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Article ; Online: Bevacizumab with Chemotherapy as a First-Line Treatment for Advanced Ovarian Cancer in a Serbian Cohort

Irena Conic / Bojan Nedovic / Slavica Stojnev / Ilinka Todorovska / Aleksandra Dimitrijevic / Miljan Krstic / Ivana Djordjevic / Biljana Djordjevic

Medicina, Vol 58, Iss 607, p

2022 Volume 607

Abstract: Background and Objectives : For stage IIIb–IV ovarian cancer, bevacizumab-containing treatment is considered the standard of care. The purpose of this study was to evaluate the efficacy of bevacizumab in combination with carboplatin and paclitaxel as a ... ...

Abstract	Background and Objectives : For stage IIIb–IV ovarian cancer, bevacizumab-containing treatment is considered the standard of care. The purpose of this study was to evaluate the efficacy of bevacizumab in combination with carboplatin and paclitaxel as a first-line treatment for advanced ovarian cancer. Materials and Methods : Eligible patients had stage IIIc–IV ovarian cancer according to the International Federation of Gynecology and Obstetrics with no clinical signs or symptoms of gastrointestinal obstruction or a history of abdominal fistulae, gastrointestinal perforation, or intra-abdominal abscess or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography, or clinical symptoms of bowel obstruction in the previous 6 months. After debulking surgery, the patients received 175 mg/m 2 paclitaxel and carboplatin (AUC 6) for the first six cycles and 7.5 mg/kg bevacizumab every three weeks up to 17 cycles until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival. The secondary endpoint was overall survival. Results : Between April 2017 and March 2020, 35 patients began study treatment. Bevacizumab was administered at 7.5 mg/kg in all the patients and for more than 7.5 months in 70% of them. The median progression-free survival was 20 months (95% CI: 16–23). The median overall survival was not reached. Conclusions : This was, to our knowledge, the first trial in Serbia to show progression-free survival and overall survival of combination regimens in advanced ovarian cancer. Based on the observed progression-free survival, bevacizumab combined with chemotherapy should be considered as a standard option in advanced ovarian cancer.
Keywords	bevacizumab ; ovarian cancer ; progression-free survival ; overall survival ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Association between NOTCH3 expression and the clinical outcome in the urothelial bladder cancer patients

Ana Ristic Petrovic / Dragana Stokanović / Slavica Stojnev / Milena Potić Floranović / Miljan Krstić / Ivana Djordjević / Aleksandar Skakić / Ljubinka Janković Veličković

Bosnian Journal of Basic Medical Sciences (2022)

2022

Abstract: Disrupted NOTCH activity is a driving event in urothelial bladder cancer (UBC). After activation by hypoxia, the NOTCH3 receptor participates in tumor cell proliferation, acquisition of the epithelial-mesenchymal transition phenotype, and angiogenesis. ... ...

Abstract	Disrupted NOTCH activity is a driving event in urothelial bladder cancer (UBC). After activation by hypoxia, the NOTCH3 receptor participates in tumor cell proliferation, acquisition of the epithelial-mesenchymal transition phenotype, and angiogenesis. The aim was to analyze the association of NOTCH3 expression with histopathological and clinical parameters, and to determine its predictive impact on the clinical outcome in UBC patients. The present research included 614 UBC samples incorporated in paraffin tissue microarrays, evaluated by immunohistochemistry for NOTCH3 expression. The accrual period was four years, while the follow-up period was two years. The membranous expression was semi-quantified (0-3), and the mean degree was 1.81±0.94. Criteria for semi-quantification the NOTCH3 expression were the intensity of the staining and the percentage of positive cells. The samples with negative (0) and weak (1) NOTCH3 immunohistochemical (IHC) score were considered negative, while the samples that showed moderate (2) and strong (3) expression were considered positive. Higher degree of positivity was associated with higher risk of cancer-specific mortality (p<0.001). Independent predictors for cancer-specific mortality were NOTCH3 expression and high stage (p<0.001). NOTCH3 expression was not a statistically significant predictor of recurrence-free survival (p=0.816). This study indicated that NOTCH3 is a predictor of poor outcome, suggesting that the NOTCH3 could be potentially reliable IHC marker for selecting the UBC patients that would require more intensive follow-up, especially if they diagnosed in higher stage, with divergent differentiation in pathological report, and without recurrences which would lead them to more frequent medical assessments.
Keywords	bladder cancer ; clinical outcome ; NOTCH pathway ; NOTCH3 ; immunohistochemistry ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Functioning of whole bone marrow cell population in a model of L-arginine-induced pancreatitis

Nikola M Stojanović / Katarina V Mitić / Slavica Stojnev / Dušan Sokolović / Marija Vukelić Nikolić / Dragana Tričković-Vukić / Pavle J Randjelović / Miljan Krstić / Niko S Radulović

European Journal of Inflammation, Vol

2023 Volume 21

Abstract: Objective The present study aimed to investigate the metabolic activity and adherence capacity of the whole bone marrow cell (wBMC) population and changes in bone marrow (BM) architecture after acute pancreatitis (AP) induction. Methods The disease was ... ...

Abstract	Objective The present study aimed to investigate the metabolic activity and adherence capacity of the whole bone marrow cell (wBMC) population and changes in bone marrow (BM) architecture after acute pancreatitis (AP) induction. Methods The disease was induced by injecting L-arginine (350 mg/100 g; i.p. ). The control animals, animals injected with L-arginine, and animals pre-treated with allopurinol were included in this study. Serum and routine pathohistological analysis were conducted to confirm the induction of AP. The metabolic activity and adherence capacity of wBMC were evaluated in the MTT assay and methylene-blue test, respectively, and the alterations in pancreatic tissue and BM were examined on histological sections. In addition, immunohistochemical expression of β-catenin was assessed in the pancreatic tissue. Results The wBMC adherence capacity and their total number significantly increased after AP induction. The adherence capability of wBMC was reduced in rats pre-treated with allopurinol. There were no statistically significant changes in the metabolic activity of wBMCs. In the BM isolated from AP and allopurinol pre-treated animals, a discrete left shift in granulocytopoiesis was found, with a slight increase in the myeloid-to-erythroid ratio. Conclusions After AP induction, it was shown that wBMCs expressed increased adherence capacity and unchanged metabolic activity, while the alterations in BM may reflect the general activation of myelopoiesis, which would agree with the increased mobilization of mesenchymal stem cells. Also, a significant decrease in β-catenin expression in the pancreatic tissue was noticed.
Keywords	Medicine ; R
Subject code	630
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transformation of primary cutaneous follicle centre lymphoma into primary cutaneous diffuse large B-cell lymphoma of other type

Ivan Z. Petković / Ivica Pejčić / Danica Tiodorović / Miljan Krstić / Slavica Stojnev / Svetislav Vrbić

Advances in Dermatology and Allergology, Vol 34, Iss 6, Pp 625-

2017 Volume 628

Keywords	Dermatology ; RL1-803 ; Internal medicine ; RC31-1245
Language	English
Publishing date	2017-12-01T00:00:00Z
Publisher	Termedia Publishing House
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer

Slavica Stojnev / Miljan Krstić / Jovana Čukuranović Kokoris / Irena Conić / Ivan Petković / Sonja Ilić / Jelena Milosević-Stevanović / Ljubinka Janković Veličković

Medicina, Vol 55, Iss 6, p

2019 Volume 302

Abstract: Background and objectives : Dysregulation of TGF-β signaling plays multiple roles in cancer development and progression. In the canonical TGF-β pathway, TGF-β regulates the expression of hundreds of target genes via interaction with Smads, signal ... ...

Abstract	Background and objectives : Dysregulation of TGF-β signaling plays multiple roles in cancer development and progression. In the canonical TGF-β pathway, TGF-β regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-β1, Smad2, and Smad4, the key components of canonical TGFβ pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients’ outcome. Materials and Methods : Immunohistochemical analysis of TGF-β1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. Results : High expression of TGF-β1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-β1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage ( p < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade ( p = 0,003, p = 0.048, respectively), and low tumor stage ( p < 0.001, p = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors ( p = 0.014). High TGF-β1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death ( p = 0.043, p = 0.003, and p = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression ( p < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival ( p = 0.003, p = 0.034, respectively), while in multivariate regression analysis TGF-β1 manifested as an independent predictor of poor outcome. Conclusions : Unraveling the complex roles and significance of TGF-β signaling in urothelial bladder cancer might have important implications for therapy of this ...
Keywords	urothelial bladder cancer ; TGF-β ; Smad2 ; Smad4 ; immunohistochemistry ; prognosis ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A retrospective review of 139 major and minor salivary gland tumors

Marija Trenkić Božinović / Dragan Krasić / Vuka Katić / Miljan Krstić

Medicinski Glasnik, Vol 12, Iss 1, Pp 73-

2015 Volume 78

Abstract: Aim To describe demographic and histomorphological characteristics of 139 patients with epithelial salivary gland tumors in the Southeastern Serbia population. Methods A total number of 139 patients with epithelial tumors arising in major and minor ... ...

Abstract	Aim To describe demographic and histomorphological characteristics of 139 patients with epithelial salivary gland tumors in the Southeastern Serbia population. Methods A total number of 139 patients with epithelial tumors arising in major and minor salivary glands in the period 2010-2012 was evaluated. After standard tissue proceeding, the routine haematoxylin-eosin (HE) and histochemical alcian blue-periodic acid-Schiff (AB - PAS) methods were used for histomorphological examination. Results Among 139 patients, 102 (73.38%) had benign, and 37 (26.62%) malignant tumors. The majority of tumors were localized in the parotid gland, in 117 (84.17%) patients. Among benign tumors there were 50 (49.02%) pleomorphic adenoma, 48 (47.06%) Warthin’s tumor, two (1.96%) myoepithelioma, and two (1.96%) oncocytoma. In the group of malignant tumors the most common was mucoepidermoid carcinoma, in 12 (32.43%) patients, carcinoma ex pleomorphic adenoma in six (16.22%), adenoid cystic carcinoma in five (13.51%), and oncocytic carcinoma in three (8.11%) patients. Conclusion Benign tumors were more common than malignant ones, with predominance of pleomorphic adenoma. Malignant tumors are less common than benign in the large salivary glands, and more common in the minor salivary glands. Histochemical AB-PAS method helps in the diagnosis of mucinous salivary gland carcinoma.
Keywords	benign ; carcinoma ; epidemiology ; histopathology ; Medicine ; R
Subject code	616
Language	English
Publishing date	2015-02-01T00:00:00Z
Publisher	Medical Association of Zenica-Doboj Canton
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Interplay between STAT3, Cell Adhesion Molecules and Angiogenesis-Related Parameters in Gastric Carcinoma. Does STAT3 Really Have a Prognostic Value?

Miljan Krstić / Nikola M. Stojanović / Slavica Stojnev / Goran Radenković / Jovana Čukuranović Kokoris / Bojan Mladenović / Ljubinka Janković Veličković

Medicina, Vol 55, Iss 6, p

2019 Volume 300

Abstract: Background and objectives: Gastric cancer (GC) is one of the deadliest malignancies, with the underlying pathophysiological mechanisms still not completely understood. In this study, we aimed to investigate the signal transducer and activator of ... ...

Abstract	Background and objectives: Gastric cancer (GC) is one of the deadliest malignancies, with the underlying pathophysiological mechanisms still not completely understood. In this study, we aimed to investigate the signal transducer and activator of transcription 3 (STAT3) moleculeconnection with the pathological features of GCs, and the expression of cell adhesive molecules (E-cadherin and β-catenin) and angiogenesis-related factors (vascular endothelial growth factor (VEGF), HIF1α, and CD31)). Materials and Methods: This study comprised 136 cases of GCs with data related to the patients’ demographic characteristics (age, gender) and pathological features (tumor location, gross type, Laurens’ type of GC, histological differentiation, invasion depth, lymphovascular invasion and the presence of metastases) which were correlated with STAT3 expression. Additionally, STAT3 expression and the expression of adhesive molecules and angiogenesis-related factors were studied by immunohistochemical methods. Results: The expression of STAT3 was found to be significantly associated with the occurrence of poorly differentiated GCs in the lower portion of the stomach and with the presence of distant metastases. Interestingly, none of the investigated parameters related to cell adhesion or to angiogenesis were found to be related to the expression of STAT3. Conclusions: The lack of significant differences between the studied STAT3 expression and some of the molecules associated with different cancer features might be due to the characteristics of the studied population sample associated with the origin, heterogeneity, and cancer pathophysiological background. Nonetheless, the results of our study suggest that STAT3 could be a useful marker for the presence of distant GC metastases, which further indicates that STAT3 action might involve some other signaling molecules/pathways that warrant further elucidation.
Keywords	gastric cancer ; STAT3 ; cancer aggressiveness ; angiogenesis ; cell adhesion ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Number of decidual natural killer cells & macrophages in pre-eclampsia

Jelena Milosevic-Stevanovic / Miljan Krstic / Dragana Radovic-Janosevic / Jasmina Popovic / Marija Tasic / Slavica Stojnev

Indian Journal of Medical Research, Vol 144, Iss 6, Pp 823-

2016 Volume 830

Abstract: Background & objectives: The process of human placentation is complex and still not well understood. This study was aimed to examine the relationship between clinical features of pre-eclampsia and degree of trophoblastic invasion after its ... ...

Abstract	Background & objectives: The process of human placentation is complex and still not well understood. This study was aimed to examine the relationship between clinical features of pre-eclampsia and degree of trophoblastic invasion after its immunohistochemical visualization in the context of possible alterations in the number of natural killer (NK) cells and macrophages in the decidua. Methods: This prospective study included a study group comprising 30 pregnant women with pre-eclampsia delivered by caesarean section and a control group comprising 20 healthy pregnant women also delivered by caesarean section. Samples of placental bed obtained during caesarean section were analyzed after immunohistochemical labelling CD56 + NK cells, CD68 + macrophages and cytokeratin 7 trophoblastic cells. Results: In pre-eclampsia, there was a significantly lower number of CD56 + NK cells in the decidua (P<0.001) and a higher number of CD68 + macrophages (P<0.001) compared to control group. In the subgroup of pre-eclampsia with intrauterine growth retardation (IUGR), a significantly greater number of NK cells (P<0.05) was recorded, as well as an increased number of macrophages, but not significantly compared to pre-eclampsia without IUGR. There was no significant difference in the distribution of these cells in the decidua in relation to the severity of pre-eclampsia. CD56 + NK cells were significantly less (P<0.05) and macrophages were more (P<0.05) in the group with poor trophoblastic invasion. Interpretation & conclusions: Alterations in the number of immune cells in relation to the degree of trophoblastic invasion indicated their role in aetiopathogenesis of pre-eclampsia, while the direct association between their number and severity of pre-eclampsia was not confirmed.
Keywords	Decidua - macrophages - natural killer cells - preeclampsia - trophoblast ; Medicine ; R
Subject code	610
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Wolters Kluwer Medknow Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prognostic Value and Immunohistochemical Analysis of Mismatch Repair Deficiency in Patients with Stage II and III Colorectal Carcinoma—A Single-Center Study

Tijana Denčić / Miljan Krstić / Aleksandar Petrović / Maja Jovičić-Milentijević / Goran Radenković / Marko Jović / Nikola Živković / Sonja Šalinger-Martinović / Branko Branković / Simona Stojanović

Medicina, Vol 56, Iss 676, p

2020 Volume 676

Abstract: Background and objectives: Deficient mismatch repair (MMR) status is associated with good prognosis but poor therapeutic response to adjuvant chemotherapy in patients with colorectal cancer. However, there are some opposed arguments considering ... ...

Abstract	Background and objectives: Deficient mismatch repair (MMR) status is associated with good prognosis but poor therapeutic response to adjuvant chemotherapy in patients with colorectal cancer. However, there are some opposed arguments considering therapeutic outcomes in patients with evidenced MMR deficiency in colorectal cancer. The aim of the study was the investigation of prognostic value and immunohistochemical analysis of the MMR-deficiency tumors. Materials and Methods: The study enrolled 104 patients with resected stage II and III colorectal cancer samples from the period 2018–2019. Results: The tumors with deficient MMR status were significantly associated with age up to 50 years and right-sided localization ( p < 0.001). During the follow-up period of 22.43 ± 6.66 months, 21 patients (20.2%) died, whereas 14 patients (13.5%) had relapses. The loss of mutL homologue 1/postmeiotic segregation increased 2 (MLH1/PMS2) expression, compared to proficient MMR tumors, was associated with shorter disease-free survival in patients with lymphovascular invasion ( p < 0.05), perineural invasion ( p < 0.01), stage III ( p < 0.05) and high-grade tumor ( p < 0.05). Conclusions: This retrospective pilot study of a single-center cohort of patients with stage II and III colorectal cancer highlights the clinical importance of using immunohistochemistry (IHC) analysis as a guide for diagnostic algorithm in a country with limited resources, but with a high prevalence of colorectal carcinoma in the young patients. MMR-deficiency tumors compared with proficient MMR colorectal cancer was not shown to be a significant predictor of disease-free and overall survival.
Keywords	adjuvant chemotherapy ; mismatch repair deficiency ; colorectal cancer ; immunohistochemical analysis ; Medicine (General) ; R5-920
Subject code	610 ; 616
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma

Nikola Jovanović / Tatjana Mitrović / Vladimir J. Cvetković / Svetlana Tošić / Jelena Vitorović / Slaviša Stamenković / Vesna Nikolov / Aleksandar Kostić / Nataša Vidović / Miljan Krstić / Tatjana Jevtović-Stoimenov / Dušica Pavlović

Medicina, Vol 55, Iss 2, p

2019 Volume 34

Abstract: Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA ... ...

Abstract	Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA methyltransferase ( MGMT ) gene promoter as a key prognostic factor in primary glioblastoma. The aim of our study was to screen Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Materials and methods: A cohort of 30 Serbian primary glioblastoma patients treated with radiation therapy and chemotherapy were analyzed for MGMT promoter methylation and correlated with clinical data. Results: MGMT methylation status was determined in 25 out of 30 primary glioblastomas by methylation-specific PCR (MSP). MGMT promoter hypermethylation was detected in 12 out of 25 patients (48%). The level of MGMT promoter methylation did not correlate with patients’ gender ( p = 0.409), age ( p = 0.536), and OS ( p = 0.394). Treatment with TMZ significantly prolonged the median survival of a patient (from 5 to 15 months; p < 0.001). Conclusions: Due to a small cohort of primary GBM patients, our study is not sufficient for definitive conclusions regarding the prognostic value of MGMT methylation for the Serbian population. Our preliminary data suggest a lack of association between MGMT promoter methylation and overall survival and a significant correlation of TMZ treatment with overall survival. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma.
Keywords	glioblastoma ; MGMT methylation ; temozolomide ; overall survival ; prognosis ; methylation-specific polymerase chain reaction (MSP) ; Medicine (General) ; R5-920
Subject code	570
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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