1. Treatment of vulvar cancer recurrences with electrochemotherapy : a detailed analysis of possible causes for unsuccessful treatmentGregor Vivod, Tanja Jesenko, Gorana Gašljević, Nina Kovačević, Maša Omerzel, Gregor Serša, Sebastjan Merlo, Maja Čemažar, 2023, izvirni znanstveni članek Povzetek: Background. Electrochemotherapy has good local effectiveness in the treatment of vulvar cancer. Most studies have reported the safety and effectiveness of electrochemotherapy for palliative treatment of gynecological cancers and mostly vulvar squamous cell carcinoma. Some tumors, however, fail to respond to electrochemotherapy. The biological features/determinants for the nonresponsiveness are not determined yet. Patient and methods. A recurrence of vulvar squamous cell carcinoma was treated by electrochemotherapy using intravenous administration of bleomycin. The treatment was performed by hexagonal electrodes according to standard operating procedures. We analyzed the factors that could determine nonresponsiveness to electrochemotherapy. Results. Based on the presented case of nonresponsive vulvar recurrence to electrochemotherapy, we hypothesize that the vasculature of the tumors prior to treatment may predict the response to electrochemotherapy. The histological analysis showed minimal presence of blood vessels in the tumor. Thus, low perfusion may reduce drug delivery and lead to a lower response rate because of the minor antitumor effectiveness of vascular disruption. In this case, no immune response in the tumor was elicited by electrochemotherapy. Conclusions. In this case, of nonresponsive vulvar recurrence treated by electrochemotherapy, we analyzed possible factors that could predict treatment failure. Based on histological analysis, low vascularization of the tumor was observed, which hampered drug delivery and distribution and resulted in no vascular disrupting action of electrochemotherapy. All these factors could contribute to ineffective treatment with electrochemotherapy.
Ključne besede: electrochemotherapy, bleomycin, vulvar cancer
Objavljeno v DiRROS: 25.07.2024; Ogledov: 108; Prenosov: 92
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2. Treatment of skin tumors with intratumoral interleukin 12 gene electrotransfer in the head and neck region : a first-in-human clinical trial protocolAleš Grošelj, Maša Omerzel, Tanja Jesenko, Maja Čemažar, Boštjan Markelc, Primož Strojan, Gregor Serša, 2022, izvirni znanstveni članek Povzetek: Immune therapies are currently under intensive investigation providing in many cases excellent re-sponses in different tumors. Other possible approach for immunotherapy is a targeted intratumoral delivery of inter-leukin 12 (IL-12), a cytokine with anti-tumor effectiveness. Due to its immunomodulatory action, it can be used as an imunostimulating component to in situ vaccinating effect of local ablative therapies. We have developed a phIL12 plasmid devoid of antibiotic resistance marker with a transgene for human IL-12 p70 protein. The plasmid can be delivered intratumorally by gene electrotransfer (GET). Patients and methods. Here we present a first-in-human clinical trial protocol for phIL12 GET (ISRCTN15479959, ClinicalTrials NCT05077033). The study is aimed at evaluating the safety and tolerability of phIL12 GET in treatment of basal cell carcinomas in patients with operable tumors in the head and neck region. The study is designed as an ex-ploratory, dose escalating study with the aim to determine the safety and tolerability of the treatment and to identify the dose of plasmid phIL12 that is safe and elicits its biological activity. Conclusions. The results of this trail protocol will therefore provide the basis for the use of phIL12 GET as an adjuvant treatment to local ablative therapies, to potentially increase their local and elicit a systemic response.
Ključne besede: skin tumors, gene electrotransfer, interleukin 12, clinical trial
Objavljeno v DiRROS: 24.07.2024; Ogledov: 84; Prenosov: 34
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3. Sunitinib potentiates the cytotoxic effect of electrochemotherapy in pancreatic carcinoma cellsMaša Omerzel, Tanja Jesenko, Boštjan Markelc, Anja Cerovšek, Gregor Serša, Maja Čemažar, 2022, izvirni znanstveni članek Povzetek: One of the new treatment options for unresectable locally advanced pancreatic cancer is electro-chemotherapy (ECT), a local ablative therapy that potentiates the entry of chemotherapeutic drugs into the cells, by the application of an electric field to the tumor. Its feasibility and safety were demonstrated in preclinical and clinical studies; however, there is a lack of preclinical studies assessing the actions of different drugs used in ECT, their mechanisms and interactions with other target drugs that are used in clinical practice. Materials and methods. The aim of the study was to determine the cytotoxicity of two chemotherapeutic drugs usually used in ECT (bleomycin and cisplatin) in the BxPC-3 human pancreatic carcinoma cell line and evaluate the interactions of ECT with the targeted drug sunitinib. First, the cytotoxicity of ECT using both chemotherapeutics was determined. In the next part, the interactions of ECT and sunitinib were evaluated through determination of combined cytotoxicity, sunitinib targets and kinetics of cell death.Results. The results demonstrate that ECT is effective in pancreatic cancer cell line, especially when bleomycin is used, with the onset of cell death in the first hours after the treatment, reaching a plateau at 20 hours after the treat-ment. Furthermore, we provide the rationale for combining ECT with bleomycin and the targeted drug sunitinib to potentiate cytotoxicity. The combined treatment of sunitinib and ECT was synergistic for bleomycin only at the high-est used concentration of bleomycin 0.14 μM, whereas with lower doses of bleomycin, this effect was not observed. The interaction of ECT and treatment with sunitinib was confirmed by course of the cell death, also indicating on synergism
Ključne besede: electrochemotherapy, pancreas, sunitinib, pancreatic cancer
Objavljeno v DiRROS: 24.07.2024; Ogledov: 86; Prenosov: 59
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4. Morphological features of breast cancer circulating tumor cells in blood after physical and biological type of isolationTanja Jesenko, Živa Pišljar, Cvetka Grašič-Kuhar, Maja Čemažar, Urška Matkovič, Simona Miceska, Jerneja Varl, Anamarija Kuhar, Veronika Kloboves-Prevodnik, 2021, izvirni znanstveni članek Povzetek: Background. Circulating tumor cells (CTCs) have become an important biomarker in breast cancer. Different iso-lation tech-niques based on their biological or physical features were established. Currently, the most widely used methods for visualization after their separation are based on immunofluorescent staining, which does not provide the information on the morphology.Materials and methods. The aim of this study was to evaluate how two different separation techniques affect cell morphology and to analyse cell morphology with techniques used in routine cytopathological laboratory. A direct side-by-side comparison of physical (Parsortix%) and biological (MACS%) separation technique was performed.Results. In the preclinical setting, both isolation techniques retained the viability and antigenic characteristics of MCF7 breast cancer cells. Some signs of degeneration such as cell swelling, cytoplasmic blebs, villous projections and vacuolization were observed. In metastatic breast cancer patient cohort, morphological features of isolated CTCs were dependent on the separation technique. After physical separation, CTCs with preserved cell morphology were detected. After biological separation the majority of the isolated CTCs were so degenerated that their identity was difficult to confirm.Conclusions. Taken together, physical separation is a suitable technique for detection of CTCs with preserved cell morphology for the use in a routine cytopathological laboratory.
Ključne besede: circulating tumor cells, breast cancer, morphology
Objavljeno v DiRROS: 22.07.2024; Ogledov: 144; Prenosov: 136
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6. Electrochemotherapy with bleomycin is effective in BRAF mutated melanoma cells and interacts with BRAF inhibitorsTanja Jesenko, Lara Prosen, Maja Čemažar, Tjaša Potočnik, Gregor Serša, 2016, izvirni znanstveni članek Povzetek: The aim of the study was to explore the effectiveness of electrochemotherapy (ECT) during the treatment of melanoma patients with BRAF inhibitors. Its effectiveness was tested on BRAF mutated and non-mutated melanoma cells in vitro and in combination with BRAF inhibitors. Materials and methods. ECT with bleomycin was performed on two human melanoma cell lines, with (SK-MEL-28) or without (CHL-1) BRAF V600E mutation. Cell survival was determined using clonogenic assay to determine the effectiveness of ECT in melanoma cells of different mutation status. Furthermore, the effectiveness of ECT in concomitant treatment with BRAF inhibitor vemurafenib was also determined in BRAF mutated cells SK-MEL-28 with clonogenic assay. Results. The survival of BRAF V600E mutated melanoma cells was even lower than non-mutated cells, indicating that ECT is effective regardless of the mutational status of melanoma cells. Furthermore, the synergistic interaction between vemurafenib and ECT with bleomycin was demonstrated in the BRAF V600E mutated melanoma cells. Conclusions. The effectiveness of ECT in BRAF mutated melanoma cells as well as potentiation of its effectiveness during the treatment with vemurafenib in vitro implies on clinical applicability of ECT in melanoma patients with BRAF mutation and/or during the treatment with BRAF inhibitors.
Ključne besede: electrochemotherapy, BRAF inhibitors, vemurafenib, melanoma
Objavljeno v DiRROS: 30.04.2024; Ogledov: 342; Prenosov: 88
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7. Safety and efficacy of IL-12 plasmid DNA transfection into pig skin : supportive data for human clinical trials on gene therapy and vaccinationUrša Lampreht Tratar, Tanja Jesenko, Maša Omerzel, Alenka Seliškar, Urban Stupan, Mihajlo Djokić, Jerneja Sredenšek, Blaž Trotovšek, Gregor Serša, Maja Čemažar, 2024, izvirni znanstveni članek Povzetek: Gene electrotransfer (GET) of plasmids encoding interleukin 12 (IL-12) has already been used for the treatment of various types of tumors in human oncology and as an adjuvant in DNA vaccines. In recent years, we have developed a plasmid encoding human IL-12 (phIL12) that is currently in a phase I clinical study. The aim was to confirm the results of a non-clinical study in mice on pharmacokinetic characteristics and safety in a porcine model that better resembled human skin. The GET of phIL12 in the skin was performed on nine pigs using different concentrations of plasmid phIL12 and invasive (needle) or noninvasive (plate) types of electrodes. The results of our study demonstrate that the GET of phIL-12 with needle electrodes induced the highest expression of IL-12 at the protein level on day 7 after the procedure. The plasmid was distributed to all tested organs; however, its amount decreased over time and was at a minimum 28 days after GET. Based on plasmid copy number and expression results, together with blood analysis, we showed that IL-12 GET is safe in a porcine animal model. Furthermore, we demonstrated that pigs are a valuable model for human gene therapy safety studies.
Ključne besede: interleukin 12, gene electrotransfer, immunotherapy
Objavljeno v DiRROS: 18.04.2024; Ogledov: 316; Prenosov: 142
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8. Effects of electrochemotherapy on immunologically important modifications in tumor cellsUrša Kešar, Boštjan Markelc, Tanja Jesenko, Katja Uršič Valentinuzzi, Maja Čemažar, Primož Strojan, Gregor Serša, 2023, izvirni znanstveni članek Povzetek: Electrochemotherapy (ECT) is a clinically acknowledged method that combines the use of anticancer drugs and electrical pulses. Electrochemotherapy with bleomycin (BLM) can induce immunogenic cell death (ICD) in certain settings. However, whether this is ubiquitous over different cancer types and for other clinically relevant chemotherapeutics used with electrochemotherapy is unknown. Here, we evaluated in vitro in the B16-F10, 4T1 and CT26 murine tumor cell lines, the electrochemotherapy triggered changes in the ICD-associated damage-associated molecular patterns (DAMPs): Calreticulin (CRT), ATP, High Mobility Group Box 1 (HMGB1), and four immunologically important cellular markers: MHCI, MHC II, PD-L1 and CD40. The changes in these markers were investigated in time up to 48 h after ECT. We showed that electrochemotherapy with all three tested chemotherapeutics induced ICD-associated DAMPs, but the induced DAMP signature was cell line and chemotherapeutic concentration specific. Similarly, electrochemotherapy with CDDP, OXA or BLM modified the expression of MHC I, MHC II, PD-L1 and CD40. The potential of electrochemotherapy to change their expression was also cell line and chemotherapeutic concentration specific. Our results thus put the electrochemotherapy with clinically relevant chemotherapeutics CDDP, OXA and BLM on the map of ICD inducing therapies.
Ključne besede: electrochemotherapy, cisplatin, immune response
Objavljeno v DiRROS: 21.03.2024; Ogledov: 335; Prenosov: 202
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9. Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicityAleš Sedlar, Tanja Jesenko, Boštjan Markelc, Lara Prosen, Simona Kranjc Brezar, Maša Omerzel, Tanja Blagus, Maja Čemažar, Gregor Serša, 2012, izvirni znanstveni članek Objavljeno v DiRROS: 21.03.2024; Ogledov: 297; Prenosov: 108
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10. Razvoj in karakterizacija mišjega modela za študije HPV-pozitivnega raka glave in vratuŽiva Pišljar, Maja Čemažar, Boštjan Markelc, Andrej Cör, Gregor Serša, Simona Kranjc Brezar, Tanja Jesenko, 2023, objavljeni povzetek znanstvenega prispevka na konferenci Ključne besede: miši, rak glave in vratu, gensko zdravljenje
Objavljeno v DiRROS: 19.06.2023; Ogledov: 521; Prenosov: 234
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