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Papers accepted for publication

1. Immunohistochemical diagnosis of Krukenberg tumors

Melania Ioana Craciun, Iacob Domsa

The diagnosis of Krukenberg tumors, as in other types of metastatic tumors of unknown primary origin, can often be a challenge for clinicians. In many cases, traditional diagnostic methods are insufficient, requiring immunohistochemistry analysis for identifying the origin of metastatic tumors. In our study, we examined a total of 34 female patients with Krukenberg tumors with different sites of the primary tumor: gastric (n=18), colorectal (n=6) or breast (n=7) and tumors with unknown origin (n=3). Cytokeratin (CK) 7 and CK20, carcinoembryonic antigen (CEA) and cancer antigen (CA) 125 were applied. The analysis of immunohistochemical profiles for CEA and CA125 showed that, regardless of the histological origin, the predominant immunohistochemical profile was CEA(+)/CA125(-). CK7/CK20 profile was different depending on the histological origin of the Krukenberg tumors. Thus, for the cases of gastric origin, CK7(-)/CK20(-) was present in 66.7% (12/18) of the cases. For the cases with colorectal origin, the predominant immunohistochemical profile was CK7(-)/CK20(+), in a percentage of 66.7% (4/6). The combination CK7(+)/CK20(-) was found in 85.7% (6/7) among cases of breast origin. Consequently, the immunohistochemical profile CK7/CK20 can have a key role in identifying the primary tumor in patients with Krukenberg tumors of unknown origin.

Corresponding author: Melania Ioana Craciun, MD, PhD; e-mail:

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2. Immunoexpression of transcription factors in urothelial bladder carcinomas

Alex Emilian Stepan, Raluca Niculina Ciurea, Petru Octavian Dragoescu, Mirela Marinela Florescu, Mioara-Desdemona Stepan

Transcription factors play a central role in the epithelial-mesenchymal transition (EMT), which is one of the biomolecular mechanisms involved in the progression of urothelial carcinomas of the bladder (UCB). In this study, we analyzed the immunoexpression of Twist 1, Snail, Slug and beta-catenin in relation to histopathological prognostic parameters of UCB. The obtained results indicated the association of Snail and beta-catenin expression with low grade and early stage of UCB, as well as the association of Twist 1 and Slug expression with high grade and advanced stage lesions. The specific or sequential action of transcription factors in the bladder tumoral EMT may be useful for identifying the aggressive lesions.

Corresponding author: Raluca Niculina Ciurea, Professor, MD, PhD; e-mail:

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3. Lymphoproliferative disorder in a twin female teenager post kidney transplantation

Raluca Isac, Rodica Costa, Dorela Codruta Lazureanu, Cristina-Ioana Olariu, Adriana Milena Muntean, Cornel Olimpiu Aldea, Gabriela Simona Doros, Mihai Gafencu

Post-transplant lymphoproliferative disorder (PTLD) is defined as a heterogeneous group of lymphoid and plasmocytic proliferations with variable malignant potential. They often arise in immunocompromised post solid organ transplant (SOT) patients linked with Epstein-Barr virus (EBV) infection. Clinical manifestations include fever, lymphadenopathy and organ involvement. Diagnosis of PTLD requires morphopathological tissue examination. Treatment of EBV-related PTLD in SOT patients includes immunosuppressive (IS) agents reduction, use of antiviral medication, anti-B-lymphocyte antibodies and chemotherapy for high-risk patients. We report a case of late EBV-related PTLD occurring in a young female, coming from twins, nine years after renal transplant from deceased donor. Both sisters were diagnosed at the age of 10 with chronic kidney disease (CKD) based on nephronophthisis and underwent the first simultaneous renal transplant from deceased donor in Romania. PTLD Hodgkin s-like lymphoma and EBV-positive lesions were to be found in autopsy. Routine EBV viral load testing and immune condition in SOT patients could identify PTLD risk factors therefore early treatment can be applied. Monitoring EBV serology and immunological parameters are preferred as strategy for PTLD prevention.

Corresponding author: Gabriela Simona Doros, MD; e-mail:; Cornel Olimpiu Aldea, MD; e-mail:

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4. Protective and therapeutic possibility of medical herbs for liver cirrhosis

Vesna Stankovic, Vladimir Mihailovic, Slobodanka Mitrovic, Vladimir Jurisic

Liver damage is a serious medical problem worldwide and is caused by primary or secondary metabolic, microbiological, toxicological, immunological and circulatory etiological factors. The objective of this paper is to analyze the hepatoprotective effect of various plants, their biologically active compounds and extracts and the possibility of these compounds to attenuate complex pathophysiology processes during chronic inflammation and the development of liver cirrhosis. This review summarizes several plants whose hepatoprotective effects have been demonstrated and partially describes the mechanisms of inflammation inhibition. It is known that fibrosis includes an oxidative damage, inflammatory and immune response and star-shaped cells and their activation in hepatocytes. Effects of particular phytocompounds and their anti-inflammatory mechanisms have been studied in several cell lines in vitro, in vivo in different animal models, as well as in some clinical studies. Results suggest that mechanisms include reduction of oxidative stress, suppression of the inflammatory and immune response, as well as the inhibition of the activation of hepatic stellate cells (HSCs), decreasing extracellular matrix (ECM) deposition and induction of apoptosis, protection of hepatocytes from apoptosis and creating apoptotic bodies, which are phagocytic and activate HSCs. Medical herbs are abundant, economical and versatile and thus are potential alternative agents with anti-inflammatory mechanism. They can be a source of bioactive compounds, and with the aim of preventing the formation and progression of fibrosis, they can find wide applications in medical practice. The obtained results should promote further research in order to identify safe and effective protective and therapeutic resources.

Corresponding author: Vladimir Jurisic, Professor, MD, PhD; e-mail:

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5. Non-Hodgkin s lymphoma, rare localization at the base of the tongue - case presentation

Daniel Mirea, Liliana Elena Mirea, Cornelia Nitipir, Mirela Tiglis, Ioana Cristina Grintescu, Tiberiu Paul Neagu, Carmen Aurelia Mogoanta, Ioana Marina Grintescu

The extranodal malignant lymphomas occur mainly in the region of the head and neck, after the gastrointestinal tract. The most common site of the head and neck lymphoma is at the lymphatics ring of Waldeyer, followed by the nasosinusal region. Localization at the base of the tongue is extremely rare. The authors reported a case of a 50-year-old male with a non-Hodgkin s lymphoma, which developed at the base of tongue. An unusual sensation described as a foreign body at the hypopharyngeal region associated with progressive dysphagia were the main symptoms for which the patient was referred to our Hospital. The fibroscopic exam has revealed an oval tumor of the base of tongue, with large dimensions, sessile emergent base and smooth superficial mucosa. The tumor was removed using an endoscopic transoral approach, followed by the histopathological and immunohistochemical examination, which have been suggestive for non-Hodgkin s lymphoma with small B-cells. The treatment continued with chemotherapy, while radiotherapy was not necessary due to the fact that the tumor was completely removed.

Corresponding author: Liliana Elena Mirea, MD, PhD; e-mail:

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6. Eosinophilic colitis: experience in a large tertiary hospital

Cristina Diaz Del Arco, Carlos Taxonera, Lourdes Estrada Munoz, David Olivares, Maria Jesus Fernandez Acenero

Background: Eosinophilic colitis (EC) is a rare and ill-defined entity with an unknown pathogenesis and an unsatisfactory treatment response. The standard histopathological criteria for EC diagnosis lack specificity and not all the cases fulfilling those criteria are considered clinically as EC and treated. The objective of this study is to refine diagnostic criteria for EC. Methods: Retrospective study of all the cases with a histopathological diagnosis of EC in Hospital Clinico San Carlos (Madrid, Spain) from 2006 to 2016. We have reviewed their clinical and pathological features and tried to define the features differentiating cases considered EC on clinical grounds. Results: We identified 106 EC cases. In 22 cases, a clinical EC diagnosis was established. Confirmed EC was associated with younger age, female gender, diarrhea, higher maximum number of eosinophils/HPF (high-power field), intraepithelial eosinophils, architectural distortion and absence of acute inflammation. We chose a cut-off point of 40 for both mean and maximum number of eosinophils/HPF. A mean number of eosinophils/HPF higher than 40 was related to architectural distortion, mucosal atrophy, signs of eosinophil activation and submucosal infiltration. Cases with a maximum number of eosinophils/HPF higher than 40 showed more architectural distortion, intraepithelial eosinophils, submucosal infiltration and lack of lymphoplasmacytic infiltration. Conclusions: Histopathological diagnosis of EC is not well correlated with clinical EC. An increase in specificity can be achieved by raising the cut-off point to 40 eosinophils/HPF and by combining mean and maximum number of eosinophils with other microscopic and clinical features suggestive of EC.

Corresponding author: Cristina Diaz del Arco, MD; e-mail:

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7. Granular ameloblastoma: report of two cases with atypical cytological aspects

Shelly Arora, Aadithya Basavaraj Urs, Priya Kumar, Jeyaseelan Augustine, Ravindra Kumar Saran

Ameloblastoma is an aggressive odontogenic tumor, which arises from odontogenic epithelium. Ameloblastomas can present in several clinical and histomorphological patterns. The granular cell variant accounts for only 3.5% to 5% of ameloblastomas. We have presented two cases of granular cell ameloblastoma (GCA) occurring in a 44-year-old and 50-year-old man, respectively. Case No. 1 on incisional biopsy was diagnosed as unicystic ameloblastoma (UA), which later after excisional biopsy was finally diagnosed as GCA owing to the features observed in excisional biopsied tissue. Case No. 2 on incisional biopsy showed darker and lighter stained cells arranged in small follicular pattern, and anastomosing cords. Meticulous immunohistochemistry, histochemical examination and careful literature search helped us to diagnose it as GCA. We have made an attempt to elucidate the diagnosis of GCA especially in cases of GCA with unusual granular component.

Corresponding author: Shelly Arora, Senior Lecturer, BDS, MDS; e-mail:

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8. Malignant cutaneous mixed tumor with sebaceous differentiation

Angel Fernandez-Flores, David Samuel Cassarino

Malignant cutaneous mixed tumor (CMT) is a very rare adnexal tumor with biphasic differentiation. In rare cases, a benign CMT (chondroid syringoma) undergoes malignant transformation. Sebaceous differentiation in a cutaneous malignant mixed tumor has not been previously reported. We present a malignant CMT with sebaceous differentiation, which occurred on the scalp of an 81-year-old man. The tumor showed epithelial elements composed of relatively small and bland-appearing ductal and cord-like structures lined by small, cuboidal-shaped adnexal cells, with a few large, dilated gland-like spaces lined by larger, apocrine-appearing cells with abundant eosinophilic-staining cytoplasm. However, the majority of the epithelial component was composed of nests and islands of markedly enlarged and atypical cells with pale/clear to ground-glass cytoplasm. Focally, there was sebaceous differentiation identified, in the form of prominent multivacuolated cytoplasm, with nuclear indentations. The stroma showed a mixture of myxoid and hyalinized/chondroid-appearing areas with focal calcifications. There was strong and diffuse staining of the sebaceous cells by cytokeratin (CK) 7, epithelial membrane antigen (EMA), and androgen receptor (AR). Mismatch repair proteins were investigated by immunohistochemistry, without evidence of loss of expression of MutS protein homolog 6 (MSH6), MutS protein homolog 2 (MSH2), MutL protein homolog 1 (MLH1), or postmeiotic segregation increased 2 (PMS2) in the sebaceous cells.

Corresponding author: Angel Fernandez-Flores, MD, PhD; e-mail:

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9. Esophageal atresia with distal fistula - unusual case series. Considerations related to epidemiological aspects, malformative associations, and prenatal diagnosis

Maria Livia Ognean, Laura Corina Zgarcea, Laura Balanescu, Oana Boanta, Raluca Elena Dumitra, Florin Grosu, Dan Georgian Bratu, Adrian Gheorghe Boicean, Liliana Coldea, Radu Chicea

Background: Esophageal atresia (EA) is the most frequent and severe congenital anomaly of the esophagus, occurring in 1:2500-1:4500 live births. Five types of EA have been described, EA with tracheoesophageal fistula (TEF) being the most frequent. Aim: The aim of this paper is to evaluate epidemiological aspects, malformative associations, and prenatal diagnosis in an unusual case series of EA with distal TEF. Case presentations: The authors are analyzing a series of seven cases of EA with distal TEF. The seven cases of EA with TEF presented occurred during a period of two years, resulting in an unusually increased rate - 1.1:1000 live births. Except a late suspicion of EA (one day before delivery), EA was not diagnosed during prenatal scans despite association with polyhydramnios in two cases and single umbilical artery in four cases. None of the two cases of unilateral renal agenesis or anorectal malformations were diagnosed on prenatal ultrasound scans. In two of the cases, EA was part of VACTERL (vertebral defects, anorectal malformations, heart defects, EA with or without TEF, renal anomalies/dysplasia, and limb defects) association. Despite lack of prenatal diagnosis, postnatal diagnosis of EA was suspected at birth in four cases, at two hours in one case. Conclusions: An increased index of suspicion for congenital structural defects, particularly for EA, should be maintained in the presence of a single umbilical artery and/or polyhydramnios on prenatal ultrasound scan. Prenatal diagnosis of EA offers the chance for parental counseling, planned birth and transfer for corrective surgery and decreases the risk for postnatal aspiration pneumonia associated with early feedings.

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

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10. Pulmonary Langerhans cell histiocytosis in a 26-year-old female: still a diagnostic challenge

Edith Simona Ianosi, Mihaela Muresan, Simona Gurzu, Eugenia Corina Budin, Ioan Jung, Tivadar Bara, Gabriela Jimborean

Langerhans cell histiocytosis (LCH) is a rare disorder caused by monoclonal Langerhans cells proliferation in bone, skin, lung, lymph nodes, liver, spleen, nervous or hematopoietic system. Pulmonary LCH is a diagnostic trap that is displayed on computed tomography (CT) as an interstitial disorder with honeycomb aspect. In this paper, we present an unusual case of a 26-year-old female that was hospitalized with progressive worsening dyspnea and history of recurrent pneumonia. Lung biopsy showed fibrosis of the interalveolar septa, architectural distortion and large cells with foamy cytoplasm and convoluted nuclei that were marked by CD68, S-100 and the specific antibody CD1a that allowed establishing the diagnosis of pulmonary LCH. The only extrapulmonary manifestations were femoral bone cysts that were radiologically seen 10 years before and were not modified along the years. The therapy consisted on smoking cessation and oral corticosteroids without significant improvement of the clinical symptoms and enlargement of the cystic spaces during six months of follow-up. This case highlights for a rare disorder of the lung that should be taken into account in young patients with progressive pulmonary fibrosis.

Corresponding author: Simona Gurzu, Professor, MD, PhD; e-mail:

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11. Genetic disorder in carbohydrates metabolism: hereditary fructose intolerance associated with celiac disease

Daniela Pacurar, Gabriela Lesanu, Irina Dijmarescu, Iulia Florentina Tincu, Mihaela Gherghiceanu, Dumitru Oraseanu

Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye s-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age.

Corresponding author: Iulia Florentina Tincu, MD, PhD Student; e-mail:

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12. Bilateral serous surface papillary borderline ovarian tumor in 19-year-old patient. Ultrasound, immunohistochemical and therapeutic particularities of reproductive age

Roxana Elena Bohiltea, Nicolae Bacalbasa, Natalia Turcan, Monica Mihaela Cirstoiu, Dana Cristina Terzea, George Simion, Octavian Munteanu, Costin Berceanu, Elvira Bratila

Borderline tumors have a histological aspect of atypical epithelial proliferation without stromal invasion and typically occur in fertile ages, approximately one-third of women diagnosed are younger than 40. Serous borderline tumors are the most encountered and they can present micropapillary features that are associated with a higher rate of recurrence and the possibility of peritoneal implants. We present the case of a serous borderline ovarian tumor in a young patient and the diagnosis and treatment particularities. The patient presented with no symptoms, for a specialist advice, in the context of failure obtaining spontaneous pregnancy over a period of seven months. Paraclinical, the only modified parameter was CA 125, respectively a slight increase of its value. The atypical appearance on abdominal and transvaginal ultrasound indicated a presumptive diagnosis; both ovaries with multiple irregular vegetation, moderately vascular on Doppler examination, with the starting point in epithelial capsule shell, that appeared thick and hyperechogenic. About 7 cm of pelvic fluid was also present. During exploratory laparoscopic intervention, the surrounding tissue of both ovaries was biopsied and the fragments were sent for histopathological and immunohistochemical exam. Immunohistochemical assays correlated with the histopathological analysis and anatomical clinical data confirmed the diagnosis. After informed consent, the patient underwent radical surgery with a quick and uneventful recovery. The series of investigations had the objective to establish the best management of the case and reviewing the possibility of a conservative surgery. Patient clinical aspect matched with the patterns of ovarian borderline tumors by the asymptomatic presence of the bilateral adnexal masses.

Corresponding author: Costin Berceanu, Associate Professor, MD, PhD; e-mail:

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13. Middle mesial canal of the permanent mandibular first molars: an anatomical challenge directly related to the outcome of endodontic treatment

Paula Perlea, Cristina-Coralia Nistor, Marina Imre, Irina-Maria Gheorghiu, Alexandru-Andrei Iliescu

To effectively clean and shape the mandibular permanent first molars it is mandatory to understand in detail their complex internal anatomy. The middle mesial canal is an additional canal located between the usual mesiobuccal and mesiolingual canals in the mesial root of mandibular first molars. The incidence of the middle mesial canal, its relationship with main canals of the mesial root and the possibility for it to be negotiated is an important practical issue in endodontics. To identify the presence of this canal is mandatory. Accordingly, a modified endodontic access, the use of the operating microscope and periapical radiographs in two different horizontal projections are indicated to enhance the long-term favorable outcome of the endodontic treatment.

Corresponding author: Marina Imre, Associate Professor, DDS, PhD; e-mail:

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14. E-cadherin, beta-catenin and Snail immunoexpression in laryngeal squamous cell carcinoma

Liliana Cercelaru, Alex Emilian Stepan, Claudiu Margaritescu, Andrei Osman, Ionelia-Carmen Popa, Mirela Marinela Florescu, Cristiana Eugenia Simionescu

E-cadherin, beta-catenin and Snail are important molecules involved in cellular adhesion and epithelial-mesenchymal transition. Loss of E-cadherin expression, nuclear relocation of beta-catenin and high expression of Snail are connected to tumor progression, rapid cell growth and metastasis. The aim of our study was to analyze the immunohistochemical expression of beta-catenin, E-cadherin and Snail, depending on clinico-morphological aspects of the laryngeal squamous cell carcinomas. Our results revealed variable E-cadherin, beta-catenin and Snail expression, depending on differentiation degree and tumor stage. These markers can be helpful in identifying the aggressive laryngeal squamous carcinomas.

Corresponding author: Alex Emilian Stepan, Lecturer, MD, PhD; e-mail:

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15. PV-1 expression could distinguish the subset of caveolae-presenting telocytes that are endothelial progenitors

Alexandra Diana Vrapciu, Mugurel Constantin Rusu

Telocytes (TCs) are stromal cells with characteristic long, thin and moniliform prolongations termed telopodes. They were formerly termed interstitial Cajal-like cells. A characteristic set of markers to identify TCs in light microscopy has not been established until now. Transmission electron microscopy (TEM) is a better tool for identifying TCs. Telocytes display caveolae and can express caveolin-1. On the other hand, endothelial cells (ECs) as well as endothelial progenitor cells (EPCs) have caveolae. Recent evidence suggests that a subset of TCs are in fact EPCs. The distinction of this progenitor subset of TCs can be easily made by a specific set of ultrastructure markers, as follows. Caveolae of endothelial cells present stomatal diaphragms (SDs). The plasmalemma vesicle-associated protein-1 (PV-1), which is identical with the Pathologische Anatomie Leiden endothelium (PAL-E), is specifically identifying the ECs SDs of caveolae. We therefore raise the reasonable hypothesis that the EPCs subset of caveolae-presenting TCs could be accurately identified, without exploration in TEM, by the positive expression of PV-1 or PAL-E in the SDs.

Corresponding author: Mugurel Constantin Rusu, Professor, MD, Dr. Hab., Dr. Med., Dr. Biol.; e-mail:

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16. Collagen I and III, MMP-1 and TIMP-1 immunoexpression in dilated cardiomyopathy

Alexandru Radu Mihailovici, Ruxandra Camelia Deliu, Claudiu Margaritescu, Cristiana Eugenia Simionescu, Ionut Donoiu, Octavian Istratoaie, Diana Rodica Tudorascu, Elena-Anca Tartea, Dan Ionut Gheonea

The extracellular matrix (ECM) remodeling represents the pathological substrate of dilated cardiomyopathy (DCM). In this study, we statistically analyzed the immunoexpression of collagen I and III, matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor-1 (TIMP-1) in the myocardial tissue in 18 cases of DCM compared to a control group. We observed a significant increase in the immunoexpression of collagen I and III in patients with DCM and a significant reduction in the immunoexpression of MMP-1 compared with the control group. Also, the collagen I and TIMP-1 expression indicated a positive linear correlation and respectively a negative linear relationship with collagen III and MMP-1. The analyzed markers in this study can be used to quantify the degree of collagen sclerosis from the ECM of DCM.

Corresponding author: Cristiana Eugenia Simionescu, Professor, MD, PhD; e-mail:

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17. Ethical dilemmas in communicating bad news following histopathology examination

Dan Alexandru Constantin, Ionut-Horia Cioriceanu, Marilena Monica Tantu, Daniela Popa, Dana Badau, Victoria Burtea, Gabriela Codruta Nemet, Liliana Marcela Rogozea

Purpose: The study proposes an analysis of the ethical aspects that occur in communicating bad news following histopathology laboratory tests in medical practice, in particular in the case of the anatomical pathology diagnosis confirming a medical condition of poor prognosis. Background: Over the last decades, the progress of science and technology in the medical field, as well as the explosive increase of specialist information available on the Internet have led to unprecedented ethical issues related to the communication modality of histopathology test results to patients. Content: The paper analyses from an ethical and legislative perspective the main ethical dilemmas that occur when choosing a modality for communicating test results. Discussion and Conclusions: While communicating bad news is an essential ability for medical professionals, it should be used within the context of observing the patients’ right to decide whether they wish to receive such information or not and their right to their own autonomy, by means of a personalized protocol for communicating bad news in current medical practice.

Corresponding author: Ionut-Horia Cioriceanu, MD, PhD Student; e-mail:

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