Revisiting beta-2 microglobulin as a prognostic marker in diffuse large B-cell lymphoma.

BACKGROUND: Several clinical prognostic models for diffuse large B-cell lymphoma (DLBCL) have been proposed, including the most commonly used International Prognostic Index (IPI), the National Comprehensive Cancer Network IPI (NCCN-IPI), and models incorporating beta-2 microglobulin (ß2M). However, the role of ß2M in DLBCL patients is not fully understood. METHODS: We identified 6075 patients with newly diagnosed DLBCL treated with immunochemotherapy registered in the Danish Lymphoma Registry. RESULTS: A total of 3232 patients had data available to calculate risk scores from each of the nine considered risk models for DLBCL, including a model developed from our population. Three of four models with ß2M and NCCN-IPI performed better than the International Prognostic Indexes (IPI, age-adjusted IPI, and revised IPI). Five-year overall survival for high- and low-risk patients were 43.6% and 86.4% for IPI and 34.9% and 96.2% for NCCN-IPI. In univariate analysis, higher levels of ß2M were associated with inferior survival, higher tumor burden (advanced clinical stage and bulky disease), previous malignancy and increased age, and creatinine levels. Furthermore, we developed a model (ß2M-NCCN-IPI) by adding ß2M to NCCN-IPI (c-index 0.708) with improved discriminatory ability compared to NCCN-IPI (c-index 0.698, p < 0.05) and 5-year OS of 33.1%, 56.2%, 82.4%, and 96.4% in the high, high-intermediate, low-intermediate and low-risk group, respectively. CONCLUSION: International Prognostic Indices, except for NCCN-IPI, fail to accurately discriminate risk groups in the rituximab era. ß2M, a readily available marker, could improve the discriminatory performance of NCCN-IPI and should be re-evaluated in the development setting of future models for DLBCL.

Trends in oesophageal cancer mortality in Montenegro, 1990-2018.

BACKGROUND: Oesophageal cancer (OC) is a significant public health issue, despite the decreasing trends in OC mortality rates observed globally in the past decades. The objective of our study is to analyze the pattern of OC mortality in Montenegro between 1990 and 2018 and contribute to the development of a national long-term strategy for the prevention and control of this malignancy. METHODS: The data on OC death cases in Montenegro between 1990 and 2018 were collected. The mortality rates were standardized according to the World Standard Population. The Joinpoint, Linear and Poisson regressions were applied to analyze the OC mortality trend. RESULTS: Joinpoint regression analysis showed an increase in death rates for men and the overall level which were not statistically significant. However, the number of cases increases significantly with an average annual percentage change (AAPC) increase of 2.6% for the overall level [AAPC (95% CI)=2.6 (1.0-4.2); P = 0.002] at the expense of the increase in men, which on average was 2.6% annually [AAPC (95%CI) = 2.6 (1.2-4.1); P = 0.001]. The age groups 55-64 and 65-74 have the highest percentage of deaths cases from OC with 30.6% and 31.4%, respectively. CONCLUSION: Montenegro has witnessed a recent increase in the number of deaths from OC, although the mortality rates remain stable. National strategies to further reduce mortality rates for OC are necessary. Individuals aged 55-64 and 65-74 need specific attention during the ongoing monitoring of this cancer.

Venous thromboembolism in patients with acute myeloid leukemia: development of a predictive model.

BACKGROUND: Patients with acute myeloid leukemia (AML) are at increased risk of venous thromboembolic events (VTE). However, thromboprophylaxis is largely underused. OBJECTIVES: This study aimed to determine possible VTE development risk factors and to develop a novel predictive model. METHODS: We conducted a retrospective cohort study of adult patients with newly diagnosed AML. We used univariate and multivariable logistic regression to estimate binary outcomes and identify potential predictors. Based on our final model, a dynamic nomogram was constructed with the goal of facilitating VTE probability calculation. RESULTS: Out of 626 eligible patients with AML, 72 (11.5%) developed VTE during 6 months of follow-up. Six parameters were independent predictors: male sex (odds ratio [OR] 1.82, 95% confidence interval [CI]: 1.077-2.065), prior history of thrombotic events (OR 2.27, 95% CI: 1.4-4.96), international normalized ratio (OR 0.21, 95% CI: 0.05-0.95), Eastern Cooperative Oncology Group performance status (OR 0.71, 95% CI: 0.53-0.94), and intensive therapy (OR 2.05, 95% CI: 1.07-3.91). The C statistics for the model was 0.68. The model was adequately calibrated and internally validated. The decision-curve analysis suggested the use of thromboprophylaxis in patients with VTE risks between 8 and 20%. CONCLUSION: We developed a novel and convenient tool that may assist clinicians in identifying patients whose VTE risk is high enough to warrant thromboprophylaxis.

Should we use nomograms for risk predictions in diffuse large B cell lymphoma patients? A systematic review.

Models based on risk stratification are increasingly reported for Diffuse large B cell lymphoma (DLBCL). Due to a rising interest in nomograms for cancer patients, we aimed to review and critically appraise prognostic models based on nomograms in DLBCL patients. A literature search in PubMed/Embase identified 59 articles that proposed prognostic models for DLBCL by combining parameters of interest (e.g., clinical, laboratory, immunohistochemical, and genetic) between January 2000 and 2024. Of them, 40 studies proposed different gene expression signatures and incorporated them into nomogram-based prognostic models. Although most studies assessed discrimination and calibration when developing the model, many lacked external validation. Current nomogram-based models for DLBCL are mainly developed from publicly available databases, lack external validation, and have no applicability in clinical practice. However, they may be helpful in individual patient counseling, although careful considerations should be made regarding model development due to possible limitations when choosing nomograms for prognostication.

Trends in gastric cancer mortality in Montenegro, 1990 - 2018: joinpoint regression.

Background Gastric cancer (GC) remains a significant global public health problem, despite the decreasing trends in GC mortality rates in the last five decades. Our study aimed to examine the pattern of GC mortality in Montenegro between 1990 and 2018 and to contribute to the future designing a national long-term strategy for the control and prevention of GC. Methods Gastric cancer mortality data in Montenegro from 1990 to 2018 were collected. Mortality rates were age-standardized to the World Standard Population for estimating both the overall and gender-specific trends. The joinpoint regression model was used to assess GC mortality and identified significant changes in the linear time trend. Linear and Poisson regressions were also applied for additional trend analyses. Results Joinpoint regression reveals a statistically significant decrease in the age-standardized rate for the overall level, on average by 1.4% per year (AAPC (95% IP)= -1.4 (-2.4)-(-0.4); P= 0.007), which was due to a decrease in the age-standardized rate in men with an average annual change of -1.8% (AAPC (95% IP)= -1.8 (-2.9)-(-0.6); P=0.003), while in women the rates were stable (p=0.565). The results for age groups indicate that a decline was registered at the overall level, and among men, as a consequence of the trend of decreasing age-specific rates for the age group 55-64 on average annually by 2% among men (AAPC (95% IP)= -2 ((-3.8)-(-0.1)); P=0.035), and for the overall level (AAPC (95% IP)= -2 ((-3.7)-(-0.3)); P=0.026). Conclusions Our findings indicate a noteworthy decline in age-standardized overall GC mortality rates among men in Montenegro, while rates for women have remained constant. National strategies to further reduce mortality rates for GC are necessary.

Diagnostic and prognostic value of 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT in a single-center cohort of neuroendocrine tumors.

Introduction: The aim was to assess the diagnostic value of 99mTc-Tektrotyd scintigraphy (TCT) and positron emission tomography/computed tomography using F-18 fluorodeoxyglucose (18F-FDG PET/CT) in the detection and follow-up of neuroendocrine tumors (NETs), and their predictive value for disease progression. Material and methods: In this retrospective cohort, TCT and 18F-FDG PET/CT were performed in 90 patients (37 men, 53 women, mean age 52.7 ±15.1), with NET. Correlation of Ki67 and tumor grade versus Krenning score and SUVmax was assessed, Kaplan-Meier analysis was used for progression-free survival (PFS), and Cox regression analysis was performed to identify the association between progression-related factors and PFS. Results: Out of 90, true positive TCT was detected in 56 (62.2%) patients, true negative in 19 (21.1%), false positive in 4 (4.4%), false negative in 11 (12.2%), while 18F-FDG PET/CT was true positive in 69 (76.7%) patients, true negative in 10 (11.1%), false positive in 5 (5.5%), false negative in 6 (6.7%). Mean 18F-FDG PET/CT SUVmax was 6.8 ±6.2. Diagnostic sensitivity of TCT was 83.6%, specificity 82.6%, accuracy 83.3% vs. 18F-FDG PET/CT sensitivity was 92.0%, specificity 66.7%, accuracy 87.8%. A significant correlation between Ki67 and SUVmax was found in positive 18F-FDG PET/CT findings, unlike the correlation between Ki67 and Krenning score. Median PFS was 25 months (95% CI: 18.2-31.8), in 18F-FDG PET/CT positive patients 23 months (95% CI: 16.3-29.7) and 18F-FDG PET/CT negative 26 months (p = 0.279). Progression-free survival predictors were SUVmax and Krenning score. Conclusions: In our study, TCT and 18F-FDG PET/CT have high diagnostic accuracy in detection of NET. Higher Krenning score on TCT and SUVmax in positive 18F-FDG PET/CT findings are predictors of disease progression. 99mTc-Tektrotyd scintigraphy and 18F-FDG PET/CT can be useful complementary tools in management of patients with NETs and in predicting patients' outcome.

Prognostic indices in diffuse large B-cell lymphoma: a population-based comparison and validation study of multiple models.

Currently, the International Prognostic Index (IPI) is the most used and reported model for prognostication in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). IPI-like variations have been proposed, but only a few have been validated in different populations (e.g., revised IPI (R-IPI), National Comprehensive Cancer Network IPI (NCCN-IPI)). We aimed to validate and compare different IPI-like variations to identify the model with the highest predictive accuracy for survival in newly diagnosed DLBCL patients. We included 5126 DLBCL patients treated with immunochemotherapy with available data required by 13 different prognostic models. All models could predict survival, but NCCN-IPI consistently provided high levels of accuracy. Moreover, we found similar 5-year overall survivals in the high-risk group (33.4%) compared to the original validation study of NCCN-IPI. Additionally, only one model incorporating albumin performed similarly well but did not outperform NCCN-IPI regarding discrimination (c-index 0.693). Poor fit, discrimination, and calibration were observed in models with only three risk groups and without age as a risk factor. In this extensive retrospective registry-based study comparing 13 prognostic models, we suggest that NCCN-IPI should be reported as the reference model along with IPI in newly diagnosed DLBCL patients until more accurate validated prognostic models for DLBCL become available.

COVID-19 and Cutaneous Squamous Cell Carcinoma-Impact of the Pandemic on Unequal Access to Healthcare.

Most skin tumors are not fatal, but if not treated in a timely manner, they can lead to significant morbidity. Due to the COVID-19 pandemic and in order to create more capacities for the treatment of COVID-19-positive patients as well as to contain the spread of the virus, the healthcare system was reorganized worldwide, leading to decreased access to preventive screening programs. The aim of this study was to evaluate the impact of the pandemic on healthcare accessibility to cutaneous squamous cell carcinoma patients in Serbia. This retrospective study was conducted at the Clinic for Burns, Plastic, and Reconstructive Surgery, University Clinical Center of Serbia in Belgrade. Patient demographics and pathohistological findings of tumors of patients living in and outside the capital in the period before, during, and after the pandemic were compared. The two groups did not show any differences regarding the largest tumor diameter prior and during the pandemic; however, this difference became extremely noticeable after the pandemic (15 mm vs. 27 mm; p < 0.001). While cSCCs are commonly slow-growing tumors, the impact of the COVID-19 pandemic is not negligible. This study found a population at a significant risk of cSCC metastasis, with additional evidence likely to emerge in the upcoming years.

Effects of successful parathyroidectomy on neuropsychological and cognitive status in patients with asymptomatic primary hyperparathyroidism.

PURPOSE: Besides typical clinical symptoms, primary hyperparathyroidism (pHPT) is associated with impaired quality of life and cognitive status. The aim of this study was to evaluate the quality of life and cognitive impairment in patients with pHPT, before and after parathyroidectomy. METHODS: We conducted a panel study, which included asymptomatic pHPT patients scheduled for parathyroidectomy. Besides demographic and clinical data, patients' quality of life and cognitive capacity were recorded before, 1 month, and 6 months following parathyroidectomy using the Short Form 36 questionnaire (RAND-36), Beck Depression Inventory (BDI), Depression Anxiety Stress Scales (DASS), Mini-Mental State Examination (MMSE), and Symptom Check List 90-revised version (SCL90R). RESULTS: During a 2-year follow-up, 101 patients entered the study (88 women), with an average age of 60.7 years. The Global score of RAND-36 test ameliorated by almost 50% 6 months after parathyroidectomy. The most sustained subscores of the RAND-36 test were role functioning/physical and health change, with an improvement of more than 125%. According to the BDI, DASS depression subscore, and SCL90R depression subscore, the extent of depressive symptoms reduction was approximately 60% 6 months postoperatively. The level of anxiety was reduced by 62.4%, measured by both the DASS and SCL90R anxiety subscores. The stress level was almost halved according to the DASS stress subscore (from 10.7 to 5.6 points). The results of the MMSE test showed a significant improvement postoperatively, for 1.2 points (4.4%). A worse preoperative score of each tool was related to the higher magnitude of improvement 6 months after parathyroidectomy. CONCLUSION: A considerable number of pHPT patients, even without other typical symptoms, show signs of impaired quality of life and neurocognitive status preoperatively. After a successful parathyroidectomy, there is an improvement in quality of life, declined levels of depression, anxiety, and stress, as well as amelioration of cognitive status. Patients with more impaired quality of life and pronounced neurocognitive symptoms may expect more benefits from the surgery.

Oligoelements in serum and intestinal tissue of pediatric IBD patients.

INTRODUCTION: Inflammatory bowel disease (IBD) develops through complex interplay of genetic, microbial, immune, and environmental factors. Trace elements alterations are commonly present in IBD and may have influence on IBD development. Heavy metal pollution is one of the major environmental issues nowadays and IBD incidence is rising in countries where industry starts to develop. Metals are implicated in processes that are connected to IBD pathogenesis. AIM: The aim of this study was to investigate toxic and trace element levels in pediatric population of IBD patients both in serum and intestinal mucosa. MATERIALS AND METHODS: This prospective study enrolled children newly diagnosed with IBD in University children's hospital in Belgrade. Concentrations of thirteen elements: Al, As, Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Se and Zn in serum and intestinal mucosa of 17 newly diagnosed children with IBD (10 Crohn's disease (CD) and 7ulcerative colitis (UC)) and 10 controls were assessed using inductively coupled plasma mass spectrometry (ICP-MS). Intestinal mucosa samples were taken from terminal ileum and six different colon segments (cecum, ascending colon, colon transversum, descending and sigmoid colon and rectum). RESULTS: The results demonstrated significant alterations in serum and intestinal mucosa concentrations of investigated elements. Serum iron was significantly decreased in IBD and CD group, compared to controls while serum Cu significantly differed between three investigated groups with highest concentration observed in CD children. Serum manganese was the highest in the UC subgroup. Terminal ileums of IBD patients contained significantly lower amount of Cu, Mg, Mn and Zn with Mn being significantly decreased also in CD patients compared to control. IBD patients' caecum contained significantly less Mg and Cu while colon transversum tissue samples from IBD and Crohn's patients contained significantly more chromium than controls. Moreover, sigmoid colon of IBD patients were poorer in Mg than controls (p < 0.05). Colon Al, As and Cd were significantly reduced in IBD, and UC children compared to control. Correlations of investigated elements in CD and UC groups were different from controls. Biochemical and clinical parameters showed correlation with element concentrations in intestines. CONCLUSION: Sera of CD, UC and control children significantly differ in Fe, Cu and Mn levels. Serum manganese was the highest in the UC subgroup creating the most prominent and only significant difference between UC and CD subgroups. Terminal ileum of IBD patients contained significantly lower amount of majority of investigated essential trace elements and toxic elements were significantly reduced in colon of IBD and UC patients. Investigation of macro- and microelement alterations in children and adults has potential to further elucidate IBD pathogenesis.

Arterial Thrombosis in Patients with Acute Myeloid Leukemia: Incidence and Risk Factors.

BACKGROUND: Patients with hematological malignancies have an increased risk of arterial thrombotic events (ATEs) after diagnosis, compared to matched controls without cancer. However, data about incidence and risk factors for ATE development in patients with acute myeloid leukemia (AML) are missing. AIM: The objectives of this study were to determine the incidence of ATE in non-promyelocytic-AML patients and to define the potential risk factors for ATE development. METHODS: We conducted a retrospective cohort study of adult patients with newly diagnosed AML. The primary outcome was the occurrence of confirmed ATE, defined as myocardial infarction, stroke or critical limb ischemia. RESULTS: Out of 626 eligible AML patients, 18 (2.9%) patients developed ATE in the median time of 3 (range: 0.23-6) months. Half of these patients died due to ATE complications. Five parameters were predictors of ATE: BMI > 30 (p = 0.000, odds ratio [OR] 20.488, 95% CI: 6.581-63.780), prior history of TE (p = 0.041, OR 4.233, 95% CI: 1.329-13.486), presence of comorbidities (p = 0.027, OR 5.318, 95% CI: 1.212-23.342), presence of cardiovascular comorbidities (p < 0.0001, OR 8.0168, 95% CI: 2.948-21.800) and cytogenetic risk score (p = 0.002, OR 2.113, 95% CI: 1.092-5.007). CONCLUSIONS: Our study showed that patients with AML are at increased risk of ATE. The risk was increased in patients with cardiovascular comorbidities, previous thrombosis, adverse cytogenetic risk as well as BMI > 30.

Prediction of Cervical Lymph Node Metastasis in Clinically Node-Negative T1 and T2 Papillary Thyroid Carcinoma Using Supervised Machine Learning Approach.

Papillary thyroid carcinoma (PTC) is generally considered an indolent cancer. However, patients with cervical lymph node metastasis (LNM) have a higher risk of local recurrence. This study evaluated and compared four machine learning (ML)-based classifiers to predict the presence of cervical LNM in clinically node-negative (cN0) T1 and T2 PTC patients. The algorithm was developed using clinicopathological data from 288 patients who underwent total thyroidectomy and prophylactic central neck dissection, with sentinel lymph node biopsy performed to identify lateral LNM. The final ML classifier was selected based on the highest specificity and the lowest degree of overfitting while maintaining a sensitivity of 95%. Among the models evaluated, the k-Nearest Neighbor (k-NN) classifier was found to be the best fit, with an area under the receiver operating characteristic curve of 0.72, and sensitivity, specificity, positive and negative predictive values, F1 and F2 scores of 98%, 27%, 56%, 93%, 72%, and 85%, respectively. A web application based on a sensitivity-optimized kNN classifier was also created to predict the potential of cervical LNM, allowing users to explore and potentially build upon the model. These findings suggest that ML can improve the prediction of LNM in cN0 T1 and T2 PTC patients, thereby aiding in individual treatment planning.

Invasive Fungal Infections: The Early Killer after Liver Transplantation.

BACKGROUND: Liver transplantation is a standard of care and a life-saving procedure for end-stage liver diseases and certain malignancies. The evidence on predictors and risk factors for poor outcomes is lacking. Therefore, we aimed to identify potential risk factors for mortality and to report on overall 90-day mortality after orthotopic liver transplantation (OLT), especially focusing on the role of fungal infections. METHODS: We retrospectively reviewed medical charts of all patients undergoing OLT at a tertiary university center in Europe. RESULTS: From 299 patients, 214 adult patients who received a first-time OLT were included. The OLT indication was mainly due to tumors (42%, 89/214) and cirrhosis (32%, 68/214), including acute liver failure in 4.7% (10/214) of patients. In total, 8% (17/214) of patients died within the first three months, with a median time to death of 15 (1-80) days. Despite a targeted antimycotic prophylaxis using echinocandins, invasive fungal infections occurred in 12% (26/214) of the patients. In the multivariate analysis, patients with invasive fungal infections had an almost five times higher chance of death (HR 4.6, 95% CI 1.1-18.8; p = 0.032). CONCLUSIONS: Short-term mortality after OLT is mainly determined by infectious and procedural complications. Fungal breakthrough infections are becoming a growing concern. Procedural, host, and fungal factors can contribute to a failure of prophylaxis. Finally, invasive fungal infections may be a potentially modifiable risk factor, but the ideal perioperative antimycotic prophylaxis has yet to be determined.

Factors associated with preoperative and early and late postoperative seizures in patients with supratentorial meningiomas.

OBJECTIVE: Risk factors for epilepsy in meningioma patients are not yet clearly defined, however, seizure freedom is a significant factor for quality of life after surgery. METHODS: We performed a retrospective study of the 333 adult patients who received surgery for supratentorial meningioma at our center. Various clinical, radiological, and surgical variables were included in the multivariate regression, and the outcomes measured were the occurrence of seizure(s) preoperatively, during the hospitalization, and during the follow-up period. RESULTS: A total of 89 (26.7%) patients experienced preoperative seizures, of whom 62.9% were seizure free after the surgery. Of 244 patients without epilepsy before surgery, 11.9% had at least one seizure postoperatively. In total, 63 of our patients (18.9%) experienced seizures after the surgery, of whom 20 had refractory epilepsy. Multivariate analysis identified the following predictors of preoperative seizures: the absence of headache (OR: 0.23, CI: 2.55-8.50), the presence of significant peritumoral edema (OR: 4.35, CI: 2.57-7.35), and younger age (OR: 0.97 per year increase, CI: 0.95-0.99). Factors associated with early postoperative seizures were: younger age (OR: 0.96 per year increase, CI: 0.93-0.99) and the presence of preoperative seizures (OR: 2.73, CI: 1.13-6.57), while the presence of preoperative seizures (OR: 4.73, CI: 2.05-10.92), tumor progression (OR: 5.38, CI: 2.25-12.89), and neurological worsening (OR: 5.21 CI: 1.72-15.81) were significant for late postoperative seizures. SIGNIFICANCE: Our results from a single-center meningioma cohort confirm, in general, data from some previous studies regarding patients' characteristics for both preoperative and overall postoperative epilepsy. Besides previously described risk factors, younger age was important for preoperative and early postoperative seizures. Epilepsy is common in patients with recurrence of meningioma, but the variables of significance for refractory seizures in these patients require further examination.

Platelet kinetics in patients with chronic immune thrombocytopaenia treated with thrombopoietin receptor agonists.

INTRODUCTION: Thrombopoietin receptor agonists (TPO-RAs) increase platelet counts (PC) in the majority of patients with chronic immune thrombocytopaenia (ITP). Platelet kinetics study (PKS) might contribute to the understanding of mechanisms that lead to durable response. OBJECTIVES: To evaluate the effects of TPO-RAs on PKS parameters in chronic ITP patients. METHODS: Fifteen chronic ITP patients, aged 59 years [range: 22-84], female/male: 10/5, splenectomised 7/15, were treated with TPO-RAs (eltrombopag/romiplostim: 11/4). Durable response was defined as PC ≥30 × 109 /L at 6 months. Autologous 111 Indium-oxinate PKS was performed before and 5 months after TPO-RAs initiation. Accordingly, platelet survival (PS), platelet turnover, production ratio and sequestration site were assessed. RESULTS: Durable response was achieved in 13/15 of patients (eltrombopag/romiplostim: 10/3). Pre-treatment parameters were: PC 10 × 109 /L [range: 1-110], PS 0.5 days [range: 0.1-1.7 (normal values: 7-10)], platelet turnover 30 857 Plt/µL/day [range: 944-103 500] and platelet production ratio 0.64 [range: 0.01-3.2 (normal values: 1 ± 0.2)]. Post-treatment assessment showed significantly higher: PC 92.5 × 109 /L [range: 28-260, p = .001], PS 2.2 days [range: 0.1-3.6, p = .008], platelet turnover 70 213 Plt/µL/day [range: 2800-462 236, p = .02] and platelet production ratio 1.8 [range: 0.5-37.9, p = .011] compared to the pre-treatment values. Platelet sequestration site altered in 3/15 treated with TPO-RAs. CONCLUSIONS: TPO-RAs could increase PC by simultaneous increasing of platelet production and decreasing of platelet destruction.

The Expression of Hypoxia-Related Biomarkers: A Significance of HIF-1α C1772T Polymorphism as Predictor of Laryngeal Carcinoma Relapse.

INTRODUCTION: The association between the expression of HIF-1α in the laryngeal carcinoma and the prognosis of disease is quite well documented, but the significance of HIF-1α C1772T polymorphism and its relation to disease phenotype have to be clarified. The aim of this study was to investigate the influence of C1772T polymorphism on the clinical-pathological characteristics and disease-free survival after initial surgical treatment of patients with laryngeal carcinoma. MATERIALS AND METHODS: The prospective cohort study included 65 patients with laryngeal carcinoma. Two representative tumor tissue specimens were taken in each patient during surgery; 1 specimen was used to asses HIF-1α C1772T polymorphism and the other 1 to determine the immunohistochemical expression of HIF-1α, VEGF, as well as CD 34 proteins. The comparison of polymorphism frequency between study and control population was conducted by collecting a 5 mL of peripheral venous blood samples in each subject. RESULTS: Clinicopathological characteristics of laryngeal carcinoma didn't affect the expression of hypoxia-related biomarkers, such as HIF-1α, VEGF or MVD. The statistically significant association between HIF-1α and VEGF expression was found (P = .034), but not between HIF-1α expression and MVD value (P = .696). The expression of HIF-1α was significantly higher among CT heterozygotes (P = .029). We found a significantly more recurrence among CT heterozygotes compared with patients with CC homozygous alleles (57.10% and 24.30%, respectively; P = .007). Patients with C1772T polymorphic variants had significantly worse disease-free survival compared with patients without polymorphism (Log-rank test, P = .007). CONCLUSION: HIF-1α C1772T polymorphism was significantly associated with worse disease-free survival which nominates it as a predictor of laryngeal carcinoma relapse. The preoperative assessment of hypoxia-related biomarkers should be used in everyday practice in order to determine the treatment modalities for laryngeal carcinoma.

Serum Uromodulin, a Potential Biomarker of Tubulointerstitial Damage, Correlates Well with Measured GFR and ERPF in Patients with Obstructive Nephropathy.

Background and Objectives: In chronic kidney obstruction, the severity of tubulointerstitial damage correlates best with the loss of kidney function and the risk for progression to end-stage kidney disease. The present study aimed to investigate the potential clinical significance of serum uromodulin (sUmod) as a marker of early kidney disfunction in patient with obstructive nephropathy (ON). Materials and Methods: Serum Umod level was measured by sensitive ELISA method in 57 adult patients with obstructive nephropathy and 25 healthy subjects in control group. Kidney function was precisely evaluated via measured glomerular filtration rate (mGFR) (renal clearance of 99 mTc-diethylenetriamine penta-acetic acid), effective renal plasma flow (ERPF) and Cystatin C level. Recruited patients were divided into subgroups based on the mGFR: group I­GFR ≤ 60 mL/min/1.73 m2 (N = 31), group II­GFR > 60 mL/min/1.73 m2 (N = 26). Results: A significantly lower level of serum uromodulin was measured in patients with ON (50.2 ± 26.3 ng/mL) compared to the control group (78.3 ± 24.5 ng/mL) (p < 0.001). The mean level of serum Umod was significantly different between group I (30.5 ng/mL ± 11.1) and group II (73.6 ng/mL ± 18.6) (p < 0.001), but not between group II (73.6 ng/mL ± 18.6) and control group (78.3 ± 24.5 ng/mL). There was a positive correlation between sUmod and mGFR (R = 0.757, p < 0.001) and ERPF (R = 0.572 p < 0.001), with lower sUmod levels in patients with impaired renal function. An inverse relationship was detected between sUmod and filtration markers­cystatin C (R = −0.625, p < 0.001), creatinine, urea and uric acid. ROC analysis of sUmod to differentiate between ON patients with GFR below 60 mL/min/1.73 m2 and above 60 mL/min/1.73 m2 resulted in AUC of 0.98 (p < 0.001, 95% CI 0.922 vs. 0.998) at a cut-off value of 46 ng/mL (specificity 96.8%, sensitivity 92.2%). Conclusions: The significant correlation of sUmod with kidney function parameters may imply potential clinical significance as a noninvasive biomarker of early kidney disfunction in obstructive nephropathy.

Circulating levels of IL-6 and TGF-ß1 in patients with prostate cancer undergoing radiotherapy: associations with acute radiotoxicity and fatigue symptoms.

BACKGROUND: The goal of research was to investigate the possible relations between serum concentrations of IL-6 and TGF-ß1, individual and clinical characteristics, and adverse effects of radiotherapy in patients with prostate cancer: acute and late genitourinary and gastrointestinal toxicity, and fatigue. METHODS: Thirty-nine patients with localized or locally advanced prostate cancer who were treated with radiotherapy were enrolled in this study. The acute radiotoxicity grades and fatigue levels were assessed during the radiotherapy and 1 month after the radiotherapy. Estimation of the late radiotoxicity was performed every three months in the first year, every four months in the second year, and then every six months. Serum levels of IL-6 and TGF-ß1 were determined before radiotherapy and after the 25th radiotherapy fraction by ELISA. RESULTS: The significant positive association between diabetes mellitus and changes in acute genitourinary toxicity grades during the radiotherapy was observed in prostate cancer patients. In addition, patients who were smokers had significantly higher maximum fatigue levels in comparison with patients who were non-smokers. The circulating IL-6 levels were significantly higher after the 25th radiotherapy fraction in comparison with levels determined before radiotherapy. The significant positive correlations between pretreatment TGF-ß1 levels and maximum genitourinary toxicity grades and between TGF-ß1 levels after the 25th fraction and genitourinary toxicity grades after the 25th fraction, were found. The pretreatment IL-6 concentrations and TGF-ß1 concentrations after the 25th fraction were positively correlated with maximum genitourinary toxicity grades. The IL-6 levels after the 25th fraction were positively associated with genitourinary toxicity grades after this fraction. The pretreatment IL-6 concentrations were significantly positively correlated with maximum fatigue scores. The significant positive correlation between IL-6 concentrations and fatigue scores after the 25th fraction was determined. The positive correlations between IL-6 and TGF-ß1 concentrations measured after the 25th fraction and maximum fatigue scores were observed. CONCLUSIONS: Our results suggest that serum levels of IL-6 and TGF-ß1 might influence the severity of acute genitourinary radiotoxicity and fatigue in patients with prostate cancer. Combining clinical parameters and circulating cytokine levels might be useful for the prediction of adverse reactions to radiotherapy.

Evaluation of Clinical and Genetic Determinants of Treatment OutCome In EGFR Mutation Positive Advanced Lung Adenocarcinoma.

Background: The aim of this research was to evaluate clinical and low-cost genetic determinants of treatment outcome in EGFR mutation positive advanced lung adenocarcinoma patients. Material and Methods: EGFR mutation testing and EGFR 181946C>T genotyping were performed in 101 advanced lung adenocarcinoma patients using qRT-PCR and PCR-RFLP, respectively. Progression-free survival was defined as the time from the start of TKI therapy to date of progression, and overall survival as the time from diagnosis to death from any cause. Pain level was evaluated using a Numerical Rating Scale and the Verbal Descriptor Scale. Statistical significance was considered for P < .05. Results: Patients were treated with EGFR-TKIs for a period of 1-39months (median 9), with a median PFS of 12.0 months (10.4-13.6, CI 95%), and a median OS of 19.0 months (15.1-22.7, CI 95%). The presence of pain was significantly correlated with the existence of bone (P < .001) and adrenal glands metastases (P = .029). Genetic factors did not have a direct impact on pain management but had a significant effect on the response to TKIs leading to pain alleviation. Conclusions: EGFR mutation subtype and the EGFR 181946 C>T SNP had a significant effect on the response to TKI inducing an indirect anti-dolorous effect.

Dual function miR-205 is positively associated with ER and negatively with five-year survival in breast cancer patients.

BACKGROUND: Precise molecular characterization of breast cancer, especially triple negative (TNBC) as the most lethal subtype, is needed to stratify patients for the individual treatment approach. MicroRNA-205 (miR-205) has tumor-suppressive and oncogenic functions across different cancers. Therefore, miR-205 might have a different role in TNBC and estrogen receptor (ER) positive BC. Our aim was to investigate how miR-205 expression is associated with ER/progesteron receptor status, clinical parameters, pathohistological characteristics of BC, and survival of patients METHODS: We determined miR-205 relative expressions in 73 primary breast tumors (50 TNBC and 23 ER+) by quantitative Real-time polymerase chain reaction (qPCR) and compared it to clinicopathological characteristics and outcome. RESULTS: The highest levels of miR-205 were in the ER+ /PR+ group, and the lowest in the TNBC group (p = 0.009). Significantly higher levels of miR-205 were also observed in the ER+ compared with the ER-negative group, regardless of the PR status (p = 0.002). Low miR-205 expression level was associated with prognostic stage III in TNBC samples (p = 0.049). Patients who received adjuvant chemotherapy had significantly lower levels of miR-205 (p = 0.016). Patients who received hormone therapy had significantly higher levels of miR-205 (p = 0.007). The low-miR-205 patients had significantly higher 5-year survival rates (p = 0.041). CONCLUSION: The expression of miR-205 in BC is subtype-specific and high expression is associated with the ER+ tumors. The miR-205 expression might be a useful marker of TNBC progression. High miR-205 expression had a detrimental effect on BC patient outcome. Our results indicate that miR-205 might be utilized in clinical practice as a biomarker and an adjunct parameter for the selection of the most effective therapeutic modality.