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Aleksandar Bogdanovic,1,2 Jovana Despotovic,3 Danijel Galun,1,2 Nemanja Bidzic,1,2 Aleksandra Nikolic,3 Jovana Rosic,2 Zoran Krivokapic1,2,4 1HPB Unit, Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade, 11 000, Serbia; 2School of Medicine, University of Belgrade, Belgrade 11 000, Serbia; 3Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, 11 000, Serbia; 4Serbian Academy of Sciences and Arts, Belgrade 11 000, SerbiaCorrespondence: Aleksandar BogdanovicClinical Center of Serbia – Clinic for Digestive Surgery, Koste Todorovica 6, Belgrade 11 000, SerbiaTel +381 64 2461104Email aleksandarbogdanovic81@yahoo.comPurpose: There are limited data on expression of epithelial–mesenchymal transition (EMT) markers in patients with colorectal liver metastases (CRLM). The study aim was to evaluate the expression and prognostic significance of E-cadherin (CDH1), fibronectin (FN1) and vimentin (VIM) in patients with CRLM after curative-intent liver resection.Patients and Methods: Thirty patients with CRLM managed by curative-intent liver resection were included in this prospective pilot study. Blood samples, colorectal liver metastases and surrounding non-tumor liver tissue were collected. Expression of CDH1, FN1 and VIM was analyzed by quantitative real-time polymerase chain reaction. Expression in CRLM and non-tumor liver tissue was compared, while expression in serum was correlated with CRLM expression. One-year recurrence-free survival was compared between patients with low and high CDH1, FN1 and VIM expression.Results: The expression of CDH1 was similar in CRLM and non-tumor liver tissues, while FN1 and VIM expression was significantly lower in metastatic tissue (P=0.003 and pP< 0.001, respectively). Serum expression of CDH1 and VIM was detected in 66.7% and 93.3% of patients, respectively, while FN1 was not detected in any of the patients. The correlation of CDH1 and VIM expression between CRLM and serum was not statistically significant. Decreased CDH1 expression in CRLM and decreased VIM expression in serum were associated with early recurrence after surgical treatment of CRLM.Conclusion: Lower expression of CDH1 in CRLM and lower serum expression of VIM were found to be associated with early recurrence after liver resection for CRLM.Keywords: epithelial–mesenchymal transition, CDH1, VIM, FN1, colorectal liver metastasis, colorectal cancer

Assesses the design flows for the locations of the rainfall-runoff catchments in Serbia, Yugoslavia. Requirements for the design concept; Estimation of the design peak flows and volumes in the storm drainage system at the catchment; Return periods of flooding events.

From 4--7 December 1997 the 3rd International Workshop on Rainfall in Urban Areas took place in Pontresina, Switzerland. Forty-five participants from 20 countries around the world made it a success. Presentations and discussions represented a high scientific level without neglecting the practioners point of view. In fact, future trends, such as coupling of models of different origins for rainfall forecasting, detailed spatial analysis of rainfall, methods for quality control ofmeasured data, and aspects of climatic change were cornerstones of the workshop. In the following, the outcome of the sessions are briefly highlighted. (c) 1999 IAWQ. Published by Elsevier Science Ltd. [ABSTRACT FROM AUTHOR]

Traditional design method for urban drainage systems is based on design storms and its major drawback is that frequencies of peak flows in the system an considered equal to frequencies of design storms. An alternative is to use historical storms with rainfall-runoff models to produce a series of possible flows in the system and their frequencies. The latter approach involves more computations and can be laborious for larger catchments. This paper considers ways to reduce the set of historical storms to be involved in design procedure and yet to lead to realistic flow frequencies. Frequencies obtained by rainfall-runoff simulation at an experimental catchment are compared with frequencies of observed peak flows in the system. (c) 1998 Published by Elsevier Science Ltd. [ABSTRACT FROM AUTHOR]

Objectives: To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH)., Design: A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004-2014., Methods: Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with selected clinical variables. We constructed Kaplan-Meier curves and a Cox proportional hazards model to evaluate the impact of T/T on survival., Results: Two thousand, one hundred and nine children were sampled. The incidence density of thrombocytopenia was 1 per 57.9 (95% confidence interval [CI] 50.3-66.8) CWH-years. Thrombocytopenia was higher in children with WHO Stage III/IV, lower in children on zidovudine, and had no association with use of lamivudine or nevirapine, CD4 + suppression, age, and nutrition status. Thrombocytopenia was independently associated with 2.2-fold higher mortality (95% CI 1.62-3.08). The incidence density of thrombocytosis was 1 per 11.4 (95% CI 10.7-12.1) CWH-years. Thrombocytosis was associated with higher CD4 + cell count, younger age, and use of lamivudine or nevirapine, and did not impact survival., Conclusions: Platelet count is a clinically valuable biomarker of HIV clinical progression and mortality. Laboratory studies are necessary to elucidate the mechanisms of T/T., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Romiplostim is a thrombopoietin (TPO) receptor agonist approved for children and adults with immune thrombocytopenia (ITP) for ≥6 months, recommended as second-line treatment. This phase 3b, single-arm, multicenter study investigated long-term efficacy and safety of romiplostim in children ≥1 to <18 years old with ≥6 months' ITP duration and platelet counts ≤30 × 109/L. Children received weekly subcutaneous romiplostim (1 μg/kg titrated to 10 μg/kg) to maintain platelets within 50 to 200 × 109/L. A subset underwent bone marrow examinations. The primary end point was percentage of time with platelet response during the first 6 months' treatment (counts ≥50 × 109/L without rescue medication within the preceding 4 weeks). Overall, 203 patients (median age, 10.0 years) received ≥1 dose of romiplostim, median treatment duration was ∼3 years, and median average weekly dose was 6.9 μg/kg. Ninety-five (46.8%) discontinued (lack of efficacy, n = 43 [21.2%]). Platelet responses were achieved a median (interquartile range) of 50.0% (16.7%-83.3%) of the time during the first 6 months, increasing to 78.2% (26.7%-90.4%) during the overall 36-month treatment period. Eleven patients (5.4%) achieved sustained responses (consecutive counts ≥50 × 109/L without ITP medications for ≥24 weeks). Treatment-related adverse events (AEs) occurred in 56 patients (27.6%), with 8 (3.9%) experiencing serious treatment-related AEs; all of these led to discontinuation, including 4 cases of neutralizing antibodies (romiplostim, n = 3; TPO, n = 1). Bleeding occurred in 141 patients (69.5%), decreasing over time; grade ≥3 bleeding events occurred in 20 (9.9%). At year 2, eight of 63 evaluable patients (12.7%) had grade 2 reticulin. Long-term romiplostim resulted in sustained on-treatment platelet responses with an overall safety profile consistent with previous studies. This trial was registered at www.clinicaltrials.gov as #NCT02279173., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objectives: To establish the incidence, risk factors and prognostic effect of anemia in children living with HIV (CLWH)., Design: Retrospective nested case-control study of patients 0-18 years in five centers in sub-Saharan Africa, 2004-2014., Methods: Incident cases of anemia were identified from electronic records and matched with CLWH without anemia. We calculated the incidence density of anemia and used conditional logistic regression to evaluate its association with risk factors, stratified by severity and type of anemia. We used a Cox proportional hazards model to evaluate the impact of anemia on survival., Results: Two thousand, one hundred and thirty-seven children were sampled. The incidence density of anemia was 1 per 6.6 CLWH-years. Anemia was moderate in 31.8% and severe in 17.3% of anemia cases, which had 10-year mortality hazards of 3.4 and 4.5, respectively. Microcytic anemia (36% cases) was associated with 2.3-fold hazard of 10-year mortality, and with malnutrition and CD4 + suppression. Normocytic anemia (50.5% cases) was associated with 2.6-fold hazards of 10-year mortality, and with more severe malnutrition, CD4 + suppression, and WHO stage, but inversely associated with lamivudine and nevirapine therapy. Macrocytic anemia (13.5% cases) was neither associated with higher 10-year mortality nor with severe malnutrition or CD4 + suppression but was associated with WHO stage II/III and negatively associated with lamivudine therapy., Conclusion: This large multicountry study of CLWH found a high incidence density of anemia. Higher severity, normocytic and microcytic types of anemia were independently associated with long-term mortality. Laboratory studies are needed to decipher the mechanisms of anemia and how it impacts mortality in CLWH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Metastatic colorectal cancer (mCRC) patients are treated with standard chemotherapeutic drugs in the form of FOLFOX and FOLFIRI regimens. There are no reliable markers that could predict response to chemotherapy for mCRC. TGF-β signaling which interacts with microRNA (miRNA) network has important roles in tumor progression and chemotherapy resistance, thus the interplay between TGF-β signaling and miRNAs could be crucial for treatment response. The aim of this study was to analyze the effect of chemotherapy for mCRC on TGF-β signaling and related miRNAs. Hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p were selected out of 316 miRNAs with multiple targets within the TGF-β signaling by in silico analysis. SW620 cells were treated with chemotherapeutic drugs for mCRC for 1, 3 and 6 days and expression of selected miRNAs, PAI-1, CDH1 and VIM was measured. Expression of TGF-β signaling-related hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p was time-dependently altered in SW620 cells treated with chemotherapeutics for mCRC. The expression of hsa-miR-93-5p remained downregulated after 6 days under combined treatments FOX and FIRI as well as the hsa-miR-17-5p expression under FIRI. Chemotherapy regimens for mCRC increased expression of a major TGF-β signaling target gene PAI-1, independently of the selected miRNAs expression. These treatments also increased the expression of epithelial-mesenchymal transition (EMT) markers CDH1 and VIM on day 3 resulting in decrease of mesenchymal-like characteristics. However, their expression returned close to basal level on day 6. In conclusion, after initial response to chemotherapeutic drugs SW620 cells start to return close to the basal mesenchymal state while the long-term downregulated expression pattern of hsa-miR-93-5p and hsa-miR-17-5p makes them candidates worth testing as biomarkers for monitoring combined chemotherapeutic treatments therapy response in mCRC patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-β signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Eltrombopag is a thrombopoietin-receptor agonist used to restore platelet count to hemostatic levels in chronic immune thrombocytopenia. The drug has shown to have hepatobiliary adverse effects, but also positive interference with the analytical measurement of bilirubin. Understanding the degree of interference of this drug with bilirubin testing becomes relevant in the clinical management of these patients., Methods: Eltrombopag at concentrations ranging from 10 to 150 µg/ml was spiked into plasma samples with different baseline concentrations of bilirubin. Total bilirubin, conjugated, and unconjugated bilirubin were measured for each sample using VITROS TBILI and BuBc slides on the Vitros 5600 automated chemistry platform, and interference was assessed., Results: Plasma samples spiked with eltrombopag yielded falsely elevated bilirubin measurements compared to baseline, with the degree of elevation increasing with greater concentrations of eltrombopag. Bilirubin values were increased relative to baseline across all groups, except in conjugated bilirubin measurements in samples with low baseline conjugated bilirubin. For samples with low total bilirubin at baseline, >100 µg/ml of eltrombopag resulted in an error of >+0.6 mg/dl on the measured total bilirubin. For samples with low unconjugated bilirubin at baseline, the error for the same concentrations was >+0.7 mg/dl., Conclusion: Our results show that, at supra-physiologically high concentrations, eltrombopag can positively interfere with bilirubin measurements on Vitros 5600 platform., (© 2021 Wiley Periodicals LLC.)

Background: Treatment for chronic immune thrombocytopenia (cITP) in children is largely limited to immunosuppressive agents. Thrombopoietin receptor agonists (TRAs) have been used to treat cITP in adults for over a decade. The objective of this integrated analysis was to examine the safety and efficacy of the TRA romiplostim in children with ITP., Methods: We examined efficacy and safety in children with ITP across five romiplostim trials: final data from two double-blind placebo-controlled trials and two open-label extensions, and interim data from an ongoing single-arm trial., Results: Patients (n = 24 initially placebo; n = 262 initially romiplostim) had a median age of 10.0 years (Q1: 6.0, Q3: 13.0), ITP duration of 1.9 years (Q1: 1.0, Q3: 4.0), and baseline platelet count of 14.3 × 10 9 /L (Q1: 7.5, Q3: 23.0). Among 282 patients receiving romiplostim, median treatment duration was 65 weeks (range 8-471 weeks) and median weekly dose was 6.6 μg/kg (range 0.1-9.7 μg/kg). Overall, 89% of romiplostim-treated patients had platelet responses. Nineteen patients (7%) maintained treatment-free responses for ≥6 months while withholding all ITP therapy. Grade 3 and 4 adverse events of bleeding occurred in 10% and <1% of romiplostim-treated patients, respectively. Twenty-five percent of patients had a serious adverse event, most commonly epistaxis (6%). Seven patients (2%) had neutralizing antibodies against romiplostim postbaseline and none had neutralizing antibodies against endogenous thrombopoietin. Efficacy and safety results appeared similar between children with ITP for ≤12 months and >12 months at baseline., Conclusions: Across five pediatric clinical trials, romiplostim was well tolerated. Most patients had a platelet response; some maintained responses for at least 6 months while withholding all ITP therapy., (© 2020 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Children with immune thrombocytopenia for ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 μg/kg targeting platelet counts of 50-200×10 9 /L) in this extension to examine romiplostim's long-term safety and efficacy. Sixty-five children received romiplostim for a median of 2.6 years (range: 0.1-7.0 years). Median baseline age was 11 years (range: 3-18 years) and platelet count was 28×10 9 /L (range: 2-458×10 9 /L). No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 mg/kg (range: 0.1-10 mg/kg); median platelet counts remained >50×10 9 /L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50×10 9 /L, no rescue medication in the previous 4 weeks), 72% had responded at ≥75% of visits, and 58% had responded at ≥90% of visits. Treatment-free response (platelets ≥50×10 9 /L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15 of 65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of four years (range: 1-12 years) and had received romiplostim for two years (range: 1-6 years). At last observation, treatment-free responses lasted for a median of one year (range: 0.4-2.1 years), with 14 of 15 patients still in treatment-free response. Younger age at first dose and platelet count >200×10 9 /L in the first four weeks were associated with treatment-free responses. In this 7-year open-label extension, three-quarters of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (Registered at clinicaltrials.gov identifier: 01071954 )., (Copyright© 2019 Ferrata Storti Foundation.)

Autoimmune cytopenias (AIC) post-hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post-HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft-versus-host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post-HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post-HSCT patients., (© 2018 Wiley Periodicals, Inc.)

Eltrombopag is currently the only US Food and Drug Administration-approved thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia (ITP) in children. This oral, once-per-day therapy has shown favorable efficacy and adverse effect profiles in children. Two multicenter, double-blind, placebo controlled clinical trials (PETIT [Efficacy and Safety Study of Eltrombopag in Pediatric Patients With Thrombocytopenia From Chronic Idiopathic Thrombocytopenic Purpura (ITP)] and PETIT2 [Study of a New Medication for Childhood Chronic Immune Thrombocytopenia (ITP), a Blood Disorder of Low Platelet Counts That Can Lead to Bruising Easily, Bleeding Gums, and/or Bleeding Inside the Body]) demonstrated efficacy in raising platelet counts, reducing bleeding, and reducing the need for concomitant ITP therapies with relatively few adverse effects. The most commonly reported drug-related adverse effects include headache, nausea, and hepatobiliary laboratory abnormalities. Long-term safety data in children are limited, and studies in adults have not revealed a clinically significant increased incidence of thrombosis, marrow fibrosis, or cataract formation. Eltrombopag has also been approved for treating refractory severe aplastic anemia (AA) and has potential for expanded use in ITP and severe AA as well as in other conditions associated with thrombocytopenia., (© 2018 by The American Society of Hematology.)

Background: Data on second-line treatment options for pediatric patients with immune thrombocytopenia (ITP) are limited. Thrombopoietin receptor agonists (TPO-RA) provide a nonimmunosuppressive option for children who require an increased platelet count., Procedure: We performed a multicenter retrospective study of pediatric ITP patients followed at ITP Consortium of North America (ICON) sites to characterize TPO-RA use., Results: Seventy-nine children had a total of 87 treatments (28 eltrombopag, 43 romiplostim, and eight trialed on both). The majority had primary ITP (82%) and most (60.8%) had chronic ITP. However, 22% had persistent ITP and 18% had newly diagnosed ITP. During the first 3 months of treatment, 89% achieved a platelet count ≥ 50 × 10(9) /l (86% romiplostim, 81% eltrombopag, P = 0.26) at least once in the absence of rescue therapy. The average time to a response was 6.4 weeks for romiplostim and 7.0 weeks for eltrombopag (P = 0.83). Only 40% of patients demonstrated a stable response with consistent dosing over time. An intermittent response with constant dose titration was seen in 15%, and an initial response that waned to no response was seen in 13%. Significant adverse events were minimal with the exception of two patients with thrombotic events and one who developed a neutralizing antibody., Conclusions: Our results demonstrate that TPO-RA agents are being used in children with ITP of varying duration and severity. The response was similar to clinical trials, but the sustainability of response varied. Future studies need to focus on the ideal timing and rationale for these medications in pediatric patients., (© 2016 Wiley Periodicals, Inc.)

Background: The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration., Methods: In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 μg/kg to 10 μg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417., Findings: Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events., Interpretation: In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia., Funding: Amgen Inc., (Copyright © 2016 Elsevier Ltd. All rights reserved.)