ROMANIAN JOURNAL of MORPHOLOGY and EMBRYOLOGY
Vol. 60 No. 3, July-September 2019
1. Ovarian hydatid cyst - systematic review of clinicopathological and immunohistochemical characteristics of an unusual entity
Ludmila Lozneanu, Raluca Anca Balan, Simona Eliza Giusca, Irina-Draga Caruntu, Cornelia Amalinei, Adriana Grigoras
Primary ovarian hydatid disease (HD) is a rare entity, produced by the larval stage of Echinococcus granulosus. HD commonly involves liver, lung, abdomen cavity, spleen and is unusually identified in pelvic organs. Based on our knowledge, the paper reviews 27 literature reports of ovarian HD, diagnosed during the last 20 years, providing a valuable database. Patients ages ranged between 12-76 years, the gross appearance was that of 40-330 mm diameter hydatid cysts (HCs), 66.66% of them being primary. According to these reports, ovarian HD has non-specific clinical manifestations, such as abdominal or pelvic pain, nausea, dysmenorrhea or amenorrhea. The diagnosis may be achieved by abdominal ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI), serological exams, such as eosinophilia (in 10-30% of patients) or indirect hemagglutination and immunoglobulin (IgG) antibodies detection. Ovarian HC microscopic pattern is characterized by three layers: pericyst or adventitia (host origin), germinal layer (endocyst), and laminated membrane (ectocyst). The immunoreaction triggered by parasites is initially rich in macrophages and neutrophils, followed by eosinophils and lymphocytes, with numerous cluster of differentiation 8 (CD8)-positive T-cells in active lesions and progressive forms. Concomitant ovarian diseases are relatively rare, being represented by borderline tumors (n=2 cases), mucinous cystadenoma (n=1 case), hemorrhagic cyst (n=1 case), and serous adenocarcinoma (n=1 case). In conclusion, the ovarian location of HD should be considered in any differential diagnosis of a cystic lesion, while it does not exclude synchronous ovarian tumors. These cases reinforce the necessity of better measures of prophylaxis and screening of HD in endemic areas.
Corresponding author: Cornelia Amalinei, Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Ovarian hydatid cyst - systematic review of clinicopathological and immunohistochemical characteristics of an unusual entity PDF
2. Update in pediatric primary brain tumors - from histology to genetically defined tumors
Elena Cojocaru, Doina Mihaila, Maria-Magdalena Leon-Constantin, Roxana Gabriela Cobzaru, Carmen Valerica Ripa, Mioara Florentina Trandafirescu, Laura Mihaela Trandafir
In childhood and in adolescence, primary tumors of the central nervous system (CNS) are the second most common malignancy after leukemia. The most common entities are gliomas, craniopharyngiomas and embryonal tumors, including primitive neuroectodermal tumors of the CNS, such as medulloblastoma. Proper management of malignancies requires a histological diagnosis, especially in childhood, since diagnostic errors have a significant negative influence on the treatment and subsequently on the patient s care. Experimental research conducted in the last years regarding the genomic and epigenetic landscape of pediatric brain tumors has provided considerable help in understanding their pathogenesis. New mutations and new signaling pathways have been associated with pediatric neoplasia, according to recent studies. Current therapeutic protocols recommend triple therapy, consisting in the surgical resection of the tumor, radiotherapy and chemotherapy. However, the success of the therapy depends on the precociousness of establishing the diagnosis and initiating the treatment, age of the child, type of surgery (total/partial), result of the histological examination, chemotherapy protocols and type of radiotherapy. Although immunotherapy and gene therapy continue to be a challenge, extensive studies are needed in order to confirm their promising role in the management of pediatric brain tumors.
Corresponding author: Maria Magdalena Leon-Constantin, Lecturer, MD, PhD; e-mail: firstname.lastname@example.org; Mioara Florentina Trandafirescu, Lecturer, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Update in pediatric primary brain tumors - from histology to genetically defined tumors PDF
3. The role of HPV infection in oropharyngeal cancer
Vlad Andrei Budu, Tatiana Decuseara, Nicolae Constantin Balica, Carmen Aurelia Mogoanta, Luminita Mihaela Radulescu, Magdalena Chirila, Alma Aurelia Maniu, Diana Maria Mistra, Gabriela Cornelia Musat, Ioana Cristina Opriscan, Madalina Gabriela Georgescu
Background: Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has been recognized as a distinct disease entity associated with oral HPV infection with high-risk serotypes, mainly among white man at younger age. Lifetime number of oral sex partners of HPV-positive OPSCC patients is the strongest risk factor associated. HPV type 16 is now established as oncogenic and it is the main cause (over the 80%) of this type of OPSCC, followed by HPV 18 (3%). Nowadays, it is reported a dramatic rising of HPV-positive OPSCC, mainly in developed countries, including Australia, Canada, Denmark, Netherlands, Norway, Sweden, Poland, Slovakia, Switzerland, Estonia, France, Japan, United States (US) and United Kingdom. At present, the yearly number of new incidence OPSCC cases given to HPV worldwide has been estimated of 29 000 by the International Agency for Research on Cancer (IARC). If incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to overcome the annual number of cervical cancers by the year 2020, in the US. Aim: The aim of this paper is to review the recent data about several topics including risk factors of HPV-positive OPSCCs, guidelines in diagnostic evaluation, treatment, prognosis and prevention strategies, through prophylactic HPV vaccine on both sexes. Nowadays, HPV detection is a clinical standard of care for oropharyngeal malignancy by reporting tumors as HPV positive or p16 positive.
Corresponding author: Carmen Aurelia Mogoanta, Senior Lecturer, MD, PhD; e-mail: firstname.lastname@example.org; Gabriela Cornelia Musat, Senior Lecturer, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF The role of HPV infection in oropharyngeal cancer PDF
4. The extremely rare concha of Zuckerkandl reviewed and reported
Mugurel Constantin Rusu, Mihai Sandulescu, Carmen Aurelia Mogoanta, Adelina Maria Jianu
Background: Usual descriptions indicate three or maximum four nasal turbinates (conchae) attached to the lateral nasal wall. The middle, superior and, occasionally, supreme ones belong to the ethmoid bone. Few authors include in descriptions the concha that Zuckerkandl described as the fourth or supreme ethmoidal turbinate. Despite some inconsistencies in Zuckerkandl s description, the concha bearing his name lies above Santorini s supreme concha, which, in turn, is above Morgagni s superior concha. Few other authors preferred to name Santorini s concha as the first supreme one and Zuckerkandl s concha as the second supreme one. Methods: We retrospectively documented, with various purposes, the archived cone-beam computed tomography files of 350 patients. Results: We found in just one case a unilateral sequence of five nasal turbinates. On the opposite side, only four turbinates were detected. Three-dimensional renderizations confirmed that when two supreme turbinates are found, they are joined in a common posterior tail, which, in turn, joins the tail of the superior turbinate. Conclusions: Co-existence of two supreme conchae could either indicate their origin from different ethmoturbinals, or from the split of a commonly unique supreme one. Zuckerkandl s concha deserves therefore to be considered when anatomical descriptions, or studies, are delivered.
Corresponding author: Mugurel Constantin Rusu, Professor, MD, PhD, Dr. Hab.; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF The extremely rare concha of Zuckerkandl reviewed and reported PDF
5. Neuroinflammation in systemic lupus erythematosus - a review
Andreea Lili Barbulescu, Raluca Elena Sandu, Ananu Florentin Vreju, Paulina Lucia Ciurea, Cristina Criveanu, Sineta Cristina Firulescu, Andreea Beatrice Chisalau, Cristina Dorina Parvanescu, Dana Alexandra Ciobanu, Mirela Radu, Vlad Padureanu, Mihail Virgil Boldeanu, Valeria-Carmen Albu
Neuroinflammation is a complex process that contributes to the pathogenesis of both immune mediated and neurodegenerative pathologies. Systemic lupus erythematosus (SLE) is the prototype of connective tissue diseases that can present the complete spectrum of neurological and psychiatric dysfunctions. The precise etiological diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is rather difficult to be established and it is still controversial the exact timing of neuropsychiatric (NPS) events: either central nervous system (CNS) is the initial target of autoimmune abnormalities, either NPS symptoms are a part of multisystem involvement. Ischemic and inflammatory mechanisms have an important input on NPSLE pathogenesis. Neuroinflammation, consequent to blood-brain barrier (BBB) damage, local and systemic production of autoantibodies, determine neuronal injury and apoptosis, further responsible for diffuse cerebral events, mostly cognitive dysfunction and psychotic disorder. Moreover, SLE complications or therapy complications can interfere and contribute to complex clinical manifestations that can be present in SLE patients. Understanding the role of each pathogenic way can provide not only an early diagnosis, but a more accurate therapeutic approach of these patients.
Corresponding author: Mihail Virgil Boldeanu, Lecturer, MD, PhD; e-mail: email@example.com; Ananu Florentin Vreju, Associate Professor, MD, PhD, MSc; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Neuroinflammation in systemic lupus erythematosus - a review PDF
6. Toxicity and health impact of nanoparticles. Basic biology and clinical perspective
Denissa-Greta Olaru, Andrei Olaru, Ghzayel Hussein Kassem, Mircea Vasile Popescu-Driga, Leonard Radu Pinosanu, Dinu Iuliu Dumitrascu, Elena Leocadia Popescu, Dirk Matthias Hermann, Aurel Popa-Wagner
Stroke has limited restorative treatment options. In search of new therapeutic strategies for the ischemic brain, cell-based therapies offered new hope, which has been, in the meanwhile, converted into a more realistic approach recognizing difficulties related to unfavorable environments causing low survival rates of transplanted neuronal precursors. Stem cell therapies are based on the transplantation of neuronal precursor cells (NPCs), adult stem cells propagated in cell culture or inducible pluripotent cells (iPSCs) obtained from patients and trans-differentiated into neural cells. Of these, autologous iPSCs have the advantage to be used in stroke patients because they do not raise ethical concerns and the risk of graft rejection is low. However, the use of stem cells for stroke therapy in humans has to take into account many factors including, dosage, route of administration, toxicity and side effects. For example, nanoparticles (NPs) may increase the efficacy of drugs and therapeutic cells delivery to the diseased brain. Medication dosages are generally determined by clinical trials done in relatively young, healthy people. However, in vivo and clinical data evaluating the toxic effects of NPs on neural cells are still scarce especially in the aged brain, which has a decreased homeostatic capacity and a reduced ability to cope with internal and environmental stress, as compared to the young brain. Previous studies in rodents indicate that aging along with neurodegenerative diseases may promote a proinflammatory state and leads to the development of gliosis in the aged brains. On the other hand, the nonspecific interaction between the shell of NPs and brain proteins leads to the adsorption of opsonins on their surface, forming the so-called corona, thereby becoming ideal candidates to attract phagocytic microglia resulting in NPs engulfment and thus exacerbating neuronal death. Therefore, when designing NPs for clinical use, it should be considered that their systemic administration is associated with potential risks, especially in the aged subjects. Recently, NPs have been shown in recent years to play a crucial role in cell signaling processes involved in stroke recovery. Extracellular vesicles (EVs) are secreted by virtually all type of cells in the body and have been shown to reflect the physiological and metabolic status of the host cells. Thus, understanding the disease-specific contents of EVs would enable the discovery of novel predictive biomarkers.
Corresponding author: Aurel Popa-Wagner, Professor, PhD; e-mail: email@example.com; Dinu Iuliu Dumitrascu, Lecturer, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Toxicity and health impact of nanoparticles. Basic biology and clinical perspective PDF
7. Heterogeneity of human fibroblasts isolated from hypertrophic scar
Raluca Tutuianu, Ana Maria Rosca, Gabriela Florea, Vasile Pruna, Daniela Madalina Iacomi, Luminita Andreea Radulescu, Tiberiu Paul Neagu, Ioan Lascar, Irina Domnica Titorencu
Pathological wound healing states, such as hypertrophic scarring and keloids, represent a huge clinical and financial burden on healthcare system. The complex biological mechanisms occurring in hypertrophic scarring are still barely understood. To date, there is no satisfactory description of hypertrophic fibroblasts. Therefore, in the present study we focused on the comparatively characterization of the fibroblasts residing in different regions of hypertrophic scars. To achieve this aim, fibroblasts were isolated from normal skin samples (n=4) and hypertrophic scars (n=4). These cell populations were further were used for the evaluation of proliferation and migration capacity, for the gene and protein expression of extracellular matrix protein type I collagen and fibronectin and for the presence of myofibroblasts. Our results demonstrated that perilesional and intralesional fibroblasts isolated from hypertrophic scars could be considered as distinct populations, having different properties. Thus, the intralesional fibroblasts had an increased proliferation capacity and increased gene and protein expression of collagen I and fibronectin. However, the perilesional fibroblasts had augmented mobility as revealed by in vitro scratch test and contained a higher percentage of myofibroblasts [alpha-smooth muscle actin (alpha-SMA)high cells], in comparison to the intralesional population. In conclusion, our data could provide an explanation regarding the inconsistent efficacy of topic therapies for hypertrophic scars.
Corresponding author: Irina Domnica Titorencu, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Heterogeneity of human fibroblasts isolated from hypertrophic scar PDF
8. SMAD4 and TGFbetaR2 expression in pancreatic ductal carcinoma
Ion Alexandru Vaduva, Claudiu Margaritescu, Claudia-Valentina Georgescu, Andreea-Oana Enache, Rodica Padureanu, Adrian Saftoiu, Daniel Pirici
Pancreatic ductal carcinoma is the most common type of pancreatic cancer, and currently represents the fourth cause of death by cancer, worldwide. Among classical pancreatic markers that ascertain the histopathology, new emerging targets have been proposed for both diagnostic and prognostic purposes. In the present study, utilizing a group of 28 confirmed resected pancreatic ductal carcinomas, we have assessed the immunoexpression and correlation ratios of mothers against decapentaplegic homolog 4 (Drosophila) (SMAD4)/transforming growth factor beta receptor 2 (TGFbetaR2), and vimentin/cluster of differentiation 105 (CD105). SMAD4 showed an overall increase in tumors versus pancreatic control tissue, but a decrease from G1 towards poorly differentiated tumors, while TGFbetaR2, vimentin and CD105 showed higher expression values in the tumor areas. Vimentin-CD105 colocalization degree decreased in tumor tissues compared to controls, illustrating a desynchronization of these two markers, both of them being negative in the tumor epithelia. Altogether, it is highly plausible that all these key players revolve around the epithelial-to-mesenchymal transition phenomenon, and this itself modulates the clinical outcome of the patient.
Corresponding author: Adrian Saftoiu, Professor, MD, PhD; e-mail: firstname.lastname@example.org; Daniel Pirici, Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF SMAD4 and TGFbetaR2 expression in pancreatic ductal carcinoma PDF
9. Clinical, imaging and histopathological correlations of gingival overgrowth: a retrospective analysis in northeastern Romanian population
Alexandru Nemtoi, Mihaela Monica Scutariu, Ana Nemtoi, Lucian Eva, Gabriela Florenta Dumitrescu, Petru Plamadeala, Dan Ferariu, Danisia Haba, Claudia Florida Costea
Background: Gingival overgrowth refers to an increase in the size of the gingival tissue. The etiology varies, and is often a multi-factor issue; what may contribute to gingival enlargement are aspects, such as disease, local and systemic conditions and idiopathic factors. The aim of the present study is to analyze and to correlate the clinical, epidemiological, imaging and histopathological (HP) features of gingival overgrowth in northeastern Romanian population. Patients, Materials and Methods: We conducted a clinical, imaging, and pathological study on 98 patients with gingival overgrowth, who underwent a surgical intervention for a gingival biopsy in the Office of Oral and Maxillofacial Surgery, Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iasi, Romania, during a 14-month period (January 1, 2018 to February 28, 2019). All patients with localized gingival overgrowth had clinical and imaging investigations done and then were referred to an oral and maxillofacial facility. A surgeon performed the excision of the gingival overgrowth and then sent the surgical specimens to the Laboratory of Pathology for HP examination. Results: Local inflammation was found responsible for the gingival overgrowth in most of the cases, with the number of females outnumbering that of the males. A very good correlation was found between clinical and HP diagnosis when epithelial hyperplasia, peripheral giant cell granuloma and pyogenic granuloma were involved and a moderate one when fibrous hyperplasia was involved. Conclusions: These findings suggest that the occurrence of gingival overgrowth can have many causes, which highlights the importance of clinical pathology in assisting practitioners with making a better diagnosis.
Corresponding author: Monica Mihaela Scutariu, Associate Professor, DMD, PhD; e-mail: firstname.lastname@example.org; Ana Nemtoi, Assistant, DMD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Clinical, imaging and histopathological correlations of gingival overgrowth: a retrospective analysis in northeastern Romanian population PDF
10. Expression patterns of aquaporins 1 and 4 in stroke
Gabriela-Camelia Rosu, Ionica Pirici, Anca-Maria Istrate-Ofiteru, Larisa Iovan, Valerica Tudorica, Laurentiu Mogoanta, Ion Cristian Gilceava, Daniel Pirici
Ischemic stroke occurs through embolic or thrombotic obliteration of an artery from cerebral circulation and represents over 80% of all stroke cases. One of the fiercest complications after stroke is edema, which results from imbalanced water diffusion around the blood vessels walls. Water diffusion around blood vessel walls occurs physiologically mainly through two protein-formed pores, namely aquaporins (AQPs) 1 and 4. Here, we compare for the first time the expression patterns and colocalization degrees of the two AQPs in control brain tissue and in peri-ischemic regions, on tissue obtained from eight patients with confirmed ischemic pathology and from five control cases. Our analysis showed that AQP4 is more abundant that AQP1, especially in the cortex and in the organized scar areas. The colocalization of the two markers was high, both located on the astrocytes membranes, but the colocalization degree decreased in the scar peri-ischemic regions. Colocalization with basement membranes was also lower for AQP1 compared to AQP4, in all regions analyzed.
Corresponding author: Daniel Pirici, Professor, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Expression patterns of aquaporins 1 and 4 in stroke PDF
11. Pathological fractures of humerus in children. Therapeutic and pathological considerations
Maria Daniela Trailescu, Adrian Ionel Pavel, Mircea Alexandru Pop, Nicoleta Zurbau-Anghel, George Alin Stoica, Radu Florin Fruntelata, Cristina Elena Singer, Maria Stoica, Cristian Constantin
Introduction: A pathological fracture appears after a low-energy trauma or minor trauma on bones with a modified histological structure; sometimes, the patient reports shoulder pain antedating the fracture. The most common benign bone tumors that cause pathological fractures in children are simple bone cysts, aneurysmal bone cysts, non-ossifying fibromas and fibrous dysplasia. This type of bone tumors is usually asymptomatic until they reach a large size and cause a pathological fracture after minor trauma. The optimal treatment remains controversial. Our objective was to describe our modern treatment strategies of the large benign osseous tumors of the humerus complicated by pathological humerus fractures and histological aspects in these cases. Patients, Materials and Methods: The study was prospective and included patients who were diagnosed with pathological humeral fractures, which required surgically orthopedic treatment. We selected three cases of pathological fractures of humerus in children each with its particularities, treated in the Department of Pediatric Surgery and Orthopedics, Emergency County Hospital, Arad, Romania. Treatment included curettage of the cyst, sampling for histopathological (HP) examination, bone substitution and titanium elastic nails (TEN) osteosynthesis. Results: No complications and no recurrence were seen in the early postoperative period. Conclusions: Osteosynthesis with TEN and bone substitution is a viable option for treatment of pathological fracture of humerus, secondary to the osseous benign tumors, which required surgically treatment, despite the different HP aspects. By using a combined treatment in these cases, we eliminate the disadvantages of isolated use of the described techniques in the literature.
Corresponding author: Maria Stoica, Senior Lecturer, MD, PhD; e-mail: email@example.com; Cristina Elena Singer, Senior Lecturer, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Pathological fractures of humerus in children. Therapeutic and pathological considerations PDF
12. Immunohistochemical evaluation of tumor budding in colorectal cancer: an important parameter with prognostic value
Cristian Mesina, Catalin Liviu Stoean, Ruxandra Stoean, Adrian Victor Sandita, Theodor Viorel Dumitrescu, Stelian Stefanita Mogoanta, Daniel Alin Cristian, Mihaela-Iustina Mesina-Botoran, George Mitroi, Corina-Lavinia Gruia, Maria Camelia Foarfa, Mihai Mesina, Daniela Ciobanu
We analyzed 82 patients with colorectal cancer (CRC) [75 patients with mucinous adenocarcinoma (ADK) and seven patients with signet ring cell ADK] using multi-cytokeratin (CK) AE1/AE3 immunohistochemical assay. In order to determine the mucinous nature of some of the lymph node metastases of the mucinous colorectal ADKs studied, Periodic Acid Schiff-Alcian Blue (PAS-AB) histochemical staining was used. The counting results were systematized in the following ranges: 0 budding areas; between 1-4 budding areas; between 5-9 budding areas; and >=10 tumor budding (TB) areas. The statistical analysis was performed using the Student s t-test. More than half of the cases of mucinous ADK revealed an increased intensity of TB, whereas in the case of signet ring cell ADK, an average intensity of this phenomenon. Mucinous ADKs, which were pT3 staged, showed an increased intensity of TB, and those in pT2 stage demonstrated, in the vast majority of cases, the absence of TB. There was a predominance of TB intensity in the absence of vascular-lymphatic invasion. Our study shows the existence of a concordance between tumor progression, the histological type of CRC, vascular-lymphatic invasion and the phenomenon of TB.
Corresponding author: Mihaela-Iustina Mesina-Botoran, Lecturer, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Immunohistochemical evaluation of tumor budding in colorectal cancer: an important parameter with prognostic value PDF
13. Comparative oncological outcomes and survival following surgery for low rectal cancer - a single center experience
Calin Molnar, Cosmin Nicolescu, Bianca Liana Grigorescu, Marian Botoncea, Vlad-Olimpiu Butiurca, Marius Daniel Petrisor, Simona Gurzu
In patients with low rectal cancer, intersphincteric resection (ISR) technique is a better alternative of abdominoperineal resection (APR), but is recommended to be done in non-locally advanced stages (<=T2) only. The aim of this study was to evaluate the long-term oncological outcome and survival rate in patients with early and locally advanced stages that underwent ISR, as compared to APR. In order to assess the quality of life and prognosis of patients with low rectal cancer, the 5-year follow-up was done in 72 consecutive cases diagnosed in pT1-T4 stage that underwent ISR or APR. Histopathological and clinical parameters were compared between the two included groups. Although the quality of life was better in patients which underwent ISR, the 5-year overall survival rate was not found to be influenced by the used surgical technique (71% for ISR and 58% for APR) either by the histological grade of differentiation (p=0.62), independently from the T stage (p=0.61). Regardless of the type of surgery, the independent prognostic factors proved to be lymph node status (p=0.001), lymph node ratio (p=0.001), and clinical stage (p=0.0001). Lymph node status remains the most important prognostic factor of patients with low rectal cancer. Independently from the histological subtype and depth of tumor infiltration, good oncological results can be obtained when performing ISR in selected cases.
Corresponding author: Vlad-Olimpiu Butiurca, MD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Comparative oncological outcomes and survival following surgery for low rectal cancer - a single center experience PDF
14. Correlations between HPV, p53 and p16 in malignancies involving the retromolar trigone-oropharynx junction
Bogdan Mihail Cobzeanu, Eugenia Popescu, Mihai Danciu, Aurelian Sorin Pasca, Octavian Dragos Palade, Sonia Patricia Vonica, Luminita Mihaela Radulescu, Loredana Beatrice Ungureanu, Mihaela Moscalu, Maria Luiza Cobzeanu, Liliana Gheorghe Moisii, Mihail Dan Cobzeanu, Constantin Volovat, Victor Vlad Costan
The aim of this study is to enhance knowledge regarding the behavior of human papilloma virus (HPV)-associated malignancies between two territories - maxillofacial and otorhinolaryngology. The HPV status and genotype, p16 and p53 expression were performed in 50 patients with malignancies located at the junction between the oropharynx and retromolar trigone alone or oropharynx spread to the junction. These were correlated with the treatment response, prognosis and survival of this kind of tumor located in oral posterior region, marking the transition between two territories (maxillofacial and otorhinolaryngology) of the selected cases. Results showed better treatment outcome and improved prognosis in HPV-positive compared to HPV-negative patients, and a strong link between HPV presence and p16 expression. Multimodal treatment including surgery, radiotherapy and chemotherapy provided the best results, although surgery was only an option in a limited number of cases, due to the advanced stage at presentation and extension in the surrounding tissues, considering the complex anatomy of the area. In the context of the increasing incidence of HPV-positive head and neck cancer, HPV testing together with molecular profiling for p16 and p53 tumor markers could help diagnose malignancies in the initial stages, and also provide important clues towards a targeted, more efficient treatment.
Corresponding author: Mihail Dan Cobzeanu, Professor, MD, PhD; e-mail: email@example.com; Mihaela Moscalu, Associate Professor, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Correlations between HPV, p53 and p16 in malignancies involving the retromolar trigone-oropharynx junction PDF
15. The performance of hyperadherence markers in anterior placenta praevia overlying the Caesarean scar
Ciprian Laurentiu Patru, Marius Cristian Marinas, Stefania Tudorache, Razvan Grigoras Capitanescu, Ovidiu Costinel Sirbu, George Lucian Zorila, Nicolae Cernea, Anca-Maria Istrate-Ofiteru, Gabriela-Camelia Rosu, Larisa Iovan, Dominic Gabriel Iliescu
Objectives: To assess the ultrasound (US) impact in diagnosing placenta accreta (PA) in patients with anterior placenta praevia localization, overlying a Caesarean scar. Patients, Materials and Methods: This is a prospective study between January 2016 and December 2017 that included patients with Caesarean scar and placenta praevia in the third trimester of pregnancy. By means of two-dimensional (2D) grayscale and color Doppler, we investigated the presence of the following US markers for placental invasion: intraplacental lacunae, abnormal blood vessels at the myometrium-bladder interface, thinning of the hyperechogenic uterine serosa-bladder wall interface, loss of normal hypoechoic retroplacental myometrial space. Definitive diagnosis was made at delivery. The US findings were correlated with intraoperative and histopathological (HP) evaluations. Results: We found 46 cases with anterior placenta praevia overlying a Caesarean scar. Twelve patients presented US criteria for PA. The confirmation was obtained (by means of intraoperative and/or HP features) in 11 of them. The US evaluation with all markers yields a sensitivity of 100% for PA detection. Among the US markers, the association of abnormal blood vessels at the myometrium-bladder interface and the intraplacental lacunae had the highest statistical correlation in the antenatal diagnosis of PA. Conclusions: Our study suggests that the antenatal US is a useful tool in predicting PA in high-risk patients. Special attention should be given to the presence of intraplacental lacunae and abnormal myometrial vessels in cases where the placental insertion overlaps a uterine scar for best identification of PA high-risk cases.
Corresponding author: Marius Cristian Marinas, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF The performance of hyperadherence markers in anterior placenta praevia overlying the Caesarean scar PDF
16. The morphofunctional impact of topical Lidocaine formulation in inflammatory pain - experimental study
Maria-Magdalena Leon-Constantin, Teodora Alexa-Stratulat, Andrei Luca, Bogdan Ionel Tamba, Laura Mihaela Trandafir, Valeria Harabagiu, Elena Cojocaru
Background: Despite all the technological progresses and conventional medical treatments, pain therapy remains a challenge for both children and adult patients. Objective: The aim of the study was to identify new transdermal Lidocaine delivery systems that will ensure a controlled release, an improved availability and will finally enhance local pain control. Materials and Methods: The experimental animals were adult Wistar rats weighing between 180-200 g. At the beginning of the experiments, we induced an inflammatory pain by administering lambda-carrageenan, using a previously known model. Subsequently, the animals were subjected to a battery of nociception tests: algesimeter, cold plate and hot plate. Once the paw edema was obtained, the tested substance containing Lidocaine or eutectic mixture of local anesthetics (EMLA) cream was applied on the hind paw. Since we wanted to identify if our substance causes any local effect, the samples were collected from the paw, from the area where it was administered. Results: At algesimetric testing, it has been showed that the tested substance enters into its action slowly, up to 15 minutes after administration and reaches it maximum effect within 15-30 minutes, then the effect diminishes but does not disappear even at two hours. When compared to EMLA, the analgesic cream that exists in the markets, our substance has superior analgesic properties at 15 and respectively 30 minutes after administration. The effect of the tested substance is still present after two hours, lower than in the maximum range (15-30 minutes), but higher than EMLA s effect. The histopathological exam revealed an inflammatory reaction in all groups. Conclusions: The tested substance proved analgesic properties longer and higher than EMLA but did not influenced the inflammatory reaction.
Corresponding author: Laura Mihaela Trandafir, Lecturer, MD, PhD; e-mail: firstname.lastname@example.org; Andrei Luca, Assistant Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF The morphofunctional impact of topical Lidocaine formulation in inflammatory pain - experimental study PDF
17. A microscopic insight of the morphological changes induced by dental zirconia prosthetic structures
Horia Octavian Manolea, Ionela Madalina Matei, Cristiana Marga Luiza Nistor, Adela Cristina Lazar, Alex-Ioan Salan, Oana Gingu, Nicoleta Cioatera, Monica Mihaela Iacov-Craitoiu, Bogdan-Mihai Galbinasu
As zirconia is today probably the dental material with the largest increase in the frequency of use in dental prosthetics, the reason for this study was based on a series of clinical observations made following its use in clinical prosthetics. Thus, we were interested in two aspects: the histological evaluation of the response of the oral soft tissues to the presence of the prosthetic structures in zirconia, and the microscopic evaluation of the abrasion lesions that appeared in the hard dental tissues of the zirconia prostheses antagonists. For the first part, samples from three zirconia-based dental prosthetics commercial products were implanted submucosal in the oral cavity of male Wistar rats. After six weeks, the oral soft tissue reaction was clinically and then histologically investigated. For the second part, we made two study groups to investigate the influence of the zirconia-glazed surface vs. polished surface to the wear pattern of the antagonist enamel, using a tribological equipment and a dedicated software. Our study showed a good clinical response of the oral soft tissues surrounding the inserted zirconia samples, with subclinical, only histological revealed, signs of inflammation, of a foreign body reaction, while polished zirconia samples determined abrasion surfaces, with a different pattern and significantly smaller dimensions, compared to zirconia glazed samples, at the level of the hard dental tissues of the antagonist teeth. Despite the generally good response of the biological structures to the presence of zirconia prosthetic structures in the oral environment, more scientifically proved information is needed to obtain the desired biological responses in all clinical situations.
Corresponding author: Ionela Madalina Matei, DMD, PhD Student; e-mail: firstname.lastname@example.org; Cristiana Marga Luiza Nistor, DMD, PhD Student; e-mail: email@example.comAbstract Open Paper Download PDF A microscopic insight of the morphological changes induced by dental zirconia prosthetic structures PDF
18. Clinico-imaging and morphological aspects of the benign serous ovarian epithelial tumors in children and adolescents
Mioara Desdemona Stepan, Cristina Adriana Becheanu, Alex Emilian Stepan, Cristiana Eugenia Simionescu, Mircea Ovidiu Ciobanu, Stefanita Bianca Vintilescu, George Alin Stoica, Elena Carmen Niculescu
Benign serous ovarian epithelial tumors represent a major area of interest in pediatric pathology through the incidence and the hormonal and reproductive implications that they induce. In this study, we analyzed 24 tumors diagnosed and surgically operated in children and adolescents, in relation to clinical, histological and immunohistochemical parameters, which can provide information on the potential for growth of lesions. The average age of diagnosis was 13.2 years, the majority of tumors being present in patients over 10 years (75%), with accompanying symptoms (83.3%), unilateral (91.7%) and dimensions of maximum 10 cm (66.7%). The histopathological aspect indicated a cystic growth pattern, sometimes papillary, and in three cases, the presence of atypical focal areas of the tumor epithelium. The Ki67 proliferation index values were higher in the case of tumors larger than 10 cm, those with papillary pattern, and in those with atypical areas, while p53 reactions were present only in cases with atypical proliferation areas. The parameters investigated in this study are useful both for assessing the risk of tumor growth and progression, as well as for stratifying patients for active clinical surveillance.
Corresponding author: Alex Emilian Stepan, Associate Professor, MD, PhD; e-mail: firstname.lastname@example.org; George Alin Stoica, Lecturer, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Clinico-imaging and morphological aspects of the benign serous ovarian epithelial tumors in children and adolescents PDF
19. Histological and immunohistochemical aspects of the atrophic dental pulp modifications of abutment teeth
Anca Gabriela Gheorghe, Veronica Mercut, Sanda Mihaela Popescu, Mihaela-Cezarina Mehedinti, Mihaela Jana Tuculina, Daniel-Alin Olimid, Adela Cristina Lazar, Oana Andreea Diaconu, Alina Iren Moraru
Background: Reducing the thickness of hard dental tissues through the preparation of teeth for fixed prosthodontics represents an aggression for the dentin-pulp complex and may cause changes in dental pulp tissues, by means of acute or chronic inflammation, or by asymptomatic, atrophic modifications. Aim: The aim of the study was to histological and immunohistochemical evaluate samples of dental pulp selected from previously prepared teeth, which had been functioning as abutment teeth for some years. Patients, Materials and Methods: The starting point of the study was a statistical study conducted on a batch of 276 patients, of which 64 needed to change the fixed prosthetic restorations. Some of the existing abutment teeth were extracted, others presented previously performed root canal treatments and others required endodontic treatment. Results: Of the 21 samples taken, 12 showed atrophic pulp modifications, represented by low cellularity, collagen fibrosis, vascular congestion, and pulpal calcifications. Conclusions: Certain irreversible atrophic changes can be observed in abutment teeth s pulps, a fact that justifies the need of performing pre-prosthetic endodontic treatment.
Corresponding author: Veronica Mercut, Professor, DMD, PhD; e-mail: firstname.lastname@example.org; Mihaela-Cezarina Mehedinti, Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Histological and immunohistochemical aspects of the atrophic dental pulp modifications of abutment teeth PDF
20. Differential expression pattern of annexin A2 during nephrogenesis and kidney carcinoma
Roshni Sadashiv, Balappa Murgappa Bannur, Praveenkumar Shetty, Udupi Shastry Dinesh, Hephzibah Rani, Jamboor Vishwanatha, Subhash Krishnarao Deshpande, Anil Bargale, Sarathkumar, Komal Ruikar
The creation of a cancer cell could be due to reactivation of repressed gene in the process of normal embryonic development. The differences in embryonic origins and functions of various components of nephron may contribute to the diversity of morphological patterns, molecular and immunohistochemical phenotypes of common renal neoplasms. Renal cell carcinomas (RCCs) are the most common amongst the genitourinary cancers. Annexin A2 (AnxA2) is a multifunctional calcium-regulated phospholipids-binding protein found in a subset of renal neoplasms. Since the tumor cells usually recapitulate embryonic cells, we studied the ontogeny of AnxA2 in developing renal tissues and compared it with those of normal adult RCCs, to better understand their role in renal development and tumorigenesis. AnxA2 immunoexpression was evaluated by immunohistochemistry from various autopsied fetuses, mature kidney and renal cancer tissue specimens. The study showed moderate membranous AnxA2 immunoexpression in the ureteric buds and collecting tubules of fetal kidneys (in all gestational ages) and in the collecting ducts of adult normal renal tissues. It is not often expressed in the proximal convoluted tubules of normal adult kidney; however, younger fetal kidneys show moderate AnxA2 immunoexpression in the proximal convoluted tubules (thought to be the origin of RCC) and the reappearance of strong membranous AnxA2 immunoexpression in the clear cell carcinoma is suggesting a deregulation of the gene during tumorigenesis. The understanding of the AnxA2 molecular immunoexpression pattern during development, its specific function and deregulated immunoexpression in different renal carcinoma types indicates the decisive role of AnxA2 in the cancer progression.
Corresponding author: Praveenkumar Shetty, Professor, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Differential expression pattern of annexin A2 during nephrogenesis and kidney carcinoma PDF
21. Histopathological and perioperative factors influencing the length of hospital stay and patients outcome after radical cystectomy for urothelial carcinoma
Bogdan Calin Chibelean, Ioan Alin Nechifor-Boila, Andrada Loghin, Adela Corina Nechifor-Boila, George Mitroi, Angela Borda
Introduction: Length of hospital stay (LOS) is considered as a key factor in estimating outcomes after radical cystectomy (RC) in urothelial carcinoma (UC) patients. We aimed to assess whether clinical perioperative (age, gender, type of urinary diversion technique) and histopathological factors [UC variant, primary tumor, node, metastasis (pTNM) staging] could be a determining factor for LOS, as well as its influence on overall survival (OS) in a single institution, retrospective cohort study. Patients, Materials and Methods: We included a total of 69 UC patients that had RC performed in our Department during November 2011 and October 2018. Regular LOS was considered arbitrarily up to 12 days. All factors were analyzed in relation to LOS, using the chi-square and the Mann-Whitney tests. Impact of LOS on survival was assessed using the Kaplan-Meier and the Cox regression methods. Results: Age was associated to increased LOS (p=0.042), as well as the type of urinary diversion (p=0.003). Patients with complex diversion were found more frequently in the prolonged LOS group (ileal conduit p=0.006, Mainz pouch p=0.15, Camey neobladder p=0.517). Histopathologically, N stage had a significant association to LOS (p=0.044). Survival analysis showed decreased survival in the prolonged LOS group (p=0.653). Cox regression found no influence of LOS (p=0.653), advanced age (p=0.518) or type of urinary diversion on OS. Conclusions: Advanced age, the complexity of urinary diversion and lymph node involvement were found as associated factors for prolonged LOS in RC patients. The impact of LOS on survival is uncertain, requiring larger, in-depth studies.
Corresponding author: Ioan Alin Nechifor-Boila, Lecturer, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Histopathological and perioperative factors influencing the length of hospital stay and patients outcome after radical cystectomy for urothelial carcinoma PDF
22. Ovarian metastases reported after adjuvant laparoscopic oophorectomies in breast cancer
Daniel Alin Cristian, Florin Andrei Grama, Gabriel Becheanu, Ileana Popa, Ana Magdalena Bratu, Traean Burcos, Cristian Viorel Poalelungi, Valeriu Surlin
Introduction: Ovarian metastases (OM) of breast cancer (BC) can occur with different rates, ranging from 3-30%, being reported after prophylactic, therapeutic ovariectomies or discovered at necropsy. The aim of the study was to review the histopathological aspects of 59 laparoscopic oophorectomies performed in our Department as part of the oncological treatment of premenopausal women with BC. A number of eight (13.55%) patients were histologically confirmed with OM. The initial tumor, node, metastasis (TNM) stage of BC tumors was advanced with no pelvic symptoms or imaging abnormalities associated. Five (62.5%) patients had unilateral ovarian involvement and three (37.5%) bilateral, two of them being associated with primary bilateral BC. The immunohistochemical markers used to confirm the breast origin of metastasis were estrogen receptor (ER), progesterone receptor (PR), gross cystic disease fluid protein 15 (GCDFP15), Wilms tumor 1 (WT1), cancer antigen-125 (CA-125), cytokeratin 7 (CK7), cytokeratin 20 (CK20). One case showed positive cytoplasmic reaction for thyroid transcription factor-1 (TTF-1). GCDFP15 was positive in all OM and almost all (seven of eight) were noted as non-immunoreactive for WT1. Although six cases of metastatic BC were positive for CK7 and negative for CK20, only four of them retain the same immunoprofile of their primary tumor for the metastatic ovarian lesions. Only one case out of eight showed weak and focal positivity for CA-125. Three cases were positive for mucin 1 (MUC1) and epithelial membrane antigen (EMA). Conclusions: The differential diagnosis between OM and primary ovarian cancer can be challenging for the pathologist as well and immunostaining is of help. GCFDP15 is the most specific for breast carcinoma. In contrast with the recent papers published in the literature, we detected TTF-1 cytoplasmic expression in invasive breast carcinoma by SPT24 clone.
Corresponding author: Florin Andrei Grama, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Ovarian metastases reported after adjuvant laparoscopic oophorectomies in breast cancer PDF
23. Red grape juice protects the rat thyroid gland against hypercholesterolemic changes. Ultrastructural and biochemical evidences
Nasra Naeim Ayuob, Amany Ahmed El-Hawwary, Etedal Abbas Huwait, Wafaa Alaa-Eldin Mubarak, Maha Jameal Balgoon
Objectives: This study aimed to assess the impact of high cholesterol diet (HCD)-induced hypercholesterolemia on the rat thyroid gland and investigate the role of grape juice (GJ) in reducing such impact through biochemical and histopathological methods. Materials and Methods: Thirty male Wistar rats sorted into three groups (the control, HCD-fed group, and the HCD+GJ fed group for 13 weeks) were used in this study. Lipid profile, blood glucose and insulin, thyroid hormones, some oxidants/antioxidants parameters were assessed. After the end of the experiment, thyroid glands were dissected out and processed for histopathological assessment using the light and electron microscopy. Results: Based on the lipid profile, HCD induced hypercholesterolemia in rats after 13 weeks. This resulted in significant (p<0.001) increase of the levels of insulin, blood glucose, thyroid-stimulating hormone (TSH) (596.4+/-17 IU/mL), thyroxine (T4) (202.8+/-14.1 ng/mL) and malondialdehyde (MDA) (21.2+/-4.9 nmol/mg protein), while the levels of triiodothyronine (T3) (12.6+/-1.9 ng/mL) and total antioxidant capacity (TAOC) (21.2+/-4.9 U/mg protein) decreased in HCD-fed rats compared to that of the controls. Structurally, thyroid gland follicles of HCD-fed rats showed cytoplasmic vacuolation, stratification and increased thickness of some lining cells. Ultrastructurally, some of follicular and parafollicular cells showed heterochromatic nuclei, degenerated mitochondria, intracytoplasmic lipid droplets and deposition of collagen fibers between the follicles. GJ could improve the lipid and antioxidants profiles, reduced blood glucose level, thyroid hormones, and alleviated the HCD-induced structural changes in the thyroid. Conclusions: GJ administrated simultaneously with HCD ameliorated the negative impact of the function and structure of the thyroid.
Corresponding author: Nasra Naeim Ayoub, MD, PhD; e-mails: email@example.com, firstname.lastname@example.orgAbstract Open Paper Download PDF Red grape juice protects the rat thyroid gland against hypercholesterolemic changes. Ultrastructural and biochemical evidences PDF
24. Designing an on-line database for morphological studies of three-dimensional liver tumors
Costin Teodor Streba, Mircea-Sebastian Serbanescu, Sorin Popescu, Roxana Cruce, Dan Ionut Gheonea, Ioana Andreea Gheonea
Introduction: Primary liver and pancreatic malignancies still make up for an increasing number of deaths worldwide. Diagnostic procedures are constantly evolving, with variable availability depending on referral center. Integrating and transmitting relevant medical data is becoming more necessary, for both medical learning and patient management. Patients, Materials and Methods: We selected a sample cohort from our larger study involving patients with liver and pancreatic primary malignancies. All patients provided informed consent and procedures were performed in accordance with usual regulations. Clinical and laboratory data of the selected patients were used to populate a database that also contained multimedia files presenting an interactive three-dimensional (3D) model of liver or pancreatic tumors. Results: The on-line interface developed to access the database had two levels of access. The public webpage only allowed interaction with the reconstructed model. The secured module allowed viewing of medical data, interaction with the complete tumor model as well as the ability to download the anonymized digital file containing the tumor reconstruction. This allowed fast printing, with a standard 3D printer, of the complete model with different levels of stiffness, for complete interaction for both teaching purposes and pre-operatory planning. Conclusion: This is the first attempt to implement a full-scale on-line solution for 3D tumor representation and manipulation, corroborated with clinical and laboratory data. This technology may bring important additional information for pre-operatory evaluation, treatment planning or medical training.
Corresponding author: Mircea-Sebastian Serbanescu, Lecturer, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Designing an on-line database for morphological studies of three-dimensional liver tumors PDF
25. Study of antimicrobial effects of functionalized silver nanoparticles
Elena Leocadia Popescu, Maria Balasoiu, Oana Mariana Cristea, Alexandra Elena Stoica, Ovidiu Cristian Oprea, Bogdan Stefan Vasile, Alexandru Mihai Grumezescu, Gabriela Bancescu, Cristina Jana Busuioc, George Dan Mogosanu, Costin Teodor Streba, Laurentiu Mogoanta
In recent decades, the study of nanoparticles (NPs) has gained a great scientific interest, due to a wide range of potential applications, in different fields: electronic, optical and biomedical. Some of the most studied effects of NPs are antibacterial ones, because the large, sometimes unjustified and uncontrolled administration of antibiotics has led to the emergence of multidrug-resistant (MDR) bacterial strains. In our study, starting from silver nitrate (AgNO3), we made approximately 30 nm spherical AgNPs that were coated with a thin layer of ethylene glycol (EG) or EG and polyvinylpyrrolidone (PVP). The microbial culture study showed that AgNPs have antibacterial effects, depending on the dose of the NPs and the type of bacteria.
Corresponding author: Cristina Jana Busuioc, Associate Professor, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Study of antimicrobial effects of functionalized silver nanoparticles PDF
26. Unilateral supplemental maxillary lateral incisor: report of three rare cases and literature review
Oana Cella Andrei, Catalina Farcasiu, Ruxandra Margarit, Mirela Ileana Dinescu, Livia Alice Tanasescu, Luminita Daguci, Mihai Burlibasa, Constantin Daguci
Additional teeth to the normal dentition are called supernumerary teeth; they can be found in higher rates in permanent than in deciduous dentition, in both sexes, associated or not with other diseases or syndromes. The aim of this article is to report three rare cases of unilateral supplemental lateral incisors, in Romanian child and adult patients, and to evaluate the treatment options in each case, considering particularities such as age, physiognomy, associated issues and occlusion. The differential diagnosis between a supernumerary lateral incisor in formation and a rudimentary is sometimes difficult to make using only panoramic X-ray, so a cone-beam computed tomography analysis can be indicated. Usually, due to the pathological issues that they can cause, the supplemental maxillary lateral incisors are removed; although, in some cases, it may be necessary to remove the normal tooth, for example in cases of major crowding, in which the normal tooth is more displaced from the line of the arch than the supplemental one, or when there is a lack of periodontal support surrounding the normal tooth. This article highlights that even if, in younger patients, the majority of these teeth is extracted because later in life they can cause difficulties in orthodontic and prosthetic treatment, there are still rare cases which do not necessitate treatment, because they are asymptomatic, rather well aligned and go unnoticed. Also, the article includes a detailed literature review of reported cases of supplemental maxillary lateral incisor.
Corresponding author: Ruxandra Margarit, Assistant, MD, PhD; e-mail: email@example.com; Livia Alice Tanasescu, Assistant, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Unilateral supplemental maxillary lateral incisor: report of three rare cases and literature review PDF
27. Behcet s disease with rapidly progressive bilateral optic neuropathy and avascular femoral neck necrosis. Literature review and management update
Simona Banicioiu-Covei, Ananu Florentin Vreju, Paulina Lucia Ciurea, Anca Rosu
Behcet s disease is a multi-systemic vasculitis of small arteriolar and venular vessels, which shows a wide range of clinical manifestations, such as oral and genital aphthosis, erythema nodosum, panuveitis, complex gastrointestinal disorders, the early onset of neurological involvement being a negative prognostic factor in evolution. We present the case of a 36-year-old patient, who was admitted in the Clinic of Rheumatology for recurrent-neglected oral aphthosis, recurrent erythema nodosum, left hip pain, reduction of visual acuity of the right eye, weight loss, profuse sweating, marked fatigability. From the personal history was retained avascular necrosis of right femoral head, with arthroplasty at this level, human leukocyte antigen-B51 (HLA-B51) positive. Ophthalmological evaluation reveals severe bilateral optic neuropathy, with confirmation of neuro-Behcet s disease (NBD) diagnosis, in a Neuro-Ophthalmological Center, based on cerebral nuclear magnetic resonance and cerebrospinal fluid analysis. Associated corticosteroid therapy with Azathioprine was initiated, with no signs of activity and progression of the disease in evolution. The case provides a necessary upgrade of the therapeutic strategies specific to the NBD pattern, emphasizing the importance of the multidisciplinary approach of a patient with complex pathology.
Corresponding author: Simona Banicioiu-Covei, Assistant Professor, MD; e-mail: email@example.comAbstract Open Paper Download PDF Behcet s disease with rapidly progressive bilateral optic neuropathy and avascular femoral neck necrosis. Literature review and management update PDF
28. A rare case of a double high-risk gastrointestinal stromal tumor of jejunum with KIT-negative/PDGFRA-positive immunophenotype
Madalina Bosoteanu, Gabriela Izabela Baltatescu, Mariana Deacu, Mariana Aschie, Catalin Adrian Bosoteanu
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that represent the second most common type in the gastrointestinal system, but clinical outcomes vary due to complex molecular changes. The aim of our study is to highlight a unique case of a 5th decade male, presenting a double primary GIST of the jejunum, associated with a rare immunophenotype and with a high risk of malignancy. Ancillary studies were performed using several biomarkers [cluster of differentiation (CD) 117/c-kit, discovered on GIST1 (DOG1), desmin, S-100, vimentin, cytokeratin 7 (CK7), Ki67, actin, platelet-derived growth factor receptor alpha (PDGFRA) and CD34], in order to confirm the diagnosis and to evaluate prognostic and predictive factors. A KIT-negative/PDGFRA-positive immunophenotype was obtained in our case and it was associated with a poor prognosis. Its unfavorable clinical evolution was sustained by recurrence as malignant (GIST) with dedifferentiation and metastases developed in less than one year after the initial diagnosis. Clinico-morphological features of GISTs with an impact on survival must be identified and a tailored therapy should be applied for each case.
Corresponding author: Gabriela Izabela Baltatescu, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF A rare case of a double high-risk gastrointestinal stromal tumor of jejunum with KIT-negative/PDGFRA-positive immunophenotype PDF
29. Replaced right hepatic artery arising from inferior pancreaticoduodenal artery, in association with left multiple renal arteries: a case report using MDCT angiography
Adina-Nadia Costea, Nicoleta Iacob, Agneta Maria Pusztai, Horia Ples, Petru Matusz
The authors illustrate a case of a 61-year-old male who presented an extremely rare association of anatomical variations highlighted by multi-detector computed tomography (MDCT) angiography, with a replaced right hepatic artery (RRHA) arising from inferior pancreaticoduodenal artery (IPDA), in association with left multiple renal arteries (RAs). The celiac trunk (CT) arises from the abdominal aorta (AA), at the level of middle 1/3 of L1 vertebral body. The superior mesenteric artery (SMA) origin was located at the anterior aspect of AA, at 2.5 mm below the origin of CT, at the level of L1/L2 intervertebral discs. The SMA has at origin an endoluminal diameter of 11.3 mm. At 22.7 mm from its aortic origin, from the right aspect of the SMA trunk, arises IPDA. At 10.4 mm from its origin in IPDA, arises RRHA with a 78.5 mm artery length and the endoluminal diameter at origin of 2.9 mm. From the arising point, the RRHA is oriented ascending to the right, passing initially posterior to the hepatic portal vein and the head of the pancreas, then lateral to the head of the pancreas and posterior to the hepatic portal vein, after entering the hepatic parenchyma to bifurcate into the anterior and posterior branches. From left aspect of AA arise three RAs: one main, one additional (from AA), and an accessory renal (from left common iliac artery). Knowledge of this hepatic and renal anatomical variation is important for interventional radiologists, vascular experts, oncologists, vascular, hepatic and urologic surgeons.
Corresponding author: Agneta Maria Pusztai, Assistant Professor, MD, PhD; e-mails: email@example.com, firstname.lastname@example.orgAbstract Open Paper Download PDF Replaced right hepatic artery arising from inferior pancreaticoduodenal artery, in association with left multiple renal arteries: a case report using MDCT angiography PDF
30. A malignant phyllodes tumor with liposarcomatous differentiation case with 3-year follow-up
Codrut-Cosmin Nistor-Ciurba, Rares Buiga, Cristian Popita, Dan Tudor Eniu, Marius Emil Puscas, Florin Laurentiu Ignat
Phyllodes tumors (PTs) are a group of rarely breast tumors of fibro-epithelial origin, counting for about 1% of the breast malignancies divided, based on histological features, in benign, borderline and malignant neoplasms, arising most of them in women in their 40 s. Among this complex group of tumors, the liposarcomatous differentiation is an even more rare lesion, counting for about 0.3% of all primary sarcomas of the breast. This article presents a case of a 48-year-old woman with a breast malignant PT with liposarcomatous differentiation, diagnosed by guided core biopsy, treated by excision and subsequent simple mastectomy followed by radiotherapy, with a 3-year follow-up.
Corresponding author: Rares Buiga, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF A malignant phyllodes tumor with liposarcomatous differentiation case with 3-year follow-up PDF
31. A rare tumor in a rare location: giant cell tumor of the sacrum and ilium - case report and current perspectives
Alexandru Poll, Vanda Roxana Nimigean, Maria Justina Roxana Virlan, Valentin Daniel Sirbu, Mariana Costache, Roxana Victoria Ivascu, Mariana Cordun, Victor Nimigean
Giant cell tumor (GCT) is considered a locally aggressive, intermediate grade benign bone neoplasm. In rare cases, GCT undergoes malignant degeneration or may cause distant metastasis, mainly in the pulmonary area. Most bone GCTs are situated in the epiphysis or metaphysis of long bones, while GCTs of the pelvis are quite rare. There is no standard treatment protocol for the GCT of pelvic bones. This paper presents the therapeutic management of a rare case of a stage III GCT, situated on the iliac tuberosity, sacral wing and partially the left iliac wing. The chosen treatment consisted in intralesional curettage, high-speed burring, phenolization and hydrogen peroxide lavage. At the six-week follow-up, the patient reported minimal disability. No complications and no local infections were revealed. Healing was confirmed by the two-year postoperative follow-up. This case report demonstrates that intralesional curettage complemented with adjuvant therapies is a viable alternative to wide resection surgery for the treatment of aggressive GCT.
Corresponding author: Vanda Roxana Nimigean, Associate Professor, DMD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF A rare tumor in a rare location: giant cell tumor of the sacrum and ilium - case report and current perspectives PDF
32. Synchronous Warthin tumor and papillary oncocytic cystadenoma in the ipsilateral parotid gland: an unreported association
Jose-Fernando Val-Bernal, Marta Maria Mayorga, Paula Martin-Soler, Sergio Obeso, Eva Maria Alonso-Fernandez, Gerardo Lopez-Rasines
The occurrence of ipsilateral, synchronous, primary salivary gland tumors of different histological type is rare. In this report, we present the case of a 52-year-old male, established smoker, who showed simultaneously two different benign tumors in the right parotid gland. The patient complained of swelling below the angle of the mandible. Ultrasonography and computed tomography imaging revealed one mass of about 2.8 cm in the right gland. Besides, one small nodule in the left parotid gland was observed. The cytological diagnosis of the right gland was benign tumor, type IVa of the Milan system, consistent with Warthin tumor (WT). The clinical diagnosis was bilateral parotid WT. The histopathological (HP) study of the surgical specimen revealed a WT in combination with a papillary oncocytic cystadenoma (POC) in the right parotid. To our knowledge, this combination of tumors has not been previously reported. In our case, the association of tumors was not detected by imaging or fine-needle aspiration cytology (FNAC). WT and POC are difficult to distinguish by FNAC because their epithelial component is very similar. POC can resemble WT without lymphoid stroma, but the totality of HP features allows the differentiation of both processes. These tumors can be related to a common causal determinant and should not be considered as a result of chance. Both tumors follow favorable courses and are curable by surgical resection.
Corresponding author: Jose-Fernando Val-Bernal, Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Synchronous Warthin tumor and papillary oncocytic cystadenoma in the ipsilateral parotid gland: an unreported association PDF
33. Unusual occurrence of avascular necrosis with bilateral involvement and ankylosing spondylitis, meningioma and Hodgkin lymphoma
Livia Dorina Stoicanescu, Mariana Lidia Cevei, Elena Maria Sirbu, Mihaela Mirela Zdrinca, Gabriela Mutiu
This case report aimed to reveal the multidisciplinary aspect and discuss an association of disorders in a complex case with Hodgkin disease, meningioma, avascular necrosis with bilateral involvement and ankylosing spondylitis. We report the case of a 47-year-old patient, diagnosed with Hodgkin lymphoma at the age of 14. Two decades later, she was diagnosed with frontal chordoid meningioma, which was surgically removed, without radiotherapy. She was re-operated 10 years later for recurrence of meningioma. At the age of 39, she was diagnosed with bilateral avascular necrosis of the humeral head, femoral head and scaphoid bones. In the same year, she was also diagnosed with ankylosing spondylitis. We considered that the occurrence of rare chordoid meningioma, avascular necrosis with multiple locations and bilateral involvement in a patient with a malignancy during childhood and an autoimmune disease was unusual and there may be some common pathways.
Corresponding author: Mariana Lidia Cevei, Associate Professor, MD, PhD; e-mail: cevei_mariana.@yahoo.comAbstract Open Paper Download PDF Unusual occurrence of avascular necrosis with bilateral involvement and ankylosing spondylitis, meningioma and Hodgkin lymphoma PDF
34. Unilateral left four renal arteries: case report using MDCT angiography
Agneta Maria Pusztai, Gratian Dragoslav Miclaus, Raul Lupulescu, Petru Matusz
We report a very rare case of a 57-year-old male who presented four left renal arteries (RAs) [one main RA and three additional renal arteries (AdRAs)] highlighted incidentally on multidetector computed tomography (MDCT) angiography, which was used to investigate the vascular system of the lower limbs. The distance between the extreme points of RAs origin (upper and lower points of origin) from abdominal aorta (AA) was in the left part of 9.83 cm. The distance between the extreme points of penetration (upper and lower points of penetration) into the left renal parenchyma was 5.23 cm. At the level of origin, the main left RA has an endoluminal diameter of 0.63 cm, much larger in comparison to the other additional left RAs (0.43 cm, 0.33 cm and 0.28 cm, respectively). The length of the main left RA was 2.16 cm, significantly shorter in comparison with the other additional left RAs (2.21 cm, 4.26 cm and 4.73 cm, respectively). The second left RA was the main RA; the first left RA was AdRA (polar superior RA); the third left RA was AdRA (hilar RA); the fourth RA was AdRA (polar inferior RA). Knowledge of this anatomical variation should be considered in planning and performing renal vessel surgery, and kidney transplantation.
Corresponding author: Petru Matusz, Professor, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Unilateral left four renal arteries: case report using MDCT angiography PDF
35. Rare variant of renal vascularization with bilateral multiple pedicles and incomplete rotation - case report
Delia Elena Zahoi, Dorina Sztika, Lucia Stoican, Ecaterina Daescu
Renal blood vessels present great morphological variability. The routine dissection of a 68-year-old male cadaver revealed multiple bilateral vascular variations associated with the incomplete rotation of both kidneys. The left kidney was supplied by three renal arteries: one superior artery and one middle artery with hilum penetration, and one inferior artery with inferior polar penetration. All three arteries arose from the aorta: two from the anterior side at levels L1 and L3, and one - the inferior artery - from the posterior side of the aorta, as a common trunk with the middle sacral artery. The right kidney had two arteries, both arising from the aorta. The superior renal artery, arising at level L1, entered the renal parenchyma at the hilum; the inferior artery, arising at the point where the abdominal aorta branches in the two common iliac arteries, entered the parenchyma at the inferior pole. Each of the five arteries was accompanied by a vein. The (bilateral) superior renal veins and the middle left vein drained into the inferior vena cava. The two inferior renal veins joined to form a common trunk that drained into the left common iliac vein. Both kidneys presented incomplete rotation, each renal pelvis being situated anterior to the renal vessels, and the ureters descending on the anterior sides of the kidneys. The presence of several vascular pedicles may represent a contraindication in laparoscopic nephrectomy or cause severe bleeding if the pedicles are injured during endopyelotomy.
Corresponding author: Delia Elena Zahoi, Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Rare variant of renal vascularization with bilateral multiple pedicles and incomplete rotation - case report PDF
36. A recurrent solitary glomus tumor of the forearm
Valeriu Ardeleanu, Cristian Radu Jecan, Alin Laurentiu Tatu, Andrei Gheorghe Marius Motoc
Glomus tumors account for 1.6% of all soft tissue tumors and the majority are localized at the level of the fingertips and do not exceed the size of 5 mm. They are usually solitary tumors, characterized by the following clinical triad - severe pain, pinpoint tenderness, and cold intolerance. We present the case of a 63-year-old patient with a fixed tumor located in the lower third of the right forearm with a long-axis diameter of 4 cm, with irregular borders and tenderness to palpation. The tumor had been surgically removed 15 years ago, but it redeveloped two months after surgery, and grew in size until the fourth month after the surgery when it stopped growing. The preoperative ultrasound showed an expansive mass suggestive of swelling/inflammation in the adjacent soft tissue and having a mass effect on the deep muscle structures. Intraoperatively, a 3/4/3 cm (antero-posterior/transversal/cranio-caudal) pink tumor was found subcutaneously, with well-defined borders, which was mobile on the deep planes, apparently encapsulated. The tumor was removed with safety margins of about 1 cm and hemostasis was performed. Postoperatively, immunohistochemistry confirmed the diagnosis of glomus tumor: alpha-smooth muscle actin (alpha-SMA) positive in the cytoplasm of malignant cells, type IV collagen positive in the basement membrane, cluster of differentiation 34 (CD34) negative in the malignant cells, CD34 positive in endothelial cells, Ki67 positive in the 1-2% of the cancer cells nuclei. The postoperative evolution was favorable, without complications and no recurrence at six months.
Corresponding author: Alin Laurentiu Tatu, Professor, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF A recurrent solitary glomus tumor of the forearm PDF
37. Cutaneous melanoma arising on pre-existing nevi - case reports
Ioana Mihaela Dogaru, Natalia Dumitrescu, Ana Maria Oproiu, Cristian Radu Jecan, Mariana Costache, Oana Maria Patrascu, Ioan Petre Florescu
Skin cancer is a common healthcare issue that affects millions of people worldwide. Only a small part of that population is suffering from melanoma and an even smaller proportion has melanoma developed on a pre-existing nevus. This paper illustrates five such cases, diagnosed over an 18-month period, with their histological particular aspects. Among the total number of patients diagnosed and treated in the Department of Plastic and Reconstructive Surgery, University Emergency Hospital, Bucharest, Romania, over approximately one year, of which half for melanoma in general or for benign nevi, only a small fraction had developed melanoma on a common or dysplastic nevus. These patients, as well as those with de novo developed melanoma, are a reason for concern since most of the lesions were diagnosed in a locally advanced stage of the disease. Though efforts are being made to screen and diagnose early, there are still a lot to be done in order to lower the mortality and morbidity rates for this pathology.
Corresponding author: Ana Maria Oproiu, Associate Professor, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Cutaneous melanoma arising on pre-existing nevi - case reports PDF
38. Difficulties in histopathology diagnosis and treatment of depressive disorder of breast cancer in male - clinical case presentation
Mara Jidveian Popescu, Aurel Slabaru, Ileana Marinescu, Andrei Popescu, Ovidiu Popa-Velea, Adela Magdalena Ciobanu
Breast cancer is less common among men than among women (about 1 in 100) and it is considered a rare disease but the evolution is significantly influenced by depression and distress. We present the case of a 63-year-old patient that was diagnosed in another Clinic with squamous skin carcinoma, but, after complete resection in our Hospital, it was proven to be breast cancer. At diagnosis, computed tomography (CT) scan showed local disease. Adjuvant treatment, consisting in chemotherapy and radiotherapy, was administered. At the beginning of hormonal therapy, the patient had a new CT scan that showed liver and bone metastases. The patient started palliative hormonal treatment with bisphosphonates. The aim of the study was to highlight both the importance of early diagnosis and treatment and the aggressiveness of male breast cancer compared with female. Depressive disorder and social distress worsens the prognosis and quality of life. Male with breast cancer has identity difficulties, body image disturbances and secondary distress.
Corresponding author: Ileana Marinescu, Lecturer, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Difficulties in histopathology diagnosis and treatment of depressive disorder of breast cancer in male - clinical case presentation PDF
39. Spermatic vein aneurysm: a report of a unique case and review of the literature
Konstantinos Sapalidis, Konstantina Tsopouridou, Maria Florou, Prodromos Hytiroglou, Alexandru Claudiu Munteanu, Valeriu Surlin, Efstathios Pavlidis, Isaak Kesisoglou, Cristina Popescu
A spermatic vessel aneurysm is a rare entity, described only a few times in the literature. In most cases, it is caused by trauma or inflammation and appears as a painful mass in the scrotum or the inguinal area. We present a case of a 22-year-old man who came to our Surgical Department with a painful, palpable mass in the right inguinal area. A spermatic vein aneurysm was diagnosed with the use of ultrasonography and it was surgically excised. The findings were confirmed by pathological examination. The patient is well, four months after surgery. A spermatic vessel aneurysm, though rare, should always be included in the differential diagnosis of a scrotal or inguinal mass. The lesion can be cured by surgical resection.
Corresponding author: Konstantinos Sapalidis, Associate Professor of Surgery, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Spermatic vein aneurysm: a report of a unique case and review of the literature PDF
40. Bridging neighboring civilizations at academic grounds: a story of Zygmunt Albert - Rector illustrissimus ac magnificus Academiae Medicae Wratislaviensis - a pathologist who visualized gamma-glutamyl transpeptidase
Andrzej Wincewicz, Piotr Woltanowski, Michal Jelen
The life stories can constitute more than simple biographies to remain great lessons of honesty, grit and steadfastness in keeping standards of medical science within a strong moral fiber and flexible wiseness in hard terms like in case of Zygmunt Albert (1908-2001). This eminent pathologist histochemically visualized tissue distribution of gamma-glutamyl transpeptidase in liver and other organs under various conditions. He was also deeply involved in experimental pathology of liver, particularly in his comprehensive studies on chrysoidin-induced hepatoma that should bear eponymic name Albert s hepatoma. As he had both German and Polish roots, he became an eminent personage that wisely and consequently bridged neighboring civilizations in hard terms of escalation of hate in prewar times, during World War II and in postwar period. After he meticulously recorded Nazi crimes in Lvov, he appealed for justice in case of Nazi massive murders of Lvov Professors. He obtained his Associate Professorship in Anatomical Pathology in Lvov (Lemberg) and was one of rebuilders of Medical Faculty in postwar Wroclaw (Breslau) to serve as the first Rector Magnificus of Medical Academy of Wroclaw.
Corresponding author: Andrzej Wincewicz, Associate Professor, MD, PhD; e-mails: firstname.lastname@example.org, email@example.comAbstract Open Paper Download PDF Bridging neighboring civilizations at academic grounds: a story of Zygmunt Albert - Rector illustrissimus ac magnificus Academiae Medicae Wratislaviensis - a pathologist who visualized gamma-glutamyl transpeptidase PDF
41. Career management and personal integration in organizational culture in medical education - case study University of Medicine and Pharmacy of Craiova, Romania
Cristina Constanta Cotocel, Raluca Eugenia Iovan, Alexandru Marian Goganau, Florina Nechita, Sorin Stefan Deca, Bogdan Virgil Cotoi, Tony Popa Nistorescu
A peculiarity in the professional training of medical staff with higher education is the fact that a large part of the teaching staff is also a practitioner of the medical profession, thus combining the activity of educator and trainer with that of doctor or nurse. The two occupations, although distinct at first glance, cannot be separated in the educational-formative process of the medical profession. Practitioners who combine the two professional activities decide to develop a parallel medical and university career, though different are complementary. In this context, through an analysis of the attitudes, opinions and behaviors of employees in medical education institutions regarding career and professional development, one can determine how they position themselves in relation to the choices made in terms of the job, the place where they want to practice it, how they work and their professional satisfaction. This article presents the results of a study conducted at the University of Medicine and Pharmacy of Craiova, Romania, on professors and auxiliary teaching staff of the Faculties of Medicine and General Medical Assistance, in order to identify how it relates to organizational culture, its own career and how satisfied with the choices they have made.
Corresponding author: Raluca Eugenia Iovan, PhD Student; e-mail: firstname.lastname@example.org; Alexandru Marian Goganau, MD, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Career management and personal integration in organizational culture in medical education - case study University of Medicine and Pharmacy of Craiova, Romania PDF
42. Trait anxiety and coping in first year medical students
Dan Nechita, Florina Nechita, Livia Mihaela Strunoiu, Dana-Maria Albulescu, Diana Lucia Vasile
In the present study, we highlight the types of anxiety and the coping strategies employed by the students at the Medicine, Pharmacy and Nursing Faculties, at the same time comparing them with the general population. This research involved 333 first year students, 18-20 years of age. We used the Endler Multidimensional Anxiety Scales-Trait (EMAS-T) and Social Anxiety Scale-Trait (SAS-T) and two coping measuring instruments, Cognitive Emotion Regulation Questionnaire (CERQ) and Strategic Approach to Coping Scale (SACS). We obtained an overview on the hierarchy of the types of anxiogenic situations for the study participants, by gender and specialization. We analyzed and discussed the correlations between anxiety and coping and we discussed the results of the factor analysis. We noticed the students predilection for maladaptive coping mechanisms and how anxiety relates to their professional choice.
Corresponding author: Florina Nechita, Lecturer, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Trait anxiety and coping in first year medical students PDF
43. Letter to the Editor: Prolonged in vitro expansion alter the biological and morphological properties of adipose stem cells
Lubos Danisovic, Martin Bohac, Marcela Kuniakova, Martina Culenova, Ivan Varga
Corresponding author: Lubos Danisovic, Associate Professor, RND, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Letter to the Editor: Prolonged in vitro expansion alter the biological and morphological properties of adipose stem cells PDF
44. Letter to the Editor: POLG1 variants may secondarily affect mtDNA load and structure
Corresponding author: Josef Finsterer, MD, PhD; e-mail: firstname.lastname@example.orgAbstract Open Paper Download PDF Letter to the Editor: POLG1 variants may secondarily affect mtDNA load and structure PDF
45. Letter to the Editor: Carbon monoxide (CO) poisoning, a silent epidemic
Vicenc Ferres-Padro, Silvia Sola Munoz, Javier Jacob Rodriguez, Silvia Membrado-Ibanez, Montserrat Amigo Tadin, Santiago Nogue Xarau
Corresponding author: Vicenc Ferres-Padro, RN, PhD; e-mail: email@example.comAbstract Open Paper Download PDF Letter to the Editor: Carbon monoxide (CO) poisoning, a silent epidemic PDF
46. Conference Announcement: The XVIIth National Symposium with international participation on Microscopic Morphology, Craiova, Romania, May 20-23, 2020
Corresponding author: -Abstract Open Paper Download PDF Conference Announcement: The XVIIth National Symposium with international participation on Microscopic Morphology, Craiova, Romania, May 20-23, 2020 PDF
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