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1. Adjuvant effects of chemotherapeutics and Metformin on MFE-319 endometrial carcinoma cell line

Isil Aydemir, Elgin Turkoz Uluer, Oya Korkmaz, Mehmet Ibrahim Tuglu, Sevinc Inan

We aimed to investigate the cytotoxicity of Metformin, Cisplatin, and Paclitaxel on MFE-319 endometrial carcinoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and immunocytochemistry assays. Half maximal inhibitory concentration (IC50) doses of three drugs alone and in the dual combinations were applied to the cells. Immunocytochemical method was performed for the cell survival and for phosphatidylinositol 3-kinase (PI3K), phosphorylated extracellular regulated kinases (pErk)-1/2, Akt-1, phosphorylated Akt (pAkt)-1/2/3 cell growth markers and angiogenic vascular endothelial growth factor (VEGF). Immunoreactivities were evaluated using H-score and analyzed using the one-way analysis of variance (ANOVA) test for statistics. It was found that these drugs caused a decrease in the immunoreactivities of these markers. Particularly, dual combination of Paclitaxel and Cisplatin decreased the immunoreactivities of PI3K, pErk-1/2, Akt-1, and pAkt-1/2/3. Cisplatin and Paclitaxel were more effective than Metformin; on the other hand, Metformin has been shown to enhance the efficacy of these two drugs. In vitro or in vivo further studies are needed to investigate the efficacy of these three drugs via PI3K/Akt signal pathway.

Corresponding author: Isil Aydemir, Assistant Professor, MD, PhD; e-mail:

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2. Different patterns of p16(INK4a) immunohistochemical expression and their biological implications in laryngeal squamous cell carcinoma

Camelia-Sidonia Lazar, Alina Simona Sovrea, Carmen Georgiu, Doinita Crisan, Stefan-Claudiu Mirescu, Marcel Cosgarea

Introduction: p16(INK4a) immunohistochemistry (IHC) is widely used to facilitate the diagnosis of human papillomavirus (HPV)-associated neoplasia, when >=70% of cells show strong nuclear and cytoplasmic positivity. In this study, we aim to compare partial expression patterns that do not fulfill the above criteria and seek biological implications in laryngeal squamous cell carcinoma (LSCC). Materials and Methods: p16(INK4a) IHC staining was conducted on representative sections of archived tissue from 88 LSCCs. Immunoreactivity was described based on four parameters: intracellular localization of immunostaining, intensity of immunostaining, distribution pattern and percentage of positive cells. Results: Six patterns of p16(INK4a) immunoexpression were observed and defined as: strong diffuse (strong immunostaining, expression in cytoplasm and nucleus in >70% of tumor cells), weak diffuse (moderate or weak immunostaining, expression in cytoplasm in >70% of tumor cells), marginal (strong cytoplasmic immunostaining, limited to the periphery of tumor islets), strong scattered (strong immunostaining, expression in cytoplasm and nucleus in <50% of tumor cells), weak scattered (moderate or weak immunostaining, expression in cytoplasm in <50% of tumor cells), negative (no expression). The pN stage of the patients was associated with p16(INK4a) immunoexpression patterns, the marginal pattern was only found in the pN0-Nx stages, while the weak diffuse pattern was more frequently observed in pN2-N3 stages. Conclusions: Partial immunostaining with architecturally distinct p16(INK4a) immunoexpression patterns may prove significant in stratifying characteristic clinicopathological subgroups among LSCC. Our observations may support the hypothesis that p16(INK4a) has different roles in different subcellular locations, with tumorigenic molecular pathways unrelated to HPV infection.

Corresponding author: Alina Simona Sovrea, Associate Professor, MD, PhD; e-mail:

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3. Involvement of inflammatory cells in chronic rhinosinusitis with nasal polyps

Irina Enache, Elena Ionita, Florin Anghelina, Carmen Aurelia Mogoanta, Mircea Sorin Ciolofan, Alina Nicoleta Capitanescu, Alina Maria Vilcea, Alma Maria Florescu, Cristiana Eugenia Simionescu

Inflammation plays an important role in the pathogenesis of nasal polyps. Understanding the biomolecular action mechanisms of inflammatory elements can contribute to improving the prognosis of these lesions. The study analyzed the distribution and immunohistochemically quantified eosinophils [eosinophil major basic protein (BMK-13)], lymphocytes [cluster of differentiation (CD) 4, CD8, CD20] and plasmocytes (CD138) in both the epithelial and stromal compartment in relation to composite scores, which included specific histopathological parameters for 50 sinonasal polyps. Inflammatory elements predominated at stromal level, the high histological composite scores being frequently associated with increased expression of inflammatory elements. Also, the numerical distribution of inflammatory elements indicated positive linear relations within the groups BMK-13/CD8 and CD4/CD20/CD138, and a negative linear relation between the two groups. This aspect can support the existence of alternative or sequential pathogenic mechanisms involved in the pathogenesis of sinonasal polyps, and the results obtained can be used for a better stratification of patients in order to optimize the therapy.

Corresponding author: Carmen Aurelia Mogoanta, Lecturer, MD, PhD; e-mail:

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4. Current classification systems and standardized terminology in cytopathology

Tibor Mezei

The history of classification systems and the search for a unified nomenclature in cytopathology spans several decades and expresses the preoccupation of all those involved to make cytopathology a reliable diagnostic tool and a trusted screening method. Early classification schemes, applicable to exfoliative and aspiration cytology, attempted to set some basic standards for how non-gynecological cytopathology findings should be reported. While useful in establishing some basic guidelines, these were not specific to the various fields of non-gynecologic cytopathology, often burdened with specific problems. Cytopathology has evolved tremendously in the last couple of decades, undoubtedly boosted by the emergence of various classification schemes that, more than ever, are based on evidence gathered by professionals across the globe. The benefit of classification systems and standardized nomenclature in cytopathology is to provide useful, clear, and clinically relevant information for clinicians and ultimately to provide the best patient care. Standardized reporting systems make cytopathology reports more meaningful and robust. It now became standard that these include by default elements, such as adequacy criteria, diagnostic groups, risk of malignancy (ROM), and recommendations for patient management. In this brief review, we attempted to summarize how these classification schemes emerged and how they are reshaping the landscape of diagnostic cytopathology.

Corresponding author: Tibor Mezei, Lecturer, MD, PhD; e-mail:

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5. Comparative clinicopathological aspects of chronic tonsillitis and adenoiditis in children

Stefanita Bianca Vintilescu, Elena Ionita, Alex Emilian Stepan, Cristiana Eugenia Simionescu, Marius Matei, Mioara Desdemona Stepan, Cristina Adriana Becheanu, Elena Carmen Niculescu

Chronic palatal and nasopharyngeal inflammations are common lesions in pediatric pathology, with major effects on children s development. The study included 34 cases of chronic tonsillitis and adenoiditis for which we quantified immunohistochemically and analyzed the distribution of inflammatory elements in the follicular, extrafollicular and epithelial compartments, in relation to the composite histological scores and the clinico-epidemiological profile of the lesions. The cases were more frequent under the age of 10, in female patients, coming from urban areas, with the diagnosis of tonsillitis. B-lymphocytes have been associated with follicular areas in tonsillitis and epithelial areas in adenoiditis. In all compartments, T-lymphocytes were more frequently associated with tonsillitis and plasma cells associated with adenoiditis. Macrophages and dendritic cells had a relatively uniform distribution for the three compartments in all cases. The results obtained indicate different inflammatory phenotypes for chronic tonsillitis and adenoiditis, an aspect that may be useful for stratifying patients for optimal therapy.

Corresponding author: Mioara Desdemona Stepan, Lecturer, MD, PhD; e-mail:; Marius Matei, Teaching Assistant, MD, PhD; e-mail:

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6. The riddle of the right ventricle

Ana-Maria Balahura, Andrada Camelia Guta, Valentin Enache, Cristian Balahura, Alexandra Emma Weiss, Cristina Japie, Elisabeta Badila, Daniela Bartos

Right ventricular (RV) myxoma is a very rare finding. Its differential diagnosis includes cardiac thrombus, and its risk of life-threatening complications mandates early diagnosis followed by surgical resection. We report the case of a patient with an incidental RV mass and a difficult differential diagnosis. A 66-year-old woman, first assessed in neurosurgery due to a lumbar herniated disc, was referred to cardiology for examination before proceeding to surgery. She complained of dyspnea on exertion present for the last few months and reported no fainting or syncope. Clinical examination showed intermittent pulmonary systolic murmur. Transthoracic echocardiography revealed an oval-shaped sessile mobile mass (42/18 mm) attached to the anterior RV wall. Computed tomography confirmed the presence of a RV mass with lower attenuation than the myocardium and extension towards the pulmonary trunk, without other abdominal or pulmonary masses that would suggest a thrombus. Cardiac magnetic resonance imaging described an ovoid mass (47/16 mm) in the right ventricle, clinging to the apical trabeculae, swinging during the cardiac cycle, causing partial obstruction of the pulmonary valve during systole. The patient underwent surgical resection of the tumor. Macroscopic specimen showed a translucent polypoid mass with hemorrhagic areas. Microscopy confirmed the diagnosis of RV myxoma. The case illustrates the difficulty of establishing the correct etiological diagnosis of a cardiac mass, especially when located in the right ventricle. Multimodality imaging remains the cornerstone of noninvasive tissue characterization of cardiac masses, still requiring histopathological confirmation, particularly in the setting of conflicting imaging results.

Corresponding author: Elisabeta Badila, Associate Professor, MD, PhD; e-mails:,

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7. The role of mediating factors involved in angiogenesis during implantation

Lidia Boldeanu, Anda Lorena Dijmarescu, Mirela Radu, Cristian Adrian Silosi, Mircea Vasile Popescu-Driga, Ioan Sabin Poenariu, Isabela Silosi, Mihail Virgil Boldeanu, Marius Bogdan Novac, Liliana Victoria Novac

Angiogenesis is a critical component of normal implantation and placentation and underlines the importance of vascularization in early pregnancy. Differentiated expression of angiogenesis factors in different decision tissues during different stages of implantation, indicates their involvement in the regulation of vascular remodeling and angiogenesis. Disorders in vascular development may play a role in the pathogenesis of recurrent abortions. The success of implantation, placentation and subsequent pregnancy evolution requires coordination of vascular development and adaptations at both sides of the maternal-fetal interface. The human implantation process is a continuous process, which begins with the apposition and attachment of the blastocyst to the apical surface of the luminal endometrial epithelium and continues throughout the first trimester of pregnancy until the extravillous trophoblast invades and remodels maternal vascularization. Numerous regulatory molecules play functional roles in many processes, including preparation of the endometrial stroma (decidualization), epithelium for implantation, control of trophoblastic adhesion and invasion. These regulatory molecules include cytokines, chemokines, and proteases, many of which are expressed by different cell types, having slightly different functions as the implant progresses.

Corresponding author: Mihail Virgil Boldeanu, Lecturer, MD, PhD; e-mails:,; Marius Bogdan Novac, Lecturer, MD, PhD; e-mail:

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8. The immunophenotype of epithelial to mesenchymal transition inducing transcription factors in salivary gland adenoid cystic carcinomas

Iulia Cristiana Belulescu, Claudiu Margaritescu, Cristiana Iulia Dumitrescu, Maria Cristina Munteanu, Luminita Daguci, Otilia Clara Margaritescu, Marius Matei

Adenoid cystic carcinoma (ACC) is the second most common malignant salivary glands neoplasms with a controversial biological behavior. Even though these tumors grow slowly, they have increased potential for recurrence and distant metastasis. In order to elucidate this behavior, our study aimed to investigate the immunoexpression in such tumors of the most important transcriptional factors [Twist, Snail, Slug, and zinc finger E-box binding homeobox 1 (ZEB1)] involved in the epithelial-mesenchymal transition process. The highest level of expression was recorded for Twist, present in all the investigated cases, followed by the Slug and Snail, while no tumor parenchyma reactivity was noticed for the ZEB1 factor. There were tumor reactivity differences regarding topography, histopathological variant, and nerve and lymph node invasion status. Thus, tumors developed from the intraoral minor salivary glands, with solid pattern, perineural invasion, locally aggressive and with lymph node metastasis were the most reactive. Therefore, these transcription factors could be useful as prognostic biomarkers and efficient therapeutic targets in such salivary malignancies.

Corresponding author: Claudiu Margaritescu, Professor, MD, PhD; e-mail:; Maria Cristina Munteanu, Lecturer, MD, PhD; e-mail:

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9. Osteopontin and osteoprotegerin in atherosclerotic plaque - are they significant markers of plaque vulnerability?

Cristina Strobescu-Ciobanu, Simona Eliza Giusca, Irina-Draga Caruntu, Cornelia Amalinei, Andreea Rusu, Elena Cojocaru, Radu Florin Popa, Cristian Dumitru Lupascu

Atherosclerosis (ATS) is still considered as a major, global health problem. For a deeper understanding of its pathogenesis, in the last years the research was translated from tissue visible events to molecular mechanisms. Osteopontin (OPN) and osteoprotegerin (OPG) are two molecules that have been associated with the initiation and progression of ATS lesions. The aim of our study was to assess the OPN and OPG expression in advanced stages of carotid ATS, to analyze the correlation between these markers and the ultrasonographic plaque properties, pointing out the identification of possible patterns that can predict plaque vulnerability and risks of restenosis. The study group comprised 49 consecutive patients (38 males and 11 females) diagnosed with carotid stenotic lesions by using ultrasonography. The carotid endarterectomy specimens were standardly processed for histopathological and immunohistochemical exams. The OPN and OPG expression was semi-quantitatively assessed. Our results sustained the relationship between histological American Heart Association (AHA) type and ultrasonographic classification (echogenic versus echolucent) (p<0.001). The semi-quantitative analysis showed that in most cases (31 plaques) OPG and OPN had opposite expressions, whereas in the remaining cases (18 plaques) the expression was similar. There were no correlations between low versus high expression of intra-plaque OPN and OPG (p=0.335). We found significant correlation for OPN and plaque echogenicity (p=0.011), but not for OPG (p=0.079). OPN expression (low versus high) was correlated with plaque type (stable versus unstable) (p=0.036), plaque ulceration (p=0.009) and inflammation (p<0.001). OPG expression (low versus high) did not reveal statistically significant differences with plaque type (stable versus unstable) and vulnerability plaque parameters, respectively. OPG and OPN co-exist in carotid atherosclerotic plaque demonstrating a modulatory role in inflammatory and calcification processes. OPG is strongly expressed in stable, calcified plaques, while OPN is poorly expressed in calcified plaques and in plaques without hemorrhage, ulceration, inflammation, or necrosis. Starting from the molecular mechanisms, further studies of biomarkers are important to identify new therapeutic resources meant to prevent and treat vascular calcification.

Corresponding author: Radu Florin Popa, Associate Professor, MD, PhD; e-mail:

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10. A fetus with an immature umbilical cord teratoma associated with exomphalos: case report and review of the literature

Andre Miguel Travessa, Susana Santo, Rita Luis, Maria Carvalho Afonso, Rui Carvalho, Emilia Vitorino, Ana Berta Sousa

Objective: To describe the antenatal and pathological features of an immature umbilical cord teratoma associated with exomphalos, and to review the literature on this subject. Case presentation: An abdominal wall defect, suspected to be an exomphalos, was identified during routine ultrasound examination performed at 13 weeks of gestation. The pregnancy was terminated. Fetopathological examination revealed an immature umbilical cord teratoma associated with exomphalos. Chromosomal microarray analysis was normal. Conclusions: Umbilical cord teratomas, albeit very rare, should be emphasized as a possible differential diagnosis when abdominal wall defects are detected. Since cord teratomas may lead to adverse fetal or neonatal outcomes, close follow-up of the fetus is recommended.

Corresponding author: Andre Miguel Travessa, MD; e-mail:

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11. Letter to the Editor: Boron enhances the antiviral activity of the curcumin against SARS-CoV-2

Ion Romulus Scorei, Andrei Bita, George Dan Mogosanu


Corresponding author: Ion Romulus Scorei, Professor, Biochem, PhD; e-mail:

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