and functional changes in all tissue including those of cardiovascular system and particularly in myocardial tissue. The authors realized a quantitative preliminary study of the main component of the myocardium, the specific muscle cells. Patients, Materials and Methods: Samples of myocardial tissue with no evident lesion coming from 95 patients deceased in hospital and autopsied were histologically processed and proportion of myocardial specific cells (myocardial fibers; MF) was assessed, on virtual slides, with a specially built computer program. For statistical comparison of data Pearson s correlation test was used. Results: The MF proportion had the smallest values in childhood and adolescence They significantly increased during young adulthood and then decreased discretely until the elderly period of life. The MF proportion had the highest values in the left ventricle wall (LV_W) from where it fell towards the interventricular septum (IVS) and had the lowest levels in the right ventricle wall (RV_W), in all main life periods, excepting the first one (childhood and adolescence), where it had the highest values in the RV_W. MF proportion has also high levels in males than in females in all main regions of cardiac wall. Also, their decrease from the LV_W to RV_W is more pronounced in females than in males. Related to the cause of death, the MF proportion had the lowest values in vascular conditions causing death (V_P), then, they increased significantly in non-vascular conditions causing death (NV_P) and they decreased slightly in sudden/violent deaths (S/V_Dths). In NV_P and S/V_Dths, MF proportion had the highest values in LV_W, then they decreased towards IVS and, finally, in RV_W. In V_P, in turn, MF proportion had the highest values in LV_W and the lowest ones in IVS. In the LV_W of NV_P and S/V_Dths groups, MF proportion values decreased from anterior to posterior cardiac wall regions whereas, in V_P group, they were almost the same in all main regions. MF proportion had a decreasing trend from left to right main cardiac wall regions, both in men and women. However, in men, the highest values were in NV_P group and the lowest, in S/V_Dths group, and, in women, the highest values were in S/V_Dths group and lowest in V_P group. Conclusions: The myocardial muscle cell compartment showed a decreasing pattern along all regions of the heart wall with age, both in men and women with higher values in former. Regarding the causes of death, the remodeling trend was the same from anterior to posterior regions of the heart wall, but with marked differences between the two sexes and the ranking of proportion values between the defined groups of causes of death.

Corresponding author: Mircea-Sebastian Serbanescu, Associate Professor, MD, PhD; e-mail: mircea_serbanescu@yahoo.com

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10. Vascular remodeling and microvessel density in inflammatory radicular cysts: a CD34 immunohistochemical analysis

Alexandra Catalina Iacov, Adrian Camen, Maria Cristina Munteanu, Oana Andreea Diaconu, Alexandru Dan Popescu, Gabriela Boldeanu, Ilona Mihaela Liliac, Elena Cristina Andrei, Carmen Aurelia Mogoanta, Ionela Teodora Dascalu, Larisa Patru, Mihaela Jana Tuculina

Background: Inflammatory radicular cysts are lesions of endodontic origin in which chronic inflammation and tissue remodeling may support cyst expansion. Aim: The present study evaluated cluster of differentiation 34 (CD34) immunoexpression as a proxy of vascular remodeling and explored a digital, artificial intelligence (AI)-assisted quantification workflow. Materials and Methods: Thirty-nine inflammatory radicular cysts were processed as formalin-fixed paraffin-embedded (FFPE) specimens and immunostained with anti-CD34 antibody. Digital quantification [Deep Learning Inferred ImmunoFluorescence (DeepLIIF) and ImageJ] was performed in selected stromal areas. Lesions were stratified by cyst size (0.5-1.0 cm, 1.0-2.0 cm, >2.0 cm). Results: Twenty-two of 39 cases were CD34-positive. In these cases, the mean proportion of CD34-positive nuclei increased with lesion size (6.67% in 0.5-1.0 cm, 15.98% in 1.0-2.0 cm, and 31.13% in >2.0 cm). Differences among size groups were significant (Kruskal-Wallis H=18.50, p=0.000096). Conclusions: Larger inflammatory radicular cysts displayed higher CD34-associated vascular signal, supporting an association between cyst size and vascular remodeling.

Corresponding author: Maria Cristina Munteanu, Lecturer, DMD, PhD; e-mail: cristina.munteanu@umfcv.ro; Oana Andreea Diaconu, Associate Professor, DMD, PhD; e-mail: oana.diaconu@umfcv.ro

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11. Ileal neuroendocrine tumors: clinicopathological features and associations with systemic inflammatory and nutritional markers

Nicolae Dragos Margaritescu, Tiberiu Stefanita Tenea-Cojan, Gabriel Florin Razvan Mogos, Stelian Stefanita Mogoanta, Liviu Vasile, Liliana Cercelaru, Laurentiu Augustus Barbu

Background: Ileal neuroendocrine tumors (NETs) are well-differentiated neoplasms with relatively indolent histological features but an often aggressive biological behavior, characterized by early lymphatic and hematogenous dissemination. Increasing evidence suggests that systemic inflammatory and nutritional status may influence tumor progression; however, data regarding these parameters in ileal NETs remain limited. Patients, Materials and Methods: A retrospective observational study was conducted on 12 consecutive patients with histologically confirmed ileal NETs who underwent surgical treatment between 2018 and 2024. Clinicopathological, morphological, immunohistochemical, and laboratory data were analyzed. Systemic inflammatory and nutritional indices, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, lymphocyte-to-monocyte ratio, and prognostic nutritional index, were calculated from preoperative blood tests and evaluated in relation to metastatic status. Results: The cohort comprised predominantly well-differentiated NETs classified as NET G1-G2. Most tumors showed deep wall infiltration and a high prevalence of regional lymph node and distant metastases at diagnosis. Patients with metastatic disease were significantly younger and had lower hemoglobin levels. Higher values of inflammatory indices and lower nutritional markers were consistently observed in the metastatic group, although these differences did not reach statistical significance. Conclusions: Ileal NETs exhibit a distinct biological behavior in which well-differentiated morphology frequently coexists with advanced disease. Systemic inflammatory and nutritional indices may reflect tumor burden and metastatic potential and could complement histopathological evaluation in the clinical assessment of ileal NETs. Larger prospective studies are warranted to clarify their prognostic value.

Corresponding author: Liviu Vasile, Lecturer, MD, PhD; e-mail: vliviu777@yahoo.com; Gabriel Florin Razvan Mogos, Lecturer, MD, PhD; e-mail: gabriel.mogos@umfcv.ro

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12. Architectural patterns of growth of colon adenocarcinoma - comparative study

Liviu Martin, Adrian Mita, Iancu Emil Plesea, Cecil Sorin Mirea, Anwar Erchid, Adriana-Roxana Lazarovici, Aminia Diana Ciobanoiu

Background and Objectives: Colorectal adenocarcinoma (CR ADK) may show either a uniform architectural pattern or intratumoral architectural heterogeneity, but the clinicopathological relevance of these growth patterns is still insufficiently characterized. Aim: The study s aim was to compare the clinical and morphological profiles of tumors with a single dominant architectural pattern and tumors with two coexisting architectural patterns. Patients, Materials and Methods: We analyzed 104 CR ADKs, divided into two groups: one group of 78 patients with a single architectural pattern all over the tumor and one group of 26 patients with two architectural patterns within the tumor. Clinical parameters and morphological parameters (macroscopic and microscopic) were comparatively assessed using, for categorical variables, the chi-squared test and, for continuous variables Student s t-test. Results: Tumors with a single morphological appearance were found in males of around 65 years old, from urban areas, located especially in the distal regions of the colon, usually circumferential and greater than 5 cm. Morphologically, they were usually fungated and ulcerative common forms of ADK with moderate degree of differentiation and, overall, with a somewhat less aggressive biological behavior. Tumors with two morphological aspects, in turn, were found often in old women, in the proximal regions of the colon and most often circumferential but with smaller dimensions than those in the first group. Morphologically, they were usually protrusive with ulcerations on the surface. Although the usually encountered patter was that of common form of well-differentiated ADK, in the deep areas, they assumed poorly differentiated forms, most often with mucinous-type secretory properties. Aggressiveness markers like intratumor necrosis or inflammation were a common presence. The biological behavior was more aggressive, especially with the invasion of regional lymph nodes. Conclusions: Our study identified a subgroup of colon epithelial malignancies with two main architectural patterns that presented distinctive clinical-morphological features and a trend toward greater biological aggressiveness, particularly through deeper mucinous/poorly differentiated transformation and more frequent necro-inflammatory changes. Further studies are necessary to include this tumor profile in routine prognostic assessment of colorectal epithelial malignancies.

Corresponding author: Adrian Mita, Lecturer, MD, PhD; e-mail: mitaadrian07@gmail.com

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13. TLR4 expression and its immunopathogenic role in inflammatory radicular cysts: a clinicopathological study

Alexandra Catalina Iacov, Ilona Mihaela Liliac, Maria Cristina Munteanu, Adrian Camen, Nina Ionovici, Mihaela Jana Tuculina, Valentin Octavian Mateescu, Alexandru Dan Popescu, Ciprian Laurentiu Patru, Carmen Aurelia Mogoanta, Elena Cristina Andrei

Inflammatory radicular cysts are among the most frequently diagnosed odontogenic cysts and arise as a consequence of chronic periapical inflammation of endodontic origin. Their development and persistence are associated with continuous microbial stimulation and activation of local immune responses. Toll-like receptor 4 (TLR4) is a member of the pattern recognition receptor (PRR) family. In periapical pathology, TLR4 is essential for detecting microbial antigens derived from the infected root canal system. The purpose of this study was to evaluate the immunohistochemical (IHC) expression of TLR4 in inflammatory radicular cysts and to assess its involvement in the local inflammatory response. Biopsy specimens from 39 patients diagnosed with radicular cysts were processed for routine histological examination and IHC analysis using anti-TLR4 antibodies. Histological evaluation revealed a chronic lymphoplasmacytic inflammatory infiltrate with a high density of macrophage-like cells and large mononuclear cells in all samples. IHC findings demonstrated strong cytoplasmic TLR4 expression in macrophage-like cells and large mononuclear cells, key innate immune cells, along with a discrete membranous distribution, supporting active recognition of pathogen-associated molecular patterns. Moderate TLR4 expression was also observed in neutrophils, suggesting focal areas of acute inflammatory activity superimposed on a chronic inflammatory background. These results indicate that TLR4 plays a significant role in the immunopathogenesis of inflammatory radicular cysts by mediating innate immune activation and sustaining local inflammation. A better understanding of TLR4 signaling involvement may contribute to improved insights into lesion behavior and support future targeted therapeutic approaches aimed at modulating persistent inflammatory processes in periapical pathology.

Corresponding author: Nina Ionovici, Associate Professor, MD, PhD; e-mail: nina.ionovici@umfcv.ro; Ciprian Laurentiu Patru, Lecturer, MD, PhD; e-mail: patru.ciprianl@gmail.com

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14. Corticosteroid therapy in chronic rhinosinusitis with nasal polyps: from histopathological tissue remodeling to patient adherence and barriers

Alex Iulian Milea, Mihai Alexandru Preda, Andreea Elena Milea, Carmen Aurelia Mogoanta, Ionut Tanase, Adelin Bordea, Caius Codrut Sarafoleanu

Background and Objectives: This study evaluated mucosal remodeling across different corticosteroid regimens and identified barriers to treatment adherence in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Patients, Materials and Methods: We enrolled 56 consecutive patients divided into two arms: Group 1 (n=22) underwent sinus surgery after topical, systemic, or combined corticosteroid therapy, with mucosal biopsies evaluated via a four-parameter histopathological (HP) score (infiltrate, eosinophils, edema, fibrosis). Group 2 (n=34; 15 excluded due to systemic steroid use) received exclusive medical treatment and was assessed for compliance using the Medication Adherence Questionnaire (MAQ) at baseline and three months. Results: In Group 1, combined therapy (topical and systemic) demonstrated significantly lower HP scores compared with the topical-only group for inflammatory infiltrate (p=0.0280), tissue eosinophils (p=0.036), intramucosal edema (p=0.0400), and fibrosis (p=0.0393). In Group 2, a strong negative correlation was established between MAQ and Medication Adherence Report Scale-5 (MARS-5) (r=-0.9216, p<0.0001), confirming validity. Early treatment discontinuation and time constraints were the primary drivers of non-adherence. Conclusions: Combined topical and systemic corticosteroid therapy yields superior tissue remodeling outcomes by significantly reducing mucosal inflammation, eosinophilia, edema, and fibrosis compared to topical therapy alone. The MAQ is a valid clinical tool, highlighting early discontinuation and time constraints as key targets to optimize patient compliance and CRSwNP management.

Corresponding author: Andreea Elena Milea, MD, PhD Student; e-mail: andreeaelena.bejenariu@yahoo.com; Carmen Aurelia Mogoanta, Associate Professor, MD, PhD; e-mail: carmen_mogo@yahoo.com

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15. A longitudinal study of dual-energy X-ray absorptiometry status in menopausal women with adrenal tumors

Alexandra-Ioana Trandafir, Nina Ionovici, Dana Cristina Terzea, Oana-Claudia Sima, Mihai Costachescu, Mara Carsote

Introduction: Adrenal tumors involve multidisciplinary challenges, including bone health impairment due to mild or fully manifested cortisol overproduction by the adrenal cortex. Aim: We aimed to assess dual-energy X-ray absorptiometry (DXA)-based category switch in non-surgery candidates who were initially diagnosed with non-functional adrenal tumors (NFATs) at computed tomography (CT). Patients, Materials and Methods: This was real-life setting associated with a longitudinal analysis in menopausal individuals (age range: 50 to 80 years) diagnosed with NFATs who had a central DXA scan at baseline and during monitorization. Exclusion criteria: malignancies, functional adrenal tumors. Results: The initial cohort (N=33) included: 21.21% of the patients had osteoporosis (group A), 60.61% had osteopenia (group B) and 18.18% had normal DXA (group C), with similar age and menopause duration, but higher body mass index (BMI) in group C vs. group A (35.33+/-8.61 vs. 26.82+/-4.00 kg/m(2); p=0.039). Hormonal and CT-based features were similar among the groups. Group C had higher osteocalcin vs. group B (30.93+/-14.07 vs. 18.88+/-8.42; p=0.051). Baseline morning (plasma) cortisol negatively correlated with DXA-bone mineral density (BMD) at femoral neck (r=-0.539, p=0.017). Median follow-up was similar among the groups (50 months, Q1-Q3 quartiles: 24 to 71 months). 66.67% of patients from group C experienced a DXA category switch vs. group B (20.00%; p=0.051). Decrease DXA category switch was more prevalent in group C vs. group A (p=0.021), respectively, group C vs. group B (p=0.013). Conclusions: Sharpest DXA-BMD decline was between 48 and 72 months. The cumulative probabilities of decrease DXA category switch-free survival were higher in osteopenia vs. normal (p-value log-rank: 0.026), indicating that patients with normal results of DXA-BMD were more likely to decrease category in comparison to the subjects initially confirmed with osteopenia. To our best knowledge, only a limited number of studies longitudinally assessed bone status in NFATs so far.

Corresponding author: Nina Ionovici, Associate Professor, MD, PhD; e-mail: nina.ionovici@umfcv.ro; Dana Cristina Terzea, MD, PhD; e-mail: danaterzea@gmail.com

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16. Evaluation of neurotrophic therapies for sciatic nerve injury in mice

Denisa Madalina Viezuina, Madalina Iuliana Musat, Andrei Gresita, Bogdan Catalin, Veronica Sfredel, Valentin Octavian Mateescu, Smaranda Ioana Mitran

Background: Peripheral nerve injuries remain a major therapeutic challenge, frequently resulting in incomplete functional recovery and long-term disability. Although microsurgical repair techniques continue to advance, there is a clear unmet need for adjunctive pharmacological strategies capable of enhancing regenerative outcomes. In this preclinical study, we investigated the functional recovery potential of Calf Blood Hemodialysate, a deproteinized ultrafiltrate enriched with low-molecular-weight peptides and intermediary metabolites, and alpha-lipoic acid (ALA), a potent mitochondrial antioxidant and metabolic modulator. Adult C57BL/6 mice were randomized into four experimental groups: untreated controls, Calf Blood Hemodialysate-treated (Actovegin), ALA-treated, and combination therapy (Actovegin+ALA). Sciatic nerve injury was induced via the standardized crush injury model, and treatment commenced for 48 hours post-operatively. Calf Blood Hemodialysate was administered intraperitoneally at 200 mg/kg/day for 10 days, whereas ALA was delivered at 20 mg/kg/day for 14 days. Functional recovery was assessed over a 50-day period using electromyography, the Basso Mouse Scale, and the Beam Walk Test. Immunohistochemical evaluation included analysis of muscle morphology and spinal cord glial fibrillary acidic protein (GFAP) expression. Both monotherapies improved neuromotor performance and electrophysiological outcomes relative to untreated controls. ALA, however, exhibited superior histological and functional benefits, promoting earlier and more sustained recovery compared to Calf Blood Hemodialysate. Notably, combined administration did not produce synergistic effects. Overall, these findings underscore the therapeutic promise of Calf Blood Hemodialysate and ALA in peripheral nerve regeneration and support future investigations utilizing localized delivery platforms, such as gelatin-based hydrogels, to achieve sustained, site-specific release and optimized clinical outcomes.

Corresponding author: Bogdan Catalin, Associate Professor, MD, PhD; e-mail: bogdan.catalin@umfcv.ro; Veronica Sfredel, Professor, MD, PhD; e-mail: veronica.sfredel@umfcv.ro

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17. SEM evaluation of dental cement surface morphology and microbial adhesion - a comparative study

George Andrei Petrescu, Cornelia Ioana Ilie, Adrian Ionut Nicoara, Roxana Trusca, Vladimir Lucian Ene, Ionela Andreea Neacsu, Anamaria Bechir

This study aimed to compare the surface morphology and antimicrobial/antibiofilm behavior of three semi-permanent cements used in implantology: FOZ (zinc oxide-based), DT (resin-based), and CIS (glass ionomer), after aging in air and artificial saliva, and after exposure to clinically relevant oral microbial strains. Surface morphology and elemental composition were analyzed by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), and antimicrobial and antibiofilm activity was quantified by determining the number of colony-forming units (CFU/mL) for Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), and fungi (Candida albicans, C. parapsilosis). FOZ exhibited a very rough surface rich in zinc, associated with the most pronounced reduction in microbial adhesion; CIS showed a relatively compact ionomer matrix with barium-rich domains and good antibiofilm activity, particularly against P. aeruginosa, while DT exhibited a predominantly organic, smooth surface with isolated inorganic aggregates and a more pronounced inhibition profile against E. coli. The results indicate that the microstructure and surface chemical composition of the cements directly influence the pattern of microbial colonization and antibiofilm efficacy, providing a rationale for selecting the cementing material based on microbiological risk and specific clinical conditions.

Corresponding author: Vladimir Lucian Ene, Associate Professor, PhD, Eng; e-mail: vladimir.ene@upb.ro

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18. Differential histopathological features and comorbidity profiles in chronic rhinosinusitis phenotypes

Alex Iulian Milea, Astrid Francu, Andreea Elena Milea, Carmen Aurelia Mogoanta, Caius Codrut Sarafoleanu

Background and Objectives: The aim of this study was to analyze histopathological (HP) changes, blood eosinophil levels, and comorbidities associated with Type 2 inflammation in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP), in order to determine the prevalence of inflammatory endotypes among chronic rhinosinusitis (CRS) patients in Romania. Patients, Materials and Methods: This retrospective, observational, nonrandomized study has been conducted between January 2021-December 2022 enrolling 186 consecutive patients with CRSwNP (Group A, n=119 patients) and CRSsNP (Group B, n=67 patients), for whom endoscopic sinus surgery (ESS) have been performed. Results: Among the CRSwNP group, 27 (23%) patients had asthma, and 22 (18.48%) patients had associated nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity, in comparison with CRSsNP group, where we found two (3.03%) patients who had associated asthma and one (1.51%) patient who had associated NSAIDs hypersensitivity. Among the CRSsNP (Group B) patients, 18 (27%) had peripheral blood hypereosinophilia, while eosinophilic infiltration was identified in the HP analysis of biopsy samples from 18 (27%) individuals in this group. Among the cohort of patients diagnosed with CRSwNP, 56 (47%) had blood hypereosinophilia, while eosinophils were detected in the HP analysis of biopsy samples from 73 (61%) individuals. Conclusions: This research reinforces the critical role of endotyping in CRS, moving beyond simple phenotypic classification. By identifying specific biological mechanisms, clinicians can better predict disease behavior and treatment response.

Corresponding author: Carmen Aurelia Mogoanta, Associate Professor, MD, PhD; e-mail: carmen_mogo@yahoo.com; Andreea Elena Milea, MD, PhD Student; e-mail: andreeaelena.bejenariu@yahoo.com

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19. Eduard Pernkopf s Atlas: morphological innovation and ethical legacy in the history of anatomical illustration

Immacolata Belviso, Ferdinando Paternostro, Domenico Ribatti

Eduard Pernkopf (1888-1955), a prominent representative of the Viennese Anatomical School, produced one of the most detailed and visually refined anatomical atlases in the history of medicine: Topographische Anatomie des Menschen. Despite its exceptional scientific and artistic value, the Atlas remains deeply controversial because of its association with National Socialist ideology and the probable use of bodies of executed prisoners during its production. This study provides a historical, morphological, and ethical analysis of Pernkopf s life, scientific work, and enduring influence on anatomical education. Special attention is devoted to the morphological and methodological innovations of Pernkopf s topographical dissection technique, including his systematic layer-by-layer anatomical stratification and the unprecedented three-dimensional realism of his anatomical illustrations. Through analysis of the historiographical and bioethical literature, the study examines the epistemological significance of Pernkopf s anatomical method, the historical context of Nazi-era anatomical science, and the ongoing debate regarding the Atlas s contemporary use. Pernkopf s Atlas emerges as both a landmark in morphological representation and a lasting ethical warning for the anatomical sciences. Its legacy underscores both the enduring methodological influence of Pernkopf s topographical anatomical approach and the necessity of integrating scientific excellence with ethical accountability in modern anatomical science.

Corresponding author: Ferdinando Paternostro, Associate Professor, MD, PhD; e-mail: ferdinando.paternostro@unifi.it

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