1. A web-application that extends functionality of medical device for tumor treatment by means of electrochemotherapyIvan Pavlović, Peter Kramar, Selma Čorović, David Cukjati, Damijan Miklavčič, 2004, izvirni znanstveni članek Povzetek: Electrochemotherapy (ECT) is a novel method for efficient tumor treatment in clinical environment. It combines local drug delivery and application of shorthigh voltage pulses, which permeabilize the plasma membrane by electroporation. Drug can enter only the cells with permeabilzed membrane. Recently, medical device CliniporatorTM for controlled electroporation was developed. Here, we present a web-application that extends the functionality of this medical device. The aim of the application is to collect, store and toallow the analysis of every ECT application using this medical device. The application helps transferring data collected by devčce during the electroporation process to the central database, and enables filling of medical records through the web forms. The application is based on technologies ASP, HTML, Flash, JavaScript, XML and others. The application main advantages are easy and rapid data access, scalability and independence of client computer operating system as well as easy application debugging and upgrading. Ključne besede: neoplasms- drug therapy, drug delivery systems, elektroporation instrumentation Objavljeno v DiRROS: 07.02.2024; Ogledov: 405; Prenosov: 107
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2. Influence of hydralazine on interstitial fluid pressure in experimental tumors - a preliminary study : Vpliv hydralazina na tlak medcelične tekočine v poskusnih tumorjihBlaž Podobnik, Damijan Miklavčič, 2000, izvirni znanstveni članek Povzetek: Background. Interstitial fluid pressure (IFP) has been recognised as the most important obstacle in macromolecular drug delivery to solid tumors. Our interest was to reduce differentialy tumor IFP with respect to IFP in surrounding and normal tissues in order to increase drug delivery to tumors aswell to increase tumor blood flow and potentialy tumor tissue oxygenation. In this preliminary study we used hydralazine, a longacting arterial vasodilator. Materials and methods. Measurements of interstitial fluid pressure were performed in vivo on CBA mice bearing SAF tumors using wick-in-needle technigue. Altogether eleven measurements were obtained on different animals with tumors of different size. Results. IFP in tumors after hydralazine administration was significantly lower than initial values in corresponding tumors. On average tumor IFP decreased for 33 % from initial value. On the contrary, no change in IFP in normal tissue was observed after hydralazine administration. Also, after injection of physiological saline instead of hydralazine there was no change in IFP neither in tumors nor in muscle. The results of our preliminary study on the effect of hydralazine on IFP in SAF tumor model is in accordance to previously reported studies. The decrease in tumor IFP was only observed in tumors, but not in muscle and surrounding subcutis. Conclusion. Hydralazine is a vasodilator which is capable of decreasing tumor IFP, reproducibly and with favorably long lasting dynamics. Ključne besede: sarcoma, experimental drug therapy, hydralazine, extracellular space, interstitial fluid pressure, manometry Objavljeno v DiRROS: 23.01.2024; Ogledov: 356; Prenosov: 108
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4. Availability and costs of medicines for the treatment of tuberculosis in EuropeGunar Günther, Lorenzo Guglielmetti, Claude Leu, Christoph Lange, Frank van Leth, 2022, pregledni znanstveni članek Povzetek: Objectives. To evaluate the access to comprehensive diagnostics and novel anti-tuberculosis medicines in European countries. Methods. We investigated access to genotypic and phenotypic M. tuberculosis drug susceptibility testing, availability of anti-tuberculosis drugs and calculated cost of drugs and treatment regimens at major tuberculosis treatment centers in countries of the World Health Organization (WHO) European region where rates of drug-resistant tuberculosis are highest among all WHO regions. Results are stratified by middle-income and high-income countries. Results. Overall, 43 treatment centers in 43 countries participated in the study. For WHO Group A drugs, the frequency of countries with availability of phenotypic drug susceptibility testing was as follows: 30/40 (75%) for levofloxacin, 33/40 (82%) for moxifloxacin, 19/40 (48%) for bedaquiline and 29/40 (72%) for linezolid, respectively. Overall, 36/43 (84%) and 24/43 (56%) of countries had access to bedaquiline and delamanid, while only 6/43 (14%) had access to rifapentine. Treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was only available in 17/43 (40%) of the countries. Median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for six months) and extensively drug-resistant tuberculosis (including bedaquiline, delamanid and a carbapenem) were € 44 (min-max € 15-152), € 764 (min-max € 542-15152) and € 8709 (min-max € 7965-11759) in middle-income countries (n=12), and € 280 (min-max-€78-1084), € 29765 (min-max 11116-40584), € 217591 (min-max € 82827-320146) in high-income countries (n=29). Conclusion. In countries of the WHO Europe Region there is a widespread lack of drug susceptibility testing capacity to new and re-purposed anti-tuberculosis drugs, lack of access to essential medications in several countries and high treatment cost for drug-resistant tuberculosis. Ključne besede: tuberculosis - drug therapy, Mycobacterium tuberculosis - drug therapy, health care costs - drug therapy, Europe Objavljeno v DiRROS: 31.08.2022; Ogledov: 920; Prenosov: 227
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5. Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP) : a retrospective analysis from an early access programOliver Illini, Hannah Fabikan, Aurélie Swalduz, Anders Vikström, Dagmar Krenbek, Michael Schumacher, Elizabeth Dudnik, Michael Studnicka, Ronny Öhman, Robert Wurm, Tanja Čufer, Katja Mohorčič, Maximilian J Hochmair, 2022, izvirni znanstveni članek Povzetek: Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5months (95% CI, 4.7–14.3), whereas it was 10.6months (95% CI, 5.5–15.7) in first-line and 9.1months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases (n=11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade⩾3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting. Ključne besede: non-small cell lung carcinoma -- drug therapy -- genetics, molecular targeted therapy, real-world data, capmatinib, targeted therapy Objavljeno v DiRROS: 24.06.2022; Ogledov: 937; Prenosov: 674
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6. Effect of hydroxychloroquine in hospitalized patients with Covid-19Peter Horby, Marion Mafham, Martin J. Landray, 2020, izvirni znanstveni članek Povzetek: Background: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. Methods: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. Results: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. Conclusions: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.). Ključne besede: Covid-19 -- drug therapy, hydroxychloroquine, chloroquine Objavljeno v DiRROS: 30.05.2022; Ogledov: 655; Prenosov: 392
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7. Dexamethasone in hospitalized patients with Covid-19Peter Horby, Wei Shen Lim, Martin J. Landray, 2021, izvirni znanstveni članek Povzetek: Background: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. Results: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). Conclusions: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.). Ključne besede: Covid-19 -- drug therapy, dexamethasone Objavljeno v DiRROS: 30.05.2022; Ogledov: 686; Prenosov: 452
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8. The effects of topical antibiotics on eradication and acquisition of third-generation cephalosporin and carbapenem-resistant Gram-negative bacteria in ICU patients : ǂa ǂpost hoc analysis from a multicentre cluster-randomized trialNienke L. Plantinga, Bastiaan H. Wittekamp, Christian Brun-Buisson, Marc J. M. Bonten, 2020, izvirni znanstveni članek Povzetek: Objectives: The aim was to quantify the effects of selective digestive tract decontamination (SDD) consisting of a mouth paste and gastro-enteral suspension, selective oropharyngeal decontamination with a mouth paste (SOD) and 1-2% chlorhexidine (CHX) mouthwash on eradication and acquisition of carriage of third-generation cephalosporin-resistant Enterobacterales (3GCR-E) and carbapenem-resistant Gram-negative bacteria (CR-GNB) in Intensive Care Unit (ICU) patients. Methods: This was a nested cohort study within a cluster-randomized cross-over trial in six European countries and 13 ICUs with 8665 patients. Eradication and acquisition during ICU stay of 3GCR-E and CRGNB were investigated separately in the rectum and respiratory tract for the three interventions and compared with standard care (SC) using Cox-regression competing events analyses. Results: Adjusted cause specific hazard ratios (CSHR) for eradication of rectal carriage for SDD were 1.76 (95% CI 1.31-2.36) for 3GCR-E and 3.17 (95% CI 1.60-6.29) for CR-GNB compared with SC. For the respiratory tract, adjusted CSHR for eradication of 3GCR-E were 1.47 (0.98-2.20) for SDD and 1.38 (0.92-2.06) for SOD compared with SC, and for eradication of CR-GNB these were 0.77 (0.41-1.45) for SDD and 0.81 (0.44-1.51) for SOD, compared with SC. Adjusted CSHRs for acquisition of rectal carriage during SDD (compared with SC) were 0.51 (0.40-0.64) for 3GCR-E and of 0.56 (0.40-0.78) for CR-GNB. Adjusted CSHRs for acquiring respiratory tract carriage with 3GCR-E compared with SC were 0.38 (0.28-0.50) for SDD and 0.55 (0.42-0.71) for SOD, and for CR-GNB 0.46 (0.33-0.64) during SDD and 0.60 (0.44-0.81) during SOD, respectively. SOD was not associated with eradication or acquisition of 3GCR-E and CR-GNB in the rectum. Conclusions: Among mechanically ventilated ICU patients, SDD was associated with more eradication and less acquisition of 3GCR-E and CR-GNB in the rectum than SC. SDD and SOD were associated with less acquisition of both 3GCR-E and CR-GNB than SC in the respiratory tract. Ključne besede: intensive care units -- analysis -- epidemiology, bacterial drug resistance, anti-infective agents -- therapeutic use decontamination, beta-lactamases, Gram-negative bacteria, gastrointestinal tract -- microbiology -- drug therapy, cohort studies, colonization, ESBL, digestive tract Objavljeno v DiRROS: 27.05.2022; Ogledov: 708; Prenosov: 275
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9. Behavioural patterns in allergic rhinitis medication in Europe : a study using 28 MASK-air® real-world dataBernardo Sousa-Pinto, Ana Sá-Sousa, Rafael José Vieira, Rita Amaral, Ludger Klimek, Wienczyslawa Czarlewski, Josep M. Antò i Boquè, Oliver Pfaar, Anna Bedbrook, Mihaela Zidarn, Joao A. Fonseca, Jean Bousquet, 2022, izvirni znanstveni članek Povzetek: Background. Co-medication is common among patients with allergic rhinitis (AR), but its dimension and patterns are unknown. This is particularly relevant since AR is understood differently across European countries, as reflected by rhinitis-related search patterns in Google Trends. This study aims to assess AR co-medication and its regional patterns in Europe, using real-world data. Methods. We analysed 2015-2020 MASK-air® European data. We compared days under no medication, monotherapy, and co-medication using the visual analogue scale (VAS) levels for overall allergic symptoms (“VAS Global Symptoms”) and impact of AR on work. We assessed the monthly use of different medication schemes, performing separate analyses by region (defined geographically or by Google Trends patterns). We estimated the average number of different drugs reported per patient within one year. Results. We analysed 222,024 days (13,122 users), including 63,887 days (28.8%) under monotherapy, and 38,315 (17.3%) under co-medication. The median “VAS Global Symptoms” was 7 for no medication days, 14 for monotherapy and 21 for co-medication (p<0.001). Medication use peaked during the spring, with similar patterns across different European regions (defined geographically or by Google Trends). Oral H1-antihistamines were the most common medication in single and co-medication. Each patient reported using an annual average of 2.7 drugs, with 80% reporting two or more. Conclusions. AR medication patterns are similar across European regions. One third of treatment days involved co-medication. These findings suggest that patients treat themselves according to their symptoms (irrespective of how they understand AR), and that co-medication use is driven by symptom severity. Ključne besede: asthma -- drug therapy, rhinitis -- drug therapy, allergic rhinitis -- drug therapy, visual analogue scale, histamine antagonists, antihistamines, behavioural patterns, medication patterns, real-world data Objavljeno v DiRROS: 14.03.2022; Ogledov: 850; Prenosov: 301
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10. Selpercatinib in RET fusion-positive non-small-cell lung cancer (SIREN) : a retrospective analysis of patients treated through an access programOliver Illini, Maximilian J Hochmair, Hannah Fabikan, Christoph Weinlinger, Amanda Tufman, Aurélie Swalduz, Kristina Lamberg, Sayed M. S. Hashemi, Florian Huemer, Anders Vikström, Katja Mohorčič, 2021, izvirni znanstveni članek Povzetek: Introduction: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown. Methods: A retrospective efficacy and safety analysis was performed on data from RET fusio-%positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021. Results: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38-89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1-8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53-81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8-22.4) after a median follow-up of 9 months. In patients with measurable brain metastases (n=8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade >/=3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death. Conclusions: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated. Ključne besede: non-small cell lung carcinoma -- drug therapy -- genetics, molecular targeted therapy, real-world data, selpercatinib, targeted therapy, tyrosine kinase inhibitor Objavljeno v DiRROS: 16.06.2021; Ogledov: 1502; Prenosov: 863
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