Head and neck cutaneous melanoma: 5-year survival analysis in a Serbian university center.

BACKGROUND: Head and neck melanoma (HNM) is specific from the anatomical and etiopathogenetic aspects. In addition to morphopathological parameters, rich vascularization and lymphatic drainage of the head and neck affect the occurrence of lymphogenic and hematogenous metastases, as well as the metastases on both sides of the neck. METHODS: A retrospective cross-sectional study included cutaneous melanoma patients who underwent surgery at a clinical center over a 10-year period. The clinical follow-up was at least 60 months. The Kaplan-Meier method was used for the survival analysis. The predictor effect of certain independent variables on a given dichotomous dependent variable (survival) was measured by the Cox regression analysis. RESULTS: The analysis of demographic and clinical characteristics of 116 patients with HNM revealed that there was no statistically significant difference in age and gender in the total sample. Thirty-three (28.45%) patients were already in stage III or IV of the disease at the first examination, which affected the overall survival rate. The overall 5-year survival was 30.2%. No statistically significant difference in 5-year survival was found in relation to age and location. The period without melanoma progression decreased progressively in the advanced stage. Forty-nine patients (42%) underwent surgery for lymphogenic metastases in the parotid region and/or neck during the follow-up. CONCLUSIONS: Patients with HNM included in this study frequently presented an advanced stage of the disease at the first examination, which is reflected in a low rate of 5-year survival. Early diagnosis and adequate primary treatment can ensure longer survival.

The importance of Myd88 L265P mutation, clinical and immunohistochemical prognostic factors for the survival of patients with diffuse large B-cell non-Hodgkin lymphoma treated by immunochemotherapy in southeast Serbia.

PURPOSE: Immunochemotherapy used in the treatment of non-Hodgkin diffuse large B-cell lymphoma (DLBCL) modifies the course of disease and has a positive effect on overall survival (OS). The purpose of this study was to verify the existence of the important Myd 88 mutation and other immunohistochemical factors on disease prognosis in patients with DLBCL in southeast Serbia. METHODS: Immunohistochemical expression of CD10, Bcl- 2, Bcl-6, Ki-67 and MUM 1 was performed using paraffin blocks of DLBCL. Molecular-genetic study of MyD88 L265P gene polymorphism was done by isolation of genomic DNA from paraffin embedded tissue by means of polymerase chain reaction (PCR). RESULTS: Immunochemotherapy (rituximab+CHOP/R-CHOP) significantly improved the overall survival (OS) of patients with DLBCL compared with patients treated with CHOP alone (p<0.0001). OS in the R-CHOP group was longest in patients with International Prognostic Index (IPI) 2 score (p=0.012) and IPI 4 score (p=0.024). Patients with Bcl-2 +, and MUM 1+ benefited from R-CHOP and their expression had no effect on OS. Analysis of restriction fragment length on the genomic DNA showed a homozygous normal TT genotype. CONCLUSION: Addition of rituximab to CHOP standard protocol improved the OS rate in patients with DLBCL and altered the character and significance of previously recognized prognostic factors. IPI score in the immunochemotherapy era could not reveal possible predictive factors of poor prognosis which would help identify a high-risk subgroup of newly diagnosed DLBCL. In the patient population from Southeast Serbia pathological signaling pathway achieved by Myd 88 L265 mutation was not responsible for the development of DLBCL.

Comparison of weight and length at birth of non-Roma and Roma newborn in Serbia.

OBJECTIVES: Roma infants tend to be smaller and are diagnosed as SGA more often than non-Roma infants, suggesting that specific anthropometric norms for these infants may be useful. We aimed to construct population-based centile, gender-specific charts for birth weight and length for singleton Roma infants born from 35 to 42 weeks of gestation and to compare it with anthropometric data of non-Roma infants. METHODS: We analyzed data on 27,602 non-Roma (53 % males) and 2235 Roma (51 % males) singleton live infants delivered from 2006 to 2012 in South East Serbia. The LMS method was used to estimate the birth weight and length centiles. RESULTS: Roma infants were up to 12 % lighter and up to 4 % shorter than non-Roma infants. Estimated centile charts for Roma males and females were constructed showing the 3rd, 10th, 25th, 50th, 75th, 90th and 97th centiles. CONCLUSIONS: We created the separate centile charts for Roma ethnic group. The sample size was sufficient to demonstrate differences in mean birth weights and lengths of at term infants born during the study period.

Therapeutic efficacy of clindamycin gel as an adjunct to scaling and root planing therapy in chronic periodontal disease.

Clindamycin, a lincosamide antibiotic, has been under-recognized as an antimicrobial agent for use in dentistry. The aim of the present work was to evaluate clinical efficacy of 2% clindamycin gel in addition to the basic mechanical periodontal therapy. At baseline, scaling and root planing (SRP) was performed at all 50 subjects (control group and test group). Clindamycin gel was applied after SRP only in the test group. Clinical measurements including periodontal pocket depth (PPD), clinical attachment level (CAL), bleeding on probing (BOP) and plaque index (PI) were done at baseline, and at 3 and 6 months after treatment. Compared to baseline, the PPD and CAL values significantly decreased in the test group (p < 0.05) and were statistically lower (p < 0.05) compared to control group. PPD reduction of 2.42 mm was obtained in the test group and could be generally considered as clinically significant. A PPD reduction greater than 2 mm indicated that clindamycin gel could be used efficiently as an adjunct to SRP. Also, between-group difference in BOP and PI scores was statistically significant 6 months after treatment. In conclusion, the application of clindamycin gel in combination with SRP enhanced the efficacy of non surgical periodontal therapy in reducing pocket depth and improving attachment levels in chronic periodontitis subjects and had additional benefits over mechanical therapy alone.

Effect of periodontal treatment in renal transplant recipients.

OBJECTIVE: To evaluate the effect of periodontal treatment on gingival overgrowth in a group of renal transplant patients. SUBJECTS AND METHODS: Twenty-five renal transplant recipients receiving immunosuppressive therapy with cyclosporine A (CsA) were randomly assigned to 2 groups. Group 1 (n = 15) included patients who had been specifically referred to a dental clinic to prevent gingival overgrowth and were given full periodontal therapy. Group 2 (n = 10) was comprised of patients who did not receive any professional periodontal cleaning. Patients from both groups were examined to determine their periodontal status before and after 3, 6 and 12 months in terms of their plaque index, gingival index and gingival overgrowth. During the examination, their overall health was stable. RESULTS: For group 1, the scores were 1.89 (baseline), 0.98 (6 months) and 0.56 (12 months), and hence there were significant reductions (p = 0.0001). The gingival indices were 1.71 (baseline), 0.76 (6 months) and 0.35 (12 months), and the reductions were also significant (p = 0.0001). A significant association was observed between poor oral hygiene and the degree of gingival overgrowth. The 1-year post-treatment follow-up showed that patients in group 1 did not develop gingival overgrowth due to the use of CsA as group 2 did without prior periodontal therapy. CONCLUSION: Oral hygiene status was the most important variable related to the development and degree of gingival overgrowth due to the use of CsA.

Tacrolimus as a part of immunosuppressive treatment in kidney transplantation patients: sex differences.

BACKGROUND: Metabolism interaction between corticosteroids and tacrolimus (Tac) exists and can be an important factor in providing rational pharmacotherapy in kidney transplantation patients. Both Tac and corticosteroids can induce adverse metabolic effects, such as hyperglycemia, post-transplantation diabetes mellitus, and dyslipidemia. OBJECTIVE: The main goal of this study was to detect corticosteroid dose influence on Tac level within the first 6 months of immunosuppressive therapy. The secondary goal of this research was to investigate sex differences on Tac-corticosteroid interaction. We also monitored biochemical-parameter changes, which are related to immunosuppressive treatment. METHODS: This retrospective pharmacokinetic study included 30 Serbian patients after kidney transplantation. Patients received a quaternary immunosuppressive regimen including Tac, mycophenolate, mofetil, basiliximab, and corticosteroids. To compare dose-normalized level and dose of Tac in different days after transplantation, we performed the Friedman test and Wilcoxon matched-pairs signed rank sum test. Mann-Whitney test was performed to compare differences in dose of Tac, level of Tac, and dose-normalized level of Tac between male and female patient groups. We used the Friedman test to compare biological and clinical data. RESULTS: Obtained results show statistical significance between dose of Tac on day 180 post transplantation and dose on days 7, 14, 21, and 60 post transplantation. There was a statistical difference in dose-normalized level of Tac between days 7 and 21 post transplantation (P < 0.01), days 7 and 60 (P < 0.01), and between days 7 and 180 (P < 0.05). There is a statistical significance between male and female levels of Tac on day 21 after transplantation (P < 0.01). Significance also exists on day 60 after transplantation between male and female dose-normalized levels (P < 0.05). There is also a statistical difference in glucose, cholesterol, triglyceride, serum creatinine, and urea level and activity of alanine aminotransferase and alkaline phosphatase before and after operation. CONCLUSION: Our study shows that dose of corticosteroid affects Tac level in kidney transplantation patients. Tac dose and level changes showed that corticosteroid-Tac interaction has more influence on male than female patients. According to biochemical monitoring, the immunosuppressive therapy used at present is quite well tolerated.

Angiogenesis in upper tract urothelial carcinoma associated with Balkan endemic nephropathy.

Upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN) is characterized by a number of aberrations in cell-cycle regulation and apoptosis. The aim of this study was to detect angiogenesis-related marker(s) specific for BEN UTUC, and to examine the influence of HIF 1α upon angiogenesis and apoptosis in UTUC. Present investigation included 110 patients with UTUC, 50 from BEN region and 60 control tumors. Altered expression of VEGFR1 was more often present in control UTUC than in BEN tumors (p<0.005). It was associated with high grade, low and high stage, solid growth, and metaplastic change of control UTUC. Microvessel density assessed by CD31 (MVD CD31) was significantly higher in UTUC with lymphovascular invasion (p<0.05), and in BEN tumors with papillary growth (p<0.05). Discriminant analysis indicated that BEN and control tumors do not differ significantly in expression of angiogenesis related markers. The most important discriminant variable that determined control UTUC was expression of VEGFR1 (p=0.002). HIF 1α in UTUC significantly correlated with the low stage, papillary growth and expression of Bcl-2, Caspase-3 index, and MVD CD34 (p<0.001; 0.0005; 0.01; 0.005; 0.01, respectively). HIF-1α may be helpful marker in evaluation of UTUC, especially when combined with angiogenesis and apoptosis.

Pro- and antiapoptotic markers in upper tract urothelial carcinoma associated with Balkan endemic nephropathy.

The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper-tract urothelial carcinoma (UTUC) has been recently confirmed. The aim of this study was to determine apoptosis-related marker(s) specific for BEN-associated UTUC. Present investigation included 105 patients with UTUC, 44 from BEN region and 61 control tumors. Altered expression of Survivin was more often present in BEN UTUC with high grade and solid growth (P < 0.005; P < 0.05) than in control tumors. Significantly lower expression of proapoptotic marker Bax was found in BEN tumors with high grade, high stage, necrosis, and without metaplastic change (P < 0.05; 0.05; 0.05; 0.05) compared to control tumors with the same features. Group (BEN-related/control), stage, growth pattern, and caspase 3 activity were significantly associated with the expression of Bax (P = 0.002, 0.034, 0.047, 0.028, resp.,). This investigation identifies Bax as specific marker of BEN-associated UTUC. Decrease of pro-apoptotic protein Bax together with alteration of Survivin may be indicative for specific disturbances of intrinsic apoptotic pathway in UTUC arising in endemic areas.

[Incidence of lip and palate clefts in children in Nis from 1990 to 2007].

INTRODUCTION: Cleft lip and palate is a complex congenital anomaly of the orofacial system in children. OBJECTIVE: The aim of this study was to determine the incidence of live-born children with cleft lip and/or palate compared to the total number of children born in the period from January 1, 1990 to December 31, 2007. METHODS: Epidemiological investigation was based on the records of live-born children at the Hospital of Gynaecology and Obstetrics of the Clinical Centre Nis. The study included 61,116 live-born children, i.e. 56,905 full-term babies. RESULTS: The total number of registered clefts during the investigation period was 43 (22 boys and 21 girls). The most frequent were the secondary palate clefts (44.2%); combined cleft were present in 34.9%, while primary palate clefts were reported in 20.9%. In respect to the season and order of birth, there was no statistically significant difference in the frequency of the primary, secondary and complete palate clefts. The age of mothers was not identified as a risk factor for the occurrence of cleft lip and palate. CONCLUSION: In the studied period, 43 children were born with the cleft lip and/or palate, equally in boys as in girls. The secondary palate clefts were most frequent. The season and order of birth had no statistical influence on the occurrence of this anomaly.

Gender differences in pharmacokinetics of tacrolimus and their clinical significance in kidney transplant recipients.

BACKGROUND: The possible influence of gender on tacrolimus disposition and response in kidney transplant recipients is an issue of medical importance. OBJECTIVE: The aim of this study was to detect interpatient pharmacokinetic variability of tacrolimus due to patients' gender and to assess the predictability of individual tacrolimus concentrations using abbreviated AUC measurements. The secondary objective was to find the best sampling time to predict the exposure of tacrolimus in kidney transplant recipients. METHODS: Gender-related first oral dose tacrolimus pharmacokinetics studies were conducted in 20 Serbian kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first tacrolimus oral dose (0.05 mg/kg) was given on day 5 post-transplant. Blood concentrations were measured by microparticle enzyme immunoassay method. Associations between each sampling time point of concentrations and 12 hours after the administration AUC (AUC(0-12)) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. RESULTS: AUC(0-12) showed remarkable interindividual variations after the first tacrolimus oral dose. There were significantly lower values of AUC in women than men (P < 0.05). The most important time point influencing AUC(0-12) was the concentration of tacrolimus measured 2 hours after administration(C(2)) in women, whereas in men the most important time points were the concentrations at 1 (C(1)), 4 (C(4)), and 12 (C(12)) hours as an abbreviated AUC. CONCLUSION: Our results show significant differences between men and women. C(2) seems to be indicator of total body exposure to tacrolimus in the early period after kidney transplant in women. The three-point sampling method seems to be a good indicator of abbreviated AUC for a tacrolimus monitoring strategy in men.

Divergent squamous differentiation in upper urothelial carcinoma-comparative clinicopathological and molecular study.

Upper urothelial carcinoma (UUC) has a plasticity to demonstrate divergent differentiation with squamous metaplastic elements. There was no previous study exploring profiling of molecular markers in metaplastic squamous upper urothelial carcinoma (SUUC) and conventional upper urothelial carcinoma (CUUC). The aims of this study was to compare expression of the phenotypic characteristics of tumors and molecular markers (p53, p16, cyclin D1, E-cadherin, HER-2, Ki-67, Bcl-2, Bax) in SUUC and CUUC. SUUC was detected in 20% of 44 patients. There was significant difference between SUUC and CUUC in the pathological stage, grade, growth and presence of lymphovasular invasion (p < 0.05; 0.05; 0.05; 0.01 respectively). The mean Ki-67 and p53 labeling index was significantly higher in SUUC than in CUUC (p < 0.05; 0.05). There was no significant difference in the expression of p16, cyclin D1, E-cadherin, HER-2, Bcl-2 and Bax between SUUC and CUUC. Univariant model showed that SUUC was significantly associated with lymphovascular invasion (p = 0.007), Ki-67 activity (p = 0.016) and growth (p = 0.026). Exploration of UUC with squamous divergent differentiation showed changes in phenotypic characteristics and Ki-67, as well as similar molecular profile with CUUC.

White blood cell count in different stages of chronic periodontitis.

Periodontal disease is considered to be an inflammatory disorder that is related to the accumulation of oral microbial biofilm and the host response to this accumulation. The host reaction to gingival microorganisms is characterized in part by increase in the polymorphonuclear leukocyte counts, which is one of the most important steps in host defense. Exaggerated leukocytes and neutrophils of host response are a very important component in the pathogenesis of periodontal disease. The purpose of this study was to investigate the relationship between white blood cell count and periodontal disease in subjects with moderate and severe periodontitis and in control subjects with healthy periodontal tissues. Leukocytes for the present study were obtained from peripheral venous blood of 50 patients with moderate periodontitis, 50 patients with severe periodontitis and 25 healthy subjects. The clinical parameters of periodontitis including plaque index, bleeding on probing and gingival index were determined in all study subjects. In both moderate and severe periodontitis, the results indicated a significantly higher count ofneutrophils (P < 0.001), as well as of both lymphocytes and total leukocytes (P < 0.05). The values of clinical parameters (plaque index, gingival index and bleeding on probing) also showed significant between-group differences (P < 0.005 and P < 0.001, respectively). It is possible that there is a significant relationship between total leukocyte count, neutrophil count and different forms of periodontal disease.

Clinical pharmacokinetics of tacrolimus after the first oral administration in renal transplant recipients on triple immunosuppressive therapy.

Monitoring of tacrolimus blood concentration is of utmost importance in the management of renal transplant recipients because of Narrow Therapeutic Index and highly variable pharmacokinetics. The aim of this study was to detect inter-patient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times of the area under the curve (AUC) seeking to find the best sampling time to predict the exposure of tacrolimus in renal transplant recipients with triple therapy. This oral dose tacrolimus pharmacokinetics study was conducted in 18 Serbian renal transplant recipients on triple immunosuppressive therapy, including basiliximab. The first oral dose of tacrolimus (0.05 mg/kg) was given on day 5 post-transplant; blood concentration was measured by microparticle enzyme immunoassay method. Associations between each sampling time-point of concentrations and AUC(12) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses. The variance in the strength of association between predicted AUC (AUC(p)) and AUC(12) was reflected by linear regression coefficients. AUC(12) showed remarkable inter-individual variations after the first oral dose of tacrolimus. The area of the maximum AUC was four times higher than that of the minimum AUC. C(4) seems to be an indicator of total body exposure to tacrolimus. Alternatively, the concentrations at 1.5, 4 and 8 hr as an abbreviated AUC were as good a predictor as a full pharmacokinetic study. Our results show a significant difference between men and women. A three-point sampling method seemed to be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.

Extended orbital exenteration in the treatment of advanced periocular skin cancer with primary reconstruction with a galeacutaneous flap.

Extended orbital exenteration includes the removal of orbital contents together with the surrounding orbital wall(s). Skin cancers (basal cell cancer and squamous cell skin cancer) arising in the periorbital region could present as invasive tumours infiltrating the orbit and orbital walls. We describe the treatment of advanced invasive skin cancers of the periorbital region by extended orbital exenteration. A retrospective consecutive series over a nine-year period, included 21 extended orbital exenterations treated in a tertiary referral centre. The margins of excision were clear in 18. Twenty postoperative defects were reconstructed using galea-skin flaps, and one defect was left to heal by secondary intention. Two patients died of their disease during the three-year follow up. The reconstruction with frontal or frontoparietal galea-skin flap is a suitable option. The technique is versatile and simple, and gives acceptable aesthetic results. The operating time is shorter than that required for microvascular reconstructions, and the complication rate is low. The secondary defect can be closed primarily or by skin grafting. Extended orbital exenteration offers the best chances of cure in the treatment of non-melanotic skin cancers that have infiltrated the orbit and orbital walls.

E-cadherin expression in upper urothelial carcinoma in Balkan Endemic Nephropathy and non-endemic regions.

There is a high incidence of upper urothelial carcinoma (UUC) in regions affected by Balkan Endemic Nephropathy (BEN). The aim of this study was to compare E-cadherin expression in UUC, in regions affected by BEN, and in control rural and city populations free of BEN. Another aim was to determine the influence of some morphological parameters on the E-cadherin status. In the samples of 85 UUC patients, of whom 40 lived in BEN settlements and 45 served as control subjects, immunoreactions were performed using monoclonal anti-human E-cadherin antibody. Aberrant expression of E-cadherin was more frequent in BEN tumors than in control tumors (p<0.01). Decreased E-cadherin expression was linked to high grade and solid growth in control and BEN tumors (p<0.0001 and <0.05 versus p<0.05 and <0.05, respectively), and to the stage in control tumors (p<0.01). However, BEN low grade and low stage tumors showed aberrant expression more often than did control tumors (p<0.05 and <0.005, respectively). In control tumors, using univariate analysis, E-cadherin status was found to be influenced by grade, stage, and tumor growth (p=0.001, 0.017, 0.015, respectively). In the same group, only the grade was significant according to multistep logistic regression analysis (Wald=6.429 and p=0.011). The growth pattern had a predominant influence on E-cadherin expression in BEN tumors (p=0.005). A significant influence on normal membranous or abnormal cytoplasmic expression of E-cadherin in UUC is exerted by tumor grade, stage, growth, and metaplastic change (p=0.002, 0.048, 0.019, 0.011, respectively), but only by tumor grade in the multistep logistic regression model. These results suggest that decreased expression of E-cadherin in BEN tumors may be linked to tumor growth, while expression of E-cadherin in control tumors may be associated with tumor grade.